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InternalMed_Harrison. (From MR Starling: Physiology of myocardial contraction, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 3rd ed, WS Colucci and E Braunwald [eds]. Philadelphia: Current Medicine, 2002, pp 19–35.) 265e-10 Normal as from the cell’s breakdown of its glycogen stores Disorders of the Cardiovascular System


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InternalMed_Harrison. Disorders of the Cardiovascular System FIGURE 265e-10 The responses of the left ventricle to increased afterload, (glycogenolysis). These two principal sources of acetyl coenzyme A in cardiac muscle vary reciprocally. Glucose is broken down in the cytoplasm into a three-carbon product, pyruvate, which passes into the mitochondria, where it is metabolized to the two-carbon fragment, acetyl-CoA, and undergoes oxidation. FFAs are converted to acyl-CoA in the cytoplasm and acetyl-CoA in the mitochondria. Acetyl-CoA enters the citric acid (Krebs) cycle to produce ATP by oxidative phosphorylation within the mitochondria; ATP then enters the cytoplasm from the mitochondrial compartment. Intracellular ADP, resulting from the breakdown of ATP, enhances mitochondrial ATP production.


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InternalMed_Harrison. In the fasted, resting state, circulating FFA concentrations and their myocardial uptake are high, and they furnish most of the heart’s acetyl-CoA (~70%). In the fed state, with elevations of blood increased preload, and increased and reduced contractility are shown in the glucose and insulin, glucose oxidation increases and pressure-volume plane. Left. Effects of increases in preload and afterload on the


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InternalMed_Harrison. FFA oxidation subsides. Increased cardiac work, the pressure-volume loop. Because there has been no change in contractility, the administration of inotropic agents, hypoxia, and mild end-systolic pressure-volume relationship (ESPVR) is unchanged. With an increase in ischemia all enhance myocardial glucose uptake, glu afterload, stroke volume falls (1 → 2); with an increase in preload, stroke volume rises cose production resulting from glycogenolysis, and (1 → 3). Right. With increased myocardial contractility and constant left ventricular glucose metabolism to pyruvate (glycolysis). By con end-diastolic volume, the ESPVR moves to the left of the normal line (lower end trast, β-adrenergic stimulation, as occurs during stress, systolic volume at any end-systolic pressure) and stroke volume rises (1 → 3). With raises the circulating levels and metabolism of FFAs reduced myocardial contractility, the ESPVR moves to the right; end-systolic volume is in favor of glucose. Severe ischemia


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InternalMed_Harrison. rises (1 → 3). With raises the circulating levels and metabolism of FFAs reduced myocardial contractility, the ESPVR moves to the right; end-systolic volume is in favor of glucose. Severe ischemia inhibits the cyto increased, and stroke volume falls (1 → 2).


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InternalMed_Harrison. plasmic enzyme pyruvate dehydrogenase, and despite The end-systolic left ventricular pressure-volume relationship is a both glycogen and glucose breakdown, glucose is metabolized only to lactic acid (anaerobic glycoly particularly useful index of ventricular performance because it does sis), which does not enter the citric acid cycle. Anaerobic glycolysis not depend on preload and afterload (Fig. 265e-10). At any level of produces much less ATP than does aerobic glucose metabolism, in myocardial contractility, left ventricular end-systolic volume varies which glucose is metabolized to pyruvate and subsequently oxidized to inversely with end-systolic pressure; as contractility declines, endCO2. High concentrations of circulating FFAs, which can occur when adrenergic stimulation is superimposed on severe ischemia, reduce systolic volume (at any level of end-systolic pressure) rises.


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InternalMed_Harrison. Ventricular filling is influenced by the extent and speed of myocardial relaxation, which in turn depends on the rate of uptake of Ca2+ by the SR; the latter may be enhanced by adrenergic activation and reduced by ischemia, which reduces the ATP available for pumping Ca2+ into the SR (see above). The stiffness of the ventricular wall also may impede filling. Ventricular stiffness increases with hypertrophy and conditions that infiltrate the ventricle, such as amyloid, or is caused by an extrinsic constraint (e.g., pericardial compression) (Fig. 265e-11).


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InternalMed_Harrison. Ventricular filling can be assessed by continuously measuring the velocity of flow across the mitral valve using Doppler ultrasound. Normally, the velocity of inflow is more rapid in early diastole than during atrial systole; with mild to moderately impaired relaxation, the rate of early diastolic filling declines, whereas the rate of presystolic filling rises. With further impairment of filling, the pattern is “pseudonormalized,” and early ventricular filling becomes more rapid as left atrial pressure upstream to the stiff left ventricle rises.


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InternalMed_Harrison. The heart requires a continuous supply of energy (in the form of ATP) not only to perform its mechanical pumping functions, but also to regulate intracellular and transsarcolemmal ionic movements and concentration gradients. Among its pumping functions, the development of tension, the frequency of contraction, and the level of myocardial oxidative phosphorylation and also cause ATP wastage; the myocardial content of ATP declines and impairs myocardial contraction. In addition, products of FFA breakdown can exert toxic effects on cardiac cell membranes and may be arrhythmogenic. contractility are the principal determinants of the heart’s substantial FIGURE 265e-11 Mechanisms that cause diastolic dysfunction energy needs, making its O2 requirements approximately 15% of that reflected in the pressure-volume relation. The bottom half of the of the entire organism. pressure-volume loop is depicted. Solid lines represent normal sub-


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InternalMed_Harrison. Most ATP production depends on the oxidation of substrate (glu-jects; broken lines represent patients with diastolic dysfunction. (From cose and free fatty acids [FFAs]). Myocardial FFAs are derived from JD Carroll et al: The differential effects of positive inotropic and vasodilator circulating FFAs, which result principally from lipolysis in adipose therapy on diastolic properties in patients with congestive cardiomyopatissue, whereas the myocyte’s glucose derives from plasma as well thy. Circulation 74:815, 1986; with permission.) 265e-11 development, such as NKX2-5 and GATA4. Mutations in these genes are responsible for some forms of inherited congenital heart disease. Cardiac precursors coalesce to form a midline heart tube composed of a single cell layer of endocardium surrounded by a single layer of myocardial precursors. The caudal, inflow region of the heart tube, which is destined to adopt a more rostral final position, represents the atrial anlagen, whereas the rostral,


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InternalMed_Harrison. by a single layer of myocardial precursors. The caudal, inflow region of the heart tube, which is destined to adopt a more rostral final position, represents the atrial anlagen, whereas the rostral, outflow portion of the tube forms the truncus arteriosus, which divides to produce the aorta and the proximal pulmonary artery. Between these extremes lie the structural precursors of the ventricles. The linear heart tube undergoes an asymmetric looping process (the first gross evidence of left-right asymmetry in the developing embryo), which positions the portion of the heart tube destined to become the left ventricle to the left of the more rostral precursors of the right ven-tricle and outflow tract. Looping is coordinated with chamber specifi-cation and ballooning of various regions of the heart tube to produce the presumptive atria and ventricles. Relatively recent work has demonstrated that significant portions of the right ventricle are formed by cells that are added to the


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InternalMed_Harrison. of the heart tube to produce the presumptive atria and ventricles. Relatively recent work has demonstrated that significant portions of the right ventricle are formed by cells that are added to the developing heart after looping has occurred. These cells, which are derived from what is called the second heart field, migrate to the heart from the ventral pharynx and express markers that allow for their identification, including Islet-1. Different embryologic origins of cells within the right and left ventricles may help explain why some forms of congenital and adult heart diseases affect these regions of the heart to varying degrees. After looping and chamber formation, a series of septation events divide the left and right sides of the heart, separate the atria from the ventricles, and form the aorta and pulmonary artery from the truncus arteriosus. Cardiac valves form between the atria and the ventricles and between the ventricles and the out-flow vessels. Early in development, the


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InternalMed_Harrison. the aorta and pulmonary artery from the truncus arteriosus. Cardiac valves form between the atria and the ventricles and between the ventricles and the out-flow vessels. Early in development, the single layer of myocardial cells secretes an extracellular matrix rich in hyaluronic acid. This extracellular matrix, termed “cardiac jelly,” accumulates within the endocardial cushions, precursors of the cardiac valves. Signals from overlying myocardial cells, including members of the transforming growth factor β family, trigger migration, invasion, and pheno-typic changes of underlying endocar-dial cells, which undergo an epithelial-mesenchymal transformation and invade the cardiac jelly to cellularize the endocardial cushions. Mesenchymal components proliferate and remodel to form the mature valve leaflets. The great vessels form as a series of bilaterally symmetric aortic arch arteries that undergo asymmetric remodel-ing events to form the mature vascula-ture. The immigration of neural


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InternalMed_Harrison. valve leaflets. The great vessels form as a series of bilaterally symmetric aortic arch arteries that undergo asymmetric remodel-ing events to form the mature vascula-ture. The immigration of neural crest regions Second heart field RA RV RV LVLV LA First heart field coelom Forming heart ABCDE


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InternalMed_Harrison. Myocardial energy is stored as creatine phosphate (CP), which is in equilibrium with ATP, the immediate source of energy. In states of reduced energy availability, the CP stores decline first. Cardiac hypertrophy, fibrosis, tachycardia, increased wall tension resulting from ventricular dilation, and increased intracytoplasmic [Ca2+] all contribute to increased myocardial energy needs. When coupled with reduced coronary flow reserve, as occurs with obstruction of coronary arteries or abnormalities of the coronary microcirculation, an imbalance in myocardial ATP production relative to demand may occur, and the resulting ischemia can worsen or cause heart failure.


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InternalMed_Harrison. Developmental Biology of the Cardiovascular System The heart is the first organ to form during embryogenesis (Fig. 265e-12) and must accomplish the simultaneous challenges of circulating blood, nutrients, and oxygen to the other forming organs while continuing to grow and undergo complex morphogenetic changes. Early progenitors of the heart arise within very early crescent-shaped fields of lateral splanchnic mesoderm under the influence of multiple signals, including those derived from neural ectoderm long before neural tube closure. Early cardiac precursors express genes encoding regulatory transcription factors that play reiterated roles in cardiac CHAPTER 265e Basic Biology of the Cardiovascular System


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InternalMed_Harrison. FIGURE 265e-12 A. Schematic depiction of a transverse section through an early embryo depicts cells that arise in the dorsal neural tube the bilateral regions where early heart tubes form. B. The bilateral heart tubes subsequently orchestrates this process. These cells are migrate to the midline and fuse to form the linear heart tube. C. At the early cardiac crescent stage required for aortic arch remodeling and of embryonic development, cardiac precursors include a primary heart field fated to form the linear septation of the truncus arteriosus. They heart tube and a second heart field fated to add myocardium to the inflow and outflow poles of develop into smooth-muscle cells within the heart. D. Second heart field cells populate the pharyngeal region before subsequently migrat-the tunica media of the aortic arch, the ing to the maturing heart. E. Large portions of the right ventricle and outflow tract and some cells ductus arteriosus, and the carotid arterwithin the atria derive


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InternalMed_Harrison. media of the aortic arch, the ing to the maturing heart. E. Large portions of the right ventricle and outflow tract and some cells ductus arteriosus, and the carotid arterwithin the atria derive from the second heart field. F. The aortic arch arteries form as symmetric ies. Smooth-muscle cells within the sets of vessels that then remodel under the influence of the neural crest to form the asymmetric descending aorta arise from a differ-mature vasculature. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. ent embryologic source, the lateral plate 265e-12 mesoderm, and smooth muscle of the proximal outflow tract arises from the second heart field. Neural crest cells are sensitive to both vitamin A and folic acid, and congenital heart disease involving abnormal remodeling of the aortic arch arteries has been associated with maternal deficiencies of these vitamins. Congenital heart disease involving the outflow tract can be associated with other defects of neural


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InternalMed_Harrison. of the aortic arch arteries has been associated with maternal deficiencies of these vitamins. Congenital heart disease involving the outflow tract can be associated with other defects of neural crest, such as cleft palate or craniofacial abnormalities. Coronary artery formation requires yet another cell population that initiates extrinsic to the embryonic heart fields. Epicardial cells arise in the proepicardial organ, a derivative of the septum transversum, which also contributes to the fibrous portion of the diaphragm and to the liver. Proepicardial cells contribute to the smooth-muscle cells of the coronary arteries and are required for their proper patterning. Other cell types within the heart, including fibroblasts and potentially some myocardial and endocardial cells, also can arise from the proepicardium. The cardiac conduction system, which functions both to generate and to propagate electrical impulses, develops primarily from multi-potential cardiac precursors, which also


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InternalMed_Harrison. from the proepicardium. The cardiac conduction system, which functions both to generate and to propagate electrical impulses, develops primarily from multi-potential cardiac precursors, which also give rise to cardiac muscle. The conduction system is composed of slow-conducting (proximal) components, such as the sinoatrial (SA) and atrioventricular (AV) nodes, as well as fast-conducting (distal) components, including the His bundle, bundle branches, and Purkinje fibers. The AV node primarily serves to delay the electrical impulse between atria and ventricles (manifesting decremental conduction), whereas the distal conduction system rapidly delivers the impulse throughout the ventricles. Significant recent attention has been focused on the embryo-logic origins of various components of the specialized conduction


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InternalMed_Harrison. PART 10 Disorders of the Cardiovascular System network. Precursors within the sinus venosus give rise to the SA node, whereas those within the AV canal mature into heterogeneous cell types that compose the AV node. Myocardial cells transdifferentiate into Purkinje fibers to form the distal conduction system. Fast and slow conducting cell types within the nodes and bundles are characterized by expression of distinct gap junction proteins, including connexins, and ion channels that characterize unique cell fates and electrical properties of the tissues. Developmental defects in conduction system morphogenesis and lineage determination can lead to various electrophysiologic disorders, including congenital heart block and preexcitation syndromes such as the Wolff-Parkinson-White syndrome (Chap. 276).


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InternalMed_Harrison. Studies of cardiac stem and progenitor cells suggest that progressive lineage restriction results in the gradual and stepwise determination of mature cell fates within the heart, with early precursors capable of adopting endothelial, smooth-muscle, or cardiac phenotypes, and subsequent further specialization into atrial, ventricular, and specialized conduction cell types. Until very recently, adult mammalian myocardial cells were viewed as fully differentiated and without regenerative potential. Evidence currently supports the existence of limited regenerative potential of the mature heart. Considerable current effort is being devoted to evaluating the utility of various putative stem cell populations and regenerative approaches to enhance cardiac repair after injury. The success of such approaches would offer the exciting possibility of reconstructing an infarcted or failing ventricle (Chaps. 88 and 90e).


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InternalMed_Harrison. Epidemiology of Cardiovascular Disease Thomas A. Gaziano, J. Michael Gaziano Cardiovascular disease (CVD) is now the most common cause of death worldwide. Before 1900, infectious diseases and malnutrition were the 266e Stage Description Deaths Related to CVD, % Predominant CVD Type most common causes, and CVD was responsible for less than 10% of all deaths. In 2010, CVD accounted for approximately 16 million deaths worldwide (30%), including nearly 40% of deaths in high-income countries and about 28% in lowand middle-income countries.


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InternalMed_Harrison. The global rise in CVD is the result of an unprecedented transformation in the causes of morbidity and mortality dur ing the twentieth century. Known as the epidemiologic transition, this shift is driven by industrialization, urbanization, and associated lifestyle changes and is taking place in every part of the world among all races, ethnic groups, and cultures. The transition is divided into four basic stages: pestilence and famine, receding pandemics, degenerative and man-made diseases, and delayed degenerative diseases. A fifth stage, characterized by an epidemic of inactivity and obesity, is emerging in some countries (Table 266e-1).


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InternalMed_Harrison. The age of pestilence and famine is marked by malnutrition, infectious diseases, and high infant and child mortality that are offset by high fertility. Tuberculosis, dysentery, cholera, and influenza are often fatal, resulting in a mean life expectancy of about 30 years. CVD, which accounts for less than 10% of deaths, takes the form of rheumatic heart disease and cardiomyopathies due to infection and malnutrition. Approximately 10% of the world’s population remains in the age of pestilence and famine.


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InternalMed_Harrison. Per capita income and life expectancy increase during the age of receding pandemics as the emergence of public health systems, cleaner water supplies, and improved nutrition combine to drive down deaths from infectious disease and malnutrition. Infant and childhood mortality also decline, but deaths due to CVD increase to between 10 and 35% of all deaths. Rheumatic valvular disease, hypertension, coronary heart disease (CHD), and stroke are the predominant forms of CVD. Almost 40% of the world’s population is currently in this stage.


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InternalMed_Harrison. The age of degenerative and man-made diseases is distinguished 266e-1 by mortality from noncommunicable diseases—primarily CVD— surpassing mortality from malnutrition and infectious diseases. Caloric intake, particularly from animal fat, increases. CHD and stroke are prevalent, and between 35 and 65% of all deaths can be traced to CVD. Typically, the rate of CHD deaths exceeds that of stroke by a ratio of 2:1 to 3:1. During this period, average life expectancy surpasses the age of 50. Roughly 35% of the world’s population falls into this category.


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InternalMed_Harrison. In the age of delayed degenerative diseases, CVD and cancer remain the major causes of morbidity and mortality, with CVD accounting for 40% of all deaths. However, age-adjusted CVD mortality declines, aided by preventive strategies (for example, smoking cessation programs and effective blood pressure control), acute hospital management, and technologic advances, such as the availability of bypass surgery. CHD, stroke, and congestive heart failure are the primary forms of CVD. About 15% of the world’s population is now in the age of delayed degenerative diseases or is exiting this age and moving into the fifth stage of the epidemiologic transition.


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InternalMed_Harrison. In the industrialized world, physical activity continues to decline while total caloric intake increases. The resulting epidemic of overweight and obesity may signal the start of the age of inactivity and obesity. Rates of type 2 diabetes mellitus, hypertension, and lipid abnormalities are on the rise, trends that are particularly evident in children. If these risk factor trends continue, age-adjusted CVD mortality rates could increase in the coming years.


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InternalMed_Harrison. Unique regional features have modified aspects of the transition in various parts of the world. High-income countries experienced declines in CVD death rates by as much as 50–60% over the last 60 years, whereas CVD death rates increased by 15% over the past 20 years in the lowand middle-income range. However, given the large amount of available data, the United States serves as a useful reference point for comparisons. The age of pestilence and famine occurred before 1900, with a largely agrarian economy and population. Infectious diseases accounted for more deaths than any other cause. By the 1930s, the country proceeded through the age of receding pandemics. The establishment of public health infrastructures resulted in dramatic declines in infectious disease mortality rates. Lifestyle changes due to rapid urbanization resulted in a simultaneous increase in CVD mortality rates, reaching approximately 390 per 100,000. Between 1930 and 1965, the country entered the age of degenerative


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InternalMed_Harrison. CHAPTER 266e Epidemiology of Cardiovascular Disease Pestilence and famine Predominance of malnutrition and infectious diseases <10 as causes of death; high rates of infant and child mortality; low mean life expectancy Receding pandemics Improvements in nutrition and public health lead to 10–35 decrease in rates of deaths related to malnutrition and infection; precipitous decline in infant and child mortality rates man-made diseases cal activity lead to emergence of hypertension and atherosclerosis; with increase in life expectancy, mortality from chronic, noncommunicable diseases exceeds mortality from malnutrition and infectious disease Delayed degenerative CVD and cancer are the major causes of morbidity and 40–50 diseases mortality; better treatment and prevention efforts help avoid deaths among those with disease and delay primary events; age-adjusted CVD morality declines; CVD affecting older and older individuals


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InternalMed_Harrison. Inactivity and obesity Overweight and obesity increase at alarming rate; 33 diabetes and hypertension increase; decline in smoking rates levels off; a minority of the population meets physical activity recommendations Rheumatic heart disease, cardiomyopathies caused by infection and malnutrition Rheumatic valvular disease, hypertension, CHD, and stroke (predominantly hemorrhagic) CHD, stroke, and congestive heart failure CHD, stroke, and congestive heart failure, peripheral vascular disease Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease. Source: Adapted from AR Omran: The epidemiologic transition: A theory of the epidemiology of population change. Milbank Mem Fund Q 49:509, 1971; and SJ Olshansky, AB Ault: The fourth stage of the epidemiologic transition: The age of delayed degenerative diseases. Milbank Q 64:355, 1986.


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InternalMed_Harrison. PART 10 Disorders of the Cardiovascular System 266e-2 and man-made diseases. Infectious disease mortality rates fell to fewer than 50 per 100,000 per year, whereas CVD mortality rates reached peak levels with increasing urbanization and lifestyle changes in diet, physical activity, and tobacco consumption. The age of delayed degenerative diseases took place between 1965 and 2000. New therapeutic approaches, preventive measures, and exposure to public health campaigns promoting lifestyle modifications led to substantial declines in age-adjusted mortality rates and a steadily rising age at which a first CVD event occurs. Currently, the United States is entering what appears to be a fifth phase. The decline in the age-adjusted CVD death rate of 3% per year through the 1970s and 1980s has tapered off in the 1990s to 2%. However, CVD death rates have declined by 3–5% per year during the first decade of the new millennium. Competing trends appear to be at play. One the one hand, an increase


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InternalMed_Harrison. off in the 1990s to 2%. However, CVD death rates have declined by 3–5% per year during the first decade of the new millennium. Competing trends appear to be at play. One the one hand, an increase in the prevalence of diabetes and obesity, a slowing in the rate of decline in smoking, and a leveling off in the rate of detection and treatment for hypertension are in the negative column. On the other hand, cholesterol levels continue to decline in the face of increased statin use. Many high-income countries (HICs)—which together account for 15% of the population—have proceeded through four stages of the epidemiologic transition in roughly the same pattern as the United States. CHD is the dominant form of CVD in these countries, with rates that tend to be twoto five-fold higher than stroke rates. However, variations exist. Whereas North America, Australia, and central northwestern European HICs experienced significant increases then rapid declines in CVD rates, southern and central


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InternalMed_Harrison. rates. However, variations exist. Whereas North America, Australia, and central northwestern European HICs experienced significant increases then rapid declines in CVD rates, southern and central European countries experienced a more gradual rise and fall in rates. More specifically, central European countries (i.e., Austria, Belgium, and Germany) declined at slower rates compared to their northern counterparts (i.e., Finland, Sweden, Denmark, and Norway). Countries such as Portugal, Spain, and Japan never reached the high mortality rates that the United States and other countries did, with CHD mortality rates at 200 per 100,000, or less. The countries of Western Europe also exhibit a clear north/south gradient in absolute rates of CVD, with rates highest in northern countries (i.e., Finland, Ireland, and Scotland) and lowest in Mediterranean countries (i.e., France, Spain, and Italy). Japan is unique among the HICs, most likely due to the unique dietary patterns of its population.


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InternalMed_Harrison. Ireland, and Scotland) and lowest in Mediterranean countries (i.e., France, Spain, and Italy). Japan is unique among the HICs, most likely due to the unique dietary patterns of its population. Although stroke rates increased dramatically, CHD rates did not rise as sharply in Japan. However, Japanese dietary habits are undergoing substantial changes, reflected in an increase in cholesterol levels.


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InternalMed_Harrison. Global deaths by cause, 2010 Patterns in lowand middle-income countries (LMICs; gross national income per capita less than U.S. $12,615) depend, in part, on cultural differences, secular trends, and responses at the country level, with regard to both public health and treatment infrastructure. Although communicable diseases continue to be a major cause of death, CVD has emerged as a significant health concern in LMICs. With 85% of the world’s population, LMICs are driving the rates of change in the global burden of CVD (Fig. 266e-1). In most LMICs, an urban/rural gradient has emerged for CHD, stroke, and hypertension, with higher rates in urban centers.


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InternalMed_Harrison. However, although CVD rates are rapidly rising, vast differences exist among the regions and countries, and even within the countries themselves (Fig. 266e-2). The East Asia and Pacific regions appear to be straddling the second and third phases of the epidemiologic transition. CVD is a major cause of death in China, but like Japan, stroke causes more deaths than CHD in a ratio of about three to one. Vietnam and Cambodia, on the other hand, are just emerging from the pestilence and famine transition. The Middle East and North Africa regions also appear to be entering the third phase of the epidemiologic transition, with increasing life expectancy and CVD death rates just below those of HICs. In general, Latin America appears to be in the third phase of the transition, although there is vast regional heterogeneity with some areas in the second phase of the transition and some in the fourth. The Eastern Europe and Central Asia regions, however, are firmly in the peak of the third phase,


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InternalMed_Harrison. regional heterogeneity with some areas in the second phase of the transition and some in the fourth. The Eastern Europe and Central Asia regions, however, are firmly in the peak of the third phase, with the highest death rates due to CVD (~66%) in the world. Importantly, deaths due to CHD are not limited to the elderly in this region and have a significant effect on working-age populations. South Asia—and more specifically, India, which accounts for the greatest proportion of the region’s population—is experiencing an alarming increase in heart disease. The transition appears to be in the Western style, with CHD as the dominant form of CVD. However, rheumatic heart disease continues to be a major cause of morbidity and mortality. As in South Asia, rheumatic heart disease is also an important cause of CVD morbidity and mortality in sub-Saharan Africa, which largely remains in the first phase of the epidemiologic transition.


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InternalMed_Harrison. Many factors contribute to this heterogeneity among LMICs. First, the regions are in various stages of the epidemiologic transition. Second, vast differences in lifestyle and behavioral risk factors exist. Third, racial and ethnic differences may lead to altered susceptibilities to various forms of CVD. In addition, it should be noted that for most countries in these regions, accurate country-wide data on cause-specific mortality are not complete. FIGuRE 266-1 Global deaths by cause, 2010. CMNN, communicable, maternal, neonatal, and nutritional disorders; CVD, cardiovascular diseases; INJ, injuries; ONC, other noncommunicable diseases. (Based on data from Global Burden of Disease Study 2010: Global Burden of Disease Study 2010 Mortality Results 1970–2010. Seattle, Institute for Health Metrics and Evaluation, 2012.) Latin American and the Caribbean Middle East and North Africa Europe and Central Asia 266e-3 28.8% 42.3% 58.2% (601 million) (422 million) (404 million)


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InternalMed_Harrison. Latin American and the Caribbean Middle East and North Africa Europe and Central Asia 266e-3 28.8% 42.3% 58.2% (601 million) (422 million) (404 million) High-income 35.8% (970 million) South Asia 20.4% (1,609 million) Sub-Saharan Africa East Asia and Pacific 8.8% 35.7%(823 million) (1,991 million) FIGuRE 266-2 Cardiovascular disease deaths as a percentage of total deaths and total population in seven economic regions of the world defined by the World Bank.(Based on data from Global Burden of Disease Study 2010: Global Burden of Disease Study 2010 Mortality Results CHAPTER 266e Epidemiology of Cardiovascular Disease 1970–2010. Seattle, Institute for Health Metrics and Evaluation, 2012.)


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InternalMed_Harrison. CHAPTER 266e Epidemiology of Cardiovascular Disease 1970–2010. Seattle, Institute for Health Metrics and Evaluation, 2012.) CVD accounts for nearly 30% of deaths worldwide, a number that is expected to increase. In 2010, CHD accounted for 13.3% of all deaths globally and the largest portion of global years of life lost (YLLs) and disability-adjusted life-years (DALYs). The second largest cause of death was stroke (11.1% of all deaths), which was also the third largest contributor to global YLLs and DALYs (Table 266e-2). Together, CHD and stroke accounted for nearly a quarter of all deaths worldwide. The burden of stroke is of growing concern among LMICs. The impact of stroke on DALYs and mortality rates is more than three times greater in LMICs as compared to HICs. By 2030, the number of deaths due to stroke is projected to increase by more than 30%, the majority of which will occur in LMICs.


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InternalMed_Harrison. With nearly 85% of the world’s population, LMICs largely drive global CVD rates and trends. Ten million CVD deaths occurred in TAblE 266e-2 moRbiDiTy RElATED To HEART DiSEASE: 2010–2030 Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease. Source: Adapted from Global Burden of Disease Study 2010: Global Burden of Disease Study 2010 Mortality Results 1970-2010. Seattle, Institute for Health Metrics and Evaluation, 2012; J Mackay, G Mensah: Atlas of Heart Disease and Stroke. Geneva, World Health Organization, 2004. LMICs in 2010, compared to 5.6 million in HICs. Globally, there is evidence of significant delays in age of occurrence and/or improvements in case fatality rates; between 1990 and 2010, the number of CVD deaths increased by 31%, but age-adjusted death rates decreased by 21.2% in the same period.


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InternalMed_Harrison. Although HIC population growth will be fueled by emigration from LMICs, the populations of HICs will shrink as a proportion of the world’s population. The modest decline in CVD death rates that began in the HICs in the latter third of the twentieth century will continue, but the rate of decline appears to be slowing. However, these countries are expected to see an increase in the prevalence of CVD, as well as the absolute number of deaths as the population ages. Significant portions of the population living in LMICs have entered the third phase of the epidemiologic transition, and some are entering the fourth stage. Changing demographics play a significant role in future predictions for CVD throughout the world. For example, the population growth rate in Eastern Europe and Central Asia was 0.7% in 2012, whereas it was 1.3% in South Asia.


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InternalMed_Harrison. CVD rates will also have an economic impact. Even assuming no increase in CVD risk factors, most countries, but especially India and South Africa, will see a large number of people between 35 and 64 die of CVD over the next 30 years, as well as an increasing level of morbidity among middle-aged people related to heart disease and stroke. In China, it is estimated that there will be 9 million deaths from CVD in 2030—up from 2.4 million in 2002—with half occurring in individuals between 35 and 64 years old. The global variation in CVD rates is related to temporal and regional variations in known risk behaviors and factors. Ecological analyses of major CVD risk factors and mortality demonstrate high correlations between expected and observed mortality rates for the three main risk factors—smoking, serum cholesterol, and hypertension—and suggest


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InternalMed_Harrison. PART 10 Disorders of the Cardiovascular System 266e-4 that many of the regional variations are based on differences in conventional risk factors.


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InternalMed_Harrison. Behavioral Risk Factors • TOBACCO Over 1.3 billion people use tobacco worldwide, a number that is projected to increase to 1.6 billion by 2030. Tobacco use currently causes about 5 million deaths annually (9% of all deaths), approximately 1.6 million of which are CVD-related. If current smoking patterns continue, the global burden of disease attributable to tobacco will reach 10 million deaths by 2030. Although tobacco use has been greatest in HICs historically, consumption has shifted dramatically to LMICs in recent decades. Some of the highest tobacco use now occurs in the East Asia and Pacific region. A unique feature of LMICs is easy access to smoking during the early stages of the epidemiologic transition due to the availability of relatively inexpensive tobacco products. In South Asia, the prominence of other locally produced forms of tobacco besides manufactured cigarettes makes control of consumption more challenging. Secondhand smoke is another well-established cause of CHD,


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InternalMed_Harrison. the prominence of other locally produced forms of tobacco besides manufactured cigarettes makes control of consumption more challenging. Secondhand smoke is another well-established cause of CHD, responsible for 600,000 deaths of nonsmokers in 2011. Although smoking bans have both immediate and long-term benefits, implementation varies greatly between countries.


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InternalMed_Harrison. DIET Total caloric intake per capita increases as countries develop. With regard to CVD, a key element of dietary change is an increase in intake of saturated animal fats and hydrogenated vegetable fats, which contain atherogenic trans fatty acids, along with a decrease in intake of plant-based foods and an increase in simple carbohydrates. Fat contributes less than 20% of calories in rural China and India, less than 30% in Japan, and well above 30% in the United States. Caloric contributions from fat appear to be falling in the HICs. In the United States, between 1971 and 2010, the percentage of calories derived from saturated fat decreased from 13% to 11%.


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InternalMed_Harrison. PHYSICAL INACTIVITY The increased mechanization that accompanies the economic transition leads to a shift from physically demanding, agriculture-based work to largely sedentary industryand office-based work. In the United States, approximately one-quarter of the population does not participate in any leisure-time physical activity, and only 51.6% of adults report engaging in physical activity three or more times a week. Physical inactivity is similarly high in other regions of the world and is increasing in countries that are rapidly urbanizing as part of their economic transition. In urban China, for example, the proportion of adults who participate in moderateor high-level activity has decreased significantly, whereas those who participate in low-level activity has increased.


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InternalMed_Harrison. Examination of trends in metabolic risk factors provides insight into changes in the CVD burden globally. Here we describe four metabolic risk factors—lipid levels, hypertension, obesity, and diabetes mellitus—using data from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2010). The GBD project identified and compiled mortality and morbidity data from 187 countries from 1980 to 2010.


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InternalMed_Harrison. Lipid Levels Worldwide, high cholesterol levels are estimated to play a role in 56% of ischemic heart disease events and 18% of strokes, amounting to 4.4 million deaths annually. Although mean population plasma cholesterol levels tend to rise as countries move through the epidemiologic transition, mean serum total cholesterol levels have decreased globally between 1980 and 2008 by 0.08 mmol/L per decade in men and 0.07 mmol/L per decade in women. In 2008, age-standardized mean total cholesterol was 4.64 mmol/L (179.4 mg/dL) in men and 4.76 mmol/L (184.2 mg/dL) in women. Large declines occurred in Australasia, North America, and Western Europe (0.19–0.21 mmol/L). Countries in the East Asia and Pacific region experienced increases of greater than 0.08 mmol/L in both men and women. Social and individual changes that accompany urbanization clearly play a role because plasma cholesterol levels tend to be higher among urban residents than among rural residents. This shift is largely driven


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InternalMed_Harrison. individual changes that accompany urbanization clearly play a role because plasma cholesterol levels tend to be higher among urban residents than among rural residents. This shift is largely driven by greater consumption of dietary fats—primarily from animal products and processed vegetable oils—and decreased physical activity. In HICs, in general, mean population cholesterol levels are falling, whereas wide variation is seen in the LMICs.


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InternalMed_Harrison. Hypertension Elevated blood pressure is an early indicator of the epidemiologic transition. Worldwide, approximately 62% of strokes and 49% of CHD are attributable to suboptimal (>115 mmHg systolic) blood pressure, which is believed to account for more than 7 million deaths annually. Remarkably, nearly half of this burden occurs among those with systolic blood pressure less than 140 mmHg, even as this level is used at the arbitrary threshold for defining hypertension in many national guidelines. Between 1980 and 2008, the age-standardized prevalence of uncontrolled prevalence has decreased even as the number of people with uncontrolled hypertension has increased. This trend results largely from population growth and aging. Rising mean population blood pressure also occurs as populations industrialize and move from rural to urban settings. For example, the prevalence of hypertension in urban India is 25%, but varies between 10% and 15% in rural communities. One major concern in LMICs


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InternalMed_Harrison. industrialize and move from rural to urban settings. For example, the prevalence of hypertension in urban India is 25%, but varies between 10% and 15% in rural communities. One major concern in LMICs is the high rate of undetected, and therefore untreated, hypertension. This may explain, at least in part, the higher stroke rates in these countries in relation to CHD rates during the early stages of the transition. The high rates of hypertension throughout Asia, especially undiagnosed hypertension, likely contribute to the high prevalence of hemorrhagic stroke in the region. Globally, however, mean systolic blood pressure has decreased among both genders (0.8 mmHg per decade among men; 1.0 mmHg per decade among women).


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InternalMed_Harrison. Obesity Although clearly associated with increased risk of CHD, much of the risk posed by obesity may be mediated by other CVD risk factors, including hypertension, diabetes mellitus, and lipid profile imbalances. According to the latest GBD data, nearly 1.46 billion adults were overweight (body mass index ≥25 kg/m2) in 2008, and approximately 508 million were obese (BMI ≥30 kg/m2). Obesity is increasing throughout the world, particularly in developing countries, where the trajectories are steeper than those experienced by the developed countries. In many of the LMICs, obesity appears to coexist with undernutrition and malnutrition. Adolescents are at particular risk. Currently, 1 in 10 children are estimated to be overweight, a number that is increasing worldwide. Women are also more affected than men, with the number of overweight women generally exceeding underweight women based on data from 36 LMICs.


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InternalMed_Harrison. Diabetes Mellitus As a consequence of, or in addition to, increasing body mass index and decreasing levels of physical activity, worldwide rates of diabetes—predominantly type 2 diabetes—are on the rise. According to the most recent data from the GBD project, mean fasting plasma glucose levels have increased globally between 1980 and 2008. An estimated 346 million people worldwide have diabetes. The International Diabetes Foundation predicts that this number will reach 522 million by 2030, a yearly rate of growth that is higher than that of the world’s adult population. Nearly 50% of people with diabetes are undiagnosed, and 80% live in LMICs. The highest regional prevalence for diabetes occurs in the Middle East and North Africa, where an estimated 12.5% of the adult population has diabetes. Future growth will also largely occur in this region, along with other LMICs in South Asia and sub-Saharan Africa. There appear to be clear genetic susceptibilities to diabetes mellitus of


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InternalMed_Harrison. diabetes. Future growth will also largely occur in this region, along with other LMICs in South Asia and sub-Saharan Africa. There appear to be clear genetic susceptibilities to diabetes mellitus of various racial and ethnic groups. For example, migration studies suggest that South Asians and Indians tend to be at higher risk than those of European extraction.


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InternalMed_Harrison. Although CVD rates are declining in the HICs, they are increasing in virtually every other region of the world. The consequences of this preventable epidemic will be substantial on many levels, including individual mortality and morbidity, family suffering, and staggering economic costs. Three complementary strategies can be used to lessen the impact. First, the overall burden of CVD risk factors can be lowered through population-wide public health measures, such as national campaigns CHAPTER 266e Epidemiology of Cardiovascular Disease


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InternalMed_Harrison. Disorders of the Cardiovascular SystemPhysical Examination of the Cardiovascular System Patrick T. O’Gara, Joseph Loscalzo The approach to a patient with known or suspected cardiovascular disease begins with the time-honored traditions of a directed history and a targeted physical examination. The scope of these activities depends on the clinical context at the time of presentation, rang-ing from an elective ambulatory follow-up visit to a more focused emergency department encounter. There has been a gradual decline in physical examination skills over the last two decades at every level, from student to faculty specialist, a development of great concern to both clinicians and medical educators. Classic cardiac findings are recognized by only a minority of internal medicine and family practice residents. Despite popular perceptions, clinical performance does not improve predictably as a function of experience; instead, the acquisi-tion of new examination skills may become more


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InternalMed_Harrison. practice residents. Despite popular perceptions, clinical performance does not improve predictably as a function of experience; instead, the acquisi-tion of new examination skills may become more difficult for a busy individual practitioner. Less time is now devoted to mentored cardio-vascular examinations during the training of students and residents. One widely recognized outcome of these trends is the progressive overutilization of noninvasive imaging studies to establish the pres-ence and severity of cardiovascular disease even when the examina-tion findings imply a low pretest probability of significant pathology. Educational techniques to improve bedside skills include repetition, patient-centered teaching conferences, and visual display feedback of auscultatory events with Doppler echocardiographic imaging. The evidence base that links the findings from the history and physi-cal examination to the presence, severity, and prognosis of cardiovas-cular disease has been established


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InternalMed_Harrison. imaging. The evidence base that links the findings from the history and physi-cal examination to the presence, severity, and prognosis of cardiovas-cular disease has been established most rigorously for coronary artery disease, heart failure, and valvular heart disease. For example, obser-vations regarding heart rate, blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes. Observations from the physical examination in this set-ting can inform clinical decision making before the results of cardiac biomarkers testing are known. The prognosis of patients with systolic heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the


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InternalMed_Harrison. or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overestimated. THE GENERAL PHYSICAL EXAMINATION Any examination begins with an assessment of the general appear-ance of the patient, with notation of age, posture, demeanor, and 267 SEC Tion 2 DiAgnoSiS oF CARDiovASCulAR DiSoRDERS overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body positions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be


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InternalMed_Harrison. dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be appreciated readily and provide additional clues. A chronically ill-appearing emaciated patient may suggest the presence of long-standing heart failure or another systemic disorder, such as a malignancy. Various genetic syndromes, often with cardiovascular involvement, can also be recognized easily, such as trisomy 21, Marfan’s syndrome, and Holt-Oram syndrome. Height and weight should be measured routinely, and both body mass index and body surface area should be calculated. Knowledge of the waist circumference and the waist-to-hip ratio can be used to predict long-term cardiovascular risk. Mental status, level of alertness, and mood should be assessed continuously during the interview and examination.


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InternalMed_Harrison. Skin Central cyanosis occurs with significant right-to-left shunting at the level of the heart or lungs, allowing deoxygenated blood to reach the systemic circulation. Peripheral cyanosis or acrocyanosis, in contrast, is usually related to reduced extremity blood flow due to small vessel constriction, as seen in patients with severe heart failure, shock, or peripheral vascular disease; it can be aggravated by the use of β-adrenergic blockers with unopposed α-mediated constriction. Differential cyanosis refers to isolated cyanosis affecting the lower but not the upper extremities in a patient with a large patent ductus arteriosus (PDA) and secondary pulmonary hypertension with right-to-left to shunting at the great vessel level. Hereditary telangiectasias on the lips, tongue, and mucous membranes, as part of the Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), resemble spider nevi and can be a source of right-to-left shunting when also present in the lung. Malar


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InternalMed_Harrison. membranes, as part of the Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia), resemble spider nevi and can be a source of right-to-left shunting when also present in the lung. Malar telangiectasias also are seen in patients with advanced mitral stenosis and scleroderma. An unusually tan or bronze discoloration of the skin may suggest hemochromatosis as the cause of the associated systolic heart failure. Jaundice, which may be visible first in the sclerae, has a broad differential diagnosis but, in the appropriate setting, can be consistent with advanced right heart failure and congestive hepatomegaly or late-term “cardiac cirrhosis.” Cutaneous ecchymoses are seen frequently among patients taking vitamin K antagonists or antiplatelet agents such as aspirin and thienopyridines. Various lipid disorders sometimes are associated with subcutaneous xanthomas, particularly along the tendon sheaths or over the extensor surfaces of the extremities. Severe hypertriglyceridemia


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InternalMed_Harrison. Various lipid disorders sometimes are associated with subcutaneous xanthomas, particularly along the tendon sheaths or over the extensor surfaces of the extremities. Severe hypertriglyceridemia can be associated with eruptive xanthomatosis and lipemia retinalis. Palmar crease xanthomas are specific for type III hyperlipoproteinemia. Pseudoxanthoma elasticum, a disease associated with premature atherosclerosis, is manifested by a leathery, cobblestoned appearance of the skin in the axilla and neck creases and by angioid streaks on funduscopic examination. Extensive lentiginoses have been described in a variety of development delay–cardiovascular syndromes, including Carney’s syndrome, which includes multiple atrial myxomas. Cutaneous manifestations of sarcoidosis such as lupus pernio and erythema nodosum may suggest this disease as a cause of an associated dilated cardiomyopathy, especially with heart block, intraventricular conduction delay, or ventricular tachycardia.


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InternalMed_Harrison. Head and Neck Dentition and oral hygiene should be assessed in every patient both as a source of potential infection and as an index of general health. A high-arched palate is a feature of Marfan’s syndrome and other connective tissue disease syndromes. Bifid uvula has been described in patients with Loeys-Dietz syndrome, and orange tonsils are characteristic of Tangier disease. The ocular manifestations of hyperthyroidism have been well described. Many patients with congenital heart disease have associated hypertelorism, low-set ears, or micrognathia. Blue sclerae are a feature of osteogenesis imperfecta. An arcus senilis pattern lacks specificity as an index of coronary heart disease risk. The funduscopic examination is an often underused method by which to assess the microvasculature, especially among patients with established atherosclerosis, hypertension, or diabetes mellitus. A mydriatic agent may be necessary for optimal visualization. A funduscopic examination should be


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InternalMed_Harrison. especially among patients with established atherosclerosis, hypertension, or diabetes mellitus. A mydriatic agent may be necessary for optimal visualization. A funduscopic examination should be performed routinely in the assessment of patients with suspected endocarditis and those with a history of acute visual change. Branch retinal artery occlusion or visualization of a Hollenhorst plaque can narrow the differential diagnosis rapidly in the appropriate setting. Relapsing polychondritis may manifest as an inflamed pinna or, in its later stages, as a saddle-nose deformity because of destruction of nasal cartilage; granulomatosis with polyangiitis (Wegener’s) can also lead to a saddle-nose deformity.


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InternalMed_Harrison. Chest Midline sternotomy, left posterolateral thoracotomy, or infraclavicular scars at the site of pacemaker/defibrillator generator implantation should not be overlooked and may provide the first clue regarding an underlying cardiovascular disorder in patients unable to provide a relevant history. A prominent venous collateral pattern may suggest subclavian or vena caval obstruction. If the head and neck appear dusky and slightly cyanotic and the venous pressure is grossly elevated without visible pulsations, a diagnosis of superior vena cava syndrome should be entertained. Thoracic cage abnormalities have been well described among patients with connective tissue disease syndromes. They include pectus carinatum (“pigeon chest”) and pectus excavatum (“funnel chest”). Obstructive lung disease is suggested by a barrel chest deformity, especially with tachypnea, pursed-lip breathing, and use of accessory muscles. The characteristically severe kyphosis and compensatory lumbar, pelvic, and


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InternalMed_Harrison. is suggested by a barrel chest deformity, especially with tachypnea, pursed-lip breathing, and use of accessory muscles. The characteristically severe kyphosis and compensatory lumbar, pelvic, and knee flexion of ankylosing spondylitis should prompt careful auscultation for a murmur of aortic regurgitation (AR). Straight back syndrome refers to the loss of the normal kyphosis of the thoracic spine and has been described in patients with mitral valve prolapse (MVP) and its variants. In some patients with cyanotic congenital heart disease, the chest wall appears to be asymmetric, with anterior displacement of the left hemithorax. The respiratory rate and pattern should be noted during spontaneous breathing, with additional attention to depth, audible wheezing, and stridor. Lung examination can reveal adventitious sounds indicative of pulmonary edema, pneumonia, or pleuritis.


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InternalMed_Harrison. Abdomen In some patients with advanced obstructive lung disease, the point of maximal cardiac impulse may be in the epigastrium. The liver is frequently enlarged and tender in patients with chronic heart failure. Systolic pulsations over the liver signify severe tricuspid regurgitation (TR). Splenomegaly may be a feature of infective endocarditis, particularly when symptoms have persisted for weeks or months. Ascites is a nonspecific finding but may be present with advanced chronic right heart failure, constrictive pericarditis, hepatic cirrhosis, or an intraperitoneal malignancy. The finding of an elevated JVP implies a cardiovascular etiology. In nonobese patients, the aorta typically is palpated between the epigastrium and the umbilicus. The sensitivity of palpation for the detection of an abdominal aortic aneurysm (pulsatile and expansile mass) decreases as a function of body size. Because palpation alone is not sufficiently accurate to establish this diagnosis, a screening


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InternalMed_Harrison. of an abdominal aortic aneurysm (pulsatile and expansile mass) decreases as a function of body size. Because palpation alone is not sufficiently accurate to establish this diagnosis, a screening ultrasound examination is advised. The 1443 presence of an arterial bruit over the abdomen suggests high-grade atherosclerotic disease, although precise localization is difficult.


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InternalMed_Harrison. Extremities The temperature and color of the extremities, the presence of clubbing, arachnodactyly, and pertinent nail findings can be surmised quickly during the examination. Clubbing implies the presence of central right-to-left shunting, although it has also been described in patients with endocarditis. Its appearance can range from cyanosis and softening of the root of the nail bed, to the classic loss of the normal angle between the base of the nail and the skin, to the skeletal and periosteal bony changes of hypertrophic osteoarthropathy, which is seen rarely in patients with advanced lung or liver disease. Patients with the Holt-Oram syndrome have an unopposable, “fingerized” thumb, whereas patients with Marfan’s syndrome may have arachnodactyly and a positive “wrist” (overlapping of the thumb and fifth finger around the wrist) or “thumb” (protrusion of the thumb beyond the ulnar aspect of the hand when the fingers are clenched over the thumb in a fist) sign. The Janeway


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InternalMed_Harrison. of the thumb and fifth finger around the wrist) or “thumb” (protrusion of the thumb beyond the ulnar aspect of the hand when the fingers are clenched over the thumb in a fist) sign. The Janeway lesions of endocarditis are non- tender, slightly raised hemorrhages on the palms and soles, whereas Osler’s nodes are tender, raised nodules on the pads of the fingers or toes. Splinter hemorrhages are classically identified as linear petechiae in the midposition of the nail bed and should be distinguished from the more common traumatic petechiae, which are seen closer to the distal edge.


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InternalMed_Harrison. Lower extremity or presacral edema in the setting of an elevated JVP defines volume overload and may be a feature of chronic heart failure or constrictive pericarditis. Lower extremity edema in the absence of jugular venous hypertension may be due to lymphatic or venous obstruction or, more commonly, to venous insufficiency, as further suggested by the appearance of varicosities, venous ulcers (typically medial in location), and brownish cutaneous discoloration from hemosiderin deposition (eburnation). Pitting edema can also be seen in patients who use dihydropyridine calcium channel blockers. A Homan’s sign (posterior calf pain on active dorsiflexion of the foot against resistance) is neither specific nor sensitive for deep venous thrombosis. Muscular atrophy or the absence of hair along an extremity is consistent with severe arterial insufficiency or a primary neuromuscular disorder.


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InternalMed_Harrison. CARDIOVASCULAR EXAMINATION Jugular Venous Pressure and Waveform JVP is the single most important bedside measurement from which to estimate the volume status. The internal jugular vein is preferred because the external jugular vein is valved and not directly in line with the superior vena cava and right atrium. Nevertheless, the external jugular vein has been used to discriminate between high and low central venous pressure (CVP) when tested among medical students, residents, and attending physicians. Precise estimation of the central venous or right atrial pressure from bedside assessment of the jugular venous waveform has proved difficult. Venous pressure traditionally has been measured as the vertical distance between the top of the jugular venous pulsation and the sternal inflection point (angle of Louis). A distance >4.5 cm at 30° elevation is considered abnormal. However, the actual distance between the mid-right atrium and the angle of Louis varies considerably as a function of


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InternalMed_Harrison. (angle of Louis). A distance >4.5 cm at 30° elevation is considered abnormal. However, the actual distance between the mid-right atrium and the angle of Louis varies considerably as a function of both body size and the patient angle at which the assessment is made (30°, 45°, or 60°). The use of the sternal angle as a reference point leads to systematic underestimation of CVP, and this method should be used less for semiquantification than to distinguish a normal from an abnormally elevated CVP. The use of the clavicle may provide an easier reference for standardization. Venous pulsations above this level in the sitting position are clearly abnormal, as the distance between the clavicle and the right atrium is at least 10 cm. The patient should always be placed in the sitting position, with the legs dangling below the bedside, when an elevated pressure is suspected in the semisupine position. It should also be noted that bedside estimates of CVP are made in centimeters of water but


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InternalMed_Harrison. with the legs dangling below the bedside, when an elevated pressure is suspected in the semisupine position. It should also be noted that bedside estimates of CVP are made in centimeters of water but must be converted to millimeters of mercury to provide correlation with accepted hemodynamic norms (1.36 cmH2O = 1.0 mmHg).


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InternalMed_Harrison. Physical Examination of the Cardiovascular System 1444 The venous waveform sometimes can be difficult to distinguish from the carotid pulse, especially during casual inspection. Nevertheless, the venous waveform has several characteristic features, and its individual components can be appreciated in most patients (Fig. 267-1). The arterial pulsation is not easily obliterated with palpation; the venous waveform in patients with sinus rhythm is usually biphasic, while the carotid pulse is monophasic; and the jugular venous pulsation should change with changes in posture or inspiration (unless the venous pressure is quite elevated). The venous waveform is divided into several distinct peaks. The a wave reflects right atrial presystolic contraction and occurs just after the electrocardiographic P wave, preceding the first heart sound (S1). A prominent a wave is seen in patients with reduced right ventricular compliance; a cannon a wave occurs with atrioventricular (AV) dissociation and


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InternalMed_Harrison. P wave, preceding the first heart sound (S1). A prominent a wave is seen in patients with reduced right ventricular compliance; a cannon a wave occurs with atrioventricular (AV) dissociation and right atrial contraction against a closed tricuspid valve. In a patient with a wide complex tachycardia, the appreciation of cannon a waves in the jugular venous waveform identifies the rhythm as ventricular in origin. The a wave is not present with atrial fibrillation. The x descent defines the fall in right atrial pressure after inscription of the a wave. The c wave interrupts this x descent and is followed by a further descent. The v wave represents atrial filling (atrial diastole) and occurs during ventricular systole. The height of the v wave is determined by right atrial compliance as well as the volume of blood returning to the right atrium either antegrade from the cavae or retrograde through an incompetent tricuspid valve. In patients with TR, the v wave is accentuated and the


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InternalMed_Harrison. well as the volume of blood returning to the right atrium either antegrade from the cavae or retrograde through an incompetent tricuspid valve. In patients with TR, the v wave is accentuated and the subsequent fall in pressure (y descent) is rapid. With progressive degrees of TR, the v wave merges with the c wave, and the right atrial and jugular vein waveforms become “ventricularized.” The y descent, which follows the peak of the v wave, can become prolonged or blunted with obstruction to right ventricular inflow, as may occur with tricuspid stenosis or pericardial tamponade. Normally, the venous pressure should fall by at least 3 mmHg with inspiration. Kussmaul’s sign is defined by either a rise or a lack of fall of the JVP with inspiration and is classically associated with constrictive pericarditis, although it has been reported in patients with restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and advanced left ventricular systolic heart


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InternalMed_Harrison. pericarditis, although it has been reported in patients with restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and advanced left ventricular systolic heart failure. It is also a common, isolated finding in patients after cardiac surgery without other hemodynamic abnormalities. Venous hypertension sometimes can be elicited by performance of the abdominojugular reflex or with passive leg elevation. When these signs are positive, a volume-overloaded state with limited compliance of an overly distended or constricted venous system is present. The abdominojugular reflex is elicited with firm and consistent pressure over the upper portion of the abdomen, preferably over the right upper quadrant, for at least 10 s. A positive response is defined by a sustained rise of more than 3 cm in JVP for at least 15 s after release of the hand. Patients must be coached to refrain from breath holding or a Valsalva-like maneuver during the procedure. The


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InternalMed_Harrison. by a sustained rise of more than 3 cm in JVP for at least 15 s after release of the hand. Patients must be coached to refrain from breath holding or a Valsalva-like maneuver during the procedure. The abdominojugular reflex is useful in predicting a pulmonary artery wedge pressure in excess of 15 mmHg in patients with heart failure. Although the JVP estimates right ventricular filling pressure, it has a predictable relationship with the pulmonary artery wedge pressure. In a large study of patients with advanced heart failure, the presence of a right atrial pressure >10 mmHg (as predicted on bedside examination) had a positive value of 88% for the prediction of a pulmonary artery wedge pressure of >22 mmHg. In addition, an elevated JVP has prognostic significance in patients with both symptomatic heart failure and asymptomatic left ventricular systolic dysfunction. The presence of an elevated JVP is associated with a higher risk of subsequent hospitalization for heart failure, death


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InternalMed_Harrison. heart failure and asymptomatic left ventricular systolic dysfunction. The presence of an elevated JVP is associated with a higher risk of subsequent hospitalization for heart failure, death from heart failure, or both.


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InternalMed_Harrison. Assessment of Blood Pressure Measurement of blood pressure usually is delegated to a medical assistant but should be repeated by the clinician. Accurate measurement depends on body position, arm size, time of measurement, place of measurement, device, device size, technique, and examiner. In general, physician-recorded blood pressures are higher than both nurse-recorded pressures and self-recorded pressures at home. Blood pressure is best measured in the seated position with


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InternalMed_Harrison. FIGURE 267-1 A. Jugular venous pulse wave tracing (top) with heart sounds (bottom). The A wave represents right atrial presystolic contraction and occurs just after the electrocardiographic P wave and just before the first heart sound (I). In this example, the A wave is accentuated and larger than normal due to decreased right ventricular compliance, as also suggested by the right-sided S4 (IV). The C wave may reflect the carotid pulsation in the neck and/or an early systolic increase in right atrial pressure as the right ventricle pushes the closed tricuspid valve into the right atrium. The x descent follows the A wave just as atrial pressure continues to fall. The V wave represents atrial filling during ventricular systole and peaks at the second heart sound (II). The y descent corresponds to the fall in right atrial pressure after tricuspid valve opening. B. Jugular venous wave forms in mild (middle) and severe (top) tricuspid regurgitation, compared with normal, with


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InternalMed_Harrison. corresponds to the fall in right atrial pressure after tricuspid valve opening. B. Jugular venous wave forms in mild (middle) and severe (top) tricuspid regurgitation, compared with normal, with phonocardiographic representation of the corresponding heart sounds below. With increasing degrees of tricuspid regurgitation, the waveform becomes “ventricularized.” C. Electrocardiogram (ECG) (top), jugular venous waveform (JVP) (middle), and heart sounds (bottom) in pericardial constriction. Note the prominent and rapid y descent, corresponding in timing to the pericardial knock (K). (From J Abrams: Synopsis of Cardiac Physical Diagnosis, 2nd ed. Boston, Butterworth Heinemann, 2001, pp 25–35.) the arm at the level of the heart, using an appropriately sized cuff, after 5–10 min of relaxation. When it is measured in the supine position, the arm should be raised to bring it to the level of the mid-right atrium. The length and width of the blood pressure cuff bladder should be 80% and 40% of


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InternalMed_Harrison. When it is measured in the supine position, the arm should be raised to bring it to the level of the mid-right atrium. The length and width of the blood pressure cuff bladder should be 80% and 40% of the arm’s circumference, respectively. A common source of error in practice is to use an inappropriately small cuff, resulting in marked overestimation of true blood pressure, or an inappropriately large cuff, resulting in underestimation of true blood pressure. The cuff should be inflated to 30 mmHg above the expected systolic pressure and the pressure released at a rate of 2–3 mmHg/s. Systolic and diastolic pressures are defined by the first and fifth Korotkoff sounds, respectively. Very low (even 0 mmHg) diastolic blood pressures may be recorded in patients with chronic, severe AR or a large arteriovenous fistula because of enhanced diastolic “run-off.” In these instances, both the phase IV and phase V Korotkoff sounds should be recorded. Blood pressure is best assessed at the brachial


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InternalMed_Harrison. arteriovenous fistula because of enhanced diastolic “run-off.” In these instances, both the phase IV and phase V Korotkoff sounds should be recorded. Blood pressure is best assessed at the brachial artery level, though it can be measured at the radial, popliteal, or pedal pulse level. In general, systolic pressure increases and diastolic pressure decreases when measured in more distal arteries. Blood pressure should be measured in both arms, and the difference should be less than 10 mmHg. A blood pressure differential that exceeds this threshold may be associated with atherosclerotic or inflammatory subclavian artery disease, supravalvular aortic stenosis, aortic coarctation, or aortic dissection. Systolic leg pressures are usually as much as 20 mmHg higher than systolic arm pressures. Greater leg–arm pressure differences are seen in patients with chronic severe AR as well as patients with extensive and calcified lower extremity peripheral arterial disease. The ankle-brachial index


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InternalMed_Harrison. Greater leg–arm pressure differences are seen in patients with chronic severe AR as well as patients with extensive and calcified lower extremity peripheral arterial disease. The ankle-brachial index (lower pressure in the dorsalis pedis or posterior tibial artery divided by the higher of the two brachial artery pressures) is a powerful predictor of long-term cardiovascular mortality.


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InternalMed_Harrison. The blood pressure measured in an office or hospital setting may not accurately reflect the pressure in other venues. “White coat hypertension” is defined by at least three separate clinic-based measurements >140/90 mmHg and at least two non-clinic-based measurements <140/90 mmHg in the absence of any evidence of target organ damage. Individuals with white coat hypertension may not benefit from drug therapy, although they may be more likely to develop sustained hypertension over time. Masked hypertension should be suspected when normal or even low blood pressures are recorded in patients with advanced atherosclerotic disease, especially when evidence of target organ damage is present or bruits are audible.


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InternalMed_Harrison. Orthostatic hypotension is defined by a fall in systolic pressure >20 mmHg or in diastolic pressure >10 mmHg in response to assumption of the upright posture from a supine position within 3 min. There may also be a lack of a compensatory tachycardia, an abnormal response that suggests autonomic insufficiency, as may be seen in patients with diabetes or Parkinson’s disease. Orthostatic hypotension is a common cause of postural lightheadedness/syncope and should be assessed routinely in patients for whom this diagnosis might pertain. It can be exacerbated by advanced age, dehydration, certain medications, food, deconditioning, and ambient temperature.


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InternalMed_Harrison. Arterial Pulse The carotid artery pulse occurs just after the ascending aortic pulse. The aortic pulse is best appreciated in the epigastrium, just above the level of the umbilicus. Peripheral arterial pulses that should be assessed routinely include the subclavian, brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial. In patients in whom the diagnosis of either temporal arteritis or polymyalgia rheumatica is suspected, the temporal arteries also should be examined. Although one of the two pedal pulses may not be palpable in up to 10% of normal subjects, the pair should be symmetric. The integrity of the arcuate system of the hand is assessed by Allen’s test, which is performed routinely before instrumentation of the radial artery. The pulses should be examined for their symmetry, volume, timing, contour, amplitude, and duration. If necessary, simultaneous auscultation of the heart can help identify a delay in the arrival of an arterial pulse. Simultaneous


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InternalMed_Harrison. for their symmetry, volume, timing, contour, amplitude, and duration. If necessary, simultaneous auscultation of the heart can help identify a delay in the arrival of an arterial pulse. Simultaneous palpation of the radial and femoral pulses may reveal a femoral delay in a patient with hypertension and suspected aortic coarctation. The carotid upstrokes should never be examined simultaneously or before listening for a bruit. Light pressure should always be used to avoid precipitation of carotid hypersensitivity 1445 syndrome and syncope in a susceptible elderly individual. The arterial pulse usually becomes more rapid and spiking as a function of its distance from the heart, a phenomenon that reflects the muscular status of the more peripheral arteries and the summation of the incident and reflected waves. In general, the character and contour of the arterial pulse depend on the stroke volume, ejection velocity, vascular compliance, and systemic vascular resistance. The pulse


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InternalMed_Harrison. and reflected waves. In general, the character and contour of the arterial pulse depend on the stroke volume, ejection velocity, vascular compliance, and systemic vascular resistance. The pulse examination can be misleading in patients with reduced cardiac output and in those with stiffened arteries from aging, chronic hypertension, or peripheral arterial disease.


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InternalMed_Harrison. The character of the pulse is best appreciated at the carotid level (Fig. 267-2). A weak and delayed pulse (pulsus parvus et tardus) defines severe aortic stenosis (AS). Some patients with AS may also have a slow, notched, or interrupted upstroke (anacrotic pulse) with a thrill or shudder. With chronic severe AR, by contrast, the carotid upstroke has a sharp rise and rapid fall-off (Corrigan’s or water-hammer pulse). Some patients with advanced AR may have a bifid or bisferiens pulse, in which two systolic peaks can be appreciated. A bifid pulse is also described in patients with hypertrophic obstructive cardiomyopathy (HOCM), with inscription of percussion and tidal waves. A bifid pulse is easily appreciated in patients on intraaortic balloon counterpulsation (IABP), in whom the second pulse is diastolic in timing.


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InternalMed_Harrison. Pulsus paradoxus refers to a fall in systolic pressure >10 mmHg with inspiration that is seen in patients with pericardial tamponade but also is described in those with massive pulmonary embolism, hemorrhagic shock, severe obstructive lung disease, and tension pneumothorax.


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InternalMed_Harrison. FIGURE 267-2 Schematic diagrams of the configurational changes in carotid pulse and their differential diagnoses. Heart sounds are also illustrated. A. Normal. S4, fourth heart sound; S1, first heart sound; A2 aortic component of second heart sound; P2 pulmonic component of second heart sound. B. Aortic stenosis. Anacrotic pulse with slow upstroke to a reduced peak. C. Bisferiens pulse with two peaks in systole. This pulse is rarely appreciated in patients with severe aortic regurgitation. D. Bisferiens pulse in hypertrophic obstructive cardiomyopathy. There is a rapid upstroke to the first peak (percussion wave) and a slower rise to the second peak (tidal wave). E. Dicrotic pulse with peaks in systole and diastole. This waveform may be seen in patients with sepsis or during intraaortic balloon counterpulsation with inflation just after the dicrotic notch. (From K Chatterjee, W Parmley [eds]: Cardiology: An Illustrated Text/Reference. Philadelphia, Gower Medical Publishers, 1991.)


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InternalMed_Harrison. Physical Examination of the Cardiovascular System 1446 Pulsus paradoxus is measured by noting the difference between the patient with calf claudication, a decrease in pulse amplitude between systolic pressure at which the Korotkoff sounds are first heard (dur-the common femoral and popliteal arteries will localize the obstrucing expiration) and the systolic pressure at which the Korotkoff tion to the level of the superficial femoral artery, although inflow sounds are heard with each heartbeat, independent of the respiratory obstruction above the level of the common femoral artery may coexist. phase. Between these two pressures, the Korotkoff sounds are heard Auscultation for carotid, subclavian, abdominal aortic, and femoral only intermittently and during expiration. The cuff pressure must be artery bruits should be routine. However, the correlation between the decreased slowly to appreciate the finding. It can be difficult to mea-presence of a bruit and the degree of vascular


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InternalMed_Harrison. must be artery bruits should be routine. However, the correlation between the decreased slowly to appreciate the finding. It can be difficult to mea-presence of a bruit and the degree of vascular obstruction is poor. A sure pulsus paradoxus in patients with tachycardia, atrial fibrillation, cervical bruit is a weak indicator of the degree of carotid artery steno-or tachypnea. A pulsus paradoxus may be palpable at the brachial sis; the absence of a bruit does not exclude the presence of significant artery or femoral artery level when the pressure difference exceeds luminal obstruction. If a bruit extends into diastole or if a thrill is pres15 mmHg. This inspiratory fall in systolic pressure is an exaggerated ent, the obstruction is usually severe. Another cause of an arterial bruit consequence of interventricular dependence. is an arteriovenous fistula with enhanced flow.


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InternalMed_Harrison. Pulsus alternans, in contrast, is defined by beat-to-beat variability of The likelihood of significant lower extremity peripheral arterial pulse amplitude. It is present only when every other phase I Korotkoff disease increases with typical symptoms of claudication, cool skin, sound is audible as the cuff pressure is lowered slowly, typically in a abnormalities on pulse examination, or the presence of a vascular patient with a regular heart rhythm and independent of the respiratory bruit. Abnormal pulse oximetry (a >2% difference between finger and cycle. Pulsus alternans is seen in patients with severe left ventricular toe oxygen saturation) can be used to detect lower extremity peripheral systolic dysfunction and is thought to be due to cyclic changes in intra-arterial disease and is comparable in its performance characteristics to cellular calcium and action potential duration. When pulsus alternans the ankle-brachial index. is associated with electrocardiographic T-wave alternans,


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InternalMed_Harrison. in its performance characteristics to cellular calcium and action potential duration. When pulsus alternans the ankle-brachial index. is associated with electrocardiographic T-wave alternans, the risk for an arrhythmic event appears to be increased. Inspection and Palpation of the Heart The left ventricular apex beat


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InternalMed_Harrison. Ascending aortic aneurysms can rarely be appreciated as a pulsa-may be visible in the midclavicular line at the fifth intercostal space tile mass in the right parasternal area. Appreciation of a prominent in thin-chested adults. Visible pulsations anywhere other than this abdominal aortic pulse should prompt noninvasive imaging for better expected location are abnormal. The left anterior chest wall may heave characterization. Femoral and/or popliteal artery aneurysms should be in patients with an enlarged or hyperdynamic left or right ventricle. sought in patients with abdominal aortic aneurysm disease. As noted previously, a visible right upper parasternal pulsation may be The level of a claudication-producing arterial obstruction can often suggestive of ascending aortic aneurysm disease. In thin, tall patients be identified on physical examination (Fig. 267-3). For example, in a and patients with advanced obstructive lung disease and flattened


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InternalMed_Harrison. Anterior superior Posterior tibial a. External iliac a. Deep femoral a. Palpatation of Blood pressure popliteal artery pulse cuff Femoral a. Popliteal a. Dorsalis pedis a. Dorsalis pedis a. A Major arteries of the lower limb B Measurement of ankle systolic pressure FIGURE 267-3 A. Anatomy of the major arteries of the leg. B. Measurement of the ankle systolic pressure. (From NA Khan et al: JAMA 295:536, 2006.) diaphragms, the cardiac impulse may be visible in the epigastrium and should be distinguished from a pulsatile liver edge. Palpation of the heart begins with the patient in the supine position at 30° and can be enhanced by placing the patient in the left lateral decubitus position. The normal left ventricular impulse is less than 2 cm in diameter and moves quickly away from the fingers; it is better appreciated at end expiration, with the heart closer to the anterior chest wall. Characteristics such as size, amplitude, and rate of force development should be noted.


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InternalMed_Harrison. Enlargement of the left ventricular cavity is manifested by a leftward and downward displacement of an enlarged apex beat. A sustained apex beat is a sign of pressure overload, such as that which may be present in patients with AS or chronic hypertension. A palpable presystolic impulse corresponds to the fourth heart sound (S4) and is indicative of reduced left ventricular compliance and the forceful contribution of atrial contraction to ventricular filling. A palpable third sound (S3), which is indicative of a rapid early filling wave in patients with heart failure, may be present even when the gallop itself is not audible. A large left ventricular aneurysm may sometimes be palpable as an ectopic impulse, discrete from the apex beat. HOCM may very rarely cause a triple cadence beat at the apex with contributions from a palpable S4 and the two components of the bisferiens systolic pulse.


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InternalMed_Harrison. Right ventricular pressure or volume overload may create a sternal lift. Signs of either TR (cv waves in the jugular venous pulse) and/or pulmonary arterial hypertension (a loud single or palpable P2) would be confirmatory. The right ventricle can enlarge to the extent that left-sided events cannot be appreciated. A zone of retraction between the right and left ventricular impulses sometimes can be appreciated in patients with right ventricle pressure or volume overload when they are placed in the left lateral decubitus position. Systolic and diastolic thrills signify turbulent and high-velocity blood flow. Their locations help identify the origin of heart murmurs.


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InternalMed_Harrison. CARDIAC AUSCULTATION Heart Sounds Ventricular systole is defined by the interval between the first (S1) and second (S2) heart sounds (Fig. 267-4). The first heart sound (S1) includes mitral and tricuspid valve closure. Normal splitting can be appreciated in young patients and those with right bundle branch block, in whom tricuspid valve closure is relatively delayed. The intensity of S1 is determined by the distance over which the anterior leaflet of the mitral valve must travel to return to its annular plane, leaflet mobility, left ventricular contractility, and the PR interval. S1 is classically loud in the early phases of rheumatic mitral stenosis (MS) and in patients with hyperkinetic circulatory states or short PR intervals. S1 becomes softer in the later stages of MS when the leaflets are rigid and calcified, after exposure to β-adrenergic receptor blockers, with long PR intervals, and with left ventricular contractile dysfunction. The intensity of heart sounds, however, can be


InternalMed_Harrison

InternalMed_Harrison. are rigid and calcified, after exposure to β-adrenergic receptor blockers, with long PR intervals, and with left ventricular contractile dysfunction. The intensity of heart sounds, however, can be reduced by any process that increases the distance between the stethoscope and the responsible cardiac event, including mechanical ventilation, obstructive lung disease, obesity, pneumothorax, and a pericardial effusion.


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InternalMed_Harrison. Aortic and pulmonic valve closure constitutes the second heart sound (S2). With normal or physiologic splitting, the A2–P2 interval increases with inspiration and narrows during expiration. This physiologic interval will widen with right bundle branch block because of the further delay in pulmonic valve closure and in patients with severe MR because of the premature closure of the aortic valve. An unusually narrowly split or even a singular S2 is a feature of pulmonary arterial hypertension. Fixed splitting of S2, in which the A2–P2 interval is wide and does not change during the respiratory cycle, occurs in patients with a secundum atrial septal defect. Reversed or paradoxical splitting refers to a pathologic delay in aortic valve closure, such as that which occurs in patients with left bundle branch block, right ventricular pacing, severe AS, HOCM, and acute myocardial ischemia. With reversed or paradoxical splitting, the individual components of S2 are audible at end expiration,


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InternalMed_Harrison. bundle branch block, right ventricular pacing, severe AS, HOCM, and acute myocardial ischemia. With reversed or paradoxical splitting, the individual components of S2 are audible at end expiration, and their interval narrows with inspiration, the opposite of what would be expected under normal physiologic conditions. P2 is considered loud when its intensity exceeds that of A2 at the base, when it can be palpated in the area of the proximal main pulmonary


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InternalMed_Harrison. C Expiratory splitting with inspiratory S1 S2S1 S2 increase (RBBB, idiopathic dilatation PA) P2 (LBBB, aortic stenosis) S1 S2 S1 S2 FIGURE 267-4 Heart sounds. A. Normal. S1, first heart sound; S2, second heart sound; A2, aortic component of the second heart sound; P2, pulmonic component of the second heart sound. B. Atrial septal defect with fixed splitting of S2. C. Physiologic but wide splitting of S2 with right bundle branch block (RBBB). PA, pulmonary artery. D. Reversed or paradoxical splitting of S2 with left bundle branch block (LBBB). E. Narrow splitting of S2 with pulmonary hypertension. (From NO Fowler: Diagnosis of Heart Disease. New York, Springer-Verlag, 1991, p 31.) artery (second left interspace), or when both components of S2 can be appreciated at the lower left sternal border or apex. The intensity of A2 and P2 decreases with aortic and pulmonic stenosis, respectively. In these conditions, a single S2 may result.


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InternalMed_Harrison. Systolic Sounds An ejection sound is a high-pitched early systolic sound that corresponds in timing to the upstroke of the carotid pulse. It usually is associated with congenital bicuspid aortic or pulmonic valve disease; however, ejection sounds are also sometimes audible in patients with isolated aortic or pulmonary root dilation and normal semilunar valves. The ejection sound that accompanies bicuspid aortic valve disease becomes softer and then inaudible as the valve calcifies and becomes more rigid. The ejection sound that accompanies pulmonic stenosis (PS) moves closer to the first heart sound as the severity of the stenosis increases. In addition, the pulmonic ejection sound is the only right-sided acoustic event that decreases in intensity with inspiration. Ejection sounds are often heard more easily at the lower left sternal border than they are at the base. Nonejection sounds (clicks), which occur after the onset of the carotid upstroke, are related to MVP and may be single


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InternalMed_Harrison. heard more easily at the lower left sternal border than they are at the base. Nonejection sounds (clicks), which occur after the onset of the carotid upstroke, are related to MVP and may be single or multiple. The nonejection click may introduce a murmur. This click-murmur complex will move away from the first heart sound with maneuvers that increase ventricular preload, such as squatting. On standing, the click and murmur move closer to S1.


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InternalMed_Harrison. Diastolic Sounds The high-pitched opening snap (OS) of MS occurs after a very short interval after the second heart sound. The A2–OS interval is inversely proportional to the height of the left atrial–left ventricular diastolic pressure gradient. The intensity of both S1 and the OS of MS decreases with progressive calcification and rigidity of the anterior mitral leaflets. The pericardial knock (PK) is also high-pitched


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InternalMed_Harrison. Physical Examination of the Cardiovascular System 1448 and occurs slightly later than the OS, corresponding in timing to the abrupt cessation of ventricular expansion after tricuspid valve opening and to an exaggerated y descent seen in the jugular venous waveform in patients with constrictive pericarditis. A tumor plop is a lower-pitched sound that rarely can be heard in patients with atrial myxoma. It may be appreciated only in certain positions and arises from the diastolic prolapse of the tumor across the mitral valve. The third heart sound (S3) occurs during the rapid filling phase of ventricular diastole. It can be a normal finding in children, adolescents, and young adults; however, in older patients, it signifies heart failure. A left-sided S3 is a low-pitched sound best heard over the left ventricular (LV) apex. A right-sided S3 is usually better heard over the lower left sternal border and becomes louder with inspiration. A left-sided S3 in patients with chronic heart


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InternalMed_Harrison. over the left ventricular (LV) apex. A right-sided S3 is usually better heard over the lower left sternal border and becomes louder with inspiration. A left-sided S3 in patients with chronic heart failure is predictive of cardiovascular morbidity and mortality. Interestingly, an S3 is equally prevalent among heart failure patients with and without LV systolic dysfunction. The fourth heart sound (S4) occurs during the atrial filling phase of ventricular diastole and indicates LV presystolic expansion. An S4 is more common among patients who derive significant benefit from the atrial contribution to ventricular filling, such as those with chronic LV hypertrophy or active myocardial ischemia. An S4 is not present with atrial fibrillation.


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InternalMed_Harrison. Cardiac Murmurs Heart murmurs result from audible vibrations that are caused by increased turbulence and are defined by their timing within the cardiac cycle. Not all murmurs are indicative of structural heart disease, and the accurate identification of a benign or functional systolic murmur often can obviate the need for additional testing in healthy subjects. The duration, frequency, configuration, and intensity of a heart murmur are dictated by the magnitude, variability, and duration of the responsible pressure difference between two cardiac chambers, the two ventricles, or the ventricles and their respective great arteries. The intensity of a heart murmur is graded on a scale of 1 to 6; a thrill is present with murmurs of grade 4 or greater intensity. Other attributes of the murmur that aid in its accurate identification include its location, radiation, and response to bedside maneuvers. Although clinicians can detect and correctly identify heart murmurs with only fair


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InternalMed_Harrison. murmur that aid in its accurate identification include its location, radiation, and response to bedside maneuvers. Although clinicians can detect and correctly identify heart murmurs with only fair reliability, a careful and complete bedside examination usually can identify individuals with valvular heart disease for whom transthoracic echocardiography and clinical follow-up are indicated and exclude subjects for whom no further evaluation is necessary.


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InternalMed_Harrison. Systolic murmurs can be early, mid, late, or holosystolic in timing (Fig. 267-5). Acute severe MR results in a decrescendo early systolic murmur, the characteristics of which are related to the progressive attenuation of the left ventricular to left atrial pressure gradient during systole because of the steep and rapid rise in left atrial pressure in this context. Severe MR associated with posterior leaflet prolapse or flail radiates anteriorly and to the base, where it can be confused with the murmur of AS. MR that is due to anterior leaflet involvement radiates posteriorly and to the axilla. With acute TR in patients with normal pulmonary artery pressures, an early systolic murmur that may increase in intensity with inspiration may be heard at the left lower sternal border, with regurgitant cv waves visible in the jugular venous pulse.