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Pathophysiology of Heart Disease - 6th Ed 2016, Manuais, Projetos, Pesquisas de Medicina

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Baixe Pathophysiology of Heart Disease - 6th Ed 2016 e outras Manuais, Projetos, Pesquisas em PDF para Medicina, somente na Docsity! O o RD Pi o YO Etr Epa pe a Tui ça, a pa (Efe T AE ei)! ve eBook with complete content ARE ig in iio ao (ao * | Medical Students | and Faculty PGE PARRA “N “sf Eodedea ledicos.org a RR ERR Ee ANITA E ) 6 EDITION A COLLA BORATIVE P ROJECT OF MED ICA L STU D ENTS A ND FACU LTY Pathophysiology of Heart Disease Dedicated to Carolyn, Jonathan, Rebecca, Douglas, Deborah, Norma and David Lilly vi STUDENT CONTRIBUTORS Andrey V. Dolinko (MD 2016) Joshua Drago (MD 2015) David B. Fischer (MD 2016) P. Connor Johnson (MD 2015) Zena L. Knight (MD 2015) Michael T. Kuntz (MD 2015) Jacob E. Lemieux, D.Phil. (MD 2015) Diana M. López (MD 2016) David Miranda (MD 2016) Morgan J. Prust (MD 2015) Sruthi Renati (MD 2015) Elizabeth Ryznar, MSc (MD 2015) Sarrah Shahawy (MD 2016) Jayme Wilder (MD 2015) FACULTY CONTRIBUTORS Elliott M. Antman, MD Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Eugene Braunwald, MD (Foreword) Distinguished Hersey Professor of Medicine Harvard Medical School Founding Chairman, TIMI Study Group Brigham and Women’s Hospital Boston, Massachusetts David W. Brown, MD Associate Professor of Pediatrics Harvard Medical School Cardiology Division Children’s Hospital Boston, Massachusetts Patricia Challender Come, MD Associate Professor of Medicine Harvard Medical School Cardiologist, Harvard Vanguard Medical Associates Boston, Massachusetts Mark A. Creager, MD Professor of Medicine Geisel School of Medicine at Dartmouth Director, Heart and Vascular Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire G. William Dec, MD Roman W. DeSanctis Professor of Medicine Harvard Medical School Chief (Emeritus), Cardiology Division Massachusetts General Hospital Boston, Massachusetts Elazer R. Edelman, MD, PhD Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology Massachusetts Institute of Technology Director, Harvard–MIT Biomedical Engineering Center Professor of Medicine Harvard Medical School Boston, Massachusetts Michael A. Fifer, MD Professor of Medicine Harvard Medical School Director, Cardiac Catheterization Laboratory Director, Hypertrophic Cardiomyopathy Program Massachusetts General Hospital Boston, Massachusetts List of Contributors Gregory D. Lewis, MD Assistant Professor of Medicine Harvard Medical School Director, Cardiology Intensive Care Unit Massachusetts General Hospital Boston, Massachusetts Peter Libby, MD Mallinckrodt Professor of Medicine Harvard Medical School Senior Physician Brigham and Women’s Hospital Boston, Massachusetts Leonard S. Lilly, MD Professor of Medicine Harvard Medical School Chief, Brigham and Women’s/ Faulkner Cardiology Brigham and Women’s Hospital Boston, Massachusetts Patrick T. O’Gara, MD Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Marc S. Sabatine, MD, MPH Professor of Medicine Harvard Medical School Chairman, TIMI Study Group Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts William G. Stevenson, MD Professor of Medicine Harvard Medical School Director, Clinical Cardiac Electrophysiology Program Brigham and Women’s Hospital Boston, Massachusetts Gary R. Strichartz, PhD Professor of Anesthesia (Pharmacology) Harvard Medical School Director, Pain Research Center Vice Chairman of Research, Department of Anesthesia Brigham and Women’s Hospital Boston, Massachusetts Gordon H. Williams, MD Professor of Medicine Harvard Medical School Director, Specialized Center of Research in Hypertension Director, Center for Clinical Investigation Brigham and Women’s Hospital Boston, Massachusetts List of Contributors vii x Preface Finally, a project of this magnitude could not be undertaken without the support and patience of my family, and for that, I am very grateful. On behalf of the contributors, I hope that this book enhances your understanding of car- diovascular diseases and provides a solid foundation for further learning and clinical care of your patients. Leonard S. Lilly, MD Boston, Massachusetts xi List of Contributors vi Foreword viii Preface ix Chapt e r 1 Normal Cardiac Structure and Function 1 Jacob E. Lemieux, Elazer R. Edelman, Gary R. Strichartz, and Leonard S. Lilly Chapt e r 2 The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs 26 David B. Fischer and Leonard S. Lilly Chapt e r 3 Cardiac Imaging and Catheterization 43 Diana M. López and Patricia Challender Come Chapt e r 4 The Electrocardiogram 74 David B. Fischer and Leonard S. Lilly Chapt e r 5 Atherosclerosis 112 Sarrah Shahawy and Peter Libby Chapt e r 6 Ischemic Heart Disease 134 Jayme Wilder, Marc S. Sabatine, and Leonard S. Lilly Chapt e r 7 Acute Coronary Syndromes 162 Jayme Wilder, Marc S. Sabatine, and Leonard S. Lilly Chapt e r 8 Valvular Heart Disease 192 Elizabeth Ryznar, Patrick T. O’Gara, and Leonard S. Lilly Chapt e r 9 Heart Failure 220 David Miranda, Gregory D. Lewis, and Michael A. Fifer Chapt e r 1 0 The Cardiomyopathies 249 P. Connor Johnson, G. William Dec, and Leonard S. Lilly Chapt e r 1 1 Mechanisms of Cardiac Arrhythmias 268 Morgan J. Prust, William G. Stevenson, Gary R. Strichartz, and Leonard S. Lilly Chapt e r 1 2 Clinical Aspects of Cardiac Arrhythmias 287 Morgan J. Prust, William G. Stevenson, and Leonard S. Lilly Chapt e r 1 3 Hypertension 310 Joshua Drago, Gordon H. Williams, and Leonard S. Lilly Chapt e r 1 4 Diseases of the Pericardium 334 Leonard S. Lilly Chapt e r 1 5 Diseases of the Peripheral Vasculature 350 Sruthi Renati and Mark A. Creager Chapt e r 1 6 Congenital Heart Disease 373 Zena L. Knight and David W. Brown Chapt e r 1 7 Cardiovascular Drugs 400 Andrey V. Dolinko, Michael T. Kuntz, Elliott M. Antman, Gary R. Strichartz, and Leonard S. Lilly Index 456 Table of Contents 1 C h a p t e r O u t l i n e Cardiac Anatomy and Histology Pericardium Sur ace Anatomy o the Heart Internal Structure o the Heart Impulse-Conducting System Cardiac Innervation Cardiac Vessels Histology o Ventricular Myocardial Cells Basic Electrophysiology Ion Movement and Channels Resting Potential Action Potential Re ractory Periods Impulse Conduction Normal Sequence o Cardiac Depolarization Excitation–Contraction Coupling Contractile Proteins in the Myocyte Calcium-Induced Calcium Release and the Contractile Cycle Introduction to Cardiac Signaling Systems β-Adrenergic and Cholinergic Signaling Knowledge o normal structure and unction o the heart is crucial to understanding diseases that a f ict the cardiovas- cular system. The purpose o this chapter is to describe the heart’s basic anatomy, its electrical system, and the cellular and molecular mechanisms o contraction that allow the heart to serve its critical unctions. CARDIAC ANATOMY AND HISTOLOGY Although the study o cardiac anatomy dates back to ancient times, interest in this eld has recently gained momentum. The application o sophisticated cardiac imaging tech- niques such as coronary angiography, echocardiography, computed tomography, and magnetic resonance imaging requires an intimate knowledge o the spatial relationships o cardiac structures. Such in ormation also proves help- ul in understanding the pathophysiology o heart disease. This section emphasizes the aspects o cardiac anatomy that are important to the clinician—that is, the “ unctional” anatomy. Pericardium The heart and roots o the great vessels are enclosed by a broserous sac called the pericardium (Fig. 1-1). This struc- ture consists o two layers: a strong outer brous layer and an inner serosal layer. The inner serosal layer adheres to the external wall o the heart and is called the visceral pericar- dium. The visceral pericardium ref ects back on itsel and lines the outer brous layer, orming the parietal pericar- dium. The space between the visceral and parietal layers contains a thin lm o pericardial f uid that allows the heart to beat in a minimal- riction environment. Normal Cardiac Structure and Function Jacob E. Lemieux Elazer R. Edelman Gary R. Strichartz Leonard S. Lilly 1 4 Chapter 1 cardiac muscle cells, the histology o which is described later in the chapter. External to the myocardium is a layer o connective tissue and adipose tissue through which pass the larger blood vessels and nerves that supply the heart muscle. The epicardium is the outermost layer o the heart and is identical to, and just another term or, the visceral pericardium previously described. Right Atrium and Ventricle Opening into the right atrium are the superior and in erior venae cavae and the coronary sinus (Fig. 1-4). The venae cavae return deoxygenated blood rom the systemic veins into the right atrium, whereas the coronary sinus carries venous return rom the coronary arteries. The interatrial septum orms the posteromedial wall o the right atrium and separates it rom the le t atrium. The tricuspid valve is located in the f oor o the atrium and opens into the right ventricle. The right ventricle (see Fig. 1-4) is roughly triangular in shape, and its superior aspect orms a cone-shaped outf ow tract, which leads to the pulmonary artery. Although the inner wall o the outf ow tract is smooth, the rest o the ventricle is covered by a number o irregular bridges (termed trabeculae carneae) that give the right ventricular wall a spongelike appear- ance. A large trabecula that crosses the ventricular cavity is called the moderator band. It carries a component o the right bundle branch o the conducting system to the ventricular muscle. The right ventricle contains three papillary muscles, which project into the chamber and via their thin, stringlike chordae tendineae attach to the edges o the tricuspid valve leaf ets. The leaf ets, in turn, are attached to the brous ring that supports the valve between the right atrium and ventricle. Contraction o the papillary muscles prior to other regions o the ven- tricle tightens the chordae tendineae, helping to align and restrain the leaf ets o the tricuspid valve as they are orced closed. This action prevents blood rom regurgitating into the right atrium during ventricular contraction. At the apex o the right ventricular outf ow tract is the pulmonic valve, which leads to the pulmonary artery. This valve consists o three cusps attached to a brous ring. During relax- ation o the ventricle, elastic recoil o the pulmonary arteries orces blood back toward the Anterior Pos terior Aortic va lve Pulmonic valve Tricuspid va lve Annulus fibrosus Mitra l va lve Annulus fibrosus FIGURE 1-3. The four heart valves viewed from above with atria removed. The f gure depicts the period o ventricular f lling (diastole) during which the tricuspid and mitral valves are open and the semilunar valves (pulmonic and aortic) are closed. Each annulus f brosus surrounding the mitral and tricuspid valves is thicker than those surrounding the pulmonic and aortic valves; all our contribute to the heart’s f brous skeleton, which is composed o dense connective tissue. Normal Cardiac Structure and Function 5 heart, distending the valve cusps toward one another. This action closes the pulmonic valve and prevents regurgitation o blood back into the right ventricle. Left Atrium and Ventricle Entering the posterior hal o the left atrium are the our pulmonary veins (Fig. 1-5). The wall o the le t atrium is about 2 mm thick, being slightly greater than that o the right atrium. The mitral valve opens into the le t ventricle through the in erior wall o the le t atrium. The cavity o the left ventricle is approximately cone shaped and longer than that o the right ventricle. In a healthy adult heart, the wall thickness is 9 to 11 mm, roughly three times that o the right ventricle. The aortic vestibule is a smooth-walled part o the le t ventricular cavity located just in erior to the aortic valve. In erior to this region, most o the ventricle is covered by trabeculae carneae, which are ner and more numerous than those in the right ventricle. The le t ventricular chamber (see Fig. 1-5B) contains two large papillary muscles. These are larger than their counterparts in the right ventricle, and their chordae tendineae are thicker but less numerous. The chordae tendineae o each papillary muscle distribute to both leaf ets o the mitral valve. Similar to the case in the right ventricle, tensing o the chordae tendineae during le t ventricular contraction helps restrain and align the mitral leaf ets, enabling them to close properly and preventing the backward leakage o blood. The aortic valve separates the le t ventricle rom the aorta. Surrounding the aortic valve opening is a brous ring to which is attached the three cusps o the valve. Just above the right and le t aortic valve cusps in the aortic wall are the origins o the right and le t coronary arteries (see Fig. 1-5B). Interventricular Septum The interventricular septum is the thick wall between the le t and right ventricles. It is com- posed o a muscular and a membranous part (see Fig. 1-5B). The margins o this septum can be traced on the sur ace o the heart by ollowing the anterior and posterior interven- tricular grooves. Owing to the greater hydrostatic pressure within the le t ventricle, the large Superior vena cava Pulmonary a rte ry Pulmonic va lve Inte rventricula r septum Modera tor band Trabeculae carneae Papilla ry muscles Aorta Right a trium Inferior vena cava Coronary s inus Tricuspid va lve Right ventricle FIGURE 1-4. Interior structures of the right atrium and right ventricle. (Modif ed rom Goss CM. Gray’s Anatomy. 29th ed. Philadelphia, PA: Lea & Febiger; 1973:547.) 6 Chapter 1 FIGURE 1-5. Interior structures of the left atrium and left ventricle. A. The le t atrium and le t ventricular (LV) in ow region. B. Interior structures o the LV cavity. (Modif ed rom Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:142–143.) Pulmonary ve ins Left a tria l appendage Fibrous ring of le ft AV orifice Chordae tendineae Papilla ry muscles Anterior cusp of mitra l va lve To aortic ves tibule Left a trium Left ventricle A Ascending aorta Pos te rior cusp of aortic va lve Orifice of le ft coronary a rte ry Orifice of right coronary a rte ry Left cusp of aortic va lve Anterior cusp of mitra l va lve Chordae tendineae Anterior papilla ry muscle Trabeculae carneae Pos te rior papilla ry muscle Inte rventricula r septum, muscula r part Inte rventricula r septum, membranous part Right aortic s inus Right cusp of aortic va lve Pulmonary a rte ry Right ventricle B Normal Cardiac Structure and Function 9 heart to the apex and supplies blood to the in erior and posterior walls o the ventricles and the posterior one third o the interventricular septum. Just be ore giving o the posterior descending branch, the RCA usually gives o the AV nodal artery. The posterior descending and AV nodal arteries arise rom the RCA in 85% o the population, and in such people, the coronary circulation is termed right dominant. In approximately 8% , the posterior descending artery arises rom the circumf ex artery instead, resulting in a left dom- inant circulation. In the remaining population, the heart’s posterior blood supply is contributed to rom branches o both the RCA and the circumf ex, orming a codominant circulation. Pulmonary a rte ry Left circumflex coronary a rte ry Left main coronary a rte ry Aorta Left ante rior descending coronary a rte ry Right coronary arte ry Right coronary arte ry Acute margina l branch Left circumflex coronary a rtery Left ante rior descending coronary a rtery Diagona l branch Left circumflex coronary a rtery Obtuse margina l branches Pos te rior descending coronary a rte ry Right coronary arte ry A B C FIGURE 1-7. Coronary artery anatomy. A. Schematic representation o the right and le t coronary arteries demonstrates their orientation to one another. The le t main artery bi urcates into the circumf ex artery, which per uses the lateral and posterior regions o the le t ventricle (LV), and the anterior descending artery, which per uses the LV anterior wall, the anterior portion o the intraventricular septum, and a portion o the anterior right ventricular (RV) wall. The right coronary artery (RCA) per uses the right ventricle and variable portions o the posterior le t ventricle through its terminal branches. The posterior descending artery most o ten arises rom the RCA. B. Anterior view o the heart demonstrating the coronary arteries and their major branches. C. Posterior view o the heart demonstrating the terminal portions o the right and circumf ex coronary arteries and their branches. 10 Chapter 1 The blood supply to the SA node is also most o ten (70% o the time) derived rom the RCA. However, in 25% o normal hearts, the SA nodal artery arises rom the circumf ex artery, and in 5% o cases, both the RCA and the circumf ex artery contribute to this vessel. From their epicardial locations, the coronary arteries send per orating branches into the ventricular muscle, which orm a richly branching and anastomosing vasculature in the walls o all the cardiac chambers. From this plexus arise a massive number o capillaries that orm an elaborate network surrounding each cardiac muscle ber. The muscle bers located just beneath the endocardium, particularly those o the papillary muscles and the thick le t ven- tricle, are supplied either by the terminal branches o the coronary arteries or directly rom the ventricular cavity through tiny vascular channels, known as thebesian veins. Collateral connections, usually less than 200 µm in diameter, exist at the subarteriolar level between the coronary arteries. In the normal heart, ew o these collateral vessels are visible. However, they may become larger and unctional when atherosclerotic disease obstructs a coronary artery, thereby providing blood f ow to distal portions o the vessel rom a nonob- structed neighbor. Coronary Veins The coronary veins ollow a distribution similar to that o the major coronary arteries. These vessels return blood rom the myocardial capillaries to the right atrium predominantly via the coronary sinus. The major veins lie in the epicardial at, usually super cial to their arterial counterparts. The thebesian veins, described earlier, provide an additional potential route or a small amount o direct blood return to the cardiac chambers. Lymphatic Vessels The heart lymph is drained by an extensive plexus o valved vessels located in the subendo- cardial connective tissue o all our chambers. This lymph drains into an epicardial plexus rom which are derived several larger lymphatic vessels that ollow the distribution o the coronary arteries and veins. Each o these larger vessels then combines in the AV groove to orm a single lymphatic conduit, which exits the heart to reach the mediastinal lymphatic plexus and ultimately the thoracic duct. Histology of Ventricular Myocardial Cells The mature myocardial cell (also termed the myocyte) measures up to 25 µm in diameter and 100 µm in length. The cell shows a cross-striated banding pattern similar to that o the skeletal muscle. However, unlike the multinucleated skeletal myo bers, myocardial cells contain only one or two centrally located nuclei. Surrounding each myocardial cell is connective tissue with a rich capillary network. Each myocardial cell contains numerous myof brils, which are long chains o individual sarcomeres, the undamental contractile units o the cell (Fig. 1-8). Each sarcomere is made up o two groups o overlapping laments o contractile proteins. Biochemical and biophysi- cal interactions occurring between these myo laments produce muscle contraction. Their structure and unction are described later in the chapter. Within each myocardial cell, the neighboring sarcomeres are all in register, producing the characteristic cross-striated banding pattern seen by light microscopy. The relative den- sities o the cross bands identi y the location o the contractile proteins. Under physiologic conditions, the overall sarcomere length (Z-to-Z distance) varies between 2.2 and 1.5 µm during the cardiac cycle. The larger dimension ref ects the ber stretch during ventricular lling, whereas the smaller dimension represents the extent o ber shortening during contraction. Normal Cardiac Structure and Function 11 The myocardial cell membrane is named the sarcolemma. A specialized region o the mem- brane is the intercalated disk, a distinct characteristic o cardiac muscle tissue. Intercalated disks are seen on light microscopic study as darkly staining transverse lines that cross chains o cardiac cells at irregular intervals. They represent the gap junction complexes at the inter ace o adjacent cardiac f bers and establish structural and electrical continuity between the myocardial cells. Another unctional eature o the cell membrane is the transverse tubular system (or T tubules). This complex system is characterized by deep, f ngerlike invaginations o the sarcolemma (Fig. 1-9; see also Fig. 1-8). Similar to the intercalated disks, transverse tubular membranes establish pathways or rapid transmission o the excitatory electrical impulses that initiate contraction. The T tubule system increases the sur ace area o the sarcolemma Myofibril Z ZMyosin TitinActin Sarcolemma Mitochondrion Sarcoplasmic re ticulum T tubule Sarcomere FIGURE 1-8. Myocardial cell. Top. Schematic representation o the ultrastructure o the myocardial cell. The cell consists o multiple parallel myof brils surrounded by mitochondria. The T tubules are invaginations o the cell membrane (the sarcolemma) that increase the sur ace area or ion transport and transmission o electrical impulses. The intracellular sarcoplasmic reticulum houses most o the intracellular calcium and abuts the T tubules. (Modif ed rom Katz AM. Physiology of the Heart. 2nd ed. New York, NY: Raven Press; 1992:21). Bottom. Expanded view o a sarcomere, the basic unit o contraction. Each myof bril consists o serially connected sarcomeres that extend rom one Z line to the next. The sarcomere is composed o alternating thin (actin) and thick (myosin) myof laments. Titin is a protein that tethers myosin to the Z line and provides elasticity. T tubule Sarcolemma Termina l cis te rnae ATPase Sarcoplasmic re ticulum Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ FIGURE 1-9. Schematic view of the tubular systems of the myocardial cell. The T tubules, invaginations o the sarcolemma, abut the sarcoplasmic reticulum at right angles at the terminal cisternae sacs. This relationship is important in linking membrane excitation with intracellular release o calcium rom the sarcoplasmic reticulum. 14 Chapter 1 raction o channels is open at a given time. There ore, the gating o channels is said to be voltage sensitive. As the membrane voltage changes during depolarization and repolariza- tion o the cell, speci c channels open and close, with corresponding alterations in the ion f uxes across the sarcolemma. An example o voltage-sensitive gating is apparent in the cardiac channel known as the fast sodium channel. The transmembrane protein that orms this channel assumes various con- ormations depending on the cell’s membrane potential (Fig. 1-11). At a voltage o −90 mV Activa tion ga te Rapid depola riza tion R e p o la riz a tio n S p o n ta n e o u s Inac tiva tion ga te Outs ide A C CHANNEL CLOSED (RESTING) CHANNEL CLOSED (INACTIVE) Na+ Cell membrane Ins ide + + + + + + + + – – – – – – – – III IV II B CHANNEL OPEN Na+ Na+ + + + + + + + + – – – – – – – – + + + + + + + + – – – – – – – – FIGURE 1-11. Schematic representation of gating of fast sodium channels. A. Four covalently linked transmembrane domains (I, II, III, and IV) form the sodium channel, which is guarded by activation and inactivation gates. (Here, domain I is cut away to show the transmembrane pore.) In the resting membrane, most channels are in a closed state. Even though the inactivation gate is open, Na+ ions cannot easily pass through because the activation gate is closed. B. A rapid depolarization changes the cell membrane voltage and forces the activation gate to open, presumably mediated by translocation of the charged portions of a segment in each domain. With the channel in this conformation (in which both the activation and inactivation gates are open), Na+ ions permeate into the cell. C. As the inactivation gate spontaneously closes, the sodium current ceases. The inactivation gating function is thought to be achieved by a peptide loop that connects domains III and IV, which translocates into the intracellular opening of the channel pore (black arrow). The channel cannot reopen directly from this closed, inactive state. Cellular repolarization returns the channel to the resting condition (A) . During repolarization, as high negative membrane voltages are reachieved, the activation gate closes and the inactivation gate reopens. Normal Cardiac Structure and Function 15 (the typical resting voltage o a ventricular muscle cell), the channels are predominantly in a closed, resting state, such that Na+ ions cannot pass through (Fig. 1-11A). In this resting state, the channels are available or conversion to the open con guration. A rapid wave o depolarization renders the membrane potential less negative, and this acti- vates the resting channels to change con ormation to the open state (see Fig. 1-11B). Na+ ions readily permeate through the open channels, constituting an inward Na+ current that urther depolarizes the cell. However, the activated channels remain open or only a brie time, a ew thousandths o a second, and then spontaneously close to an inactive state (see Fig. 1-11C). Channels in the inactivated con ormation cannot be directly converted back to the open state. The inactivated state persists until the membrane voltage has been repolarized nearly back to its original resting level. Until then, the inactivated channel con ormation maintains a closed pore that prevents any f ow o sodium ions. Thus, during normal cellular depolariza- tion, the voltage-dependent ast sodium channels conduct or a short period and then inac- tivate, unable to conduct current again until the cell membrane has nearly ully repolarized, and the channels recover rom the inactivated to the closed resting state. Another important attribute o cardiac ast sodium channels should be noted. I the trans- membrane voltage o a cardiac cell is slowly depolarized and maintained chronically at levels less negative than the usual resting potential, inactivation o channels occurs without ini- tial opening and current f ow. Furthermore, as long as this partial depolarization exists, the closed, inactive channels cannot recover to the resting state. Thus, the ast sodium channels in such a cell are persistently unable to conduct Na+ ions. This is the typical case in cardiac pacemaker cells (e.g., the SA and AV nodes) in which the membrane voltage is generally less negative than −70 mV throughout the cardiac cycle. As a result, the ast sodium channels in pacemaker cells are persistently inactivated and do not play a role in the generation o the action potential in these cells. Calcium and potassium channels in cardiac cells also act in voltage-dependent ashions, but they behave di erently than the sodium channels, as described later. Resting Potential In nonpacemaker cardiac cells at rest, prior to excitation, the electrical charge di erential between the inside and outside o a cell corresponds to the resting potential. The magnitude o the resting potential o a cell depends on two main properties: (1) the concentration gra- dients or all the di erent ions between the inside and outside o the cell and (2) the relative permeabilities o ion channels that are open at rest. As in other tissues such as nerve cells and skeletal muscle, the potassium concentra- tion is much greater inside cardiac cells compared with outside. This is attributed mainly to the cell membrane transporter Na+K+-ATPase (see Fig. 1-10). This protein “pump” actively extrudes 3 Na+ ions out o the cell in exchange or the inward movement o 2 K+ ions in an ATP-dependent process. This acts to maintain intracellular Na+ at low levels and intracellular K+ at high levels. Cardiac myocytes contain a set o potassium channels (termed inward rectif er potassium channels) that are open in the resting state, at a time when other ionic channels (e.g., sodium and calcium) are closed. There ore, the resting cell membrane is much more permeable to potassium than to other ions. As a result, K+ f ows in an outward direction down its concentration gradient, removing positive charges rom the cell. As potassium ions exit the cell, negatively charged anions that are impermeant to passage are le t behind, causing the interior o the cell to become electrically negative with respect to the outside. As the interior o the cell becomes more negatively charged by the outward f ux o potas- sium, the positively charged K+ ions are attracted back by the electrical potential toward the cellular interior, slowing their net exit rom the cell. Thus, the K+ concentration gradient and the electrostatic orce oppose each other (Fig. 1-12). At equilibrium, these orces are 16 Chapter 1 balanced, and there is zero net movement o K+ across the membrane. The electrical poten- tial at which that occurs is known as the potassium equilibrium potential and in ventricular myocytes is −91 mV, as calculated by the Nernst equation, shown in Figure 1-12. Since at rest the membrane is almost exclusively permeable to potassium ions alone, this value closely approximates the cell’s resting potential. The permeability o the cardiac myocyte cellular membrane or sodium is minimal in the resting state because the channels that conduct that ion are essentially closed. However, there is a slight leak o sodium ions into the cell at rest. This small inward current o positively charged ions explains why the actual resting potential is slightly less negative (−90 mV) than would be predicted i the cell membrane were truly only permeable to potassium. The sodium ions that slowly leak into the myocyte at rest (and the much larger amount that enters during the action potential) are continuously removed rom the cell and returned to the extracellular environment by Na+K+-ATPase, as previously described. Action Potential When the cell membrane’s voltage is altered, its permeability to specif c ions changes because o the voltage-gating characteristics o the ion channels. Each type o channel has a charac- teristic pattern o activation and inactivation that determines the progression o the electrical signal. The ionic currents that pass through the channels discussed in this chapter are listed in Table 1-1. This description begins by ollowing the development o the action potential in a typical cardiac muscle cell (Fig. 1-13). The unique characteristics o action potentials in cardiac pacemaker cells are described therea ter. Equilibrium (Ne rns t) pote ntia l = –26.7 ln ([K+]in/[K +]out) = –91mV Ins ide ce ll Open potass ium channels CONCENTRATION GRADIENT [K+]out (5 mM) ELECTRICAL FORCE K+ + + + + – – – – [K+]in (150 mM) FIGURE 1-12. The resting potential of a cardiac muscle cell is determined by the balance between the concentration gradient and electrostatic forces for potassium, because only potassium channels are open at rest. The concentration gradient avors outward movement o K+, whereas the electrical orce attracts the positively charged K+ ions inward. The resting potential is approximated by the Nernst equation or potassium, as shown here. TABLE 1-1 Transmembrane Cardiac Ionic Currents Described in This Chapter Current Description I Pacemaker current; responsible or phase 4 depolarization in pacemaker cells INa Na+ + current; responsible or phase 0 rapid depolarization in nonpacemaker cells ICa.L Slow, long-lasting Ca+ + current; responsible or phase 0 depolarization in pacemaker cells, and major contributor to inward current during phase 2 o nonpacemaker cells IK1 Maintains resting potential; current o the inward recti ying potassium channel Ito Transient outward potassium current; responsible or phase 1 o action potential IKs, IKr Delayed rectif er potassium currents o slow (IKs) and rapid (IKr) types; repolarizing currents that are active during phases 2 and 3 o action potential Normal Cardiac Structure and Function 19 Cells that display pacemaker behavior include the SA node (the “natural pacemaker” o the heart) and the AV node. Although atrial and ventricular muscle cells do not normally display automaticity, they may do so under disease condi- tions such as ischemia. The shape o the action potential o a pace- maker cell is di erent rom that o a ventricular muscle cell in three ways: 1. The maximum negative voltage o pacemaker cells is approximately −60 mV, substantially less negative than the resting potential o ven- tricular muscle cells (−90 mV). The persistently less negative membrane voltage of pacemaker cells causes the fast sodium channels within these cells to remain inactivated. 2. Unlike that o cardiac muscle cells, phase 4 o the pacemaker cell action potential is not f at but has an upward slope, representing sponta- neous gradual depolarization. This spontane- ous depolarization is the result o an ionic f ux known as the pacemaker current (denoted by If; see Table 1-1). The pacemaker current is car- ried predominantly by Na+ ions. The ion chan- nel through which the pacemaker current passes is di erent rom the ast sodium channel responsible or phase 0 o the action potential. Importantly, this pacemaker channel opens in the very negative voltage ranges reached during repolarization o the cell. The inf ux o positively charged Na+ ions through the pacemaker channel causes the membrane potential to become progressively less negative during phase 4, ultimately depolarizing the cell to its threshold voltage (see Fig. 1-14). 3. The phase 0 upstroke o the pacemaker cell action potential is less rapid and reaches a lower amplitude than that o a cardiac muscle cell. These characteristics result rom the ast sodium channels o the pacemaker cells being inactivated and the upstroke o the action potential relying solely on Ca+ + inf ux through the relatively slow calcium channels. Repolarization o pacemaker cells occurs in a ashion similar to that o ventricular muscle cells and relies on inactivation o the calcium channels and increased activation o potassium channels with enhanced K+ e f ux rom the cell. Refractory Periods Compared with electrical impulses in nerves and skeletal muscle, the cardiac action potential is much longer in duration, supporting prolonged Ca+ + entry and muscle contraction during systole. This results in a prolonged period o channel inactivation during which the muscle is re ractory (unresponsive) to restimulation. Such a long period is physiologically necessary because it allows the ventricles su cient time to relax and re ll be ore the next contraction. There are di erent levels o re ractoriness during the action potential o a myocyte, as illustrated in Figure 1-15. The degree o re ractoriness primarily ref ects the percentage o ast Na+ channels that have recovered rom their inactive state and are capable o reopening. As phase 3 o the action potential progresses, an increasing number o Na+ channels recover rom inactivated to resting states and can then open in response to the next depolarization. This, in turn, corresponds to an increasing probability that a stimulus will trigger an action potential and result in a propagated impulse. M e m b r a n e p o t e n t i a l ( m V ) 0 K+ efflux (IKs and IKr) Ca++ influx (ICa.L) lf Time –40 –80 4 0 FIGURE 1-14. Action potential of a pacemaker cell. Phase 4 is characterized by gradual, spontaneous depolarization owing to the pacemaker current (I ). When the threshold potential is reached, at about −40 mV, the upstroke o the action potential ollows. The upstroke o phase 0 is less rapid than in nonpacemaker cells because the current represents Ca++ inf ux through the relatively slow calcium channels (Ica.L). Repolarization occurs with inactivation o the calcium channels and K+ e f ux rom the cell through potassium channels (IKs and IKr). 20 Chapter 1 The absolute re ractory period re ers to the time during which the cell is completely unexcit- able to any new stimulation. The effective re ractory period includes the absolute re ractory period but extends beyond it to include a short interval o phase 3, during which stimulation produces a localized action potential that is not strong enough to propagate urther. The relative re ractory period is the interval during which stimulation triggers an action potential that is conducted, but the rate o rise o the action potential is lower during this period because some o the Na+ chan- nels are inactivated and some o the delayed recti er K+ channels remain activated, thus reducing the available net inward current. Following the relative re ractory period, a short “supranormal” period is present in which a less-than-normal stimulus can trigger an action potential. The re ractory period o atrial cells is shorter than that o ventricular muscle cells, such that atrial rates can generally exceed ventricular rates during rapid arrhythmias (see Chapter 11). Impulse Conduction During depolarization, the electrical impulse spreads along each cardiac cell, and rapidly rom cell to cell because each myocyte is connected to its neighbors through low-resistance gap junc- tions. Gap junctions are a special type o ion channel that provide electrical and biochemical coupling between cardiac myocytes, allowing the action potential to spread rapidly through the myocardium. The speed o tissue depolarization (phase 0) and the conduction velocity along the cell depend on the net inward current (which is largely dependent on the number o sodium channels), on the value o the resting potential (which sets the degree o Na+ channel inactiva- tion), and on the resistance to current f ow between cells though the gap junctions. Tissues with a high concentration o Na+ channels, such as Purkinje bers, have a large, ast inward current, which spreads quickly within and between cells to support rapid conduction. However, the less negative the resting potential, the greater the raction o ast sodium channels that are in the inactivated state and the less rapid the upstroke velocity (Fig. 1-16). Thus, alterations in the rest- ing potential signi cantly impact the upstroke and conduction velocity o the action potential. Normal Sequence of Cardiac Depolarization Electrical activation o the heartbeat is normally initiated at the SA node (see Fig. 1-6). The impulse spreads to the surrounding atrial muscle through the intercellular gap junctions, pro- viding electrical continuity between the cells. Ordinary atrial muscle bers participate in the propagation o the impulse rom the SA to the AV node, although in certain regions the bers are more densely arranged, lowering intercellular resistance and thus acilitating conduction. Fibrous tissue surrounds the tricuspid and mitral valves, such that there is no direct elec- trical connection between the atrial and ventricular chambers other than through the AV M e m b r a n e p o t e n t i a l ( m V ) 0 Absolute RP Effective RP Rela tive RP Supranormal period –50 –100 1 2 3 FIGURE 1-15. Refractory periods (RPs) of the myocyte. During the absolute refractory period (ARP), the cell is unexcitable to stimulation. The effective refractory period includes a brief time beyond the ARP during which stimulation produces a localized depolarization that does not propagate (curve 1). During the relative refractory period, stimulation produces a weak action potential (AP) that propagates, but more slowly than usual (curve 2). During the supranormal period, a weaker-than-normal stimulus can trigger an AP (curve 3). Normal Cardiac Structure and Function 21 node. As the electrical impulse reaches the AV node, a delay in conduction (approximately 0.1 seconds) is encountered. This delay occurs because the small-diameter f bers in this region conduct slowly, and the action potential is o the “slow” pacemaker type (recall that the ast sodium channels are permanently inactivated in pacemaker tissues, such that the upstroke velocity relies on the slower calcium channels). The pause in conduction at the AV node is actually benef cial because it allows the atria time to contract and ully empty their contents be ore ventricular stimulation. In addition, the delay allows the AV node to serve as a “gatekeeper” o conduction rom atria to ventricles, which is critical or limiting the rate o ventricular stimulation during abnormally rapid atrial rhythms. A ter traversing the AV node, the cardiac action potential spreads into the rapidly conduct- ing bundle o His and Purkinje f bers, which distribute the electrical impulses to the bulk o the ventricular muscle cells, in a spatially synchronized manner. This allows or precisely timed stimulation and organized contraction o the ventricular myocytes, optimizing the vol- ume o blood ejected by the heart. EXCITATION–CONTRACTION COUPLING This section reviews how the electrical action potential leads to physical contraction o cardiac muscle cells, a process known as excitation–contraction coupling. During this process, chemi- cal energy in the orm o high-energy phosphate compounds is translated into the mechanical energy o myocyte contraction. Contractile Proteins in the Myocyte Several distinct proteins are responsible or cardiac muscle cell contraction (Fig. 1-17). O the major proteins, actin and myosin are the chie contractile elements. Two other proteins, tropomyosin and troponin, serve regulatory unctions. Myosin is arranged in thick f laments, each composed o lengthwise stacks o approxi- mately 300 molecules. The myosin f lament exhibits globular heads that are evenly spaced Phase 0 M e m b r a n e p o t e n t i a l ( m V ) 0 –50 –100 A B FIGURE 1-16. Dependence of speed of depolarization on resting potential. A. Normal resting potential (RP) and rapid rise of phase 0. B. Less negative RP results in slower rise of phase 0 and lower maximum amplitude of the action potential. Myos in heads Myosin thick filament TnI TnC TropomyosinActin TnT FIGURE 1-17. Schematic diagram of the main contractile proteins of the myocyte, actin, and myosin. Tropomyosin and troponin (components TnI, TnC, and TnT) are regulatory proteins. 24 Chapter 1 the sarcolemmal Na+–Ca+ + exchanger and to a lesser extent by the ATP-consuming calcium pump, sarcolemmal Ca+ +-ATPase (see Fig. 1-10). As cytosolic Ca+ + concentrations all and calcium ions dissociate rom TnC, tropomyosin once again inhibits the actin–myosin interaction, leading to relaxation o the contracted cell. The contraction–relaxation cycle can then repeat with the next action potential. INTRODUCTION TO CARDIAC SIGNALING SYSTEMS β-Adrenergic and Cholinergic Signaling There is substantial evidence that the concentration o Ca+ + within the cytosol is the major determinant o the orce o cardiac contraction with each heartbeat. Mechanisms that raise intracellular Ca+ + concentration enhance orce development, whereas actors that lower Ca+ + concentration reduce the contractile orce. β-Adrenergic stimulation is one mechanism that enhances calcium f uxes in the myocyte and thereby strengthens the orce o ventricular contraction (Fig. 1-20). Catecholamines (e.g., norepinephrine) bind to the myocyte β1-adrenergic receptor, which is coupled to and activates the G protein system (Gs) attached to the inner sur ace o the cell membrane. Gs in turn stimu- lates membrane-bound adenylate cyclase to produce cyclic AMP (cAMP) rom ATP. cAMP then activates speci c intracellular protein kinases (PKAs), which phosphorylate cellular Norepinephrine β1-adrenergic receptor Gs prote in Gi prote in Ca ++ Ca ++ Ca ++ ATP Inactive prote in kinases Active prote in kinases PL ATP Adenyla te cyclase Muscarinic receptor Sarcoplasmic re ticulum cAMP Acetylcholine + + + – FIGURE 1-20. Effects of β-adrenergic and cholinergic stimulation on cardiac cellular signaling and calcium ion movement. The binding of a ligand (e.g., norepinephrine) to the β1-adrenergic receptor induces G protein– mediated stimulation of adenylate cyclase and formation of cyclic AMP (cAMP). The latter activates protein kinases, which phosphorylate cellular proteins, including ion channels. Phosphorylation of the slow Ca++ channel enhances calcium movement into the cell and therefore strengthens the force of contraction. Protein kinases also phosphorylate phospholamban (PL), reducing the latter’s inhibition of Ca++ uptake by the sarcoplasmic reticulum. The enhanced removal of Ca++ from the cytosol facilitates relaxation of the myocyte. Cholinergic signaling, triggered by acetylcholine binding to the muscarinic receptor, activates inhibitory G proteins that reduce adenylate cyclase activity and cAMP production, thus antagonizing the effects of β-adrenergic stimulation. Normal Cardiac Structure and Function 25 proteins, including the L-type calcium channels within the cell membrane. Phosphorylation o the calcium channel augments Ca+ + inf ux, which triggers a corresponding increase in Ca+ + release rom the SR, thereby enhancing the orce o contraction. β-Adrenergic stimulation o the myocyte also enhances myocyte relaxation. The return o Ca+ + rom the cytosol to the SR is regulated by phospholamban (PL), a low molecular weight protein in the SR membrane. In its dephosphorylated state, PL inhibits Ca+ + uptake by SERCA (see Fig. 1-18). However, β-adrenergic activation o PKAs causes PL to become phosphory- lated, an action that blunts PL’s inhibitory e ect (see Fig. 1-20). The subsequently greater uptake o calcium ions by the SR hastens Ca+ + removal rom the cytosol, promoting myocyte relaxation. The increased cAMP activity also results in phosphorylation o TnI, an action that inhibits actin–myosin interactions and there ore urther enhances relaxation o the cell. Cholinergic signaling via parasympathetic inputs (mainly rom the vagus nerve) opposes the e ects o β-adrenergic stimulation (see Fig. 1-20). Acetylcholine released rom parasympathetic nerve terminals binds to the muscarinic M2 receptor on cardiac cells. This receptor also activates G proteins, but in distinction to the β-adrenergic receptor, it is coupled to Gi, an inhibitory G protein system. Gi associated with cholinergic stimulation inhibits adenylate cyclase activity and reduces cAMP ormation. At the sinus node, these actions o cholinergic stimulation serve to reduce heart rate. In the myocardium, the e ect is to counteract the orce o contraction induced by β-adrenergic stimulation. It should be noted that ventricular cells are much less sensitive to this cholinergic e ect than atrial cells, likely ref ecting di erent degrees o G protein coupling. Thus, physiologic or pharmacologic catecholamine stimulation o the myocyte β1-adrenergic receptor enhances contraction o the cell, while cholinergic stimulation opposes that enhance- ment. We will return to these important properties in later chapters. SUMMARY • This chapter has reviewed basic cardiac anatomy and cellular composition, the cardiac conduction system, excitation–contraction coupling, and cardiac signaling systems. The physiology o myocyte contraction will be described in Chapter 9. Each o these complex pieces integrate together to orm an organ system that unctions in a organized ashion, is robust to errors, and operates reliably over many years. As a result, the heart is capable o purpose ul stimulation billions o times during the li e span o a normal person. With each contraction cycle, the heart receives and propagates blood through the circulation to provide nutrients to and remove waste products rom the body’s tissues. • The ollowing chapters explore what can go wrong with this remarkable system. Ack n owled gm en t s Contributors to previous editions o this chapter were Ken Young Lin, MD; Vivek Iyer, MD; Kirsten Greineder, MD; Stephanie Harper, MD; Scott Hyver, MD; Paul Kim, MD; Rajeev Malhotra, MD; Laurence Rhines, MD; and James D. Marsh, MD. Ad d i t ion a l Rea d in g Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23–49. Christo els VM, Smits GJ, Kispert A, Moorman AFM. Development o pacemaker tissues o the heart. Circ Res. 2010;106:240–254. Courneya C, Parker MJ. Cardiovascular Physiology. A Clinical Approach. Baltimore, MD: Lippincott Williams & Wilkins; 2011. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2:185–194. Katz AM. Physiology of the Heart. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. Saucerman JJ, McCulloch AD. Cardiac beta-adrenergic signal- ing: rom subcellular microdomains to heart ailure. Ann N Y Acad Sci. 2006;1080:348–361. Smyth JW, Shaw RM. Forward tra cking o ion chan- nels: What the clinician needs to know. Heart Rhythm. 2010;7:1135–1140. Wilcox BR, Cook AC, Anderson RH. Surgical Anatomy of the Heart. 4th ed. Cambridge, MA: Cambridge University Press; 2013. Zipes DP, Jali e J, eds. Cardiac Electrophysiology: From Cell to Bedside. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013. 26 C h a p t e r O u t l i n e Cardiac Cycle Heart Sounds First Heart Sound (S1) Second Heart Sound (S2) Extra Systolic Heart Sounds Extra Diastolic Heart Sounds Murmurs Systolic Murmurs Diastolic Murmurs Continuous Murmurs Cardiac diseases o ten cause abnormal ndings on physi-cal examination, including pathologic heart sounds and murmurs. These ndings are clues to the underlying pathophysi- ology, and proper interpretation is essential or success ul diag- nosis and disease management. This chapter rst describes heart sounds in the context o normal cardiac physiology and then ocuses on the origins o pathologic heart sounds and murmurs. Many cardiac diseases are mentioned brief y in this chapter as examples o abnormal heart sounds and murmurs. Each o these conditions is described in greater detail later in the book, so it is not necessary or desirable to memorize all o the examples presented here. Rather, the goal o this chapter is to explain the mechanisms by which the abnormal sounds are produced, so that their descriptions will make sense in later chapters. CARDIAC CYCLE The cardiac cycle consists o precisely timed electrical and mechanical events that are responsible or rhythmic atrial and ventricular contractions. Figure 2-1 displays the pressure rela- tionships between the le t-sided cardiac chambers during the normal cardiac cycle and serves as a plat orm or describing key events. Mechanical systole re ers to the phase o ventricu- lar contraction, and diastole re ers to the phase o ventricular relaxation and f lling. Throughout the cardiac cycle, the right and le t atria accept blood returning to the heart rom the systemic veins and rom the pulmonary veins, respectively. During diastole, blood passes rom the atria into the ventricles across the open tricuspid and mitral valves, causing a gradual increase in ventricular diastolic pressures. In late diastole, atrial contraction propels a f nal bolus o blood into each ven- tricle, an action that produces a brie urther rise in atrial and ventricle pressures, termed the a wave (see Fig. 2-1). The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs David B. Fischer Leonard S. Lilly 2 The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs 29 HEART SOUNDS Commonly used stethoscopes contain two chest pieces or auscultation o the heart. The concave “bell” chest piece, meant to be applied lightly to the skin, accentuates low- requency sounds. Conversely, the f at “diaphragm” chest piece is designed to be pressed rmly against the skin to eliminate low requencies and there ore accentuate high- requency sounds and murmurs. Some modern stethoscopes incorporate both the bell and diaphragm unctions into a single chest piece; in these models, placing the piece lightly on the skin brings out the low- requency sounds, while rm pressure accentuates the high- requency ones. The sections below describe when, and where on the chest, to listen or high- versus low- requency sounds. First Heart Sound (S1) S1 is produced by the closure o the mitral and tricuspid valves in early systole and is loudest near the apex o the heart (Fig. 2-2). It is a high- requency sound, best heard with the diaphragm o the stethoscope. Although mitral closure usually precedes tricuspid clo- sure, they are separated by only about 0.01 seconds, such that the human ear appreciates only a single sound. An exception occurs in patients with right bundle branch block (see Chapter 4), in whom these components may be audibly split because o delayed right ventricular contraction and late closure o the tricuspid valve. Three actors determine the intensity o S1: (1) the distance separating the leaf ets o the open valves at the onset o ventricular contraction, (2) the mobility o the mitral and tricuspid leaf ets (normal, or rigid because o stenosis), and (3) the rate o rise o ventricular pressure (Table 2-1). The distance between the open valve leaf ets at the onset o ventricular contraction relates to the electrocardiographic PR interval (see Chapter 4), the period between the onset o atrial and ventricular activation. Atrial contraction at the end o diastole orces the tricuspid and mitral valve leaf ets apart. They start to passively dri t back together, but once Pulmonic area (2nd–3rd le ft inte rspace) Mitral area (apex) Tricus pid area (le ft lower s te rna l border) Aortic area (2nd–3rd right interspace) FIGURE 2-2. Standard positions of stethoscope placement for cardiac auscultation. The mitral area localizes to the cardiac apex while the aortic and pulmonic regions represent the cardiac base. I the top o the IJ column is not visible at 45 degrees, the column o blood is either too low (below the clavicle) or too high (above the jaw) to be measured in that position. In such situations, the head o the bed must be lowered or raised, respectively, so that the top o the column becomes visible. As long as the top can be ascertained, the vertical height o the JVP above or below the sternal angle will accurately ref ect RA pressure, no matter the angle o the head o the bed. Sometimes it can be di cult to distinguish the jugular venous pulsations rom the neighboring carotid artery. Unlike the carotid, the JVP is usually not pulsatile to palpation, it has a double (or triple) upstroke rather than a single one, and it declines in most patients by assuming the seated position or during inspiration. BOX 2-1 Jugular Venous Pulsations and Assessment of Right Heart Function (continued) 30 Chapter 2 ventricular contraction causes the ventricular pressure to exceed that in the atrium, the leaf ets are orced to close rom whatever positions they occupy at that moment. An accen- tuated S1 results when the PR interval is shorter than normal, because the valve leaf ets have less time to dri t back together and are there ore orced shut rom a relatively wide distance. Similarly, in mild mitral stenosis (see Chapter 8), impeded f ow through the mitral valve causes a prolonged diastolic pressure gradient between the le t atrium and ventricle, which keeps the mobile portions o the mitral leaf ets arther apart than normal during late diastole. Because the leaf ets are relatively wide apart at the onset o systole, they are orced shut loudly when the le t ventricle contracts. S1 may also be accentuated when the heart rate is more rapid than normal (i.e., tachycar- dia) because diastole is shortened and the leaf ets have less time to dri t back together be ore the ventricles contract. Conditions that reduce the intensity o S1 are also listed in Table 2-1. In rst-degree atrioventricular (AV) block (see Chapter 12), a diminished S1 results rom an abnormally prolonged PR interval, which delays the onset o ventricular contraction. Consequently, ollowing atrial contraction, the mitral and tricuspid valves have additional time to f oat back together so that the leaf ets are orced closed rom only a small distance apart and the sound is so tened. In patients with mitral regurgitation (see Chapter 8), S1 is o ten diminished in intensity because the mitral leaf ets may not come into ull contact with one another as they close. In severe mitral stenosis, the leaf ets are nearly xed in position throughout the cardiac cycle, and that reduced movement lessens the intensity o S1. In patients with a “sti ened” le t ventricle (e.g., a hypertrophied chamber), atrial contrac- tion generates a higher-than-normal ventricular pressure at the end o diastole. This greater pressure causes the mitral leaf ets to dri t together more rapidly, so that they are orced closed rom a smaller-than-normal distance when ventricular contraction begins, thus reducing the intensity o S1. Second Heart Sound (S2) The second heart sound results rom the closure o the aortic and pulmonic valves and there- ore has aortic (A2) and pulmonic (P2) components. Unlike S1, which is usually heard only as a single sound, the components o S2 vary with the respiratory cycle: they are normally used as one sound during expiration but become audibly separated during inspiration, a situation termed normal or physiologic splitting (Fig. 2-3). One explanation or normal splitting o S2 is as ollows. Expansion o the chest during inspiration causes the intrathoracic pressure to become more negative. The negative pressure TABLE 2-1 Causes o Altered Intensity o the First Heart Sound (S1) Accentuated S1 1. Shortened PR interval 2. Mild mitral stenosis 3. High cardiac output states or tachycardia (e.g., exercise) Diminished S1 1. Lengthened PR interval: f rst-degree AV nodal block 2. Mitral regurgitation 3. Severe mitral stenosis 4. “Sti ” le t ventricle (e.g., le t ventricular hypertrophy due to systemic hypertension) The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs 31 transiently increases the capacitance (and reduces the impedance) of the intrathoracic pul- monary vessels. As a result, there is a temporary delay in the diastolic “back pressure” in the pulmonary artery responsible for the closure of the pulmonic valve. Thus, P2 is delayed; that is, it occurs later during inspiration than during expiration. Inspiration has the opposite effect on aortic valve closure. Because the capacitance of the intrathoracic pulmonary veins is increased by the negative pressure generated by inspiration, P2A2 Phys iologic (normal) splitting Widened splitting Fixed splitting Paradoxica l splitting (Note reversed pos ition of A2 and P2) Expira tion Inspira tion Expira tion Inspira tion Expira tion Inspira tion Expira tion Inspira tion In expira tion, A2 and P 2 fuse as one sound • Right bundle branch block • Pulmonary s tenos is • Left bundle branch block • Advanced aortic s tenos is • Atria l septa l defect Common caus es S1 P2 P2 A2S 1 A2S 1 A2S 1 P2 FIGURE 2-3. Splitting patterns of the second heart sound (S2) . A2, aortic component; P2, pulmonic component o S2; S1, f rst heart sound. 34 Chapter 2 Because o its proximity to A2, the A2–OS sequence can be con used with a widely split second heart sound. However, care- ul auscultation at the pulmonic area during inspiration reveals three sounds occurring in rapid succession (Fig. 2-5), which cor- respond to aortic closure (A2), pulmonic closure (P2), and then the OS. The three sounds become two on expiration when A2 and P2 normally use. The severity o mitral stenosis can be approximated by the time interval between A2 and the OS: the more advanced the stenosis, the shorter the interval. This occurs because the degree o le t atrial pressure elevation corresponds to the severity o mitral stenosis. When the ventricle relaxes in diastole, the greater the le t atrial pres- sure, the earlier the mitral valve opens. Compared with severe ste- nosis, mild disease is marked by a less elevated le t atrial pressure, lengthening the time it takes or the le t ventricular pressure to all below that o the atrium. There ore, in mild mitral stenosis, the OS is widely separated rom A2, whereas in more severe stenosis, the A2–OS interval is narrower. Third Heart Sound (S3) When present, an S3 occurs in early diastole, ollowing the opening o the AV valves, during the ventricular rapid lling phase (see Fig. 2-4). It is a dull, low-pitched sound best heard with the bell o the stethoscope. A le t-sided S3 is typically loudest over the cardiac apex while the patient lies in the le t lateral decubitus position. A right-sided S3 is better appreciated at the lower le t sternal border. Production o the S3 appears to result rom tensing o the chordae tendineae during rapid lling and expansion o the ventricle. An S3 is a normal nding in children and young adults. In these groups, an S3 implies the presence o a supple ventricle capable o normal rapid expansion in early diastole. Conversely, when heard in middle-aged or older adults, an S3 is a sign o disease resulting rom a dilated ventricle (e.g., a patient with heart ailure due to impaired systolic contraction, as described in Chapter 9) or rom the increased transvalvular f ow that accompanies advanced mitral or tricuspid regurgitation (described in Chapter 8). A pathologic S3 is sometimes re erred to as a ventricular gallop. Fourth Heart Sound (S4) When an S4 is present, it occurs in late diastole and coincides with contraction o the atria (see Fig. 2-4). This sound is generated by the le t (or right) atrium ejecting blood into a sti ened ventricle. Thus, an S4 usually indicates the presence o cardiac disease—speci cally, a decrease in ventricular compliance typically resulting rom ventricular hypertrophy or myo- cardial ischemia. Like an S3, the S4 is a dull, low-pitched sound and is best heard with the bell o the stethoscope. In the case o the more common le t-sided S4, the sound is loudest at the apex, with the patient lying in the le t lateral decubitus position. S4 is sometimes re erred to as an atrial gallop. Quadruple Rhythm or Summation Gallop In a patient with both an S3 and S4, those sounds, in conjunction with S1 and S2, produce a quadruple beat. I a patient with a quadruple rhythm develops tachycardia, diastole becomes shorter in duration, the S3 and S4 coalesce, and a summation gallop results. The summation o S3 and S4 is heard as a long middiastolic, low-pitched sound, o ten louder than S1 and S2. OS OS P2A2 Expira tion Inspira tion S 1 S2 FIGURE 2-5. Timing of the opening snap (OS) in mitral stenosis does not change with respiration. On inspiration, normal splitting o the second heart sound (S2) is observed so that three sounds are heard. A2, aortic component; P2, pulmonic component o S2; S1, f rst heart sound. The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs 35 Pericardial Knock A pericardial knock is an uncommon, high-pitched sound that occurs in patients with severe constrictive pericarditis (see Chapter 14). It appears early in diastole soon a ter S2 and can be con used with an OS or an S3. However, the knock appears slightly later in dias- tole than the timing o an OS and is louder and occurs earlier than does a ventricular gallop. It results rom the abrupt cessation o ventricular lling that occurs when the expanding ventricle meets a rigid pericardium in early diastole, which is the hallmark o constrictive pericarditis. MURMURS A murmur is the sound generated by turbulent blood f ow. Under normal conditions, the movement o blood through the vascular bed is laminar, smooth, and silent. However, as a result o hemodynamic and/ or structural changes, laminar f ow can become disturbed and produce an audible noise. Murmurs result rom any o the ollowing mechanisms: 1. Flow across a partial obstruction (e.g., aortic stenosis) 2. Increased f ow through normal structures (e.g., aortic systolic murmur associated with a high-output state, such as anemia) 3. Ejection into a dilated chamber (e.g., aortic systolic murmur associated with aneurysmal dilatation o the aorta) 4. Regurgitant f ow across an incompetent valve (e.g., mitral regurgitation) 5. Abnormal shunting o blood rom one vascular chamber to a lower-pressure chamber (e.g., ventricular septal de ect [VSD]) Murmurs are described by their timing, intensity, pitch, shape, location, radiation, and response to maneuvers. Timing re ers to whether the murmur occurs during systole or dias- tole, or is continuous (i.e., begins in systole and continues into diastole). The intensity o the murmur is typically quanti ed by a grading system. In the case o systolic murmurs: And in the case o diastolic murmurs: Pitch re ers to the requency o the murmur, ranging rom high to low. High- requency mur- murs are caused by large pressure gradients between chambers (e.g., aortic stenosis) and are best appreciated using the diaphragm chest piece o the stethoscope. Low- requency murmurs imply less o a pressure gradient between chambers (e.g., mitral stenosis) and are best heard using the stethoscope’s bell piece. Grade 1/ 4 (or I/ IV): Barely audible Grade 2/ 4 (or II/ IV): Faint but immediately audible Grade 3/ 4 (or III/ IV): Easily heard Grade 4/ 4 (or IV/ IV): Very loud Grade 1/ 6 (or I/ VI): Barely audible (i.e., medical students may not hear it!) Grade 2/ 6 (or II/ VI): Faint but immediately audible Grade 3/ 6 (or III/ VI): Easily heard Grade 4/ 6 (or IV/ VI): Easily heard and associated with a palpable thrill Grade 5/ 6 (or V/ VI): Very loud; heard with the stethoscope lightly on the chest Grade 6/ 6 (or VI/ VI): Audible without the stethoscope directly on the chest wall 36 Chapter 2 Shape describes how the murmur changes in intensity rom its onset to its completion. For example, a crescendo–decrescendo (or “diamond-shaped”) murmur rst rises and then alls o in intensity. Other shapes include decrescendo (i.e., the murmur begins at its maxi- mum intensity then becomes so ter) and uniform (the intensity o the murmur does not change). Location re ers to the murmur’s region o maximum intensity and is usually described in terms o speci c auscultatory areas (see Fig. 2-2): From their primary locations, murmurs are o ten heard to radiate to other areas o the chest, and such patterns o transmission relate to the direction o the turbulent f ow. Finally, similar types o murmurs can be distinguished rom one another by simple bedside maneu- vers, such as standing upright, Valsalva ( orce ul expiration against a closed airway), or clenching o the sts, each o which alters the heart’s loading conditions and can a ect the intensity o many murmurs. Examples o the e ects o maneuvers on speci c murmurs are presented in Chapter 8. When reporting a murmur, some or all o these descriptors are mentioned. For example, you might describe a particular patient’s murmur o aortic stenosis as “A grade III/ VI high- pitched, crescendo–decrescendo systolic murmur, loudest at the upper right sternal border, with radiation toward the neck.” Systolic Murmurs Systolic murmurs are subdivided into systolic ejection murmurs, pansystolic murmurs, and late systolic murmurs (Fig. 2-6). A systolic ejection murmur is typical o aortic or pul- monic valve stenosis. It begins a ter the rst heart sound and terminates be ore or during S2, depending on its severity and whether the obstruction is o the aortic or pulmonic valve. The shape o the murmur is o the crescendo–decrescendo type (i.e., its intensity rises and then alls). Aortic area: Second to third right intercostal spaces, next to the sternum Pulmonic area: Second to third le t intercostal spaces, next to the sternum Tricuspid area: Lower le t sternal border Mitral area: Cardiac apex ClickS1 S 2 S1 S 2 S1 S 2 A. Ejection type • Aortic s tenos is • Pulmonary s tenos is • Mitra l regurgita tion • Tricuspid regurgita tion • Ventricula r septa l defect • Mitra l va lve prolapse Examples B. Pansys tolic (holosys tolic) C. La te sys tolic FIGURE 2-6. Classif cation o systolic murmurs. Ejection murmurs are crescendo– decrescendo in conf guration (A), whereas pansystolic murmurs are uni orm throughout systole (B). A late systolic murmur o ten ollows a midsystolic click and suggests mitral (or tricuspid) valve prolapse (C). The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs 39 preceded by an opening snap. The shape o this murmur is unique. Following valvular open- ing (and the OS), the murmur is at its loudest because the pressure gradient between the atrium and ventricle is at its maximum. The murmur then decrescendos or disappears totally during diastole as the transvalvular gradient decreases. The degree to which the murmur ades depends on the severity o the stenosis. I the stenosis is severe, the murmur is prolonged; i the stenosis is mild, the murmur disappears in mid-to-late diastole. Whether the stenosis is mild or severe, the murmur intensi es at the end o diastole in patients in normal sinus rhythm, when atrial contraction augments f ow (and turbulence) across the valve (see Fig. 2-9). Since the pressure gradient across a stenotic mitral valve tends to be airly low, the murmur o mitral stenosis is low pitched and is heard best with the bell o the stethoscope at the apex, while the patient lies in the le t lateral decubitus position. The much less common murmur o tricuspid stenosis is better auscultated at the lower sternum, near the xiphoid process. Hyperdynamic states such as ever, anemia, hyperthyroidism, and exercise cause increased f ow across the normal tricuspid and mitral valves and can there ore result in a diastolic mur- mur. Similarly, in patients with advanced mitral regurgitation, the expected systolic murmur can be accompanied by an additional diastolic murmur owing to the increased volume o blood that must return across the valve to the le t ventricle in diastole. Likewise, patients with either tricuspid regurgitation or an atrial septal de ect (see Chapter 16) have increased f ow across the tricuspid valve, and may there ore display a diastolic f ow murmur rom that site. Continuous Murmurs Continuous murmurs are heard throughout the cardiac cycle. Such murmurs result rom condi- tions in which there is a persistent pressure gradient between two structures during both systole and diastole. An example is the murmur o patent ductus arteriosus, in which there is an abnor- mal congenital communication between the aorta and the pulmonary artery (see Chapter 16). During systole, blood f ows rom the high-pressure ascending aorta through the ductus into the • Aortic regurgita tion • Pulmonic regurgita tion • Mild mitra l or tricuspid s tenos is • Severe mitra l or tricuspid s tenos is S1 S1S 2 S 1 S1S 2 S 1 S 1S 2 A. Early decrescendo B. Mid-to-la te C. P rolonged mid-to-la te OS OS FIGURE 2-9. Classif cation o diastolic murmurs. A. An early diastolic decrescendo murmur is typical o aortic or pulmonic valve regurgitation. B. Mid-to-late low- requency rumbling murmurs are usually the result o mitral or tricuspid valve stenosis and ollow a sharp opening snap (OS). Presystolic accentuation o the murmur occurs in patients in normal sinus rhythm because o the transient rise in atrial pressure during atrial contraction. C. In more severe mitral or tricuspid valve stenosis, the opening snap and diastolic murmur commence earlier, and the murmur is prolonged. S1, f rst heart sound; S2, second heart sound. 40 Chapter 2 lower-pressure pulmonary artery. During diastole, the aortic pressure remains greater than that in the pulmonary artery and the f ow continues across the ductus. This murmur begins in early systole, crescendos to its maximum at S2, then decrescendos until the next S1 (Fig. 2-10). The “to-and- ro” combined murmur in a patient with both aortic stenosis and aortic regur- gitation could be mistaken or a continuous murmur (see Fig. 2-10). During systole, there is a diamond-shaped ejection murmur, and during diastole, a decrescendo murmur. However, in the case o a to-and- ro murmur, the sound does not extend through S2 because it has discrete systolic and diastolic components. SUMMARY • Cardiac diseases o ten result in abnormal heart sounds and murmurs, which are clues to the underlying pathophysiology. • Systole re ers to the phase o ventricular contraction, and diastole re ers to the phase o ven- tricular relaxation and lling. • The normal cardiac cycle proceeds as ollows: (1) during diastole, the mitral valve (MV) is open, so that the le t atrial (LA) and le t ventricular (LV) pressures are equal; (2) in late diastole, LA contraction causes a small rise in pressure in both the LA and LV; (3) a ter a short delay, ventricular contraction causes the LV pressure to rise, and when the LV pres- sure exceeds the LA pressure, the MV closes, contributing to the rst heart sound (S1); (4) as LV pressure rises above the aortic pressure, the aortic valve (AV) opens, a silent event in a normal heart; (5) a ter contraction, as the ventricle relaxes and its pressure alls below that o the aorta, the AV closes, contributing to the second heart sound (S2); (6) when the LV pressure declines below that o the le t atrium, the mitral valve opens, and the cycle repeats. • Extra systolic sounds include ejection clicks, indicating aortic or pulmonic stenosis or dilatation o the aortic root or pulmonary artery, and mid-to-late clicks, indicating mitral or tricuspid valve prolapse. • Extra diastolic sounds include the opening snap (signi ying mitral stenosis), the S3 sound (indicating heart ailure or a volume overload state in older adults; an S3 is a normal sound in children and young adults), and the S4 sound (indicating reduced ventricular compliance). • Common murmurs include systolic ejection murmurs rom aortic or pulmonic stenosis, pansystolic murmurs rom mitral or tricuspid regurgitation, late systolic murmurs rom mitral valve prolapse, early diastolic murmurs rom aortic or pulmonic regurgitation, and mid-to- late diastolic murmurs rom mitral stenosis. • Tables 2-2 and 2-3 and Figure 2-11 summarize eatures o the heart sounds and murmurs described in this chapter. S1 S 1S 2 S1 S 1S 2 To-and-fro Continuous • Aortic s tenos is and regurgita tion • Pulmonic s tenos is and regurgita tion • Pa tent ductus a rte riosus FIGURE 2-10. A continuous murmur peaks at, and extends through, the second heart sound (S2) . A to-and- ro murmur is not continuous; rather, there is a systolic component and a distinct diastolic component, separated by S2. S1, f rst heart sound. TABLE 2-2 Common Heart Sounds Sound Location Pitch Signif cance S1 Apex High Normal closure of mitral and tricuspid valves S2 Base High Normal closure of aortic (A2) and pulmonic (P2) valves Extra systolic sounds Ejection clicks Aortic: apex and base High Aortic or pulmonic stenosis, or dilatation of aortic root or pulmonary arteryPulmonic: base High Mid-to-late click Mitral: apex High Mitral or tricuspid valve prolapse Tricuspid: LLSB High Extra diastolic sounds Opening snap Apex High Mitral stenosis S3 Left-sided: apex Low Normal in children Abnormal in adults: indicates heart failure or volume overload state S4 Left-sided: apex Low Reduced ventricular compliance LLSB, lower left sternal border. TABLE 2-3 Common Murmurs Murmur Type Example Location and Radiation Systolic ejection S1 S 2 Aortic stenosis Second right intercostal space → neck (but may radiate widely) Pulmonic stenosis Second to third left intercostal spaces Pansystolic S1 S 2 Mitral regurgitation Apex → axilla Tricuspid regurgitation Left lower sternal border → right lower sternal border Late systolic S2 S 2 Mitral valve prolapse Apex → axilla Early diastolic S 1S2 Aortic regurgitation Along left side of the sternum Pulmonic regurgitation Upper left side of the sternum Mid-to-late diastolic S 1S2 Mitral stenosis Apex 44 Chapter 3 Frontal and lateral radiographs are rou- tinely used to assess the heart and lungs (Fig. 3-1). The frontal view is usually a posterior–anterior image in which the x-rays are transmitted rom behind (i.e., posterior to) the patient, pass through the body, and are then captured by the lm (or electronic sensor) placed against the anterior chest. This positioning places the heart close to the x-ray recording lm plate so that its image is only minimally distorted, allowing or an accurate assess- ment o size. In the standard lateral view, the patient’s le t side is placed against the lm plate and the x-rays pass through the body rom right to le t. The rontal radio- graph is use ul or assessing the size o the le t ventricle, le t atrial appendage, pulmo- nary artery, aorta, and superior vena cava; the lateral view evaluates right ventricular size, posterior borders o the le t atrium and ventricle, and the anteroposterior diameter o the thorax. Cardiac Silhouette Chest radiographs are use u l to evaluate the size o heart chambers and the pul- monary consequences o cardiac disease. Alterations in chamber size are re lected by changes in the cardiac silhouette. In the rontal view o adults, an enlarged heart is identi ied by a cardiothoracic ratio ( the maximum width o the heart divided by the maximum internal diam- eter o the thoracic cage) o greater than 50% . In certain situations, the cardiac silhouette inaccurately ref ects heart size. For example, an elevated diaphragm, or narrow chest anteroposterior diameter, may cause the silhouette to expand transversely such that the heart appears larger than its actual dimensions. There ore, the chest anteroposterior diameter should be assessed on the lateral view be ore concluding the heart is truly enlarged. The presence o a pericardial e usion around the heart can also widen the cardiac silhouette because f uid and myocardial tissue a ect x-ray penetration similarly. Radiographs can depict dilatation o individual cardiac chambers. O note, concentric ven- tricular hypertrophy alone (i.e., without dilatation) may not result in radiographic abnor- malities, because it generally occurs at the expense o the cavity’s internal volume and produces little or no change in overall cardiac size. Major causes o chamber and great ves- sel dilatation include heart ailure, valvular lesions, abnormal intracardiac and extracardiac communications (shunts), and certain pulmonary disorders. Because dilatation takes time to FIGURE 3-1. Posteroanterior (A and B) and lateral (C and D) chest radiographs of a person without cardiopulmonary disease, illustrating cardiac chambers and valves. AO, aorta; AV, azygos vein; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage; LPA, left pulmonary artery; LV, left ventricle; MPA, main pulmonary artery; MV, mitral valve; RA, right atrium; RPA, right pulmonary artery; RV, right ventricle; SVC, superior vena cava; TV, tricuspid valve. (Reprinted from Come PC, ed. Diagnostic Cardiology: Noninvasive Imaging Techniques. Philadelphia, PA: J.B. Lippincott; 1985, with permission.) MPA AV SVC A RA RVTV IVC LV LA LAA AO B RA TV IVC RV MPA RPA LPA C AO AA D LA MV LV Cardiac Imaging and Catheterization 45 develop, recent lesions, such as acute mitral valve insu ciency, may present without appar- ent cardiac enlargement. The pattern o chamber enlargement may suggest speci c disease entities. For example, dilatation o the le t atrium and right ventricle, accompanied by signs o pulmonary hyperten- sion, suggests mitral stenosis (Fig. 3-2). In contrast, dilatation o the pulmonary artery and right heart chambers, but without enlargement o the le t-sided heart dimensions, can be seen in patients with pulmonary vascular obstruction, in those with increased pulmonary artery blood f ow (e.g., due to an atrial septal de ect), or in those with pulmonary hypertension o diverse causes (Fig. 3-3). Chest radiographs can also detect dilatation o the aorta. Causes o aortic enlargement include aneurysm, dissection, and aortic valve disease (Fig. 3-4). Normal aging and athero- sclerosis may also cause the aorta to become dilated and tortuous. Pulmonary Manifestations of Heart Disease The appearance o the pulmonary vasculature ref ects abnormalities o pulmonary arterial and venous pressures and pulmonary blood f ow. Increased pulmonary venous pressure, as occurs in le t heart ailure, causes increased vascular markings, redistribution o blood f ow rom the bases to the apices o the lungs (termed cepha liza tion o vessels), intersti- tial edema, and alveolar edema (Fig. 3-5). Cephalization appears as an increase in the number or width o vascular markings at the apex (Fig. 3-5A). Interstitial edema occurs as pulmonary congestion progresses, and the connective tissue spaces become thickened with f uid (Fig. 3-5B). Kerley B lines (short horizontal parallel lines at the periphery o the lungs adjacent to the pleura, most o ten at the lung bases) depict f uid in interlobular spaces that results rom interstitial edema (Fig. 3-5C). When f uid accumulates in the air spaces, alveolar orms o pulmonary edema produce opacity radiating rom the hilar FIGURE 3-2. Posteroanterior chest radiograph of a patient with severe mitral stenosis and secondary pulmonary vascular congestion. The radiograph shows a prominent left atrial appendage (arrowheads) with consequent straightening of the left heart border and suggestion of a double density right cardiac border (arrows) produced by the enlarged left atrium. The aortic silhouette is small, which suggests chronic low cardiac output. Radiographic signs of pulmonary vascular congestion include increased caliber of upper-zone pulmonary vessel markings and decreased caliber of lower-zone vessels. 46 Chapter 3 region bilaterally (known as a “butterf y” pattern) and air bronchograms may be seen (Fig. 3-5D). Fluid accumulation in the pleural spaces in heart ailure (i.e., pleural e u- sions) is mani est by blunting o the costophrenic angles (the angle between the ribs and the diaphragm). FIGURE 3-4. Posteroanterior chest radiograph o a patient with aortic stenosis and insu f ciency secondary to a bicuspid aortic valve. In addition to poststenotic dilatation of the ascending aorta (black arrows), the transverse aorta (white arrow) is prominent. FIGURE 3-3. Posteroanterior chest radiograph o a patient with pulmonary hypertension secondary to an atrial septal de ect. Radiographic signs of pulmonary hypertension include pulmonary artery dilatation (black arrows; compare with the appearance of left atrial appendage dilatation in Fig. 3-2) and large central pulmonary arteries (white arrows) associated with small peripheral vessels (a pattern known as peripheral pruning). Cardiac Imaging and Catheterization 49 depict transverse planes o the heart. Several di erent levels are imaged to assess the aortic valve, mitral valve, and le t ventricular wall motion. Apical TTE views are produced when the transducer is placed at the point o maximal api- cal impulse. The apical four-chamber view evaluates the mitral and tricuspid valves as well as the atrial and ventricular chambers, including the motion o the lateral, septal, and apical le t ventricular walls. The apical two-chamber view shows only the le t side o the heart, and it depicts movement o the anterior, in erior, and apical walls. In some patients, such as those with obstructive airways disease, the parasternal and api- cal views do not adequately show cardiac structures because the excessive underlying air attenuates the acoustic signal. In such patients, the subcostal view, in which the transducer is placed in erior to the rib cage, may provide a better ultrasonic window. Doppler imaging depicts blood f ow direction and velocity and identi es regions o vascu- lar turbulence. Additionally, it permits estimation o pressure gradients within the heart and great vessels. Doppler studies are based on the physical principle that waves ref ected rom a moving object undergo a requency shi t according to the moving object’s velocity relative to the source o the waves. Color f ow mapping converts the Doppler signals to a scale o colors that represent direction, velocity, and turbulence o blood f ow in a semiquantitative way. The colors are superimposed on 2D images and show the location o stenotic and regur- gitant valvular lesions and o abnormal communications within the heart and great vessels. For example, Doppler echocardiography in a patient with mitral regurgitation shows a jet o retrograde f ow into the le t atrium during systole (Fig. 3-7). RV Tricuspid va lve Mitra l va lve RA LA LV A B C RV LV Ao LA LV pos te rior wall Inte rventricula r septum Aortic va lve Mitra l va lve LV RV FIGURE 3-6. Transthoracic two- dimensional echocardiographic views. A. Parasternal long-axis view. B. Parasternal short-axis view. Notice that the le t ventricle appears circular in this view, while the right ventricle is crescent shaped. C. Apical our-chamber view. Ao, aorta; LA, le t atrium; LV, le t ventricle; RA, right atrium; RV, right ventricle. (Modif ed rom Sahn DJ, Anderson F. Two-Dimensional Anatomy of the Heart. New York, NY: John Wiley & Sons; 1982.) 50 Chapter 3 Sound requency shi ts are converted by the echo machine into blood f ow velocity measurements by the ollowing relationship: v s c f = ( ) f 2 O cosθ in which v equals the blood f ow velocity (m/ sec); fs, the Doppler re- quency shi t (kHz); c, the velocity o sound in body tissue (m/ sec); fO, the requency o the sound pulse emitted rom the transducer (MHz); and θ, the angle between the transmitted sound pulse and the mean axis o the blood f ow being assessed. Transesophageal echocardiography (TEE) uses a miniaturized transducer mounted at the end o a modi ed endoscope to trans- mit and receive ultrasound waves rom within the esophagus, thus producing very clear images o the neighboring cardiac structures (Fig. 3-8) and much o the thoracic aorta. Modern probes permit multiplanar imaging and Doppler interrogation. TEE is particularly help ul in the assessment o aortic and atrial abnormalities, con- ditions that are less well visualized by conventional transthoracic echo imaging. For example, TEE is more sensitive than transthoracic echo or the detection o thrombus within the le t atrial append- age (Fig. 3-9). The proximity o the esophagus to the heart makes TEE imaging particularly advantageous in patients or whom trans- thoracic echo images are unsatis actory (e.g., those with chronic obstructive lung disease). TEE is also advantageous in the evaluation o patients with pros- thetic heart valves. During standard transthoracic imaging, arti cial mechanical valves ref ect a large portion o ultrasound waves, thus inter ering with visualization o more posterior struc- tures (termed acoustic shadowing). TEE aids visualization in such patients and is there ore the most sensitive noninvasive technique or evaluating perivalvular leaks. In addition, TEE is RV RA RA LV LV LA LA A A. Cross-sectiona l view of aortic va lve RV RV B C B. Long axis view of ca rdiac chambers C. Short axis view of le ft venticle Esophagus R N L FIGURE 3-8. Transesophageal echocardiographic views. LA, le t atrium; LV, le t ventricle; RA, right atrium; RV, right ventricle; N, noncoronary cusp o aortic valve; L, le t coronary cusp o aortic valve; R, right coronary cusp o aortic valve. RV LV RA LA FIGURE 3-7. Doppler color f ow mapping o mitral regurgitation (MR) . The color Doppler image, recorded in systole, is superimposed on an apical our- chamber view. The color Doppler signal lling the le t atrium (LA) indicates retrograde f ow o MR rom the le t ventricle (LV) across the mitral valve (arrow). RA, right atrium; RV, right ventricle. Cardiac Imaging and Catheterization 51 more sensitive than TTE or detecting eatures o endocarditis, such as vegetations and myo- cardial abscesses. TEE is commonly used to evaluate patients with cerebral ischemic events (i.e., strokes) o unexplained etiology, because it can identi y cardiovascular sources o embolism with high sensitivity. These etiologies include intracardiac thrombi or tumors, atherosclerotic debris within the aorta, and valvular vegetations. TEE is also highly sensitive and speci c or the detection o aortic dissection. In the operating room, TEE permits immediate evaluation a ter surgical repair o cardiac lesions. In addition, imaging o ventricular wall motion can identi y periods o myocardial ischemia during surgery. New ultrasound modalities include 3D echocardiography and intracardiac echocardiog- raphy. The spatial reconstructions a orded by 3D echo are o particular bene t in the assess- ment o valvular de ects, intracardiac masses, and congenital mal ormations. Intracardiac echo utilizes a transducer mounted on a catheter to provide imaging during interventional procedures in the cardiac catheterization laboratory. Contrast echocardiography is sometimes used to supplement standard imaging to evalu- ate or abnormal intracardiac shunts. In this technique, o ten called a “bubble study,” an echocardiographic contrast agent (e.g., agitated saline) is rapidly injected into a peripheral vein. Using standard imaging, the contrast can be visualized passing through the cardiac chambers. Normally, there is rapid opaci cation o the right-sided chambers, but because the contrast is ltered out (harmlessly) in the lungs, it does not reach the le t-sided cham- bers. However, in the presence o an intracardiac shunt with abnormal right-to-le t heart blood f ow, or in the presence o an intrapulmonary shunt, bubbles o contrast will appear in the le t-sided chambers as well. Newer perf uorocarbon-based contrast agents have been developed with su ciently small particle size to intentionally pass through the pulmonary circulation. These agents are used to opaci y the le t ventricular cavity and, via the coronary arteries, the myocardium, enabling superior assessment o LV contraction and myocardial per usion. Echocardiographic techniques can identi y valvular lesions, complications o coro- nary artery disease (CAD), septal de ects, intracardiac masses, cardiomyopathy, ven- tricular hypertrophy, pericardial disease, aortic disease, and congenital heart disease. FIGURE 3-9. Echocardiographic imaging of an intracardiac thrombus. A. Transesophageal echocardiographic image demonstrates thrombus within the left atrial appendage. (Courtesy of Scott Streckenbach, MD, Massachusetts General Hospital, Boston, MA.) B. Schematic drawing of same image. LA, left atrium; LAA, left atrial appendage. A LA LAA Thrombus B 54 Chapter 3 Cardiomyopathy Cardiomyopathies are heart muscle disorders that include dilated, hypertrophic, and restric- tive orms (see Chapter 10). Echocardiography can distinguish these and permits assessment o the severity o systolic and diastolic dys unction. For example, Figure 3-10 depicts asym- metrically thickened ventricular walls in a patient with hypertrophic cardiomyopathy. Pericardial Disease Two-dimensional echocardiography can identi y abnormalities in the pericardial cavity (e.g., excessive pericardial f uid and tumor). Tamponade and constrictive pericarditis, the main complications o pericardial disease (see Chapter 14), are associated with particular echocardiographic abnormalities. In tamponade, the increased intrapericardial pressure com- presses the cardiac chambers and results in diastolic “collapse” o the right atrium and right ventricle (Fig. 3-12). Constrictive pericarditis is associated with increased thickness o the pericardial echo, abnormal patterns o diastolic le t ventricular wall motion, alterations in pulmonary and hepatic venous f ow patterns, and exaggerated changes in mitral and tricuspid valve inf ow velocities during respiration. Table 3-2 summarizes the echocardiographic eatures o common cardiac diseases. FIGURE 3-12. Echocardiogram of a patient with a pericardial effusion causing cardiac tamponade. A. Parasternal long-axis image showing a large pericardial effusion (PE) surrounding the heart. This frame was obtained in systole and shows normal appearance of the left (LV) and right (RV) ventricles during that phase. B. Same image as (A) , but this frame was obtained in early diastole and shows collapse of the RV free wall (arrow) due to compression by the effusion. C. Subcostal view, obtained in systole, demonstrating the PE surrounding the right atrium (RA), RV, left atrium (LA), and LV. D. Same image as (C) , obtained during diastole, showing inward collapse of the RA (arrow). A B C D Cardiac Imaging and Catheterization 55 CARDIAC CATHETERIZATION To diagnose many cardiovascular abnormalities, intravascular catheters are inserted to mea- sure pressures in the heart chambers, to determine cardiac output and vascular resistances, and to inject radiopaque material to examine heart structures and blood f ow. In 1929, Werner Forssmann per ormed the rst cardiac catheterization, on himself, thus ushering in the era o invasive cardiology. Much o what is known about the pathophysiology o valvular heart dis- ease and congestive heart ailure comes rom decades o subsequent hemodynamic research in the cardiac catheterization laboratory. Measurement of Pressure Be ore catheterization o an artery or vein, the patient is mildly sedated, and a local anes- thetic is used to numb the skin site o catheter entry. The catheter, attached to a pres- sure transducer outside the body, is then introduced into the appropriate blood vessel. To measure pressures in the right atrium, right ventricle, and pulmonary artery, a catheter is TABLE 3-2 Echocardiography in Common Cardiac Disorders Disorder Findings Valvular lesions Mitral stenosis • Enlarged le t atrium • Thickened mitral valve leaf ets • Decreased movement and separation o mitral valve leaf ets • Decreased mitral valve ori ce Mitral regurgitation • Enlarged le t atrium (i chronic) • Enlarged le t ventricle (i chronic) • Systolic f ow rom le t ventricle into le t atrium by Doppler Aortic stenosis • Thickened aortic valve cusps • Decreased valve ori ce • Increased le t ventricular wall thickness Aortic regurgitation • Enlarged le t ventricle • Abnormalities o aortic valve or aortic root Left ventricular function Myocardial in arction and complications • Abnormal regional ventricular wall motion • Thrombus within le t ventricle • Aneurysm o ventricular wall • Septal rupture (abnormal Doppler f ow) • Papillary muscle rupture Cardiomyopathies Dilated • Enlarged ventricular chamber sizes • Decreased systolic contraction Hypertrophic • Normal or decreased ventricular chamber sizes • Increased ventricular wall thickness • Diastolic dys unction (assessed by Doppler) Restrictive • Normal or decreased ventricular chamber sizes • Increased ventricular wall thickness • Ventricular contractile unction may be abnormal • Diastolic dys unction (assessed by Doppler) • Enlarged atria (o ten markedly so) 56 Chapter 3 inserted into a emoral, brachial, or jugular vein. Pressures in the aorta and le t ventricle are measured via catheters inserted into a radial, brachial, or emoral artery. Once in the blood vessel, the catheter is guided by f uoroscopy (continuous x-ray images) to the area o study, where pressure measurements are made. Figure 3-13 depicts normal intracardiac and intravascular pressures. The measurement o right heart pressures is per ormed with a specialized balloon-tipped catheter (a common version o which is known as the Swan–Ganz catheter) that is advanced through the right side o the heart with the aid o normal blood f ow, and into the pulmonary artery. As it travels through the right side o the heart, recorded pressure measurements iden- ti y the catheter tip’s position (see Box 3-1). RA 2–8 RV 15–30 PA 15–30 2–8 4–12 Lungs PCW 2–10 Aorta LA 2–10 LV 100–140 3–12 60–90 Aorta PCW RA RV LV LAPA 100–140 2–10 2–10 2–8 15–30 2–8 100–140 3–12 100–140 60–90 15–30 4–12 FIGURE 3-13. Diagrams indicating normal pressures in the cardiac chambers and great vessels. The top f gure shows the normal anatomic relationship o the cardiac chambers and great vessels, whereas the f gure on the bottom shows a simplif ed schematic to clari y the pressure relationships. Numbers indicate pressures in mm Hg. LA, le t atrial mean pressure; LV, le t ventricular pressure; PA, pulmonary artery pressure; PCW, pulmonary capillary wedge mean pressure; RA, right atrial mean pressure; RV, right ventricular pressure. BOX 3-1 Intracardiac Pressure Tracings When a catheter is inserted into a systemic vein and advanced into the right side o the heart, each cardiac chamber produces a characteristic pressure curve. It is important to distinguish these recordings rom one another to localize the position o the catheter tip and to derive appropriate physiologic in ormation. ECG 20 10 a c x v a v y P r e s s u r e ( m m H g ) Right ventricle Right a trium Pulmonary a rte ry Time Pulmonary capilla ry wedge Cardiac Imaging and Catheterization 59 (PCW) and closely matches the le t atrial pressure in most individuals. Furthermore, while the mitral valve is open during diastole, the pulmonary venous bed, le t atrium, and le t ventricle normally share the same pressures. Thus, the PCW can be used to estimate the le t ventricular diastolic pressure, a measurement o ventricular preload (see Chapter 9). As a result, measure- ment o PCW may be use ul in managing certain critically ill patients in the intensive care unit. Elevation o the mean PCW is seen in le t-sided heart ailure and in mitral stenosis or regur- gitation. The individual components o the PCW tracing can also become abnormally high. The a wave may be increased in conditions o decreased le t ventricular compliance, such as le t ventricular hypertrophy or acute myocardial ischemia, and in mitral stenosis. The v wave is greater than normal when there is increased le t atrial lling during ventricular contraction, as in mitral regurgitation. Measurement of Blood Flow Cardiac output is measured by either the thermodilution method or the Fick technique. In the thermodilution method, saline o a known temperature is injected rapidly through a catheter side port into the right side o the heart, at a speci c distance rom the distal tip o the cath- eter. The catheter tip, positioned in the pulmonary artery, contains a thermistor that registers the change in temperature induced by the injected saline. The cardiac output is proportional to the rate o the temperature change and is automatically calculated by the equipment. The Fick method relies on the principle that the quantity o oxygen consumed by tissues is related to the amount o O2 content removed rom blood as it f ows through the tissue capillary bed: O2 consumption = O2 content removed × Flow mL O mL O mL blood mL blood2 2 min min Or, in more applicable terms: O2 consumption = AVO2 di erence × Cardiac output where the arteriovenous O2 (AVO2) di erence equals the di erence in oxygen content between the arterial and venous compartments. Total body oxygen consumption can be determined by analyzing expired air rom the lungs, and arterial and venous O2 content is measured in blood samples. By rearranging the terms, the cardiac output can be calculated: Cardiac output O consumption AVO di erence = 2 2 A pulmonary ve in Pulmonary capilla ries Cathe te r tip occludes branch of pulmonary a rte ry Pulmonary arte ry ca the te r This a rea represents “column of blood” be tween ca the ter tip and LA LA PA FIGURE 3-14. Diagram of a pulmonary artery catheter inserted into a branch of the pulmonary artery (PA) . Flow is occluded in the arterial, arteriolar, and capillary vessels beyond the catheter; thus, these vessels act as a conduit that transmits the left atrial (LA) pressure to the catheter tip. 60 Chapter 3 For example, i the arterial blood in a normal adult contains 190 mL o O2 per liter and the venous blood contains 150 mL o O2 per liter, the arteriovenous di erence is 40 mL o O2 per liter. I this patient has a measured O2 consumption o 200 mL/ min, the calculated cardiac output is 5 L/ min. In many orms o heart disease, the cardiac output is lower than normal. In that situa- tion, the total body oxygen consumption does not change signi cantly; however, a greater percentage o O2 is extracted per volume o circulating blood by the metabolizing tissues. The result is a lower-than-normal venous O2 content and there ore an increased AVO2 di - erence. In our example, i the patient’s venous blood O2 content ell to 100 mL/ L, the AVO2 di erence would increase to 90 mL/ L and the calculated cardiac output would be reduced to 2.2 L/ min. Because the normal range o cardiac output varies with a patient’s size, it is common to report the cardiac index, which is equal to the cardiac output divided by the patient’s body sur ace area (normal range o cardiac index = 2.6 – 4.2 L/ min/ m2). Calculation of Vascular Resistance Once pressures and cardiac output have been determined, pulmonary and systemic vas- cular resistances can be calculated, based on the principle that the pressure di erence across a vascular bed is proportional to the product o f ow and resistance. The calcula- tions are: PVR MPAP LAP CO = − × 80 PVR, pulmonary vascular resistance (dynes-sec-cm−5) MPAP, mean pulmonary artery pressure (mm Hg) LAP, mean le t atrial pressure (mm Hg) CO, cardiac output (L/ min) SVR MAP RAP CO = − × 80 SVR, systemic vascular resistance (dynes-sec-cm−5) MAP, mean arterial pressure (mm Hg) RAP, mean right atrial pressure (mm Hg) CO, cardiac output (L/ min) The normal PVR ranges rom 20 to 130 dynes-sec-cm−5. The normal SVR is 700 to 1,600 dynes-sec-cm−5. Contrast Angiography This technique uses radiopaque contrast to visualize regions o the cardiovascular system. A catheter is introduced into an appropriate vessel and guided under f uoroscopy to the site o injection. Following administration o the contrast agent, x-rays are transmitted through the area o interest. A continuous series o x-ray exposures is recorded to produce a motion picture cineangiogram (o ten simply called a “cine” or “angiogram”). Selective injection o contrast into speci c heart chambers can be used to identi y valvular insu ciency, intracardiac shunts, thrombi within the heart, congenital mal ormations, and to measure ventricular contractile unction (Fig. 3-15). However, the noninvasive techniques described in this chapter (e.g., echocardiography) have largely supplanted the need or inva- sive contrast angiography or these purposes. Cardiac Imaging and Catheterization 61 An important and widespread application of contrast injection is coronary artery angiog- raphy, to examine the location and severity of coronary atherosclerotic lesions. To maximize the test’s sensitivity and reproducibility, each patient is imaged in several standard views. When necessary, angioplasty and stent placement can be performed (Figs. 3-16 and 3-17; see Chapter 6). FIGURE 3-16. Cardiac catheterization and stenting of a proximal left anterior descending artery (LAD) stenosis, shown in an anteroposterior cranial projection. A. When contrast agent is injected into the le t main coronary artery (LM), the le t circumf ex artery (LCX) lls normally, but the LAD is almost completely occluded at its origin (white arrow). B. A ter the stenosis is success ully stented, the LAD and its branches ll robustly. A LM LAD B LM LAD LCX Diagonal branch Septal perforators FIGURE 3-15. Left ventriculogram, in diastole (A) and systole (B) in the right anterior oblique projection, from a patient with normal ventricular contractility. A catheter (black arrow) is used to inject contrast into the le t ventricle (LV). The catheter can also be seen in the descending aorta (white arrowhead). AO, aortic root. A B 64 Chapter 3 myocardial tissue. Conversely, myocardial regions that are scarred (by previous in arction) or have reduced per usion during exercise (i.e., transient myocardial ischemia) do not accumu- late as much thallium as normal heart muscle. Consequently, these areas will appear on the thallium scan as light or “cold” spots. When evaluating or myocardial ischemia, an initial set o images is taken right a ter exer- cise and 201Tl injection. Well-per used myocardium will take up more tracer than ischemic or in arcted myocardium at this time. Delayed images are acquired several hours later, because 201Tl accumulation does not remain xed in myocytes. Rather, continuous redistribution o the isotope occurs across the cell membrane. A ter 3 to 4 hours o redistribution, when additional images are obtained, all viable myocytes will have equal concentrations o 201Tl. Consequently, any uptake abnormalities on the initial exercise scan that were caused by myocardial ischemia will have resolved (i.e., lled in) on the delayed scan (and are there ore termed “reversible” de ects), and those representing infarcted or scarred myocardium will persist as cold spots (“ xed” de ects). O note, some myocardial segments that demonstrate persistent 201Tl de ects on both stress and redistribution imaging are alsely characterized as nonviable, scarred tissue. Sometimes, these areas represent ischemic, noncontractile, but metabolically, active areas that have the potential to regain unction i an adequate blood supply is restored. For example, such areas may represent hibernating myocardium, segments that demonstrate diminished contractile unction owing to chronic reduction o coronary blood f ow (see Chapter 6). This viable state (in which the a ected cells can be predicted to regain unction ollowing coronary revascularization) can o ten be di erentiated rom irreversibly scarred myocardium by repeat imaging at rest a ter the injection o additional 201Tl to enhance uptake by viable cells. 99mTc-sestamibi (commonly re erred to as MIBI) is an example o a widely used 99mTc- labeled compound. This agent is a large lipophilic molecule that, like thallium, is taken up in the myocardium in proportion to blood f ow. The uptake mechanism di ers in that the com- pound crosses the myocyte membrane passively, driven by the negative membrane potential. Once inside the cell, it urther accumulates in mitochondria, driven by that organelle’s even more negative membrane potential. The myocardial distribution o MIBI ref ects per usion at the moment o injection, and in contrast to thallium, it remains xed intracellularly, that is, it redistributes only minimally over time. Consequently, per orming a MIBI procedure is more f exible, as images can be obtained up to 4 to 6 hours a ter injection and repeated as neces- sary. A MIBI study is usually per ormed as a 1-day protocol in which an initial injection o a small tracer dose and imaging are per ormed at rest. Later, a larger tracer dose is given a ter exercise, and imaging is repeated. Stress nuclear imaging studies with either 201Tl- or 99mTc-labeled compounds have greater sensitivity and speci city than standard exercise electrocardiography or the detec- tion o ischemia but are more expensive and should be ordered judiciously. Nuclear imag- ing is particularly appropriate or patients with certain baseline electrocardiogram (ECG) abnormalities o the ST segment that preclude accurate interpretation o a standard exer- cise test. Examples include patients with electronic pacemaker rhythms, those with le t bundle branch block, those with ST abnormalities due to le t ventricular hypertrophy, and those who take certain medications that alter the ST segment, such as digoxin. Nuclear scans also provide more accurate anatomic localization o the ischemic segment(s) and quanti cation o the extent o ischemia compared with standard exercise testing. In addi- tion, electronic synchronizing (gating) o nuclear images to the ECG cycle permits wall motion analysis. Patients with orthopedic or neurologic conditions, as well as those with severe physical deconditioning or chronic lung disease, may be unable to per orm an adequate exercise test on a treadmill or bicycle. In such patients, stress images can be obtained instead by adminis- tering pharmacologic agents, such as adenosine or dipyridamole. These agents induce di use Cardiac Imaging and Catheterization 65 coronary vasodilation, augmenting blood f ow to myocardium per used by healthy coronary arteries. Since ischemic regions are already maximally dilated (because o local metabolite accumulation), the drug-induced vasodilation causes a “steal” phenomenon, reducing isotope uptake in regions distal to signi cant coronary stenoses (see Chapter 6). Alternatively, dobu- tamine (see Chapter 17) can be in used intravenously to increase myocardial oxygen demand as a means to assess or ischemia. Radionuclide Ventriculography Radionuclide ventriculography (RVG, also known as blood pool imaging) is occasionally used to analyze right and le t ventricular unction. A radioisotope (usually 99mTc) is bound to red blood cells or to human serum albumin and then injected as a bolus. Nuclear images are obtained at xed time intervals as the labeled material passes through the heart and great vessels. Multiple images are displayed sequentially to produce a dynamic picture o blood f ow. Calculations, such as determination o the ejection raction, are based on the di erence between radioactive counts present in the ventricle at the end o diastole and at the end o systole. There ore, measurements are largely independent o any assumptions o ventricular geometry and are highly reproducible. Studies suggest that RVG and echocardiography pro- vide similar le t ventricular ejection raction values. RVG has been used historically to assess baseline cardiac unction in patients scheduled to undergo potentially cardiotoxic chemotherapy (e.g., doxorubicin) and to ollow cardiac unc- tion over time in such patients. However, echocardiography is usually easier to per orm, does not expose the patient to ionizing radiation, and now commonly serves this role. Assessment of Myocardial Metabolism Positron emission tomography (PET) is a specialized nuclear imaging technique used to assess myocardial per usion and viability. PET imaging employs positron-emitting isotopes (e.g., rubidium-82, nitrogen-13, and f uorine-18) attached to metabolic or f ow tracers. Sensitive detectors measure positron emission rom the tracer molecules. Myocardial perfusion is commonly assessed using nitrogen-13–labeled ammonia or rubid- ium-82. Both are taken up by myocytes in proportion to blood f ow. Myocardial viability can be determined by PET by studying glucose utilization in myocardial tissue. In normal myocardium under asting conditions, glucose is used or approximately 20% o energy pro- duction, with ree atty acids providing the remaining 80% . In ischemic conditions, however, metabolism shi ts toward glucose use, and the more ischemic the myocardial tissue, the stronger the reliance on glucose. Fluoro-18 deoxyglucose (18FDG), created by substituting f uorine-18 or hydrogen in 2-deoxyglucose, is used to study glucose uptake. This substance competes with glucose both or transport into myocytes and or subsequent phosphoryla- tion. Unlike glucose, however, 18FDG is not metabolized and becomes trapped within the myocyte. Combined evaluation o per usion and 18FDG metabolism allows assessment o both regional blood f ow and glucose uptake, respectively. PET scanning thus helps determine whether areas o ventricular contractile dys unction with decreased f ow represent irrevers- ibly damaged scar tissue or whether the region is still viable (e.g., hibernating myocardium). In scar tissue, both blood f ow to the a ected area and 18FDG uptake are decreased. Because the myocytes in this region are permanently damaged, such tissue is not likely to bene t rom revascularization. Hibernating myocardium, in contrast, shows decreased blood f ow but normal or elevated 18FDG uptake. Such tissue may bene t rom revascularization proce- dures (see Chapter 6). Table 3-5 summarizes the radionuclide imaging abnormalities associated with common cardiac conditions. 66 Chapter 3 COMPUTED TOMOGRAPHY CT uses thin x-ray beams to obtain a large series o axial plane images. An x-ray tube is pro- grammed to rotate around the body, and the generated beams are partially absorbed by body tissues. The remaining beams emerge and are captured by electronic detectors, which relay in ormation to a computer or image composition. CT scanning typically requires administra- tion o an intravenous contrast agent to distinguish intravascular contents (i.e., blood) rom neighboring so t tissue structures (e.g., myocardium). Applications o CT in cardiac imaging include assessment o the great vessels, peri- cardium, myocardium, and coronary arteries. CT is used to diagnose aortic dissections and aneurysms (Fig. 3-19). It can identi y abnormal pericardial f uid, thickening, and calci cation. Myocardial abnormalities, such as regional hypertrophy or ventricular aneu- rysms, and intracardiac thrombus ormation can be distinctly visualized by CT. A limitation o conventional CT techniques is the arti act generated by patient motion (i.e., breathing) during image acquisition. Modern spiral CT (also called helical CT) imaging allows more rapid image acquisition, o ten during a single breath-hold, at relatively lower radiation doses than conventional CT. Spiral CT is particularly important in the diagnosis o pulmo- nary embolism. When an intravenous iodine-based contrast agent is administered, emboli create the appearance o “ lling de ects” in otherwise contrast-enhanced pulmonary vessels (Fig. 3-20). Electron beam computed tomography (EBCT) uses a direct electron beam to acquire images in a matter o milliseconds. Rapid succession o images depicts cardiac structures at multiple times during a single cardiac cycle. Displaying these images in a cine ormat can provide estimates o le t ventricular volumes and ejection raction. Capable o detecting coro- nary artery calci cation, EBCT has been used primarily to screen or CAD. Because calci ed coronary artery plaques have a radiodensity similar to that o bone, they appear attenuated (white) on CT. The Agatston score, a measure o total coronary artery calcium, correlates well with atherosclerotic plaque burden and predicts the risk o coronary events, independently o other cardiac risk actors. Newer CT technology can characterize atherosclerotic stenoses in great detail. Current multidetector row CT scanners acquire as many as 320 anatomic sections with each rota- tion, providing excellent spatial resolution. Administration o intravenous contrast and computer re ormatting allows visualization o the arterial lumen and regions o coronary TABLE 3-5 Nuclear Imaging in Cardiac Disorders Disorder Findings Myocardial ischemia Stress-delayed reinjection 201Tl • Low uptake during stress with complete or partial ll-in with delayed or reinjection images Rest–stress 99mTc-labeled compounds • Normal uptake at rest with decreased uptake during stress PET (N-13 ammonia/ 18FDG) • Decreased f ow with normal or increased 18FDG uptake during stress Myocardial infarction Stress-delayed reinjection 201Tl • Low uptake during stress and low uptake a ter reinjection Rest–stress 99mTc-labeled compounds • Low uptake in rest and stress images PET (N-13 ammonia/ 18FDG) • Decreased f ow and decreased 18FDG uptake at rest Hibernating myocardium Rest-delayed 201Tl • Complete or partial ll-in o de ects a ter reinjection PET (N-13 ammonia/ 18FDG) • Decreased f ow and normal or increased 18FDG uptake at rest 18FDG, f uoro-18 deoxyglucose; N-13, nitrogen-13; PET, positron emission tomography; 99mTc, technetium-99m; 201Tl, thallium-201. O o RD Pi o YO Etr Epa pe a Tui ça, a pa (Efe T AE ei)! ve eBook with complete content ARE ig in iio ao (ao * | Medical Students | and Faculty PGE PARRA “N “sf Eodedea ledicos.org a RR ERR Ee ANITA E ) 6 EDITION A COLLA BORATIVE P ROJECT OF MED ICA L STU D ENTS A ND FACU LTY Pathophysiology of Heart Disease Dedicated to Carolyn, Jonathan, Rebecca, Douglas, Deborah, Norma and David Lilly vi STUDENT CONTRIBUTORS Andrey V. Dolinko (MD 2016) Joshua Drago (MD 2015) David B. Fischer (MD 2016) P. Connor Johnson (MD 2015) Zena L. Knight (MD 2015) Michael T. Kuntz (MD 2015) Jacob E. Lemieux, D.Phil. (MD 2015) Diana M. López (MD 2016) David Miranda (MD 2016) Morgan J. Prust (MD 2015) Sruthi Renati (MD 2015) Elizabeth Ryznar, MSc (MD 2015) Sarrah Shahawy (MD 2016) Jayme Wilder (MD 2015) FACULTY CONTRIBUTORS Elliott M. Antman, MD Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Eugene Braunwald, MD (Foreword) Distinguished Hersey Professor of Medicine Harvard Medical School Founding Chairman, TIMI Study Group Brigham and Women’s Hospital Boston, Massachusetts David W. Brown, MD Associate Professor of Pediatrics Harvard Medical School Cardiology Division Children’s Hospital Boston, Massachusetts Patricia Challender Come, MD Associate Professor of Medicine Harvard Medical School Cardiologist, Harvard Vanguard Medical Associates Boston, Massachusetts Mark A. Creager, MD Professor of Medicine Geisel School of Medicine at Dartmouth Director, Heart and Vascular Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire G. William Dec, MD Roman W. DeSanctis Professor of Medicine Harvard Medical School Chief (Emeritus), Cardiology Division Massachusetts General Hospital Boston, Massachusetts Elazer R. Edelman, MD, PhD Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology Massachusetts Institute of Technology Director, Harvard–MIT Biomedical Engineering Center Professor of Medicine Harvard Medical School Boston, Massachusetts Michael A. Fifer, MD Professor of Medicine Harvard Medical School Director, Cardiac Catheterization Laboratory Director, Hypertrophic Cardiomyopathy Program Massachusetts General Hospital Boston, Massachusetts List of Contributors Gregory D. Lewis, MD Assistant Professor of Medicine Harvard Medical School Director, Cardiology Intensive Care Unit Massachusetts General Hospital Boston, Massachusetts Peter Libby, MD Mallinckrodt Professor of Medicine Harvard Medical School Senior Physician Brigham and Women’s Hospital Boston, Massachusetts Leonard S. Lilly, MD Professor of Medicine Harvard Medical School Chief, Brigham and Women’s/ Faulkner Cardiology Brigham and Women’s Hospital Boston, Massachusetts Patrick T. O’Gara, MD Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Marc S. Sabatine, MD, MPH Professor of Medicine Harvard Medical School Chairman, TIMI Study Group Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts William G. Stevenson, MD Professor of Medicine Harvard Medical School Director, Clinical Cardiac Electrophysiology Program Brigham and Women’s Hospital Boston, Massachusetts Gary R. Strichartz, PhD Professor of Anesthesia (Pharmacology) Harvard Medical School Director, Pain Research Center Vice Chairman of Research, Department of Anesthesia Brigham and Women’s Hospital Boston, Massachusetts Gordon H. Williams, MD Professor of Medicine Harvard Medical School Director, Specialized Center of Research in Hypertension Director, Center for Clinical Investigation Brigham and Women’s Hospital Boston, Massachusetts List of Contributors vii x Preface Finally, a project of this magnitude could not be undertaken without the support and patience of my family, and for that, I am very grateful. On behalf of the contributors, I hope that this book enhances your understanding of car- diovascular diseases and provides a solid foundation for further learning and clinical care of your patients. Leonard S. Lilly, MD Boston, Massachusetts xi List of Contributors vi Foreword viii Preface ix Chapt e r 1 Normal Cardiac Structure and Function 1 Jacob E. Lemieux, Elazer R. Edelman, Gary R. Strichartz, and Leonard S. Lilly Chapt e r 2 The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs 26 David B. Fischer and Leonard S. Lilly Chapt e r 3 Cardiac Imaging and Catheterization 43 Diana M. López and Patricia Challender Come Chapt e r 4 The Electrocardiogram 74 David B. Fischer and Leonard S. Lilly Chapt e r 5 Atherosclerosis 112 Sarrah Shahawy and Peter Libby Chapt e r 6 Ischemic Heart Disease 134 Jayme Wilder, Marc S. Sabatine, and Leonard S. Lilly Chapt e r 7 Acute Coronary Syndromes 162 Jayme Wilder, Marc S. Sabatine, and Leonard S. Lilly Chapt e r 8 Valvular Heart Disease 192 Elizabeth Ryznar, Patrick T. O’Gara, and Leonard S. Lilly Chapt e r 9 Heart Failure 220 David Miranda, Gregory D. Lewis, and Michael A. Fifer Chapt e r 1 0 The Cardiomyopathies 249 P. Connor Johnson, G. William Dec, and Leonard S. Lilly Chapt e r 1 1 Mechanisms of Cardiac Arrhythmias 268 Morgan J. Prust, William G. Stevenson, Gary R. Strichartz, and Leonard S. Lilly Chapt e r 1 2 Clinical Aspects of Cardiac Arrhythmias 287 Morgan J. Prust, William G. Stevenson, and Leonard S. Lilly Chapt e r 1 3 Hypertension 310 Joshua Drago, Gordon H. Williams, and Leonard S. Lilly Chapt e r 1 4 Diseases of the Pericardium 334 Leonard S. Lilly Chapt e r 1 5 Diseases of the Peripheral Vasculature 350 Sruthi Renati and Mark A. Creager Chapt e r 1 6 Congenital Heart Disease 373 Zena L. Knight and David W. Brown Chapt e r 1 7 Cardiovascular Drugs 400 Andrey V. Dolinko, Michael T. Kuntz, Elliott M. Antman, Gary R. Strichartz, and Leonard S. Lilly Index 456 Table of Contents 1 C h a p t e r O u t l i n e Cardiac Anatomy and Histology Pericardium Sur ace Anatomy o the Heart Internal Structure o the Heart Impulse-Conducting System Cardiac Innervation Cardiac Vessels Histology o Ventricular Myocardial Cells Basic Electrophysiology Ion Movement and Channels Resting Potential Action Potential Re ractory Periods Impulse Conduction Normal Sequence o Cardiac Depolarization Excitation–Contraction Coupling Contractile Proteins in the Myocyte Calcium-Induced Calcium Release and the Contractile Cycle Introduction to Cardiac Signaling Systems β-Adrenergic and Cholinergic Signaling Knowledge o normal structure and unction o the heart is crucial to understanding diseases that a f ict the cardiovas- cular system. The purpose o this chapter is to describe the heart’s basic anatomy, its electrical system, and the cellular and molecular mechanisms o contraction that allow the heart to serve its critical unctions. CARDIAC ANATOMY AND HISTOLOGY Although the study o cardiac anatomy dates back to ancient times, interest in this eld has recently gained momentum. The application o sophisticated cardiac imaging tech- niques such as coronary angiography, echocardiography, computed tomography, and magnetic resonance imaging requires an intimate knowledge o the spatial relationships o cardiac structures. Such in ormation also proves help- ul in understanding the pathophysiology o heart disease. This section emphasizes the aspects o cardiac anatomy that are important to the clinician—that is, the “ unctional” anatomy. Pericardium The heart and roots o the great vessels are enclosed by a broserous sac called the pericardium (Fig. 1-1). This struc- ture consists o two layers: a strong outer brous layer and an inner serosal layer. The inner serosal layer adheres to the external wall o the heart and is called the visceral pericar- dium. The visceral pericardium ref ects back on itsel and lines the outer brous layer, orming the parietal pericar- dium. The space between the visceral and parietal layers contains a thin lm o pericardial f uid that allows the heart to beat in a minimal- riction environment. Normal Cardiac Structure and Function Jacob E. Lemieux Elazer R. Edelman Gary R. Strichartz Leonard S. Lilly 1 4 Chapter 1 cardiac muscle cells, the histology o which is described later in the chapter. External to the myocardium is a layer o connective tissue and adipose tissue through which pass the larger blood vessels and nerves that supply the heart muscle. The epicardium is the outermost layer o the heart and is identical to, and just another term or, the visceral pericardium previously described. Right Atrium and Ventricle Opening into the right atrium are the superior and in erior venae cavae and the coronary sinus (Fig. 1-4). The venae cavae return deoxygenated blood rom the systemic veins into the right atrium, whereas the coronary sinus carries venous return rom the coronary arteries. The interatrial septum orms the posteromedial wall o the right atrium and separates it rom the le t atrium. The tricuspid valve is located in the f oor o the atrium and opens into the right ventricle. The right ventricle (see Fig. 1-4) is roughly triangular in shape, and its superior aspect orms a cone-shaped outf ow tract, which leads to the pulmonary artery. Although the inner wall o the outf ow tract is smooth, the rest o the ventricle is covered by a number o irregular bridges (termed trabeculae carneae) that give the right ventricular wall a spongelike appear- ance. A large trabecula that crosses the ventricular cavity is called the moderator band. It carries a component o the right bundle branch o the conducting system to the ventricular muscle. The right ventricle contains three papillary muscles, which project into the chamber and via their thin, stringlike chordae tendineae attach to the edges o the tricuspid valve leaf ets. The leaf ets, in turn, are attached to the brous ring that supports the valve between the right atrium and ventricle. Contraction o the papillary muscles prior to other regions o the ven- tricle tightens the chordae tendineae, helping to align and restrain the leaf ets o the tricuspid valve as they are orced closed. This action prevents blood rom regurgitating into the right atrium during ventricular contraction. At the apex o the right ventricular outf ow tract is the pulmonic valve, which leads to the pulmonary artery. This valve consists o three cusps attached to a brous ring. During relax- ation o the ventricle, elastic recoil o the pulmonary arteries orces blood back toward the Anterior Pos terior Aortic va lve Pulmonic valve Tricuspid va lve Annulus fibrosus Mitra l va lve Annulus fibrosus FIGURE 1-3. The four heart valves viewed from above with atria removed. The f gure depicts the period o ventricular f lling (diastole) during which the tricuspid and mitral valves are open and the semilunar valves (pulmonic and aortic) are closed. Each annulus f brosus surrounding the mitral and tricuspid valves is thicker than those surrounding the pulmonic and aortic valves; all our contribute to the heart’s f brous skeleton, which is composed o dense connective tissue. Normal Cardiac Structure and Function 5 heart, distending the valve cusps toward one another. This action closes the pulmonic valve and prevents regurgitation o blood back into the right ventricle. Left Atrium and Ventricle Entering the posterior hal o the left atrium are the our pulmonary veins (Fig. 1-5). The wall o the le t atrium is about 2 mm thick, being slightly greater than that o the right atrium. The mitral valve opens into the le t ventricle through the in erior wall o the le t atrium. The cavity o the left ventricle is approximately cone shaped and longer than that o the right ventricle. In a healthy adult heart, the wall thickness is 9 to 11 mm, roughly three times that o the right ventricle. The aortic vestibule is a smooth-walled part o the le t ventricular cavity located just in erior to the aortic valve. In erior to this region, most o the ventricle is covered by trabeculae carneae, which are ner and more numerous than those in the right ventricle. The le t ventricular chamber (see Fig. 1-5B) contains two large papillary muscles. These are larger than their counterparts in the right ventricle, and their chordae tendineae are thicker but less numerous. The chordae tendineae o each papillary muscle distribute to both leaf ets o the mitral valve. Similar to the case in the right ventricle, tensing o the chordae tendineae during le t ventricular contraction helps restrain and align the mitral leaf ets, enabling them to close properly and preventing the backward leakage o blood. The aortic valve separates the le t ventricle rom the aorta. Surrounding the aortic valve opening is a brous ring to which is attached the three cusps o the valve. Just above the right and le t aortic valve cusps in the aortic wall are the origins o the right and le t coronary arteries (see Fig. 1-5B). Interventricular Septum The interventricular septum is the thick wall between the le t and right ventricles. It is com- posed o a muscular and a membranous part (see Fig. 1-5B). The margins o this septum can be traced on the sur ace o the heart by ollowing the anterior and posterior interven- tricular grooves. Owing to the greater hydrostatic pressure within the le t ventricle, the large Superior vena cava Pulmonary a rte ry Pulmonic va lve Inte rventricula r septum Modera tor band Trabeculae carneae Papilla ry muscles Aorta Right a trium Inferior vena cava Coronary s inus Tricuspid va lve Right ventricle FIGURE 1-4. Interior structures of the right atrium and right ventricle. (Modif ed rom Goss CM. Gray’s Anatomy. 29th ed. Philadelphia, PA: Lea & Febiger; 1973:547.) 6 Chapter 1 FIGURE 1-5. Interior structures of the left atrium and left ventricle. A. The le t atrium and le t ventricular (LV) in ow region. B. Interior structures o the LV cavity. (Modif ed rom Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:142–143.) Pulmonary ve ins Left a tria l appendage Fibrous ring of le ft AV orifice Chordae tendineae Papilla ry muscles Anterior cusp of mitra l va lve To aortic ves tibule Left a trium Left ventricle A Ascending aorta Pos te rior cusp of aortic va lve Orifice of le ft coronary a rte ry Orifice of right coronary a rte ry Left cusp of aortic va lve Anterior cusp of mitra l va lve Chordae tendineae Anterior papilla ry muscle Trabeculae carneae Pos te rior papilla ry muscle Inte rventricula r septum, muscula r part Inte rventricula r septum, membranous part Right aortic s inus Right cusp of aortic va lve Pulmonary a rte ry Right ventricle B Normal Cardiac Structure and Function 9 heart to the apex and supplies blood to the in erior and posterior walls o the ventricles and the posterior one third o the interventricular septum. Just be ore giving o the posterior descending branch, the RCA usually gives o the AV nodal artery. The posterior descending and AV nodal arteries arise rom the RCA in 85% o the population, and in such people, the coronary circulation is termed right dominant. In approximately 8% , the posterior descending artery arises rom the circumf ex artery instead, resulting in a left dom- inant circulation. In the remaining population, the heart’s posterior blood supply is contributed to rom branches o both the RCA and the circumf ex, orming a codominant circulation. Pulmonary a rte ry Left circumflex coronary a rte ry Left main coronary a rte ry Aorta Left ante rior descending coronary a rte ry Right coronary arte ry Right coronary arte ry Acute margina l branch Left circumflex coronary a rtery Left ante rior descending coronary a rtery Diagona l branch Left circumflex coronary a rtery Obtuse margina l branches Pos te rior descending coronary a rte ry Right coronary arte ry A B C FIGURE 1-7. Coronary artery anatomy. A. Schematic representation o the right and le t coronary arteries demonstrates their orientation to one another. The le t main artery bi urcates into the circumf ex artery, which per uses the lateral and posterior regions o the le t ventricle (LV), and the anterior descending artery, which per uses the LV anterior wall, the anterior portion o the intraventricular septum, and a portion o the anterior right ventricular (RV) wall. The right coronary artery (RCA) per uses the right ventricle and variable portions o the posterior le t ventricle through its terminal branches. The posterior descending artery most o ten arises rom the RCA. B. Anterior view o the heart demonstrating the coronary arteries and their major branches. C. Posterior view o the heart demonstrating the terminal portions o the right and circumf ex coronary arteries and their branches. 10 Chapter 1 The blood supply to the SA node is also most o ten (70% o the time) derived rom the RCA. However, in 25% o normal hearts, the SA nodal artery arises rom the circumf ex artery, and in 5% o cases, both the RCA and the circumf ex artery contribute to this vessel. From their epicardial locations, the coronary arteries send per orating branches into the ventricular muscle, which orm a richly branching and anastomosing vasculature in the walls o all the cardiac chambers. From this plexus arise a massive number o capillaries that orm an elaborate network surrounding each cardiac muscle ber. The muscle bers located just beneath the endocardium, particularly those o the papillary muscles and the thick le t ven- tricle, are supplied either by the terminal branches o the coronary arteries or directly rom the ventricular cavity through tiny vascular channels, known as thebesian veins. Collateral connections, usually less than 200 µm in diameter, exist at the subarteriolar level between the coronary arteries. In the normal heart, ew o these collateral vessels are visible. However, they may become larger and unctional when atherosclerotic disease obstructs a coronary artery, thereby providing blood f ow to distal portions o the vessel rom a nonob- structed neighbor. Coronary Veins The coronary veins ollow a distribution similar to that o the major coronary arteries. These vessels return blood rom the myocardial capillaries to the right atrium predominantly via the coronary sinus. The major veins lie in the epicardial at, usually super cial to their arterial counterparts. The thebesian veins, described earlier, provide an additional potential route or a small amount o direct blood return to the cardiac chambers. Lymphatic Vessels The heart lymph is drained by an extensive plexus o valved vessels located in the subendo- cardial connective tissue o all our chambers. This lymph drains into an epicardial plexus rom which are derived several larger lymphatic vessels that ollow the distribution o the coronary arteries and veins. Each o these larger vessels then combines in the AV groove to orm a single lymphatic conduit, which exits the heart to reach the mediastinal lymphatic plexus and ultimately the thoracic duct. Histology of Ventricular Myocardial Cells The mature myocardial cell (also termed the myocyte) measures up to 25 µm in diameter and 100 µm in length. The cell shows a cross-striated banding pattern similar to that o the skeletal muscle. However, unlike the multinucleated skeletal myo bers, myocardial cells contain only one or two centrally located nuclei. Surrounding each myocardial cell is connective tissue with a rich capillary network. Each myocardial cell contains numerous myof brils, which are long chains o individual sarcomeres, the undamental contractile units o the cell (Fig. 1-8). Each sarcomere is made up o two groups o overlapping laments o contractile proteins. Biochemical and biophysi- cal interactions occurring between these myo laments produce muscle contraction. Their structure and unction are described later in the chapter. Within each myocardial cell, the neighboring sarcomeres are all in register, producing the characteristic cross-striated banding pattern seen by light microscopy. The relative den- sities o the cross bands identi y the location o the contractile proteins. Under physiologic conditions, the overall sarcomere length (Z-to-Z distance) varies between 2.2 and 1.5 µm during the cardiac cycle. The larger dimension ref ects the ber stretch during ventricular lling, whereas the smaller dimension represents the extent o ber shortening during contraction. Normal Cardiac Structure and Function 11 The myocardial cell membrane is named the sarcolemma. A specialized region o the mem- brane is the intercalated disk, a distinct characteristic o cardiac muscle tissue. Intercalated disks are seen on light microscopic study as darkly staining transverse lines that cross chains o cardiac cells at irregular intervals. They represent the gap junction complexes at the inter ace o adjacent cardiac f bers and establish structural and electrical continuity between the myocardial cells. Another unctional eature o the cell membrane is the transverse tubular system (or T tubules). This complex system is characterized by deep, f ngerlike invaginations o the sarcolemma (Fig. 1-9; see also Fig. 1-8). Similar to the intercalated disks, transverse tubular membranes establish pathways or rapid transmission o the excitatory electrical impulses that initiate contraction. The T tubule system increases the sur ace area o the sarcolemma Myofibril Z ZMyosin TitinActin Sarcolemma Mitochondrion Sarcoplasmic re ticulum T tubule Sarcomere FIGURE 1-8. Myocardial cell. Top. Schematic representation o the ultrastructure o the myocardial cell. The cell consists o multiple parallel myof brils surrounded by mitochondria. The T tubules are invaginations o the cell membrane (the sarcolemma) that increase the sur ace area or ion transport and transmission o electrical impulses. The intracellular sarcoplasmic reticulum houses most o the intracellular calcium and abuts the T tubules. (Modif ed rom Katz AM. Physiology of the Heart. 2nd ed. New York, NY: Raven Press; 1992:21). Bottom. Expanded view o a sarcomere, the basic unit o contraction. Each myof bril consists o serially connected sarcomeres that extend rom one Z line to the next. The sarcomere is composed o alternating thin (actin) and thick (myosin) myof laments. Titin is a protein that tethers myosin to the Z line and provides elasticity. T tubule Sarcolemma Termina l cis te rnae ATPase Sarcoplasmic re ticulum Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ FIGURE 1-9. Schematic view of the tubular systems of the myocardial cell. The T tubules, invaginations o the sarcolemma, abut the sarcoplasmic reticulum at right angles at the terminal cisternae sacs. This relationship is important in linking membrane excitation with intracellular release o calcium rom the sarcoplasmic reticulum. 14 Chapter 1 raction o channels is open at a given time. There ore, the gating o channels is said to be voltage sensitive. As the membrane voltage changes during depolarization and repolariza- tion o the cell, speci c channels open and close, with corresponding alterations in the ion f uxes across the sarcolemma. An example o voltage-sensitive gating is apparent in the cardiac channel known as the fast sodium channel. The transmembrane protein that orms this channel assumes various con- ormations depending on the cell’s membrane potential (Fig. 1-11). At a voltage o −90 mV Activa tion ga te Rapid depola riza tion R e p o la riz a tio n S p o n ta n e o u s Inac tiva tion ga te Outs ide A C CHANNEL CLOSED (RESTING) CHANNEL CLOSED (INACTIVE) Na+ Cell membrane Ins ide + + + + + + + + – – – – – – – – III IV II B CHANNEL OPEN Na+ Na+ + + + + + + + + – – – – – – – – + + + + + + + + – – – – – – – – FIGURE 1-11. Schematic representation of gating of fast sodium channels. A. Four covalently linked transmembrane domains (I, II, III, and IV) form the sodium channel, which is guarded by activation and inactivation gates. (Here, domain I is cut away to show the transmembrane pore.) In the resting membrane, most channels are in a closed state. Even though the inactivation gate is open, Na+ ions cannot easily pass through because the activation gate is closed. B. A rapid depolarization changes the cell membrane voltage and forces the activation gate to open, presumably mediated by translocation of the charged portions of a segment in each domain. With the channel in this conformation (in which both the activation and inactivation gates are open), Na+ ions permeate into the cell. C. As the inactivation gate spontaneously closes, the sodium current ceases. The inactivation gating function is thought to be achieved by a peptide loop that connects domains III and IV, which translocates into the intracellular opening of the channel pore (black arrow). The channel cannot reopen directly from this closed, inactive state. Cellular repolarization returns the channel to the resting condition (A) . During repolarization, as high negative membrane voltages are reachieved, the activation gate closes and the inactivation gate reopens. Normal Cardiac Structure and Function 15 (the typical resting voltage o a ventricular muscle cell), the channels are predominantly in a closed, resting state, such that Na+ ions cannot pass through (Fig. 1-11A). In this resting state, the channels are available or conversion to the open con guration. A rapid wave o depolarization renders the membrane potential less negative, and this acti- vates the resting channels to change con ormation to the open state (see Fig. 1-11B). Na+ ions readily permeate through the open channels, constituting an inward Na+ current that urther depolarizes the cell. However, the activated channels remain open or only a brie time, a ew thousandths o a second, and then spontaneously close to an inactive state (see Fig. 1-11C). Channels in the inactivated con ormation cannot be directly converted back to the open state. The inactivated state persists until the membrane voltage has been repolarized nearly back to its original resting level. Until then, the inactivated channel con ormation maintains a closed pore that prevents any f ow o sodium ions. Thus, during normal cellular depolariza- tion, the voltage-dependent ast sodium channels conduct or a short period and then inac- tivate, unable to conduct current again until the cell membrane has nearly ully repolarized, and the channels recover rom the inactivated to the closed resting state. Another important attribute o cardiac ast sodium channels should be noted. I the trans- membrane voltage o a cardiac cell is slowly depolarized and maintained chronically at levels less negative than the usual resting potential, inactivation o channels occurs without ini- tial opening and current f ow. Furthermore, as long as this partial depolarization exists, the closed, inactive channels cannot recover to the resting state. Thus, the ast sodium channels in such a cell are persistently unable to conduct Na+ ions. This is the typical case in cardiac pacemaker cells (e.g., the SA and AV nodes) in which the membrane voltage is generally less negative than −70 mV throughout the cardiac cycle. As a result, the ast sodium channels in pacemaker cells are persistently inactivated and do not play a role in the generation o the action potential in these cells. Calcium and potassium channels in cardiac cells also act in voltage-dependent ashions, but they behave di erently than the sodium channels, as described later. Resting Potential In nonpacemaker cardiac cells at rest, prior to excitation, the electrical charge di erential between the inside and outside o a cell corresponds to the resting potential. The magnitude o the resting potential o a cell depends on two main properties: (1) the concentration gra- dients or all the di erent ions between the inside and outside o the cell and (2) the relative permeabilities o ion channels that are open at rest. As in other tissues such as nerve cells and skeletal muscle, the potassium concentra- tion is much greater inside cardiac cells compared with outside. This is attributed mainly to the cell membrane transporter Na+K+-ATPase (see Fig. 1-10). This protein “pump” actively extrudes 3 Na+ ions out o the cell in exchange or the inward movement o 2 K+ ions in an ATP-dependent process. This acts to maintain intracellular Na+ at low levels and intracellular K+ at high levels. Cardiac myocytes contain a set o potassium channels (termed inward rectif er potassium channels) that are open in the resting state, at a time when other ionic channels (e.g., sodium and calcium) are closed. There ore, the resting cell membrane is much more permeable to potassium than to other ions. As a result, K+ f ows in an outward direction down its concentration gradient, removing positive charges rom the cell. As potassium ions exit the cell, negatively charged anions that are impermeant to passage are le t behind, causing the interior o the cell to become electrically negative with respect to the outside. As the interior o the cell becomes more negatively charged by the outward f ux o potas- sium, the positively charged K+ ions are attracted back by the electrical potential toward the cellular interior, slowing their net exit rom the cell. Thus, the K+ concentration gradient and the electrostatic orce oppose each other (Fig. 1-12). At equilibrium, these orces are 16 Chapter 1 balanced, and there is zero net movement o K+ across the membrane. The electrical poten- tial at which that occurs is known as the potassium equilibrium potential and in ventricular myocytes is −91 mV, as calculated by the Nernst equation, shown in Figure 1-12. Since at rest the membrane is almost exclusively permeable to potassium ions alone, this value closely approximates the cell’s resting potential. The permeability o the cardiac myocyte cellular membrane or sodium is minimal in the resting state because the channels that conduct that ion are essentially closed. However, there is a slight leak o sodium ions into the cell at rest. This small inward current o positively charged ions explains why the actual resting potential is slightly less negative (−90 mV) than would be predicted i the cell membrane were truly only permeable to potassium. The sodium ions that slowly leak into the myocyte at rest (and the much larger amount that enters during the action potential) are continuously removed rom the cell and returned to the extracellular environment by Na+K+-ATPase, as previously described. Action Potential When the cell membrane’s voltage is altered, its permeability to specif c ions changes because o the voltage-gating characteristics o the ion channels. Each type o channel has a charac- teristic pattern o activation and inactivation that determines the progression o the electrical signal. The ionic currents that pass through the channels discussed in this chapter are listed in Table 1-1. This description begins by ollowing the development o the action potential in a typical cardiac muscle cell (Fig. 1-13). The unique characteristics o action potentials in cardiac pacemaker cells are described therea ter. Equilibrium (Ne rns t) pote ntia l = –26.7 ln ([K+]in/[K +]out) = –91mV Ins ide ce ll Open potass ium channels CONCENTRATION GRADIENT [K+]out (5 mM) ELECTRICAL FORCE K+ + + + + – – – – [K+]in (150 mM) FIGURE 1-12. The resting potential of a cardiac muscle cell is determined by the balance between the concentration gradient and electrostatic forces for potassium, because only potassium channels are open at rest. The concentration gradient avors outward movement o K+, whereas the electrical orce attracts the positively charged K+ ions inward. The resting potential is approximated by the Nernst equation or potassium, as shown here. TABLE 1-1 Transmembrane Cardiac Ionic Currents Described in This Chapter Current Description I Pacemaker current; responsible or phase 4 depolarization in pacemaker cells INa Na+ + current; responsible or phase 0 rapid depolarization in nonpacemaker cells ICa.L Slow, long-lasting Ca+ + current; responsible or phase 0 depolarization in pacemaker cells, and major contributor to inward current during phase 2 o nonpacemaker cells IK1 Maintains resting potential; current o the inward recti ying potassium channel Ito Transient outward potassium current; responsible or phase 1 o action potential IKs, IKr Delayed rectif er potassium currents o slow (IKs) and rapid (IKr) types; repolarizing currents that are active during phases 2 and 3 o action potential Normal Cardiac Structure and Function 19 Cells that display pacemaker behavior include the SA node (the “natural pacemaker” o the heart) and the AV node. Although atrial and ventricular muscle cells do not normally display automaticity, they may do so under disease condi- tions such as ischemia. The shape o the action potential o a pace- maker cell is di erent rom that o a ventricular muscle cell in three ways: 1. The maximum negative voltage o pacemaker cells is approximately −60 mV, substantially less negative than the resting potential o ven- tricular muscle cells (−90 mV). The persistently less negative membrane voltage of pacemaker cells causes the fast sodium channels within these cells to remain inactivated. 2. Unlike that o cardiac muscle cells, phase 4 o the pacemaker cell action potential is not f at but has an upward slope, representing sponta- neous gradual depolarization. This spontane- ous depolarization is the result o an ionic f ux known as the pacemaker current (denoted by If; see Table 1-1). The pacemaker current is car- ried predominantly by Na+ ions. The ion chan- nel through which the pacemaker current passes is di erent rom the ast sodium channel responsible or phase 0 o the action potential. Importantly, this pacemaker channel opens in the very negative voltage ranges reached during repolarization o the cell. The inf ux o positively charged Na+ ions through the pacemaker channel causes the membrane potential to become progressively less negative during phase 4, ultimately depolarizing the cell to its threshold voltage (see Fig. 1-14). 3. The phase 0 upstroke o the pacemaker cell action potential is less rapid and reaches a lower amplitude than that o a cardiac muscle cell. These characteristics result rom the ast sodium channels o the pacemaker cells being inactivated and the upstroke o the action potential relying solely on Ca+ + inf ux through the relatively slow calcium channels. Repolarization o pacemaker cells occurs in a ashion similar to that o ventricular muscle cells and relies on inactivation o the calcium channels and increased activation o potassium channels with enhanced K+ e f ux rom the cell. Refractory Periods Compared with electrical impulses in nerves and skeletal muscle, the cardiac action potential is much longer in duration, supporting prolonged Ca+ + entry and muscle contraction during systole. This results in a prolonged period o channel inactivation during which the muscle is re ractory (unresponsive) to restimulation. Such a long period is physiologically necessary because it allows the ventricles su cient time to relax and re ll be ore the next contraction. There are di erent levels o re ractoriness during the action potential o a myocyte, as illustrated in Figure 1-15. The degree o re ractoriness primarily ref ects the percentage o ast Na+ channels that have recovered rom their inactive state and are capable o reopening. As phase 3 o the action potential progresses, an increasing number o Na+ channels recover rom inactivated to resting states and can then open in response to the next depolarization. This, in turn, corresponds to an increasing probability that a stimulus will trigger an action potential and result in a propagated impulse. M e m b r a n e p o t e n t i a l ( m V ) 0 K+ efflux (IKs and IKr) Ca++ influx (ICa.L) lf Time –40 –80 4 0 FIGURE 1-14. Action potential of a pacemaker cell. Phase 4 is characterized by gradual, spontaneous depolarization owing to the pacemaker current (I ). When the threshold potential is reached, at about −40 mV, the upstroke o the action potential ollows. The upstroke o phase 0 is less rapid than in nonpacemaker cells because the current represents Ca++ inf ux through the relatively slow calcium channels (Ica.L). Repolarization occurs with inactivation o the calcium channels and K+ e f ux rom the cell through potassium channels (IKs and IKr). 20 Chapter 1 The absolute re ractory period re ers to the time during which the cell is completely unexcit- able to any new stimulation. The effective re ractory period includes the absolute re ractory period but extends beyond it to include a short interval o phase 3, during which stimulation produces a localized action potential that is not strong enough to propagate urther. The relative re ractory period is the interval during which stimulation triggers an action potential that is conducted, but the rate o rise o the action potential is lower during this period because some o the Na+ chan- nels are inactivated and some o the delayed recti er K+ channels remain activated, thus reducing the available net inward current. Following the relative re ractory period, a short “supranormal” period is present in which a less-than-normal stimulus can trigger an action potential. The re ractory period o atrial cells is shorter than that o ventricular muscle cells, such that atrial rates can generally exceed ventricular rates during rapid arrhythmias (see Chapter 11). Impulse Conduction During depolarization, the electrical impulse spreads along each cardiac cell, and rapidly rom cell to cell because each myocyte is connected to its neighbors through low-resistance gap junc- tions. Gap junctions are a special type o ion channel that provide electrical and biochemical coupling between cardiac myocytes, allowing the action potential to spread rapidly through the myocardium. The speed o tissue depolarization (phase 0) and the conduction velocity along the cell depend on the net inward current (which is largely dependent on the number o sodium channels), on the value o the resting potential (which sets the degree o Na+ channel inactiva- tion), and on the resistance to current f ow between cells though the gap junctions. Tissues with a high concentration o Na+ channels, such as Purkinje bers, have a large, ast inward current, which spreads quickly within and between cells to support rapid conduction. However, the less negative the resting potential, the greater the raction o ast sodium channels that are in the inactivated state and the less rapid the upstroke velocity (Fig. 1-16). Thus, alterations in the rest- ing potential signi cantly impact the upstroke and conduction velocity o the action potential. Normal Sequence of Cardiac Depolarization Electrical activation o the heartbeat is normally initiated at the SA node (see Fig. 1-6). The impulse spreads to the surrounding atrial muscle through the intercellular gap junctions, pro- viding electrical continuity between the cells. Ordinary atrial muscle bers participate in the propagation o the impulse rom the SA to the AV node, although in certain regions the bers are more densely arranged, lowering intercellular resistance and thus acilitating conduction. Fibrous tissue surrounds the tricuspid and mitral valves, such that there is no direct elec- trical connection between the atrial and ventricular chambers other than through the AV M e m b r a n e p o t e n t i a l ( m V ) 0 Absolute RP Effective RP Rela tive RP Supranormal period –50 –100 1 2 3 FIGURE 1-15. Refractory periods (RPs) of the myocyte. During the absolute refractory period (ARP), the cell is unexcitable to stimulation. The effective refractory period includes a brief time beyond the ARP during which stimulation produces a localized depolarization that does not propagate (curve 1). During the relative refractory period, stimulation produces a weak action potential (AP) that propagates, but more slowly than usual (curve 2). During the supranormal period, a weaker-than-normal stimulus can trigger an AP (curve 3). Normal Cardiac Structure and Function 21 node. As the electrical impulse reaches the AV node, a delay in conduction (approximately 0.1 seconds) is encountered. This delay occurs because the small-diameter f bers in this region conduct slowly, and the action potential is o the “slow” pacemaker type (recall that the ast sodium channels are permanently inactivated in pacemaker tissues, such that the upstroke velocity relies on the slower calcium channels). The pause in conduction at the AV node is actually benef cial because it allows the atria time to contract and ully empty their contents be ore ventricular stimulation. In addition, the delay allows the AV node to serve as a “gatekeeper” o conduction rom atria to ventricles, which is critical or limiting the rate o ventricular stimulation during abnormally rapid atrial rhythms. A ter traversing the AV node, the cardiac action potential spreads into the rapidly conduct- ing bundle o His and Purkinje f bers, which distribute the electrical impulses to the bulk o the ventricular muscle cells, in a spatially synchronized manner. This allows or precisely timed stimulation and organized contraction o the ventricular myocytes, optimizing the vol- ume o blood ejected by the heart. EXCITATION–CONTRACTION COUPLING This section reviews how the electrical action potential leads to physical contraction o cardiac muscle cells, a process known as excitation–contraction coupling. During this process, chemi- cal energy in the orm o high-energy phosphate compounds is translated into the mechanical energy o myocyte contraction. Contractile Proteins in the Myocyte Several distinct proteins are responsible or cardiac muscle cell contraction (Fig. 1-17). O the major proteins, actin and myosin are the chie contractile elements. Two other proteins, tropomyosin and troponin, serve regulatory unctions. Myosin is arranged in thick f laments, each composed o lengthwise stacks o approxi- mately 300 molecules. The myosin f lament exhibits globular heads that are evenly spaced Phase 0 M e m b r a n e p o t e n t i a l ( m V ) 0 –50 –100 A B FIGURE 1-16. Dependence of speed of depolarization on resting potential. A. Normal resting potential (RP) and rapid rise of phase 0. B. Less negative RP results in slower rise of phase 0 and lower maximum amplitude of the action potential. Myos in heads Myosin thick filament TnI TnC TropomyosinActin TnT FIGURE 1-17. Schematic diagram of the main contractile proteins of the myocyte, actin, and myosin. Tropomyosin and troponin (components TnI, TnC, and TnT) are regulatory proteins. 24 Chapter 1 the sarcolemmal Na+–Ca+ + exchanger and to a lesser extent by the ATP-consuming calcium pump, sarcolemmal Ca+ +-ATPase (see Fig. 1-10). As cytosolic Ca+ + concentrations all and calcium ions dissociate rom TnC, tropomyosin once again inhibits the actin–myosin interaction, leading to relaxation o the contracted cell. The contraction–relaxation cycle can then repeat with the next action potential. INTRODUCTION TO CARDIAC SIGNALING SYSTEMS β-Adrenergic and Cholinergic Signaling There is substantial evidence that the concentration o Ca+ + within the cytosol is the major determinant o the orce o cardiac contraction with each heartbeat. Mechanisms that raise intracellular Ca+ + concentration enhance orce development, whereas actors that lower Ca+ + concentration reduce the contractile orce. β-Adrenergic stimulation is one mechanism that enhances calcium f uxes in the myocyte and thereby strengthens the orce o ventricular contraction (Fig. 1-20). Catecholamines (e.g., norepinephrine) bind to the myocyte β1-adrenergic receptor, which is coupled to and activates the G protein system (Gs) attached to the inner sur ace o the cell membrane. Gs in turn stimu- lates membrane-bound adenylate cyclase to produce cyclic AMP (cAMP) rom ATP. cAMP then activates speci c intracellular protein kinases (PKAs), which phosphorylate cellular Norepinephrine β1-adrenergic receptor Gs prote in Gi prote in Ca ++ Ca ++ Ca ++ ATP Inactive prote in kinases Active prote in kinases PL ATP Adenyla te cyclase Muscarinic receptor Sarcoplasmic re ticulum cAMP Acetylcholine + + + – FIGURE 1-20. Effects of β-adrenergic and cholinergic stimulation on cardiac cellular signaling and calcium ion movement. The binding of a ligand (e.g., norepinephrine) to the β1-adrenergic receptor induces G protein– mediated stimulation of adenylate cyclase and formation of cyclic AMP (cAMP). The latter activates protein kinases, which phosphorylate cellular proteins, including ion channels. Phosphorylation of the slow Ca++ channel enhances calcium movement into the cell and therefore strengthens the force of contraction. Protein kinases also phosphorylate phospholamban (PL), reducing the latter’s inhibition of Ca++ uptake by the sarcoplasmic reticulum. The enhanced removal of Ca++ from the cytosol facilitates relaxation of the myocyte. Cholinergic signaling, triggered by acetylcholine binding to the muscarinic receptor, activates inhibitory G proteins that reduce adenylate cyclase activity and cAMP production, thus antagonizing the effects of β-adrenergic stimulation. Normal Cardiac Structure and Function 25 proteins, including the L-type calcium channels within the cell membrane. Phosphorylation o the calcium channel augments Ca+ + inf ux, which triggers a corresponding increase in Ca+ + release rom the SR, thereby enhancing the orce o contraction. β-Adrenergic stimulation o the myocyte also enhances myocyte relaxation. The return o Ca+ + rom the cytosol to the SR is regulated by phospholamban (PL), a low molecular weight protein in the SR membrane. In its dephosphorylated state, PL inhibits Ca+ + uptake by SERCA (see Fig. 1-18). However, β-adrenergic activation o PKAs causes PL to become phosphory- lated, an action that blunts PL’s inhibitory e ect (see Fig. 1-20). The subsequently greater uptake o calcium ions by the SR hastens Ca+ + removal rom the cytosol, promoting myocyte relaxation. The increased cAMP activity also results in phosphorylation o TnI, an action that inhibits actin–myosin interactions and there ore urther enhances relaxation o the cell. Cholinergic signaling via parasympathetic inputs (mainly rom the vagus nerve) opposes the e ects o β-adrenergic stimulation (see Fig. 1-20). Acetylcholine released rom parasympathetic nerve terminals binds to the muscarinic M2 receptor on cardiac cells. This receptor also activates G proteins, but in distinction to the β-adrenergic receptor, it is coupled to Gi, an inhibitory G protein system. Gi associated with cholinergic stimulation inhibits adenylate cyclase activity and reduces cAMP ormation. At the sinus node, these actions o cholinergic stimulation serve to reduce heart rate. In the myocardium, the e ect is to counteract the orce o contraction induced by β-adrenergic stimulation. It should be noted that ventricular cells are much less sensitive to this cholinergic e ect than atrial cells, likely ref ecting di erent degrees o G protein coupling. Thus, physiologic or pharmacologic catecholamine stimulation o the myocyte β1-adrenergic receptor enhances contraction o the cell, while cholinergic stimulation opposes that enhance- ment. We will return to these important properties in later chapters. SUMMARY • This chapter has reviewed basic cardiac anatomy and cellular composition, the cardiac conduction system, excitation–contraction coupling, and cardiac signaling systems. The physiology o myocyte contraction will be described in Chapter 9. Each o these complex pieces integrate together to orm an organ system that unctions in a organized ashion, is robust to errors, and operates reliably over many years. As a result, the heart is capable o purpose ul stimulation billions o times during the li e span o a normal person. With each contraction cycle, the heart receives and propagates blood through the circulation to provide nutrients to and remove waste products rom the body’s tissues. • The ollowing chapters explore what can go wrong with this remarkable system. Ack n owled gm en t s Contributors to previous editions o this chapter were Ken Young Lin, MD; Vivek Iyer, MD; Kirsten Greineder, MD; Stephanie Harper, MD; Scott Hyver, MD; Paul Kim, MD; Rajeev Malhotra, MD; Laurence Rhines, MD; and James D. Marsh, MD. Ad d i t ion a l Rea d in g Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23–49. Christo els VM, Smits GJ, Kispert A, Moorman AFM. Development o pacemaker tissues o the heart. Circ Res. 2010;106:240–254. Courneya C, Parker MJ. Cardiovascular Physiology. A Clinical Approach. Baltimore, MD: Lippincott Williams & Wilkins; 2011. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2:185–194. Katz AM. Physiology of the Heart. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. Saucerman JJ, McCulloch AD. Cardiac beta-adrenergic signal- ing: rom subcellular microdomains to heart ailure. Ann N Y Acad Sci. 2006;1080:348–361. Smyth JW, Shaw RM. Forward tra cking o ion chan- nels: What the clinician needs to know. Heart Rhythm. 2010;7:1135–1140. Wilcox BR, Cook AC, Anderson RH. Surgical Anatomy of the Heart. 4th ed. Cambridge, MA: Cambridge University Press; 2013. Zipes DP, Jali e J, eds. Cardiac Electrophysiology: From Cell to Bedside. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013. 26 C h a p t e r O u t l i n e Cardiac Cycle Heart Sounds First Heart Sound (S1) Second Heart Sound (S2) Extra Systolic Heart Sounds Extra Diastolic Heart Sounds Murmurs Systolic Murmurs Diastolic Murmurs Continuous Murmurs Cardiac diseases o ten cause abnormal ndings on physi-cal examination, including pathologic heart sounds and murmurs. These ndings are clues to the underlying pathophysi- ology, and proper interpretation is essential or success ul diag- nosis and disease management. This chapter rst describes heart sounds in the context o normal cardiac physiology and then ocuses on the origins o pathologic heart sounds and murmurs. Many cardiac diseases are mentioned brief y in this chapter as examples o abnormal heart sounds and murmurs. Each o these conditions is described in greater detail later in the book, so it is not necessary or desirable to memorize all o the examples presented here. Rather, the goal o this chapter is to explain the mechanisms by which the abnormal sounds are produced, so that their descriptions will make sense in later chapters. CARDIAC CYCLE The cardiac cycle consists o precisely timed electrical and mechanical events that are responsible or rhythmic atrial and ventricular contractions. Figure 2-1 displays the pressure rela- tionships between the le t-sided cardiac chambers during the normal cardiac cycle and serves as a plat orm or describing key events. Mechanical systole re ers to the phase o ventricu- lar contraction, and diastole re ers to the phase o ventricular relaxation and f lling. Throughout the cardiac cycle, the right and le t atria accept blood returning to the heart rom the systemic veins and rom the pulmonary veins, respectively. During diastole, blood passes rom the atria into the ventricles across the open tricuspid and mitral valves, causing a gradual increase in ventricular diastolic pressures. In late diastole, atrial contraction propels a f nal bolus o blood into each ven- tricle, an action that produces a brie urther rise in atrial and ventricle pressures, termed the a wave (see Fig. 2-1). The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs David B. Fischer Leonard S. Lilly 2 The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs 29 HEART SOUNDS Commonly used stethoscopes contain two chest pieces or auscultation o the heart. The concave “bell” chest piece, meant to be applied lightly to the skin, accentuates low- requency sounds. Conversely, the f at “diaphragm” chest piece is designed to be pressed rmly against the skin to eliminate low requencies and there ore accentuate high- requency sounds and murmurs. Some modern stethoscopes incorporate both the bell and diaphragm unctions into a single chest piece; in these models, placing the piece lightly on the skin brings out the low- requency sounds, while rm pressure accentuates the high- requency ones. The sections below describe when, and where on the chest, to listen or high- versus low- requency sounds. First Heart Sound (S1) S1 is produced by the closure o the mitral and tricuspid valves in early systole and is loudest near the apex o the heart (Fig. 2-2). It is a high- requency sound, best heard with the diaphragm o the stethoscope. Although mitral closure usually precedes tricuspid clo- sure, they are separated by only about 0.01 seconds, such that the human ear appreciates only a single sound. An exception occurs in patients with right bundle branch block (see Chapter 4), in whom these components may be audibly split because o delayed right ventricular contraction and late closure o the tricuspid valve. Three actors determine the intensity o S1: (1) the distance separating the leaf ets o the open valves at the onset o ventricular contraction, (2) the mobility o the mitral and tricuspid leaf ets (normal, or rigid because o stenosis), and (3) the rate o rise o ventricular pressure (Table 2-1). The distance between the open valve leaf ets at the onset o ventricular contraction relates to the electrocardiographic PR interval (see Chapter 4), the period between the onset o atrial and ventricular activation. Atrial contraction at the end o diastole orces the tricuspid and mitral valve leaf ets apart. They start to passively dri t back together, but once Pulmonic area (2nd–3rd le ft inte rspace) Mitral area (apex) Tricus pid area (le ft lower s te rna l border) Aortic area (2nd–3rd right interspace) FIGURE 2-2. Standard positions of stethoscope placement for cardiac auscultation. The mitral area localizes to the cardiac apex while the aortic and pulmonic regions represent the cardiac base. I the top o the IJ column is not visible at 45 degrees, the column o blood is either too low (below the clavicle) or too high (above the jaw) to be measured in that position. In such situations, the head o the bed must be lowered or raised, respectively, so that the top o the column becomes visible. As long as the top can be ascertained, the vertical height o the JVP above or below the sternal angle will accurately ref ect RA pressure, no matter the angle o the head o the bed. Sometimes it can be di cult to distinguish the jugular venous pulsations rom the neighboring carotid artery. Unlike the carotid, the JVP is usually not pulsatile to palpation, it has a double (or triple) upstroke rather than a single one, and it declines in most patients by assuming the seated position or during inspiration. BOX 2-1 Jugular Venous Pulsations and Assessment of Right Heart Function (continued) 30 Chapter 2 ventricular contraction causes the ventricular pressure to exceed that in the atrium, the leaf ets are orced to close rom whatever positions they occupy at that moment. An accen- tuated S1 results when the PR interval is shorter than normal, because the valve leaf ets have less time to dri t back together and are there ore orced shut rom a relatively wide distance. Similarly, in mild mitral stenosis (see Chapter 8), impeded f ow through the mitral valve causes a prolonged diastolic pressure gradient between the le t atrium and ventricle, which keeps the mobile portions o the mitral leaf ets arther apart than normal during late diastole. Because the leaf ets are relatively wide apart at the onset o systole, they are orced shut loudly when the le t ventricle contracts. S1 may also be accentuated when the heart rate is more rapid than normal (i.e., tachycar- dia) because diastole is shortened and the leaf ets have less time to dri t back together be ore the ventricles contract. Conditions that reduce the intensity o S1 are also listed in Table 2-1. In rst-degree atrioventricular (AV) block (see Chapter 12), a diminished S1 results rom an abnormally prolonged PR interval, which delays the onset o ventricular contraction. Consequently, ollowing atrial contraction, the mitral and tricuspid valves have additional time to f oat back together so that the leaf ets are orced closed rom only a small distance apart and the sound is so tened. In patients with mitral regurgitation (see Chapter 8), S1 is o ten diminished in intensity because the mitral leaf ets may not come into ull contact with one another as they close. In severe mitral stenosis, the leaf ets are nearly xed in position throughout the cardiac cycle, and that reduced movement lessens the intensity o S1. In patients with a “sti ened” le t ventricle (e.g., a hypertrophied chamber), atrial contrac- tion generates a higher-than-normal ventricular pressure at the end o diastole. This greater pressure causes the mitral leaf ets to dri t together more rapidly, so that they are orced closed rom a smaller-than-normal distance when ventricular contraction begins, thus reducing the intensity o S1. Second Heart Sound (S2) The second heart sound results rom the closure o the aortic and pulmonic valves and there- ore has aortic (A2) and pulmonic (P2) components. Unlike S1, which is usually heard only as a single sound, the components o S2 vary with the respiratory cycle: they are normally used as one sound during expiration but become audibly separated during inspiration, a situation termed normal or physiologic splitting (Fig. 2-3). One explanation or normal splitting o S2 is as ollows. Expansion o the chest during inspiration causes the intrathoracic pressure to become more negative. The negative pressure TABLE 2-1 Causes o Altered Intensity o the First Heart Sound (S1) Accentuated S1 1. Shortened PR interval 2. Mild mitral stenosis 3. High cardiac output states or tachycardia (e.g., exercise) Diminished S1 1. Lengthened PR interval: f rst-degree AV nodal block 2. Mitral regurgitation 3. Severe mitral stenosis 4. “Sti ” le t ventricle (e.g., le t ventricular hypertrophy due to systemic hypertension) The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs 31 transiently increases the capacitance (and reduces the impedance) of the intrathoracic pul- monary vessels. As a result, there is a temporary delay in the diastolic “back pressure” in the pulmonary artery responsible for the closure of the pulmonic valve. Thus, P2 is delayed; that is, it occurs later during inspiration than during expiration. Inspiration has the opposite effect on aortic valve closure. Because the capacitance of the intrathoracic pulmonary veins is increased by the negative pressure generated by inspiration, P2A2 Phys iologic (normal) splitting Widened splitting Fixed splitting Paradoxica l splitting (Note reversed pos ition of A2 and P2) Expira tion Inspira tion Expira tion Inspira tion Expira tion Inspira tion Expira tion Inspira tion In expira tion, A2 and P 2 fuse as one sound • Right bundle branch block • Pulmonary s tenos is • Left bundle branch block • Advanced aortic s tenos is • Atria l septa l defect Common caus es S1 P2 P2 A2S 1 A2S 1 A2S 1 P2 FIGURE 2-3. Splitting patterns of the second heart sound (S2) . A2, aortic component; P2, pulmonic component o S2; S1, f rst heart sound. 34 Chapter 2 Because o its proximity to A2, the A2–OS sequence can be con used with a widely split second heart sound. However, care- ul auscultation at the pulmonic area during inspiration reveals three sounds occurring in rapid succession (Fig. 2-5), which cor- respond to aortic closure (A2), pulmonic closure (P2), and then the OS. The three sounds become two on expiration when A2 and P2 normally use. The severity o mitral stenosis can be approximated by the time interval between A2 and the OS: the more advanced the stenosis, the shorter the interval. This occurs because the degree o le t atrial pressure elevation corresponds to the severity o mitral stenosis. When the ventricle relaxes in diastole, the greater the le t atrial pres- sure, the earlier the mitral valve opens. Compared with severe ste- nosis, mild disease is marked by a less elevated le t atrial pressure, lengthening the time it takes or the le t ventricular pressure to all below that o the atrium. There ore, in mild mitral stenosis, the OS is widely separated rom A2, whereas in more severe stenosis, the A2–OS interval is narrower. Third Heart Sound (S3) When present, an S3 occurs in early diastole, ollowing the opening o the AV valves, during the ventricular rapid lling phase (see Fig. 2-4). It is a dull, low-pitched sound best heard with the bell o the stethoscope. A le t-sided S3 is typically loudest over the cardiac apex while the patient lies in the le t lateral decubitus position. A right-sided S3 is better appreciated at the lower le t sternal border. Production o the S3 appears to result rom tensing o the chordae tendineae during rapid lling and expansion o the ventricle. An S3 is a normal nding in children and young adults. In these groups, an S3 implies the presence o a supple ventricle capable o normal rapid expansion in early diastole. Conversely, when heard in middle-aged or older adults, an S3 is a sign o disease resulting rom a dilated ventricle (e.g., a patient with heart ailure due to impaired systolic contraction, as described in Chapter 9) or rom the increased transvalvular f ow that accompanies advanced mitral or tricuspid regurgitation (described in Chapter 8). A pathologic S3 is sometimes re erred to as a ventricular gallop. Fourth Heart Sound (S4) When an S4 is present, it occurs in late diastole and coincides with contraction o the atria (see Fig. 2-4). This sound is generated by the le t (or right) atrium ejecting blood into a sti ened ventricle. Thus, an S4 usually indicates the presence o cardiac disease—speci cally, a decrease in ventricular compliance typically resulting rom ventricular hypertrophy or myo- cardial ischemia. Like an S3, the S4 is a dull, low-pitched sound and is best heard with the bell o the stethoscope. In the case o the more common le t-sided S4, the sound is loudest at the apex, with the patient lying in the le t lateral decubitus position. S4 is sometimes re erred to as an atrial gallop. Quadruple Rhythm or Summation Gallop In a patient with both an S3 and S4, those sounds, in conjunction with S1 and S2, produce a quadruple beat. I a patient with a quadruple rhythm develops tachycardia, diastole becomes shorter in duration, the S3 and S4 coalesce, and a summation gallop results. The summation o S3 and S4 is heard as a long middiastolic, low-pitched sound, o ten louder than S1 and S2. OS OS P2A2 Expira tion Inspira tion S 1 S2 FIGURE 2-5. Timing of the opening snap (OS) in mitral stenosis does not change with respiration. On inspiration, normal splitting o the second heart sound (S2) is observed so that three sounds are heard. A2, aortic component; P2, pulmonic component o S2; S1, f rst heart sound. The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs 35 Pericardial Knock A pericardial knock is an uncommon, high-pitched sound that occurs in patients with severe constrictive pericarditis (see Chapter 14). It appears early in diastole soon a ter S2 and can be con used with an OS or an S3. However, the knock appears slightly later in dias- tole than the timing o an OS and is louder and occurs earlier than does a ventricular gallop. It results rom the abrupt cessation o ventricular lling that occurs when the expanding ventricle meets a rigid pericardium in early diastole, which is the hallmark o constrictive pericarditis. MURMURS A murmur is the sound generated by turbulent blood f ow. Under normal conditions, the movement o blood through the vascular bed is laminar, smooth, and silent. However, as a result o hemodynamic and/ or structural changes, laminar f ow can become disturbed and produce an audible noise. Murmurs result rom any o the ollowing mechanisms: 1. Flow across a partial obstruction (e.g., aortic stenosis) 2. Increased f ow through normal structures (e.g., aortic systolic murmur associated with a high-output state, such as anemia) 3. Ejection into a dilated chamber (e.g., aortic systolic murmur associated with aneurysmal dilatation o the aorta) 4. Regurgitant f ow across an incompetent valve (e.g., mitral regurgitation) 5. Abnormal shunting o blood rom one vascular chamber to a lower-pressure chamber (e.g., ventricular septal de ect [VSD]) Murmurs are described by their timing, intensity, pitch, shape, location, radiation, and response to maneuvers. Timing re ers to whether the murmur occurs during systole or dias- tole, or is continuous (i.e., begins in systole and continues into diastole). The intensity o the murmur is typically quanti ed by a grading system. In the case o systolic murmurs: And in the case o diastolic murmurs: Pitch re ers to the requency o the murmur, ranging rom high to low. High- requency mur- murs are caused by large pressure gradients between chambers (e.g., aortic stenosis) and are best appreciated using the diaphragm chest piece o the stethoscope. Low- requency murmurs imply less o a pressure gradient between chambers (e.g., mitral stenosis) and are best heard using the stethoscope’s bell piece. Grade 1/ 4 (or I/ IV): Barely audible Grade 2/ 4 (or II/ IV): Faint but immediately audible Grade 3/ 4 (or III/ IV): Easily heard Grade 4/ 4 (or IV/ IV): Very loud Grade 1/ 6 (or I/ VI): Barely audible (i.e., medical students may not hear it!) Grade 2/ 6 (or II/ VI): Faint but immediately audible Grade 3/ 6 (or III/ VI): Easily heard Grade 4/ 6 (or IV/ VI): Easily heard and associated with a palpable thrill Grade 5/ 6 (or V/ VI): Very loud; heard with the stethoscope lightly on the chest Grade 6/ 6 (or VI/ VI): Audible without the stethoscope directly on the chest wall 36 Chapter 2 Shape describes how the murmur changes in intensity rom its onset to its completion. For example, a crescendo–decrescendo (or “diamond-shaped”) murmur rst rises and then alls o in intensity. Other shapes include decrescendo (i.e., the murmur begins at its maxi- mum intensity then becomes so ter) and uniform (the intensity o the murmur does not change). Location re ers to the murmur’s region o maximum intensity and is usually described in terms o speci c auscultatory areas (see Fig. 2-2): From their primary locations, murmurs are o ten heard to radiate to other areas o the chest, and such patterns o transmission relate to the direction o the turbulent f ow. Finally, similar types o murmurs can be distinguished rom one another by simple bedside maneu- vers, such as standing upright, Valsalva ( orce ul expiration against a closed airway), or clenching o the sts, each o which alters the heart’s loading conditions and can a ect the intensity o many murmurs. Examples o the e ects o maneuvers on speci c murmurs are presented in Chapter 8. When reporting a murmur, some or all o these descriptors are mentioned. For example, you might describe a particular patient’s murmur o aortic stenosis as “A grade III/ VI high- pitched, crescendo–decrescendo systolic murmur, loudest at the upper right sternal border, with radiation toward the neck.” Systolic Murmurs Systolic murmurs are subdivided into systolic ejection murmurs, pansystolic murmurs, and late systolic murmurs (Fig. 2-6). A systolic ejection murmur is typical o aortic or pul- monic valve stenosis. It begins a ter the rst heart sound and terminates be ore or during S2, depending on its severity and whether the obstruction is o the aortic or pulmonic valve. The shape o the murmur is o the crescendo–decrescendo type (i.e., its intensity rises and then alls). Aortic area: Second to third right intercostal spaces, next to the sternum Pulmonic area: Second to third le t intercostal spaces, next to the sternum Tricuspid area: Lower le t sternal border Mitral area: Cardiac apex ClickS1 S 2 S1 S 2 S1 S 2 A. Ejection type • Aortic s tenos is • Pulmonary s tenos is • Mitra l regurgita tion • Tricuspid regurgita tion • Ventricula r septa l defect • Mitra l va lve prolapse Examples B. Pansys tolic (holosys tolic) C. La te sys tolic FIGURE 2-6. Classif cation o systolic murmurs. Ejection murmurs are crescendo– decrescendo in conf guration (A), whereas pansystolic murmurs are uni orm throughout systole (B). A late systolic murmur o ten ollows a midsystolic click and suggests mitral (or tricuspid) valve prolapse (C). The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs 39 preceded by an opening snap. The shape o this murmur is unique. Following valvular open- ing (and the OS), the murmur is at its loudest because the pressure gradient between the atrium and ventricle is at its maximum. The murmur then decrescendos or disappears totally during diastole as the transvalvular gradient decreases. The degree to which the murmur ades depends on the severity o the stenosis. I the stenosis is severe, the murmur is prolonged; i the stenosis is mild, the murmur disappears in mid-to-late diastole. Whether the stenosis is mild or severe, the murmur intensi es at the end o diastole in patients in normal sinus rhythm, when atrial contraction augments f ow (and turbulence) across the valve (see Fig. 2-9). Since the pressure gradient across a stenotic mitral valve tends to be airly low, the murmur o mitral stenosis is low pitched and is heard best with the bell o the stethoscope at the apex, while the patient lies in the le t lateral decubitus position. The much less common murmur o tricuspid stenosis is better auscultated at the lower sternum, near the xiphoid process. Hyperdynamic states such as ever, anemia, hyperthyroidism, and exercise cause increased f ow across the normal tricuspid and mitral valves and can there ore result in a diastolic mur- mur. Similarly, in patients with advanced mitral regurgitation, the expected systolic murmur can be accompanied by an additional diastolic murmur owing to the increased volume o blood that must return across the valve to the le t ventricle in diastole. Likewise, patients with either tricuspid regurgitation or an atrial septal de ect (see Chapter 16) have increased f ow across the tricuspid valve, and may there ore display a diastolic f ow murmur rom that site. Continuous Murmurs Continuous murmurs are heard throughout the cardiac cycle. Such murmurs result rom condi- tions in which there is a persistent pressure gradient between two structures during both systole and diastole. An example is the murmur o patent ductus arteriosus, in which there is an abnor- mal congenital communication between the aorta and the pulmonary artery (see Chapter 16). During systole, blood f ows rom the high-pressure ascending aorta through the ductus into the • Aortic regurgita tion • Pulmonic regurgita tion • Mild mitra l or tricuspid s tenos is • Severe mitra l or tricuspid s tenos is S1 S1S 2 S 1 S1S 2 S 1 S 1S 2 A. Early decrescendo B. Mid-to-la te C. P rolonged mid-to-la te OS OS FIGURE 2-9. Classif cation o diastolic murmurs. A. An early diastolic decrescendo murmur is typical o aortic or pulmonic valve regurgitation. B. Mid-to-late low- requency rumbling murmurs are usually the result o mitral or tricuspid valve stenosis and ollow a sharp opening snap (OS). Presystolic accentuation o the murmur occurs in patients in normal sinus rhythm because o the transient rise in atrial pressure during atrial contraction. C. In more severe mitral or tricuspid valve stenosis, the opening snap and diastolic murmur commence earlier, and the murmur is prolonged. S1, f rst heart sound; S2, second heart sound. 40 Chapter 2 lower-pressure pulmonary artery. During diastole, the aortic pressure remains greater than that in the pulmonary artery and the f ow continues across the ductus. This murmur begins in early systole, crescendos to its maximum at S2, then decrescendos until the next S1 (Fig. 2-10). The “to-and- ro” combined murmur in a patient with both aortic stenosis and aortic regur- gitation could be mistaken or a continuous murmur (see Fig. 2-10). During systole, there is a diamond-shaped ejection murmur, and during diastole, a decrescendo murmur. However, in the case o a to-and- ro murmur, the sound does not extend through S2 because it has discrete systolic and diastolic components. SUMMARY • Cardiac diseases o ten result in abnormal heart sounds and murmurs, which are clues to the underlying pathophysiology. • Systole re ers to the phase o ventricular contraction, and diastole re ers to the phase o ven- tricular relaxation and lling. • The normal cardiac cycle proceeds as ollows: (1) during diastole, the mitral valve (MV) is open, so that the le t atrial (LA) and le t ventricular (LV) pressures are equal; (2) in late diastole, LA contraction causes a small rise in pressure in both the LA and LV; (3) a ter a short delay, ventricular contraction causes the LV pressure to rise, and when the LV pres- sure exceeds the LA pressure, the MV closes, contributing to the rst heart sound (S1); (4) as LV pressure rises above the aortic pressure, the aortic valve (AV) opens, a silent event in a normal heart; (5) a ter contraction, as the ventricle relaxes and its pressure alls below that o the aorta, the AV closes, contributing to the second heart sound (S2); (6) when the LV pressure declines below that o the le t atrium, the mitral valve opens, and the cycle repeats. • Extra systolic sounds include ejection clicks, indicating aortic or pulmonic stenosis or dilatation o the aortic root or pulmonary artery, and mid-to-late clicks, indicating mitral or tricuspid valve prolapse. • Extra diastolic sounds include the opening snap (signi ying mitral stenosis), the S3 sound (indicating heart ailure or a volume overload state in older adults; an S3 is a normal sound in children and young adults), and the S4 sound (indicating reduced ventricular compliance). • Common murmurs include systolic ejection murmurs rom aortic or pulmonic stenosis, pansystolic murmurs rom mitral or tricuspid regurgitation, late systolic murmurs rom mitral valve prolapse, early diastolic murmurs rom aortic or pulmonic regurgitation, and mid-to- late diastolic murmurs rom mitral stenosis. • Tables 2-2 and 2-3 and Figure 2-11 summarize eatures o the heart sounds and murmurs described in this chapter. S1 S 1S 2 S1 S 1S 2 To-and-fro Continuous • Aortic s tenos is and regurgita tion • Pulmonic s tenos is and regurgita tion • Pa tent ductus a rte riosus FIGURE 2-10. A continuous murmur peaks at, and extends through, the second heart sound (S2) . A to-and- ro murmur is not continuous; rather, there is a systolic component and a distinct diastolic component, separated by S2. S1, f rst heart sound. TABLE 2-2 Common Heart Sounds Sound Location Pitch Signif cance S1 Apex High Normal closure of mitral and tricuspid valves S2 Base High Normal closure of aortic (A2) and pulmonic (P2) valves Extra systolic sounds Ejection clicks Aortic: apex and base High Aortic or pulmonic stenosis, or dilatation of aortic root or pulmonary arteryPulmonic: base High Mid-to-late click Mitral: apex High Mitral or tricuspid valve prolapse Tricuspid: LLSB High Extra diastolic sounds Opening snap Apex High Mitral stenosis S3 Left-sided: apex Low Normal in children Abnormal in adults: indicates heart failure or volume overload state S4 Left-sided: apex Low Reduced ventricular compliance LLSB, lower left sternal border. TABLE 2-3 Common Murmurs Murmur Type Example Location and Radiation Systolic ejection S1 S 2 Aortic stenosis Second right intercostal space → neck (but may radiate widely) Pulmonic stenosis Second to third left intercostal spaces Pansystolic S1 S 2 Mitral regurgitation Apex → axilla Tricuspid regurgitation Left lower sternal border → right lower sternal border Late systolic S2 S 2 Mitral valve prolapse Apex → axilla Early diastolic S 1S2 Aortic regurgitation Along left side of the sternum Pulmonic regurgitation Upper left side of the sternum Mid-to-late diastolic S 1S2 Mitral stenosis Apex 44 Chapter 3 Frontal and lateral radiographs are rou- tinely used to assess the heart and lungs (Fig. 3-1). The frontal view is usually a posterior–anterior image in which the x-rays are transmitted rom behind (i.e., posterior to) the patient, pass through the body, and are then captured by the lm (or electronic sensor) placed against the anterior chest. This positioning places the heart close to the x-ray recording lm plate so that its image is only minimally distorted, allowing or an accurate assess- ment o size. In the standard lateral view, the patient’s le t side is placed against the lm plate and the x-rays pass through the body rom right to le t. The rontal radio- graph is use ul or assessing the size o the le t ventricle, le t atrial appendage, pulmo- nary artery, aorta, and superior vena cava; the lateral view evaluates right ventricular size, posterior borders o the le t atrium and ventricle, and the anteroposterior diameter o the thorax. Cardiac Silhouette Chest radiographs are use u l to evaluate the size o heart chambers and the pul- monary consequences o cardiac disease. Alterations in chamber size are re lected by changes in the cardiac silhouette. In the rontal view o adults, an enlarged heart is identi ied by a cardiothoracic ratio ( the maximum width o the heart divided by the maximum internal diam- eter o the thoracic cage) o greater than 50% . In certain situations, the cardiac silhouette inaccurately ref ects heart size. For example, an elevated diaphragm, or narrow chest anteroposterior diameter, may cause the silhouette to expand transversely such that the heart appears larger than its actual dimensions. There ore, the chest anteroposterior diameter should be assessed on the lateral view be ore concluding the heart is truly enlarged. The presence o a pericardial e usion around the heart can also widen the cardiac silhouette because f uid and myocardial tissue a ect x-ray penetration similarly. Radiographs can depict dilatation o individual cardiac chambers. O note, concentric ven- tricular hypertrophy alone (i.e., without dilatation) may not result in radiographic abnor- malities, because it generally occurs at the expense o the cavity’s internal volume and produces little or no change in overall cardiac size. Major causes o chamber and great ves- sel dilatation include heart ailure, valvular lesions, abnormal intracardiac and extracardiac communications (shunts), and certain pulmonary disorders. Because dilatation takes time to FIGURE 3-1. Posteroanterior (A and B) and lateral (C and D) chest radiographs of a person without cardiopulmonary disease, illustrating cardiac chambers and valves. AO, aorta; AV, azygos vein; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage; LPA, left pulmonary artery; LV, left ventricle; MPA, main pulmonary artery; MV, mitral valve; RA, right atrium; RPA, right pulmonary artery; RV, right ventricle; SVC, superior vena cava; TV, tricuspid valve. (Reprinted from Come PC, ed. Diagnostic Cardiology: Noninvasive Imaging Techniques. Philadelphia, PA: J.B. Lippincott; 1985, with permission.) MPA AV SVC A RA RVTV IVC LV LA LAA AO B RA TV IVC RV MPA RPA LPA C AO AA D LA MV LV Cardiac Imaging and Catheterization 45 develop, recent lesions, such as acute mitral valve insu ciency, may present without appar- ent cardiac enlargement. The pattern o chamber enlargement may suggest speci c disease entities. For example, dilatation o the le t atrium and right ventricle, accompanied by signs o pulmonary hyperten- sion, suggests mitral stenosis (Fig. 3-2). In contrast, dilatation o the pulmonary artery and right heart chambers, but without enlargement o the le t-sided heart dimensions, can be seen in patients with pulmonary vascular obstruction, in those with increased pulmonary artery blood f ow (e.g., due to an atrial septal de ect), or in those with pulmonary hypertension o diverse causes (Fig. 3-3). Chest radiographs can also detect dilatation o the aorta. Causes o aortic enlargement include aneurysm, dissection, and aortic valve disease (Fig. 3-4). Normal aging and athero- sclerosis may also cause the aorta to become dilated and tortuous. Pulmonary Manifestations of Heart Disease The appearance o the pulmonary vasculature ref ects abnormalities o pulmonary arterial and venous pressures and pulmonary blood f ow. Increased pulmonary venous pressure, as occurs in le t heart ailure, causes increased vascular markings, redistribution o blood f ow rom the bases to the apices o the lungs (termed cepha liza tion o vessels), intersti- tial edema, and alveolar edema (Fig. 3-5). Cephalization appears as an increase in the number or width o vascular markings at the apex (Fig. 3-5A). Interstitial edema occurs as pulmonary congestion progresses, and the connective tissue spaces become thickened with f uid (Fig. 3-5B). Kerley B lines (short horizontal parallel lines at the periphery o the lungs adjacent to the pleura, most o ten at the lung bases) depict f uid in interlobular spaces that results rom interstitial edema (Fig. 3-5C). When f uid accumulates in the air spaces, alveolar orms o pulmonary edema produce opacity radiating rom the hilar FIGURE 3-2. Posteroanterior chest radiograph of a patient with severe mitral stenosis and secondary pulmonary vascular congestion. The radiograph shows a prominent left atrial appendage (arrowheads) with consequent straightening of the left heart border and suggestion of a double density right cardiac border (arrows) produced by the enlarged left atrium. The aortic silhouette is small, which suggests chronic low cardiac output. Radiographic signs of pulmonary vascular congestion include increased caliber of upper-zone pulmonary vessel markings and decreased caliber of lower-zone vessels. 46 Chapter 3 region bilaterally (known as a “butterf y” pattern) and air bronchograms may be seen (Fig. 3-5D). Fluid accumulation in the pleural spaces in heart ailure (i.e., pleural e u- sions) is mani est by blunting o the costophrenic angles (the angle between the ribs and the diaphragm). FIGURE 3-4. Posteroanterior chest radiograph o a patient with aortic stenosis and insu f ciency secondary to a bicuspid aortic valve. In addition to poststenotic dilatation of the ascending aorta (black arrows), the transverse aorta (white arrow) is prominent. FIGURE 3-3. Posteroanterior chest radiograph o a patient with pulmonary hypertension secondary to an atrial septal de ect. Radiographic signs of pulmonary hypertension include pulmonary artery dilatation (black arrows; compare with the appearance of left atrial appendage dilatation in Fig. 3-2) and large central pulmonary arteries (white arrows) associated with small peripheral vessels (a pattern known as peripheral pruning). Cardiac Imaging and Catheterization 49 depict transverse planes o the heart. Several di erent levels are imaged to assess the aortic valve, mitral valve, and le t ventricular wall motion. Apical TTE views are produced when the transducer is placed at the point o maximal api- cal impulse. The apical four-chamber view evaluates the mitral and tricuspid valves as well as the atrial and ventricular chambers, including the motion o the lateral, septal, and apical le t ventricular walls. The apical two-chamber view shows only the le t side o the heart, and it depicts movement o the anterior, in erior, and apical walls. In some patients, such as those with obstructive airways disease, the parasternal and api- cal views do not adequately show cardiac structures because the excessive underlying air attenuates the acoustic signal. In such patients, the subcostal view, in which the transducer is placed in erior to the rib cage, may provide a better ultrasonic window. Doppler imaging depicts blood f ow direction and velocity and identi es regions o vascu- lar turbulence. Additionally, it permits estimation o pressure gradients within the heart and great vessels. Doppler studies are based on the physical principle that waves ref ected rom a moving object undergo a requency shi t according to the moving object’s velocity relative to the source o the waves. Color f ow mapping converts the Doppler signals to a scale o colors that represent direction, velocity, and turbulence o blood f ow in a semiquantitative way. The colors are superimposed on 2D images and show the location o stenotic and regur- gitant valvular lesions and o abnormal communications within the heart and great vessels. For example, Doppler echocardiography in a patient with mitral regurgitation shows a jet o retrograde f ow into the le t atrium during systole (Fig. 3-7). RV Tricuspid va lve Mitra l va lve RA LA LV A B C RV LV Ao LA LV pos te rior wall Inte rventricula r septum Aortic va lve Mitra l va lve LV RV FIGURE 3-6. Transthoracic two- dimensional echocardiographic views. A. Parasternal long-axis view. B. Parasternal short-axis view. Notice that the le t ventricle appears circular in this view, while the right ventricle is crescent shaped. C. Apical our-chamber view. Ao, aorta; LA, le t atrium; LV, le t ventricle; RA, right atrium; RV, right ventricle. (Modif ed rom Sahn DJ, Anderson F. Two-Dimensional Anatomy of the Heart. New York, NY: John Wiley & Sons; 1982.) 50 Chapter 3 Sound requency shi ts are converted by the echo machine into blood f ow velocity measurements by the ollowing relationship: v s c f = ( ) f 2 O cosθ in which v equals the blood f ow velocity (m/ sec); fs, the Doppler re- quency shi t (kHz); c, the velocity o sound in body tissue (m/ sec); fO, the requency o the sound pulse emitted rom the transducer (MHz); and θ, the angle between the transmitted sound pulse and the mean axis o the blood f ow being assessed. Transesophageal echocardiography (TEE) uses a miniaturized transducer mounted at the end o a modi ed endoscope to trans- mit and receive ultrasound waves rom within the esophagus, thus producing very clear images o the neighboring cardiac structures (Fig. 3-8) and much o the thoracic aorta. Modern probes permit multiplanar imaging and Doppler interrogation. TEE is particularly help ul in the assessment o aortic and atrial abnormalities, con- ditions that are less well visualized by conventional transthoracic echo imaging. For example, TEE is more sensitive than transthoracic echo or the detection o thrombus within the le t atrial append- age (Fig. 3-9). The proximity o the esophagus to the heart makes TEE imaging particularly advantageous in patients or whom trans- thoracic echo images are unsatis actory (e.g., those with chronic obstructive lung disease). TEE is also advantageous in the evaluation o patients with pros- thetic heart valves. During standard transthoracic imaging, arti cial mechanical valves ref ect a large portion o ultrasound waves, thus inter ering with visualization o more posterior struc- tures (termed acoustic shadowing). TEE aids visualization in such patients and is there ore the most sensitive noninvasive technique or evaluating perivalvular leaks. In addition, TEE is RV RA RA LV LV LA LA A A. Cross-sectiona l view of aortic va lve RV RV B C B. Long axis view of ca rdiac chambers C. Short axis view of le ft venticle Esophagus R N L FIGURE 3-8. Transesophageal echocardiographic views. LA, le t atrium; LV, le t ventricle; RA, right atrium; RV, right ventricle; N, noncoronary cusp o aortic valve; L, le t coronary cusp o aortic valve; R, right coronary cusp o aortic valve. RV LV RA LA FIGURE 3-7. Doppler color f ow mapping o mitral regurgitation (MR) . The color Doppler image, recorded in systole, is superimposed on an apical our- chamber view. The color Doppler signal lling the le t atrium (LA) indicates retrograde f ow o MR rom the le t ventricle (LV) across the mitral valve (arrow). RA, right atrium; RV, right ventricle. Cardiac Imaging and Catheterization 51 more sensitive than TTE or detecting eatures o endocarditis, such as vegetations and myo- cardial abscesses. TEE is commonly used to evaluate patients with cerebral ischemic events (i.e., strokes) o unexplained etiology, because it can identi y cardiovascular sources o embolism with high sensitivity. These etiologies include intracardiac thrombi or tumors, atherosclerotic debris within the aorta, and valvular vegetations. TEE is also highly sensitive and speci c or the detection o aortic dissection. In the operating room, TEE permits immediate evaluation a ter surgical repair o cardiac lesions. In addition, imaging o ventricular wall motion can identi y periods o myocardial ischemia during surgery. New ultrasound modalities include 3D echocardiography and intracardiac echocardiog- raphy. The spatial reconstructions a orded by 3D echo are o particular bene t in the assess- ment o valvular de ects, intracardiac masses, and congenital mal ormations. Intracardiac echo utilizes a transducer mounted on a catheter to provide imaging during interventional procedures in the cardiac catheterization laboratory. Contrast echocardiography is sometimes used to supplement standard imaging to evalu- ate or abnormal intracardiac shunts. In this technique, o ten called a “bubble study,” an echocardiographic contrast agent (e.g., agitated saline) is rapidly injected into a peripheral vein. Using standard imaging, the contrast can be visualized passing through the cardiac chambers. Normally, there is rapid opaci cation o the right-sided chambers, but because the contrast is ltered out (harmlessly) in the lungs, it does not reach the le t-sided cham- bers. However, in the presence o an intracardiac shunt with abnormal right-to-le t heart blood f ow, or in the presence o an intrapulmonary shunt, bubbles o contrast will appear in the le t-sided chambers as well. Newer perf uorocarbon-based contrast agents have been developed with su ciently small particle size to intentionally pass through the pulmonary circulation. These agents are used to opaci y the le t ventricular cavity and, via the coronary arteries, the myocardium, enabling superior assessment o LV contraction and myocardial per usion. Echocardiographic techniques can identi y valvular lesions, complications o coro- nary artery disease (CAD), septal de ects, intracardiac masses, cardiomyopathy, ven- tricular hypertrophy, pericardial disease, aortic disease, and congenital heart disease. FIGURE 3-9. Echocardiographic imaging of an intracardiac thrombus. A. Transesophageal echocardiographic image demonstrates thrombus within the left atrial appendage. (Courtesy of Scott Streckenbach, MD, Massachusetts General Hospital, Boston, MA.) B. Schematic drawing of same image. LA, left atrium; LAA, left atrial appendage. A LA LAA Thrombus B 54 Chapter 3 Cardiomyopathy Cardiomyopathies are heart muscle disorders that include dilated, hypertrophic, and restric- tive orms (see Chapter 10). Echocardiography can distinguish these and permits assessment o the severity o systolic and diastolic dys unction. For example, Figure 3-10 depicts asym- metrically thickened ventricular walls in a patient with hypertrophic cardiomyopathy. Pericardial Disease Two-dimensional echocardiography can identi y abnormalities in the pericardial cavity (e.g., excessive pericardial f uid and tumor). Tamponade and constrictive pericarditis, the main complications o pericardial disease (see Chapter 14), are associated with particular echocardiographic abnormalities. In tamponade, the increased intrapericardial pressure com- presses the cardiac chambers and results in diastolic “collapse” o the right atrium and right ventricle (Fig. 3-12). Constrictive pericarditis is associated with increased thickness o the pericardial echo, abnormal patterns o diastolic le t ventricular wall motion, alterations in pulmonary and hepatic venous f ow patterns, and exaggerated changes in mitral and tricuspid valve inf ow velocities during respiration. Table 3-2 summarizes the echocardiographic eatures o common cardiac diseases. FIGURE 3-12. Echocardiogram of a patient with a pericardial effusion causing cardiac tamponade. A. Parasternal long-axis image showing a large pericardial effusion (PE) surrounding the heart. This frame was obtained in systole and shows normal appearance of the left (LV) and right (RV) ventricles during that phase. B. Same image as (A) , but this frame was obtained in early diastole and shows collapse of the RV free wall (arrow) due to compression by the effusion. C. Subcostal view, obtained in systole, demonstrating the PE surrounding the right atrium (RA), RV, left atrium (LA), and LV. D. Same image as (C) , obtained during diastole, showing inward collapse of the RA (arrow). A B C D Cardiac Imaging and Catheterization 55 CARDIAC CATHETERIZATION To diagnose many cardiovascular abnormalities, intravascular catheters are inserted to mea- sure pressures in the heart chambers, to determine cardiac output and vascular resistances, and to inject radiopaque material to examine heart structures and blood f ow. In 1929, Werner Forssmann per ormed the rst cardiac catheterization, on himself, thus ushering in the era o invasive cardiology. Much o what is known about the pathophysiology o valvular heart dis- ease and congestive heart ailure comes rom decades o subsequent hemodynamic research in the cardiac catheterization laboratory. Measurement of Pressure Be ore catheterization o an artery or vein, the patient is mildly sedated, and a local anes- thetic is used to numb the skin site o catheter entry. The catheter, attached to a pres- sure transducer outside the body, is then introduced into the appropriate blood vessel. To measure pressures in the right atrium, right ventricle, and pulmonary artery, a catheter is TABLE 3-2 Echocardiography in Common Cardiac Disorders Disorder Findings Valvular lesions Mitral stenosis • Enlarged le t atrium • Thickened mitral valve leaf ets • Decreased movement and separation o mitral valve leaf ets • Decreased mitral valve ori ce Mitral regurgitation • Enlarged le t atrium (i chronic) • Enlarged le t ventricle (i chronic) • Systolic f ow rom le t ventricle into le t atrium by Doppler Aortic stenosis • Thickened aortic valve cusps • Decreased valve ori ce • Increased le t ventricular wall thickness Aortic regurgitation • Enlarged le t ventricle • Abnormalities o aortic valve or aortic root Left ventricular function Myocardial in arction and complications • Abnormal regional ventricular wall motion • Thrombus within le t ventricle • Aneurysm o ventricular wall • Septal rupture (abnormal Doppler f ow) • Papillary muscle rupture Cardiomyopathies Dilated • Enlarged ventricular chamber sizes • Decreased systolic contraction Hypertrophic • Normal or decreased ventricular chamber sizes • Increased ventricular wall thickness • Diastolic dys unction (assessed by Doppler) Restrictive • Normal or decreased ventricular chamber sizes • Increased ventricular wall thickness • Ventricular contractile unction may be abnormal • Diastolic dys unction (assessed by Doppler) • Enlarged atria (o ten markedly so) 56 Chapter 3 inserted into a emoral, brachial, or jugular vein. Pressures in the aorta and le t ventricle are measured via catheters inserted into a radial, brachial, or emoral artery. Once in the blood vessel, the catheter is guided by f uoroscopy (continuous x-ray images) to the area o study, where pressure measurements are made. Figure 3-13 depicts normal intracardiac and intravascular pressures. The measurement o right heart pressures is per ormed with a specialized balloon-tipped catheter (a common version o which is known as the Swan–Ganz catheter) that is advanced through the right side o the heart with the aid o normal blood f ow, and into the pulmonary artery. As it travels through the right side o the heart, recorded pressure measurements iden- ti y the catheter tip’s position (see Box 3-1). RA 2–8 RV 15–30 PA 15–30 2–8 4–12 Lungs PCW 2–10 Aorta LA 2–10 LV 100–140 3–12 60–90 Aorta PCW RA RV LV LAPA 100–140 2–10 2–10 2–8 15–30 2–8 100–140 3–12 100–140 60–90 15–30 4–12 FIGURE 3-13. Diagrams indicating normal pressures in the cardiac chambers and great vessels. The top f gure shows the normal anatomic relationship o the cardiac chambers and great vessels, whereas the f gure on the bottom shows a simplif ed schematic to clari y the pressure relationships. Numbers indicate pressures in mm Hg. LA, le t atrial mean pressure; LV, le t ventricular pressure; PA, pulmonary artery pressure; PCW, pulmonary capillary wedge mean pressure; RA, right atrial mean pressure; RV, right ventricular pressure. BOX 3-1 Intracardiac Pressure Tracings When a catheter is inserted into a systemic vein and advanced into the right side o the heart, each cardiac chamber produces a characteristic pressure curve. It is important to distinguish these recordings rom one another to localize the position o the catheter tip and to derive appropriate physiologic in ormation. ECG 20 10 a c x v a v y P r e s s u r e ( m m H g ) Right ventricle Right a trium Pulmonary a rte ry Time Pulmonary capilla ry wedge Cardiac Imaging and Catheterization 59 (PCW) and closely matches the le t atrial pressure in most individuals. Furthermore, while the mitral valve is open during diastole, the pulmonary venous bed, le t atrium, and le t ventricle normally share the same pressures. Thus, the PCW can be used to estimate the le t ventricular diastolic pressure, a measurement o ventricular preload (see Chapter 9). As a result, measure- ment o PCW may be use ul in managing certain critically ill patients in the intensive care unit. Elevation o the mean PCW is seen in le t-sided heart ailure and in mitral stenosis or regur- gitation. The individual components o the PCW tracing can also become abnormally high. The a wave may be increased in conditions o decreased le t ventricular compliance, such as le t ventricular hypertrophy or acute myocardial ischemia, and in mitral stenosis. The v wave is greater than normal when there is increased le t atrial lling during ventricular contraction, as in mitral regurgitation. Measurement of Blood Flow Cardiac output is measured by either the thermodilution method or the Fick technique. In the thermodilution method, saline o a known temperature is injected rapidly through a catheter side port into the right side o the heart, at a speci c distance rom the distal tip o the cath- eter. The catheter tip, positioned in the pulmonary artery, contains a thermistor that registers the change in temperature induced by the injected saline. The cardiac output is proportional to the rate o the temperature change and is automatically calculated by the equipment. The Fick method relies on the principle that the quantity o oxygen consumed by tissues is related to the amount o O2 content removed rom blood as it f ows through the tissue capillary bed: O2 consumption = O2 content removed × Flow mL O mL O mL blood mL blood2 2 min min Or, in more applicable terms: O2 consumption = AVO2 di erence × Cardiac output where the arteriovenous O2 (AVO2) di erence equals the di erence in oxygen content between the arterial and venous compartments. Total body oxygen consumption can be determined by analyzing expired air rom the lungs, and arterial and venous O2 content is measured in blood samples. By rearranging the terms, the cardiac output can be calculated: Cardiac output O consumption AVO di erence = 2 2 A pulmonary ve in Pulmonary capilla ries Cathe te r tip occludes branch of pulmonary a rte ry Pulmonary arte ry ca the te r This a rea represents “column of blood” be tween ca the ter tip and LA LA PA FIGURE 3-14. Diagram of a pulmonary artery catheter inserted into a branch of the pulmonary artery (PA) . Flow is occluded in the arterial, arteriolar, and capillary vessels beyond the catheter; thus, these vessels act as a conduit that transmits the left atrial (LA) pressure to the catheter tip. 60 Chapter 3 For example, i the arterial blood in a normal adult contains 190 mL o O2 per liter and the venous blood contains 150 mL o O2 per liter, the arteriovenous di erence is 40 mL o O2 per liter. I this patient has a measured O2 consumption o 200 mL/ min, the calculated cardiac output is 5 L/ min. In many orms o heart disease, the cardiac output is lower than normal. In that situa- tion, the total body oxygen consumption does not change signi cantly; however, a greater percentage o O2 is extracted per volume o circulating blood by the metabolizing tissues. The result is a lower-than-normal venous O2 content and there ore an increased AVO2 di - erence. In our example, i the patient’s venous blood O2 content ell to 100 mL/ L, the AVO2 di erence would increase to 90 mL/ L and the calculated cardiac output would be reduced to 2.2 L/ min. Because the normal range o cardiac output varies with a patient’s size, it is common to report the cardiac index, which is equal to the cardiac output divided by the patient’s body sur ace area (normal range o cardiac index = 2.6 – 4.2 L/ min/ m2). Calculation of Vascular Resistance Once pressures and cardiac output have been determined, pulmonary and systemic vas- cular resistances can be calculated, based on the principle that the pressure di erence across a vascular bed is proportional to the product o f ow and resistance. The calcula- tions are: PVR MPAP LAP CO = − × 80 PVR, pulmonary vascular resistance (dynes-sec-cm−5) MPAP, mean pulmonary artery pressure (mm Hg) LAP, mean le t atrial pressure (mm Hg) CO, cardiac output (L/ min) SVR MAP RAP CO = − × 80 SVR, systemic vascular resistance (dynes-sec-cm−5) MAP, mean arterial pressure (mm Hg) RAP, mean right atrial pressure (mm Hg) CO, cardiac output (L/ min) The normal PVR ranges rom 20 to 130 dynes-sec-cm−5. The normal SVR is 700 to 1,600 dynes-sec-cm−5. Contrast Angiography This technique uses radiopaque contrast to visualize regions o the cardiovascular system. A catheter is introduced into an appropriate vessel and guided under f uoroscopy to the site o injection. Following administration o the contrast agent, x-rays are transmitted through the area o interest. A continuous series o x-ray exposures is recorded to produce a motion picture cineangiogram (o ten simply called a “cine” or “angiogram”). Selective injection o contrast into speci c heart chambers can be used to identi y valvular insu ciency, intracardiac shunts, thrombi within the heart, congenital mal ormations, and to measure ventricular contractile unction (Fig. 3-15). However, the noninvasive techniques described in this chapter (e.g., echocardiography) have largely supplanted the need or inva- sive contrast angiography or these purposes. Cardiac Imaging and Catheterization 61 An important and widespread application of contrast injection is coronary artery angiog- raphy, to examine the location and severity of coronary atherosclerotic lesions. To maximize the test’s sensitivity and reproducibility, each patient is imaged in several standard views. When necessary, angioplasty and stent placement can be performed (Figs. 3-16 and 3-17; see Chapter 6). FIGURE 3-16. Cardiac catheterization and stenting of a proximal left anterior descending artery (LAD) stenosis, shown in an anteroposterior cranial projection. A. When contrast agent is injected into the le t main coronary artery (LM), the le t circumf ex artery (LCX) lls normally, but the LAD is almost completely occluded at its origin (white arrow). B. A ter the stenosis is success ully stented, the LAD and its branches ll robustly. A LM LAD B LM LAD LCX Diagonal branch Septal perforators FIGURE 3-15. Left ventriculogram, in diastole (A) and systole (B) in the right anterior oblique projection, from a patient with normal ventricular contractility. A catheter (black arrow) is used to inject contrast into the le t ventricle (LV). The catheter can also be seen in the descending aorta (white arrowhead). AO, aortic root. A B 64 Chapter 3 myocardial tissue. Conversely, myocardial regions that are scarred (by previous in arction) or have reduced per usion during exercise (i.e., transient myocardial ischemia) do not accumu- late as much thallium as normal heart muscle. Consequently, these areas will appear on the thallium scan as light or “cold” spots. When evaluating or myocardial ischemia, an initial set o images is taken right a ter exer- cise and 201Tl injection. Well-per used myocardium will take up more tracer than ischemic or in arcted myocardium at this time. Delayed images are acquired several hours later, because 201Tl accumulation does not remain xed in myocytes. Rather, continuous redistribution o the isotope occurs across the cell membrane. A ter 3 to 4 hours o redistribution, when additional images are obtained, all viable myocytes will have equal concentrations o 201Tl. Consequently, any uptake abnormalities on the initial exercise scan that were caused by myocardial ischemia will have resolved (i.e., lled in) on the delayed scan (and are there ore termed “reversible” de ects), and those representing infarcted or scarred myocardium will persist as cold spots (“ xed” de ects). O note, some myocardial segments that demonstrate persistent 201Tl de ects on both stress and redistribution imaging are alsely characterized as nonviable, scarred tissue. Sometimes, these areas represent ischemic, noncontractile, but metabolically, active areas that have the potential to regain unction i an adequate blood supply is restored. For example, such areas may represent hibernating myocardium, segments that demonstrate diminished contractile unction owing to chronic reduction o coronary blood f ow (see Chapter 6). This viable state (in which the a ected cells can be predicted to regain unction ollowing coronary revascularization) can o ten be di erentiated rom irreversibly scarred myocardium by repeat imaging at rest a ter the injection o additional 201Tl to enhance uptake by viable cells. 99mTc-sestamibi (commonly re erred to as MIBI) is an example o a widely used 99mTc- labeled compound. This agent is a large lipophilic molecule that, like thallium, is taken up in the myocardium in proportion to blood f ow. The uptake mechanism di ers in that the com- pound crosses the myocyte membrane passively, driven by the negative membrane potential. Once inside the cell, it urther accumulates in mitochondria, driven by that organelle’s even more negative membrane potential. The myocardial distribution o MIBI ref ects per usion at the moment o injection, and in contrast to thallium, it remains xed intracellularly, that is, it redistributes only minimally over time. Consequently, per orming a MIBI procedure is more f exible, as images can be obtained up to 4 to 6 hours a ter injection and repeated as neces- sary. A MIBI study is usually per ormed as a 1-day protocol in which an initial injection o a small tracer dose and imaging are per ormed at rest. Later, a larger tracer dose is given a ter exercise, and imaging is repeated. Stress nuclear imaging studies with either 201Tl- or 99mTc-labeled compounds have greater sensitivity and speci city than standard exercise electrocardiography or the detec- tion o ischemia but are more expensive and should be ordered judiciously. Nuclear imag- ing is particularly appropriate or patients with certain baseline electrocardiogram (ECG) abnormalities o the ST segment that preclude accurate interpretation o a standard exer- cise test. Examples include patients with electronic pacemaker rhythms, those with le t bundle branch block, those with ST abnormalities due to le t ventricular hypertrophy, and those who take certain medications that alter the ST segment, such as digoxin. Nuclear scans also provide more accurate anatomic localization o the ischemic segment(s) and quanti cation o the extent o ischemia compared with standard exercise testing. In addi- tion, electronic synchronizing (gating) o nuclear images to the ECG cycle permits wall motion analysis. Patients with orthopedic or neurologic conditions, as well as those with severe physical deconditioning or chronic lung disease, may be unable to per orm an adequate exercise test on a treadmill or bicycle. In such patients, stress images can be obtained instead by adminis- tering pharmacologic agents, such as adenosine or dipyridamole. These agents induce di use Cardiac Imaging and Catheterization 65 coronary vasodilation, augmenting blood f ow to myocardium per used by healthy coronary arteries. Since ischemic regions are already maximally dilated (because o local metabolite accumulation), the drug-induced vasodilation causes a “steal” phenomenon, reducing isotope uptake in regions distal to signi cant coronary stenoses (see Chapter 6). Alternatively, dobu- tamine (see Chapter 17) can be in used intravenously to increase myocardial oxygen demand as a means to assess or ischemia. Radionuclide Ventriculography Radionuclide ventriculography (RVG, also known as blood pool imaging) is occasionally used to analyze right and le t ventricular unction. A radioisotope (usually 99mTc) is bound to red blood cells or to human serum albumin and then injected as a bolus. Nuclear images are obtained at xed time intervals as the labeled material passes through the heart and great vessels. Multiple images are displayed sequentially to produce a dynamic picture o blood f ow. Calculations, such as determination o the ejection raction, are based on the di erence between radioactive counts present in the ventricle at the end o diastole and at the end o systole. There ore, measurements are largely independent o any assumptions o ventricular geometry and are highly reproducible. Studies suggest that RVG and echocardiography pro- vide similar le t ventricular ejection raction values. RVG has been used historically to assess baseline cardiac unction in patients scheduled to undergo potentially cardiotoxic chemotherapy (e.g., doxorubicin) and to ollow cardiac unc- tion over time in such patients. However, echocardiography is usually easier to per orm, does not expose the patient to ionizing radiation, and now commonly serves this role. Assessment of Myocardial Metabolism Positron emission tomography (PET) is a specialized nuclear imaging technique used to assess myocardial per usion and viability. PET imaging employs positron-emitting isotopes (e.g., rubidium-82, nitrogen-13, and f uorine-18) attached to metabolic or f ow tracers. Sensitive detectors measure positron emission rom the tracer molecules. Myocardial perfusion is commonly assessed using nitrogen-13–labeled ammonia or rubid- ium-82. Both are taken up by myocytes in proportion to blood f ow. Myocardial viability can be determined by PET by studying glucose utilization in myocardial tissue. In normal myocardium under asting conditions, glucose is used or approximately 20% o energy pro- duction, with ree atty acids providing the remaining 80% . In ischemic conditions, however, metabolism shi ts toward glucose use, and the more ischemic the myocardial tissue, the stronger the reliance on glucose. Fluoro-18 deoxyglucose (18FDG), created by substituting f uorine-18 or hydrogen in 2-deoxyglucose, is used to study glucose uptake. This substance competes with glucose both or transport into myocytes and or subsequent phosphoryla- tion. Unlike glucose, however, 18FDG is not metabolized and becomes trapped within the myocyte. Combined evaluation o per usion and 18FDG metabolism allows assessment o both regional blood f ow and glucose uptake, respectively. PET scanning thus helps determine whether areas o ventricular contractile dys unction with decreased f ow represent irrevers- ibly damaged scar tissue or whether the region is still viable (e.g., hibernating myocardium). In scar tissue, both blood f ow to the a ected area and 18FDG uptake are decreased. Because the myocytes in this region are permanently damaged, such tissue is not likely to bene t rom revascularization. Hibernating myocardium, in contrast, shows decreased blood f ow but normal or elevated 18FDG uptake. Such tissue may bene t rom revascularization proce- dures (see Chapter 6). Table 3-5 summarizes the radionuclide imaging abnormalities associated with common cardiac conditions. 66 Chapter 3 COMPUTED TOMOGRAPHY CT uses thin x-ray beams to obtain a large series o axial plane images. An x-ray tube is pro- grammed to rotate around the body, and the generated beams are partially absorbed by body tissues. The remaining beams emerge and are captured by electronic detectors, which relay in ormation to a computer or image composition. CT scanning typically requires administra- tion o an intravenous contrast agent to distinguish intravascular contents (i.e., blood) rom neighboring so t tissue structures (e.g., myocardium). Applications o CT in cardiac imaging include assessment o the great vessels, peri- cardium, myocardium, and coronary arteries. CT is used to diagnose aortic dissections and aneurysms (Fig. 3-19). It can identi y abnormal pericardial f uid, thickening, and calci cation. Myocardial abnormalities, such as regional hypertrophy or ventricular aneu- rysms, and intracardiac thrombus ormation can be distinctly visualized by CT. A limitation o conventional CT techniques is the arti act generated by patient motion (i.e., breathing) during image acquisition. Modern spiral CT (also called helical CT) imaging allows more rapid image acquisition, o ten during a single breath-hold, at relatively lower radiation doses than conventional CT. Spiral CT is particularly important in the diagnosis o pulmo- nary embolism. When an intravenous iodine-based contrast agent is administered, emboli create the appearance o “ lling de ects” in otherwise contrast-enhanced pulmonary vessels (Fig. 3-20). Electron beam computed tomography (EBCT) uses a direct electron beam to acquire images in a matter o milliseconds. Rapid succession o images depicts cardiac structures at multiple times during a single cardiac cycle. Displaying these images in a cine ormat can provide estimates o le t ventricular volumes and ejection raction. Capable o detecting coro- nary artery calci cation, EBCT has been used primarily to screen or CAD. Because calci ed coronary artery plaques have a radiodensity similar to that o bone, they appear attenuated (white) on CT. The Agatston score, a measure o total coronary artery calcium, correlates well with atherosclerotic plaque burden and predicts the risk o coronary events, independently o other cardiac risk actors. Newer CT technology can characterize atherosclerotic stenoses in great detail. Current multidetector row CT scanners acquire as many as 320 anatomic sections with each rota- tion, providing excellent spatial resolution. Administration o intravenous contrast and computer re ormatting allows visualization o the arterial lumen and regions o coronary TABLE 3-5 Nuclear Imaging in Cardiac Disorders Disorder Findings Myocardial ischemia Stress-delayed reinjection 201Tl • Low uptake during stress with complete or partial ll-in with delayed or reinjection images Rest–stress 99mTc-labeled compounds • Normal uptake at rest with decreased uptake during stress PET (N-13 ammonia/ 18FDG) • Decreased f ow with normal or increased 18FDG uptake during stress Myocardial infarction Stress-delayed reinjection 201Tl • Low uptake during stress and low uptake a ter reinjection Rest–stress 99mTc-labeled compounds • Low uptake in rest and stress images PET (N-13 ammonia/ 18FDG) • Decreased f ow and decreased 18FDG uptake at rest Hibernating myocardium Rest-delayed 201Tl • Complete or partial ll-in o de ects a ter reinjection PET (N-13 ammonia/ 18FDG) • Decreased f ow and normal or increased 18FDG uptake at rest 18FDG, f uoro-18 deoxyglucose; N-13, nitrogen-13; PET, positron emission tomography; 99mTc, technetium-99m; 201Tl, thallium-201. Cardiac Imaging and Catheterization 69 cardiomyopathies, and neoplastic disease (Fig. 3-23). ECG-gated and cine MRI techniques capture images at discrete times in the cardiac cycle, allowing or the evaluation o valvular and ventricular unction. Two applications o CMR deserve special mention. Coronary magnetic resonance angi- ography (coronary MRA) is a noninvasive, contrast- ree angiographic imaging modality. Laminar blood f ow appears as bright signal intensity, whereas turbulent blood f ow, at the site o stenosis, results in less bright or absent signal intensity. This technique has shown high sensitivity and accuracy or the detection o important CAD in the le t main coronary artery and in the proximal and midportions o the three major coronary vessels. Coronary MRA is also use ul in delineating coronary artery congenital anomalies. In contrast-enhanced MRI, a gadolinium-based agent is administered intravenously to identi y in arcted (irreversibly damaged) myocardium and to di erentiate it rom impaired (but viable) muscle segments. This technique is based on the act that gadolinium is excluded rom viable cells with intact cell membranes but can permeate and concentrate in in arcted zones, producing “hyperenhancement” on the image (Fig. 3-24). Owing to the high spatial resolution o this technique, the transmural extent o myocardial scar can be depicted, and the pattern o in arcting tissue can be di erentiated rom that o acute myocarditis, a condition that may present with similar clinical eatures. The use o late-enhancing gadolinium imaging also allows or the identi cation o poorly contractile “hibernating” myocardium (described in Chapter 6), tissue that is chronically ischemic, but would be expected to recover unction i adequate blood per usion is restored. FIGURE 3-22. Cardiac magnetic resonance images of a normal person. A. Three-chamber long-axis view of the heart in diastole and systole showing the left ventricle (LV), right ventricle (RV), and left atrium (LA). The mitral valve (MV), aortic valve (AV), ascending aorta (AAO), and descending aorta (DA) are also imaged. B. Midventricular short-axis view demonstrating the LV, RV, and left ventricular papillary muscles (PMs). PW, posterior wall; S, septum. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.) A B 70 Chapter 3 FIGURE 3-23. Magnetic resonance imaging of an intracardiac mass. Both images are apical four-chamber views. A. Before a gadolinium-based contrast agent is administered, an abnormal left atrial mass (indicated by the oval) demonstrates diminished signal relative to the surrounding tissue. In this respect, it resembles a nonvascular thrombus. B. After contrast injection, the mass enhances similar to the surrounding tissue, indicating that it is vascularized. Biopsy revealed a spindle cell carcinoma. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.) L V RV RA LA A LA RA RV LV B FIGURE 3-24. Gadolinium-enhanced magnetic resonance images demonstrating a region of nonviable myocardium. Both images are short-axis views. A. Imaging before administration of gadolinium demonstrates thinning of the anterior and anteroseptal myocardium (blue arrow) suggestive of infarcted tissue (compare to short-axis view of healthy myocardial wall in Fig. 3.22-B). B. After contrast injection, the subendocardial regions of the anterior and anteroseptal segments of the left ventricle selectively enhance (white arrows), indicating that scar tissue is present. Because more than half the thickness of the ventricular wall is scarred, coronary revascularization would have a low likelihood of improving contractile function of these myocardial segments. LV, left ventricle; RV, right ventricle. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.) LV RV A RV LV B Cardiac Imaging and Catheterization 71 INTEGRATION This chapter has presented an overview o imaging and catheterization techniques avail- able to assess cardiac structure and unction. Many o these tools are expensive and yield similar in ormation. For example, estimates o ventricular contractile unction can be made by echocardiography, nuclear imaging, contrast angiography, gated CT, or MRI. Myocardial viability can be assessed using nuclear imaging studies, gadolinium MRI, or dobutamine echocardiography. Determining the single best test or any given patient depends on a number o ac- tors. One is the ease by which images may be obtained. In a critically ill patient, bed- side echocardiography provides a readily acquired measure o le t ventricular systolic unction. Conversely, obtaining similar in ormation rom a nuclear or magnetic reso- nance study would require a trip to the respective scanner. Other actors to consider include the magnitude o radiation exposure and the invasiveness o a given imaging technique. Expense, available equipment, and institutional expertise also play roles in selecting an imaging approach. When used appropriately, each o these tools can pro- vide important in ormation to guide the diagnosis and management o cardiovascular disorders. SUMMARY • Imaging and catheterization techniques provide important in ormation to guide the diag- nosis and management o cardiovascular disorders; key uses are summarized here and in Table 3-6. • Chest radiography can detect chamber dilatation and visualize pulmonary signs o heart ailure. • Transthoracic echocardiography can assess ventricular systolic and diastolic dys unc- tion, identi y valvular abnormalities and vegetations, diagnose consequences o myo- cardial in arction, and demonstrate pericardial and congenital abnormalities. • Transesophageal echocardiography is used to visualize intracardiac thrombus, evaluate pros- thetic valve dys unction, identi y valvular vegetations and myocardial abscess in endocardi- tis, and diagnose aortic dissection. • Diagnostic cardiac catheterization is the “gold standard” to assess intracardiac pressures and to identi y and grade coronary artery stenoses. • Nuclear imaging can diagnose myocardial ischemia and distinguish viable myocardium rom scar tissue. • Positron emission tomography is used to assess or ischemia and can distinguish viable myo- cardium rom scar tissue. • Computed tomography is sensitive or the diagnosis o aortic dissection and pulmonary embolism, can assess pericardial conditions and detect coronary artery calcif cation and stenoses. • Magnetic resonance imaging demonstrates great detail o so t tissue structures and is used to def ne the specif c conditions listed in Table 3-6. Ack n owled gm en t s The authors are grate ul to Marcelo Di Carli, MD; Raymond Y. Kwong, MD; and Gillian Lieberman, MD or their help ul suggestions. Contributors to previous editions o this chapter were Henry Jung, MD; Ken Young Lin, MD; Nicole Martin, MD; Deborah Bucino, MD; Sharon Horesh, MD; Shona Pendse, MD; Albert S. Tu, MD; and Patrick Yachimski, MD. 74 C h a p t e r O u t l i n e Electrical Measurement—Single- Cell Model Electrocardiographic Lead Reference System Sequence of Normal Cardiac Activation Interpretation of the Electrocardiogram Calibration Heart Rhythm Heart Rate Intervals (PR, QRS, QT) Mean QRS Axis Abnormalities o the P Wave Abnormalities o the QRS Complex ST-Segment and T-Wave Abnormalities Cardiac contraction relies on the organized f ow o elec-trical impulses through the heart. The electrocardiogram (ECG) is an easily obtained recording o that activity and pro- vides a wealth o in ormation about cardiac structure and unc- tion. This chapter presents the electrical basis o the ECG in health and disease and leads the reader through the basics o interpretation. To practice using these principles and to become skill ul at interpreting ECG tracings o your patients, you should also consult one o the complete electrocardiographic manuals listed at the end o this chapter. ELECTRICAL MEASUREMENT—SINGLE- CELL MODEL This section begins by observing the propagation of an electrical impulse along a single cardiac muscle cell, illus- trated in Figure 4-1. On the right side of the diagram, a voltmeter records the electrical potential at the cell’s sur- face on graph paper. In the resting state, the cell is polar- ized; that is, the entire outside of the cell is electrically positive with respect to the inside, because of the ionic distribution across the cell membrane, as described in Chapter 1. In this resting state, the voltmeter electrodes, which are placed on opposite outside surfaces of the cell, do not record any electrical activity, because there is no electrical potential difference between them (the myocyte surface is homogeneously charged). This equilibrium is disturbed, however, when the cell is stimulated (see Fig. 4-1B). During the action potential, cat- ions rush across the sarcolemma into the cell and the polar- ity at the stimulated region transiently reverses such that the outside becomes negatively charged with respect to the inside; that is, the region depolarizes. At that moment, an electrical potential is created on the cell surface between the The Electrocardiogram David B. Fischer Leonard S. Lilly 4 The Electrocardiogram 75 depolarized area (negatively charged sur ace) and the still-polarized (positively charged sur ace) portions o the cell. As a result, an electrical current begins to f ow between these two regions. By convention, the direction o an electrical current is said to f ow rom areas that are nega- tively charged to those that are positively charged. When a depolarization current is directed toward the (+ ) electrode o the voltmeter, an upward def ection is recorded. Conversely, i it is directed away rom the (+ ) electrode, a downward def ection is recorded. Because the depolarization current in this example proceeds rom le t to right—that is, toward the (+ ) electrode—an upward def ection is recorded by the voltmeter. As the wave o depolarization propagates rightward along the cell, additional electrical orces directed toward the (+ ) elec- trode record an even greater upward def ection (see Fig. 4-1C). Once the cell has become ully depolarized (see Fig. 4-1D), its outside is completely negatively charged with respect to the inside, the opposite o the initial resting condition. However, because the sur ace charge is homogeneous once again, the external electrodes measure a potential di erence o zero and the voltmeter records a neutral “f at line” at this time. Note that in Figure 4-1E, i the voltmeter electrode positions had been reversed, such that the (+ ) pole was placed to the left o the cell, then as the wave o depolarization proceeds toward the right, the current would be directed away rom the (+ ) electrode and the recorded def ection would be downward. This relationship should be kept in mind when the polarity o ECG leads is described below. Depolarization initiates myocyte contraction and is then ollowed by repolarization, the process by which the cellular charges return to the resting state. In Figure 4-2, as the le t side + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – CARDIAC MUSCLE CELL Voltme te r (–) (+) (+) (–) + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – (+) A B Depolariza tion Current + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – (+) C + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – (+) D + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – E FIGURE 4-1. Depolarization of a single cardiac muscle cell. A. In the resting state, the sur ace o the cell is positively charged relative to the inside. Because the sur ace is homogeneously charged, the voltmeter electrodes outside the cell do not record any electrical potential di erence (“f at line” recording). B. Stimulation o the cell initiates depolarization (blue shaded area); the outside o the depolarized region becomes negatively charged relative to the inside. Because the current o depolarization is directed toward the (+ ) electrode o the voltmeter, an upward def ection is recorded. C. Depolarization spreads, creating a greater upward def ection by the recording electrode. D. The cell has become ully depolarized. The sur ace o the cell is now completely negatively charged compared with the inside. Because the sur ace is again homogeneously charged, a f at line is recorded by the voltmeter. E. Notice that i the position o the voltmeter electrodes had been reversed, the electrical current would have been directed away rom the (+ ) electrode, causing the def ection to be downward. 76 Chapter 4 o the cardiac muscle cell in our example begins to repolarize, its sur ace charge becomes positive once again. An electrical potential is there ore generated, and current ows rom the still negatively charged sur ace toward the positively charged region. Since this current is directed away rom the voltmeter’s (+ ) electrode, a downward de ection is recorded, opposite to that which was observed during the process o depolarization. Repolarization is a slower process than depolarization, so the inscribed de ection o repo- larization is usually wider and o lower magnitude. Once the cell has returned to the resting state, the sur ace charges are once again homogeneous and no urther electrical potential is detected, resulting in a neutral at line on the voltmeter recording (Fig. 4-2C). The depolarization and repolarization o a single cardiac muscle cell have been considered here. As a wave o depolarization spreads through the entire heart, each cell generates electri- cal orces, and it is the sum o these orces, measured at the skin’s sur ace, that is recorded by the ECG machine. It is important to note that in the intact heart, the sequence by which regions repolarize is actually opposite to that o their depolarization. This occurs because myocardial action potential durations are more prolonged in cells near the inner endocardium (the f rst cells stimulated by Purkinje f bers) than in myocytes near the outer epicardium (the last cells to depolarize). Thus, the cells close to the endocardium are the f rst to depolarize but are the last to repolarize. As a result, the direction o repolarization recorded by the ECG machine is usually the inverse o what was presented in the single-cell example in Figure 4-2. That is, unlike the single-cell model, the electrical de ections o depolarization and repolariza- tion in the intact heart are usually oriented in the same direction on the ECG tracing (see Fig. 4-2D). The direction and magnitude o the de ections on an ECG recording depend on how the generated electrical orces are aligned to a set o specif c re erence axes, known as ECG leads, as described in the next section. + – + – + – + – + – + – + – + – + – + – + – + – A + – + – + – + – + – + – + – + – + – + – + – + – B + – + – + – + – C D + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – + – Direc tion of Current Depolarized portion Repolarized portion (+) (+) (+) FIGURE 4-2. Sequence of repolarization of a single cardiac muscle cell. A. As repolarization commences, the sur ace o the cell at that site becomes positively charged and a current is generated rom the still negatively charged sur ace areas to the repolarized region (blue arrows). Because the current is directed away rom the (+ ) electrode o the voltmeter, a downward de ection is recorded. B. Repolarization progresses. C. Repolarization has completed, and the outside sur ace o the cell is once again homogeneously charged, so that no urther electrical potential is detected ( at line once again). D. Sequence o cardiac depolarization and repolarization as measured by an ECG machine at the skin sur ace. As described in the text, repolarization actually proceeds in the direction opposite to that o depolarization in the intact heart, such that the de ections o repolarization are inverted compared to the schematics presented in parts A–C o this f gure. There ore, the def ections o depolarization and repolarization o the normal heart are oriented in the same direction. Note that the wave o repolarization is more prolonged and o lower amplitude than that o depolarization. The Electrocardiogram 79 By overlaying these six limb leads, an axial re erence system is established (Fig. 4-5). In the f gure, each lead is presented with its (+ ) pole designated by an arrow- head and the (− ) aspect by dashed lines. Note that each 30-degree sector o the circle alls along the (+ ) or (− ) pole o one o the standard six ECG limb leads. Also note that the (+ ) pole o lead I points to 0 degrees and that, by convention, measurement o the angles proceeds clockwise rom 0 degrees as +30 degrees, + 60 degrees, and so orth. The complete ECG record- ing provides a simultaneous “snapshot” o the heart’s electrical activity, taken rom the perspective o each o these lead re erence axes. Figure 4-6 demonstrates how the magnitude and direction o electrical activity are represented by the ECG recording in each lead. This f gure should be studied until the ollowing our points are clear: –90° –60° –30° –120° +30° 0° +60° +90° +120° +150° +180° –150° aVR aVL I IIIII aVF FIGURE 4-5. The axial reference system is created by combining the six limb leads shown in Figure 4-4. Each lead has a (+ ) region indicated by the arrowhead and a (− ) region indicated by the dashed line. Lead I Lead ILead I Lead I ECG (–) (+) (–) (–) (+)(–) (+)(+) BA DC FIGURE 4-6. Relationship of the magnitude and direction of electrical activity to the ECG lead. This example uses lead I, but the same principles apply to all leads. A. The electrical vector is oriented parallel to lead I and is directed toward the (+ ) electrode; there ore, a tall upward def ection is recorded by the lead. B. The vector is still oriented toward the (+ ) electrode o lead I but not parallel to the lead, so that only a component o the orce is recorded. Thus, the recorded def ection is still upward but o lower amplitude compared with that shown in (A) . C. The electrical vector is perpendicular to lead I so that no def ection is generated. D. The vector is directed toward the (− ) region o lead I, causing the ECG to record a downward def ection. 80 Chapter 4 1. An electrical orce directed toward the (+ ) pole o a lead results in an upward de ection on the ECG recording o that lead. 2. Forces that head away rom the (+ ) electrode result in a downward de ection in that lead. 3. The magnitude o the de ection, either upward or downward, re ects how parallel the electrical orce is to the axis o the lead being examined. The more parallel the electrical orce is to the lead, the greater the magnitude o the de ection. 4. An electrical orce directed perpendicular to an electrocardiographic lead does not register any activity by that lead (a at line on the recording). The six standard limb leads examine the electrical orces in the rontal plane o the body. However, because electrical activity travels in three dimensions, recordings rom a perpen- dicular plane are also essential (Fig. 4-7). This is accomplished by the use o the six elec- trodes placed on the anterior and le t lateral aspect o the chest (see Fig. 4-3B), creating the chest (also termed “precordial”) leads. The orientation o these leads around the heart in the cross-sectional plane is shown in Figure 4-7B. These are unipolar leads and, as with the uni- polar limb leads, electrical orces directed toward these individual (+ ) electrodes result in an upward de ection on the recording o that lead, and orces heading away record a downward de ection. A complete ECG records samples rom each o the six limb leads and each o the six chest leads in a standard order, examples o which are presented later in this chapter (see Figs. 4-28 to 4-36). SEQUENCE OF NORMAL CARDIAC ACTIVATION Conduction o electrical impulses through the heart is an orderly process. The normal beat begins at the sinoatrial node, located at the junction o the right atrium and the superior vena cava (Fig. 4-8). The wave o depolarization spreads rapidly through the right and le t atria and then reaches the atrioventricular (AV) node, where it encounters an expected delay. The impulse then travels rapidly through the bundle o His and into the right and le t bundle branches. The latter divide into the Purkinje f bers, which radiate toward the myocardial f bers, stimulating them to depolarize and contract. Each heartbeat is represented on the ECG by three major de ections that record the sequence o electrical propagation (see Fig. 4-8B). The P wave represents depolarization o the atria. Following the P wave, the tracing returns to its baseline as a result o the conduc- tion delay at the AV node. The second de ection o the ECG, the QRS complex, represents depolarization o the ventricular muscle cells. A ter the QRS complex, the tracing returns to baseline once again, and a ter a brie delay, repolarization o the ventricular cells is sig- naled by the T wave. Occasionally, an additional small de ection ollows the T wave (the U wave), which is believed to represent late phases o ventricular repolarization. V6 V5 V4 V3 V2V1 LV RV BA FIGURE 4-7. The chest (precordial) leads. A. The cross-sectional plane of the chest. B. Arrangement of the six chest electrodes shown in the cross-sectional plane. Note that the right ventricle is anterior to the left ventricle. The Electrocardiogram 81 The QRS complex may take one o several shapes but can always be subdivided into indi- vidual components (Fig. 4-9). I the f rst de ection o the QRS complex is downward, it is known as a Q wave. However, i the initial de ection is upward, then that particular complex does not have a Q wave. The R wave is def ned as the f rst upward de ection, whether or not a Q wave is present. Any downward de ection following the R wave is known as an S wave. Figure 4-9 demonstrates several common variations o the QRS complex. In certain pathologic states, such as bundle branch blocks, additional de ections may be inscribed, as shown in the f gure. Please study Figure 4-9 until you can conf dently di erentiate a Q rom an S wave. Figure 4-10 illustrates the course o normal ventricular depolarization as it is recorded in the rontal plane by two o the ECG leads: aVF and aVL. The recording in aVF represents electrical activity rom the perspective o the in erior (i.e., underside) aspect o the heart, A B AV node Bundle of His Left bundle branch Right bundle branch SA node 1 2 3 QRS TP 1 2 3 4 4 4 FIGURE 4-8. Cardiac conduction pathway. A. The electrical impulse begins at the sinoatrial (SA) node (1) then traverses the atria (2). A ter a delay at the AV node (3), conduction continues through the bundle o His and into the right and le t bundle branches (4). The latter divide into Purkinje f bers, which stimulate contraction o the myocardial cells. B. Corresponding wave orms on the ECG recording: (1) the SA node discharges (too small to generate any de ection on ECG), (2) P wave inscribed by depolarization o the atria, (3) delay at the AV node, and (4) depolarization o the ventricles (QRS complex). The T wave represents ventricular repolarization. A B C D E FIGURE 4-9. Examples of QRS complexes. A. The f rst de ection is downward (Q wave), ollowed by an upward de ection (R wave), and then another downward wave (S wave). B. Because the f rst de ection is upward, this complex does not have a Q wave; rather, the downward de ection after the R wave is an S wave. C. A QRS complex without downward de ections lacks Q and S waves. D. QRS composed o only a downward de ection; this is simply a Q wave but is o ten re erred to as a QS complex. E. A second upward de ection (seen in bundle branch blocks) is re erred to as R′. 84 Chapter 4 abnormalities. Here is a commonly followed sequence of analysis, followed by a descrip- tion of each: 1. Check voltage calibration 2. Heart rhythm 3. Heart rate 4. Intervals (PR, QRS, QT) 5. Mean QRS axis 6. Abnormalities of the P wave 7. Abnormalities of the QRS (hypertrophy, bundle branch block, infarction) 8. Abnormalities of the ST segment and T wave A V1 E V6 B V1 V6 C V1 V6 D V1 V6 V1 V6 V5 V4 V3 V2 LV LV RV RV FIGURE 4-11. Sequence of depolarization in the transverse (horizontal) plane recorded by the chest (precordial) leads. A–D. Depolarization begins at the le t side o the septum. The electrical vector then progresses posteriorly toward the thick-walled le t ventricle. Thus, V1, which is an anterior lead, records an initial upward def ection ollowed by a downward wave, whereas V6, a posterior lead, inscribes the opposite. E. In the normal pattern o the QRS rom V1 to V6, the R wave becomes progressively taller and the S wave less deep. The Electrocardiogram 85 Calibration ECG machines routinely inscribe a 1.0-mV vertical signal at the beginning or end o each 12-lead tracing to document the voltage calibration o the machine. In the normal case, each 1-mm vertical box on the ECG paper represents 0.1 mV, so that the calibration signal records a 10-mm de ection (e.g., as shown later in Fig. 4-28). However, in patients with markedly increased voltage o the QRS complex (e.g., some patients with le t ventricular hypertrophy or bundle branch blocks), the very large de ections do not f t on the standard tracing. To acili- tate interpretation in such a case, the recording is o ten purposely made at hal the standard voltage (i.e., each 1-mm box = 0.2 mV), and this is indicated on the ECG tracing by a change in the height o the 1.0-mV calibration signal (at hal the standard voltage, the signal would be 5 mm tall). It is important to check the height o the calibration signal on each ECG to ensure that the voltage criteria used to def ne specif c abnormalities are applicable. Heart Rhythm The normal cardiac rhythm, initiated by depolarization o the sinus node, is known as sinus rhythm. An ECG tracing shows sinus rhythm i the ollowing criteria are met: (1) each P wave is ollowed by a QRS; (2) each QRS is preceded by a P wave; (3) the P wave is upright in leads I, II, and III; and (4) the PR interval is greater than 0.12 seconds (three small boxes). I the heart rate in sinus rhythm is between 60 and 100 bpm, then normal sinus rhythm is present. I less than 60 bpm, the rhythm is sinus bradycardia; i greater than 100 bpm, the rhythm is sinus tachycardia. Other abnormal rhythms (termed arrhythmias or dysrhythmias) are described in Chapters 11 and 12. Paper Speed: 25 mm/sec PR QT 5 mm = 0.5 mV 1 mm = 0.1 mV 5 mm = 0.2 sec (1 mm = 1 small box = 0.04 sec) QRS FIGURE 4-12. Enlarged view of an ECG strip. A standard ECG is recorded at 25 mm/ sec, so that each 1 mm on the horizontal axis represents 0.04 seconds. Each 1 mm on the vertical axis represents 0.1 mV. Measurements in this example are as follows: PR interval (from the beginning of the P wave to the beginning of the QRS) = 4 small boxes = 0.16 seconds; QRS duration (from the beginning to the end of the QRS complex) = 1.75 small boxes = 0.07 seconds; and QT interval (from the beginning of the QRS to the end of the T wave) = 8 small boxes = 0.32 seconds. The corrected QT interval QT R R = − . Because the R–R interval = 15 small boxes (0.6 seconds), the corrected QT interval 0.32 0.6 0.41 seconds= = . 86 Chapter 4 Heart Rate The standard ECG recording paper speed is 25 mm/ sec. There ore, Heart rate mm/ sec 60 sec/ min Number o mm betw beats per minute( ) = ×25 een beats or more simply, as shown in Figure 4-13: Heart rate Number o small boxes between two consecutive beat = 1 500, s It is rarely necessary, however, to determine the exact heart rate, and a more rapid determi- nation can be made with just a bit o memorization. Simply “count o ” the number o large boxes between two consecutive QRS complexes, using the sequence 300 150 100 75 60 50— — — — — which corresponds to the heart rate in beats per minute, as illustrated in Figure 4-13 (method 2). When the rhythm is irregular, these estimates cannot be easily applied, so the heart rate in such a case may be better approximated by counting the number o complexes during 6 seconds o the recording and multiplying that number by 10. ECG paper usually has time markers, spaced 3 seconds apart, printed at the top or bottom o the tracing that acilitates this measurement (see Fig. 4-13, method 3). Intervals (PR, QRS, QT) The PR interval, QRS interval, and QT interval are measured as demonstrated in Figure 4-12. For each o these, it is appropriate to take the measurement in the lead in which the interval is the longest in duration (the intervals can vary a bit in each lead). The PR interval is mea- sured rom the onset o the P wave to the onset o the QRS. The QRS interval is measured rom the beginning to the end o the QRS complex. The QT interval is measured rom the beginning o the QRS to the end o the T wave. The normal ranges o the intervals are listed in Table 4-3, along with conditions associated with abnormal values. Because the QT interval varies with heart rate (the aster the heart rate, the shorter the QT), the corrected QT interval is determined by dividing the measured QT by the square root o the RR interval (see Fig. 4-12). When the heart rate is in the normal range (60 to 100 bpm), a rapid rule can be applied: i the QT interval is visually less than hal the interval between two consecutive QRS complexes, then the QT interval is within the normal range. Mean QRS Axis The mean QRS axis represents the average o the instantaneous electrical orces generated during the sequence o ventricular depolarization as measured in the rontal plane. The nor- mal value is between −30 degrees and +90 degrees (Fig. 4-14). A mean axis that is more nega- tive than − 30 degrees implies left axis deviation, whereas an axis greater than +90 degrees represents right axis deviation. The mean axis can be determined precisely by plotting the QRS complexes o di erent leads on the axial re erence diagram or the limb leads (see Fig. 4-5), but this is tedious and is rarely necessary. The ollowing rapid approach to axis determi- nation generally provides su f cient accuracy. First, recall rom Figure 4-5 that each ECG lead has a (+ ) region and a (− ) region. Electrical activity directed toward the (+ ) hal results in an upward de ection, whereas activity toward the (− ) hal results in a downward de ection on the ECG recording o that
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