1808 PART 6 Disorders of the Cardiovascular System

TABLE 237-2 Determinants of Stroke Volume

I. Ventricular Preload

A. Blood volume

B. Distribution of blood volume

1. Body position

2. Intrathoracic pressure

3. Intrapericardial pressure

4. Venous tone

5. Pumping action of skeletal muscles

C. Atrial contraction

II. Ventricular Afterload

A. Systemic vascular resistance

B. Elasticity of arterial tree

C. Arterial blood volume

D. Ventricular wall tension

1. Ventricular radius

2. Ventricular wall thickness

III. Myocardial Contractilitya

A. Intramyocardial [Ca2+] ↑↓

B. Cardiac adrenergic nerve activity ↑↓b

C. Circulating catecholamines ↑↓b

D. Cardiac rate ↑↓b

E. Exogenous inotropic agents ↑

F. Myocardial ischemia ↓

G. Myocardial cell death (necrosis, apoptosis, autophagy) ↓

H. Alterations of sarcomeric and cytoskeletal proteins ↓

1. Genetic

2. Hemodynamic overload

I. Myocardial fibrosis ↓

J. Chronic overexpression of neurohormones ↓

K. Ventricular remodeling ↓

L. Chronic and/or excessive myocardial hypertrophy ↓

a

Arrows indicate directional effects of determinants of contractility. b

Contractility

rises initially but later becomes depressed. Ventricular performance

Maximal activity

Walking

Rest

Normal-exercise

Normal-rest

Contractile state of myocardium

Exercise

Heart failure

Fatal myocardial

depression

Dyspnea Pulmonary edema

Ventricular EDV

Stretching of myocardium

2 C

A

D

B

1

3

3′

E

4

FIGURE 237-9 The interrelations among influences on ventricular end-diastolic

volume (EDV) through stretching of the myocardium and the contractile state of the

myocardium. Levels of ventricular EDV associated with filling pressures that result

in dyspnea and pulmonary edema are shown on the abscissa. Levels of ventricular

performance required when the subject is at rest, while walking, and during maximal

activity are designated on the ordinate. The broken lines are the descending limbs of

the ventricular-performance curves, which are rarely seen during life but show the

level of ventricular performance if end-diastolic volume could be elevated to very

high levels. For further explanation, see text. (Reproduced with permission from WS

Colucci and E Braunwald, in DP Zipes et al (eds): Pathophysiology of heart failure, in

Braunwald’s Heart Disease, 7th ed. Philadelphia, Elsevier, 2005.)

Contractility Stroke volume

Afterload Heart rate

Preload

Higher

nervous

centers

Medullary

vasomotor

and cardiac

centers

Venous

return

Cardiac

output

Peripheral

resistance

Arterial

pressure

Carotid and

aortic

baroreceptors

FIGURE 237-10 Interactions in the intact circulation of preload, contractility,

and afterload in producing stroke volume. Stroke volume combined with heart

rate determines cardiac output, which, when combined with peripheral vascular

resistance, determines arterial pressure for tissue perfusion. The characteristics

of the arterial system also contribute to afterload, an increase that reduces

stroke volume. The interaction of these components with carotid and aortic arch

baroreceptors provides a feedback mechanism to higher medullary and vasomotor

cardiac centers and to higher levels in the central nervous system to affect a

modulating influence on heart rate, peripheral vascular resistance, venous return,

and contractility. (Reproduced with permission from MR Starling, in WS Colucci

and E Braunwald (eds): Physiology of myocardial contraction, in Atlas of Heart

Failure: Cardiac Function and Dysfunction, 3rd ed. Philadelphia, Current Medicine,

2002.)

other factors, such as adrenergic neuronal impulses increasing cardiac

contractility, heart rate, and venous tone, will serve as compensatory

mechanisms and sustain cardiac output in a normal individual. Ultimately, understanding the complex interactions between these different variables requires rigorous models to predict relevant outcomes,

and led to the early application of systems engineering principles in

medicine.

■ EXERCISE

The integrated response to exercise illustrates typical interactions among

the three determinants of stroke volume: preload, afterload, and contractility (Fig. 237-9). Hyperventilation, the pumping action of the exercising muscles, and venoconstriction during exercise all augment venous

return and hence ventricular filling and preload (Table 237-2). Simultaneously, the increase in neuronal and humoral adrenergic stimulation

of the myocardium and the tachycardia that occur during exercise

combine to augment the myocardial contractility (Fig. 237-9, curves

1 and 2), together elevating stroke volume and stroke work, with little

or no change in end-diastolic pressure and volume (Fig. 237-9, points

A and B). Vasodilation occurs in the exercising muscles, thus limiting

the increase in afterload that otherwise would occur as cardiac output

rises to levels as high as five times greater than basal levels during

maximal exercise. This vasodilation ultimately allows the achievement

of elevated cardiac outputs during exercise at arterial pressures only

moderately higher than the resting state.

ASSESSMENT OF CARDIAC FUNCTION

Several techniques can define impaired cardiac function in clinical

practice. Cardiac output and stroke volume may decline in the presence

of heart failure, but these variables are often within normal limits, especially at rest. A more sensitive index of cardiac function is the ejection

fraction, i.e., the ratio of stroke volume to end-diastolic volume (normal

value = 67 ± 8%), which is frequently depressed in systolic heart failure

even when stroke volume is normal. Alternatively, abnormally elevated

ventricular end-diastolic volume (normal value = 75 ± 20 mL/m2

) or

Basic Biology of the Cardiovascular System

1809CHAPTER 237

3

LV volume

ESPVR

afterload

LV pressure

1

2

preload

3

LV volume

LV pressure

1

2

Contractility

Contractility

Normal

 contractility

FIGURE 237-11 The responses of the left ventricle (LV) to increased afterload, increased preload, and increased and reduced contractility are shown in the pressurevolume plane. Left. Effects of increases in preload and afterload on the pressure-volume loop. Because there has been no change in contractility, the end-systolic pressurevolume relationship (ESPVR) is unchanged. With an increase in afterload, stroke volume falls (1 → 2); with an increase in preload, stroke volume rises (1 → 3). Right. With

increased myocardial contractility and constant left ventricular end-diastolic volume, the ESPVR moves to the left of the normal line (lower end-systolic volume at any

end-systolic pressure) and stroke volume rises (1 → 3). With reduced myocardial contractility, the ESPVR moves to the right; end-systolic volume is increased, and stroke

volume falls (1 → 2).

end-systolic volume (normal value = 25 ± 7 mL/m2

) signifies left ventricular systolic impairment.

Noninvasive techniques, particularly echocardiography, radionuclide scintigraphy, and cardiac magnetic resonance imaging (MRI)

(Chap. 241), have great value in the clinical assessment of myocardial

function. They provide measurements of end-diastolic and endsystolic volumes, ejection fraction, and systolic shortening rate, and

they allow assessment of ventricular filling (see below) as well as

regional contraction, relaxation, and tissue characterization. The latter

measurements have particular importance in ischemic heart disease, as

myocardial infarction causes regional myocardial damage.

Strong dependence on ventricular loading conditions influences the

precision of measurements of cardiac output, ejection fraction, and

ventricular volumes as indices of cardiac function. Thus, a depressed

ejection fraction and lowered cardiac output may occur in patients

with normal ventricular function but reduced preload, as occurs in

hypovolemia, or with increased afterload, as occurs in acutely elevated

arterial pressure.

The end-systolic left ventricular pressure-volume relationship has

particular value as an index of ventricular performance as it does

not depend on preload and afterload (Fig. 237-11). At any level of

myocardial contractility, left ventricular end-systolic volume varies

inversely with end-systolic pressure; as contractility declines, endsystolic volume (at any level of end-systolic pressure) rises. Invasive

measurement of end-systolic left ventricular pressure-volume loops

add rigor to research studies of left ventricular function, and integrated

cardiopulmonary exercise testing is now more broadly available, but

these techniques are less pragmatic than the more readily assessed indices obtained in routine clinical practice, such as ventricular volumes

and ejection fraction. Longitudinal measurements of some aspects of

cardiovascular physiology are increasingly feasible with implantable or

wearable devices.

■ DIASTOLIC FUNCTION

Ventricular filling is influenced by several characteristics of the myocardium, including (1) the extent and speed of myocardial relaxation

and (2) the passive stiffness of the ventricular wall. The former is

largely a function of the rate of uptake of Ca2+ by the SR that may be

enhanced by adrenergic activation and reduced by ischemia due to

limited ATP available for pumping Ca2+ into the SR (see above). For

the latter, ventricular stiffness increases with hypertrophy, fibrosis,

and conditions that infiltrate the ventricle, such as amyloid, or can

result from an extrinsic constraint (e.g., pericardial compression)

(Fig. 237-12).

Ventricular filling can be assessed by measuring flow velocity across

the mitral valve using Doppler ultrasound. Normally, inflow velocity is

more rapid in early diastole than during atrial systole. However, with

mild to moderately impaired relaxation, the rate of early diastolic filling

declines as presystolic filling rates rise. With further stiffening, flow is

“pseudo-normalized,” as early ventricular filling becomes more rapid

with rising left atrial pressure upstream of the left ventricle.

■ CARDIAC METABOLISM

The heart requires a continuous supply of energy (ATP) not only to

drive mechanical contraction but also to maintain ionic and biochemical homeostasis. The development of tension, the frequency of contraction, and myocardial contractility levels are the principal determinants

Abnormal relaxation Pericardial restraint

Chamber

dilation

Increased chamber

stiffness

Left ventricular volume

Left ventricular pressure

FIGURE 237-12 Mechanisms that cause diastolic dysfunction reflected in the

pressure-volume relation. The bottom half of the pressure-volume loop is depicted.

Solid lines represent normal subjects; broken lines represent patients with diastolic

dysfunction. (Reproduced with permission from JD Carroll et al: The differential

effects of positive inotropic and vasodilator therapy on diastolic properties in

patients with congestive cardiomyopathy. Circulation 74:815, 1986.)

1810 PART 6 Disorders of the Cardiovascular System

Mann D et al (eds): Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed. Philadelphia, Elsevier, 2015.

Page E et al (eds): Handbook of Physiology: A Critical Comprehensive

Presentation of Physiological Knowledge and Concepts. Section 2:

The Cardiovascular System, Volume I: The Heart. New York, Oxford

University Press, 2002.

Spinale FG: Assessment of cardiac function—Basic principles and

approaches. Compr Physiol 5:1911, 2015.

Srivastava D: Making or breaking the heart: From lineage determination to morphogenesis. Cell 126:1037, 2006.

Taegtmeyer H et al: Cardiac metabolism in perspective. Comp

Physiol 6:1675, 2016.

of the heart’s energy and oxygen requirements, representing ~15% of

that of the entire organism.

The heart’s ATP production requires the generation of acetyl coenzyme A (acetyl-CoA) that can be derived from (in descending order)

free fatty acids (FFAs), glucose, lactate, amino acids, and ketone bodies.

Myocardial FFAs derive from circulating FFAs, whereas the cardiomyocyte’s glucose derives from plasma as well as from myocardial glycogen

stores (glycogenolysis). These two principal sources of acetyl-CoA are

metabolized distinctly in cardiac muscle. Glucose is converted in the

cytoplasm into pyruvate, which passes into mitochondria for conversion into acetyl-CoA that then 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; ATP then enters the cytoplasm from the mitochondrial compartment. Intracellular adenosine diphosphate (ADP),

resulting from ATP breakdown, enhances ATP production.

In the fasted, resting state, circulating FFAs furnish most of the

heart’s acetyl-CoA (~70%). In the fed state, with elevations of blood

glucose and insulin, glucose oxidation increases and FFA oxidation

subsides. Increased cardiac work, inotropic agents, hypoxia, and mild

ischemia all enhance myocardial glucose uptake, production (glycogenolysis), and metabolism to pyruvate (glycolysis). Exercise raises

circulating lactate levels and myocardial utilization of acetyl-CoA.

By contrast, β-adrenergic stimulation, even from stress, raises the

circulating levels and metabolism of FFAs in favor of glucose. Severe

myocardial ischemia inhibits cytoplasmic pyruvate dehydrogenase,

producing incomplete glucose metabolism to lactic acid (anaerobic

glycolysis). Anaerobic glycolysis produces much less ATP than does

aerobic glucose metabolism. High concentrations of circulating FFAs,

which can occur when adrenergic stimulation is superimposed on

severe ischemia, reduce oxidative phosphorylation, and the myocardial content of ATP declines, impairing contraction. In addition, FFA

breakdown products may exert toxic or arrhythmogenic effects on

cardiac cell membranes.

Myocardial energy is stored as creatine phosphate (CP), which

is in equilibrium with ATP, the immediate energy source. In states

of reduced energy availability, the CP stores decline first. Cardiac

hypertrophy, fibrosis, tachycardia, increased wall tension due to 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.

■ REGENERATING CARDIAC TISSUE

Adult mammalian myocardial cells are fully differentiated and have

little or no regenerative potential; however, there is evidence that the

immature mammalian heart has some limited regenerative potential

that rapidly becomes constrained with increasing maturity and workload. Considerable current effort is being devoted to evaluating the

utility of various approaches to facilitate the transient release of these

constraints to enhance cardiac repair after injury. The success of such

approaches would offer the exciting possibility of reconstructing an

infarcted or failing ventricle (Chap. 484).

Acknowledgment

The authors wish to thank Peter Libby for his contribution to the prior

version of this chapter.

■ FURTHER READING

Bautch VL, Caron KM: Blood and lymphatic vessel formation. Cold

Spring Harb Perspect Biol 7(3):a008268, 2015.

Dejana E et al: The molecular basis of endothelial cell plasticity. Nat

Commun 8:14361, 2017.

Green DJ et al: Vascular adaptation to exercise in humans: Role of

hemodynamic stimuli. Physiol Rev 97:495, 2017.

MacLeod KT: Recent advances in understanding cardiac contractility

in health and disease. F1000Res 5(F1000 Faculty Rev):1770, 2016.

Cardiovascular disease (CVD) is now the most common cause of death

worldwide. Before 1900, infectious diseases and malnutrition were the

most common causes, and CVD was responsible for <10% of all deaths.

In 2017, CVD accounted for 17.8 million deaths worldwide (32%), with

the same rate now occurring in both high-income countries and lowand middle-income countries.

THE EPIDEMIOLOGIC TRANSITION

The global rise in CVD is the result of an unprecedented transformation in the causes of morbidity and mortality during the twentieth

century. Known as the epidemiologic transition, this shift is driven

by industrialization, urbanization, and associated lifestyle and demographic 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 238-1).

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 <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.

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.

The age of degenerative and man-made diseases is distinguished

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.

238 Epidemiology of

Cardiovascular Disease

Thomas A. Gaziano, J. Michael Gaziano

Epidemiology of Cardiovascular Disease

1811CHAPTER 238

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.

On 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 two- to fivefold 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 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. 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.

Patterns in low- and middle-income countries (LMICs; gross

national income per capita $11,666) 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. 238-1). In most LMICs, an urban/rural gradient

has emerged for CHD, stroke, and hypertension, with higher rates in

urban centers.

However, although CVD rates are rapidly rising globally, vast differences exist among the regions and countries, and even within the

TABLE 238-1 Five Stages of the Epidemiologic Transition

STAGE DESCRIPTION

DEATHS RELATED

TO CVD, % PREDOMINANT CVD TYPE

Pestilence and famine Predominance of malnutrition and infectious diseases as causes of death;

high rates of infant and child mortality; low mean life expectancy

<10 Rheumatic heart disease, cardiomyopathies

caused by infection and malnutrition

Receding pandemics Improvements in nutrition and public health lead to decrease in rates of

deaths related to malnutrition and infection; precipitous decline in infant

and child mortality rates

10–35 Rheumatic valvular disease, hypertension,

CHD, and stroke (predominantly

hemorrhagic)

Degenerative and manmade diseases

Increased fat and caloric intake and decrease in physical 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

35–65 CHD and stroke (ischemic and hemorrhagic)

Delayed degenerative

diseases

CVD and cancer are the major causes of morbidity and 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

40–50 CHD, stroke, and congestive heart failure

Inactivity and obesity Overweight and obesity increase at alarming rate; diabetes and

hypertension increase; decline in smoking rates levels off; a minority of

the population meets physical activity recommendations

38 CHD, stroke, and congestive heart failure,

peripheral vascular disease

Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease.

Source: Data 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.

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.

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

that have fallen for decades during the fourth phase could increase in

the coming years as suggested by recent data.

■ PATTERNS IN THE EPIDEMIOLOGIC TRANSITION

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 past

60 years, whereas CVD death rates increased by 15% over the past

20 years in the low- and middle-income range and the rate of change

has been faster. 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

~390 per 100,000. Between 1930 and 1965, the country entered the age

of degenerative 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.

1812 PART 6 Disorders of the Cardiovascular System

countries themselves (Fig. 238-2). 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, 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.

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 causespecific mortality are not complete.

■ GLOBAL TRENDS IN CARDIOVASCULAR DISEASE

Over the past 5 years, there have been changes in the trends of CVD

that are reflective of both trends in demographics and management of

disease, but also of the way deaths and diseases have been measured and

estimated. In 2017, the Global Burden of Disease (GBD) Study updated

its estimates with several important changes based on newly available

data, refinement in the causes of death, and the introduction of new

modeling techniques. The major changes include the addition of an

independent estimation of population and fertility, the addition of over

127 country-years of vital registration and verbal autopsy data, revisions

of some deaths from “misclassified” to dementia, Parkinson’s disease

and atrial fibrillation, and the addition of new diseases such as nonrheumatic calcific aortic and degenerative mitral valve disease. CVD

accounts for 32% of deaths worldwide, a number expected to increase.

In 2017, CHD accounted for 16.0% of all deaths globally and the largest

Highincome

countries

Low- and middleincome

countries

CVD

31.8%

INJ

8.0%

CMNN

18.6%

ONC

41.6%

CVD ONC CMNN INJ

Global deaths by cause, 2017

FIGURE 238-1 Global deaths by cause, 2017. 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 2017. Global Burden of Disease Study 2017 [GBD 2017] Results.

Seattle, United States: Institute for Health Metrics and Evaluation [IHME], 2020.)

Latin America and the Caribbean

27.4%

(582 million)

High-income

31.8%

(1075 million)

South Asia

27.3%

(1783 million)

Sub-Saharan Africa

12.3%

(1026 million)

Southeast and East Asia and Pacific

37.3%

(2159 million)

Middle East and North Africa

41.6%

(600 million)

Europe and Central Asia

43.7%

(416 million)

FIGURE 238-2 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 2017. Global Burden of Disease Study 2017 [GBD 2017] Results. Seattle, United States: Institute for Health Metrics and

Evaluation [IHME], 2020.)

Epidemiology of Cardiovascular Disease

1813CHAPTER 238

CVD deaths per 100,000

1990 1995 2000 2005

Year

2010 2015 2017

500

450

400

350

300

250

200

150

100

50

0

World bank high income

World bank low income

World bank lower middle income

World bank upper middle income

Global

FIGURE 238-3 Age-standardized cardiovascular diseases (CVD) death rate per

100,000 from 1990 to 2017, by World Bank income. (Based on data from Global

Burden of Disease Study 2017. Global Burden of Disease Study 2017 [GBD 2017]

Results. Seattle, United States: Institute for Health Metrics and Evaluation [IHME],

2020.)

Number of CVD Deaths in Millions

1990 1995 2000 2005

Year

2010 2015 2017

20

18

16

14

12

10

8

6

4

2

0

World bank high income

World bank low income

World bank lower middle income

World bank upper middle income

Global

FIGURE 238-4 Number of cardiovascular diseases (CVD) deaths from 1990 to 2017,

by World Bank income. (Based on data from Global Burden of Disease Study 2017.

Global Burden of Disease Study 2017 [GBD 2017] Results. Seattle, United States:

Institute for Health Metrics and Evaluation [IHME], 2020.)

portion (10%) of global years of life lost (YLLs) and disability-adjusted

life-years (DALYs) (7%). Stroke moved from the third to the second

largest cause of death (11.0% of all deaths) and remained the third largest contributor to global YLLs (7%) and DALYs (5%). Together, CHD

and stroke accounted for more than 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.

With 85% of the world’s population, LMICs largely drive global

CVD rates and trends. More than 14 million (14.4) CVD deaths

occurred in LMICs in 2017, compared to 3.3 million in HICs. Globally, there is evidence of significant delays in age of occurrence and/

or improvements in case fatality rates; between 1990 and 2017, the

number of CVD deaths increased by 49%, but age-adjusted death rates

decreased by 30.4% in the same period. Age-standardized death rates,

however, have declined faster in HICs than in middle-income and

lower-income regions (Fig. 238-3). Population growth has been greater

in LMICs compared to HICs. As a result of slower rates of population

growth in HICs, overall CVD deaths remained steady. However, in the

LMICs, the population aging and growth outstripped gains in ageadjusted mortality reductions such that overall CVD deaths continued

to climb over the past 25 years (Fig. 238-4).

Although HIC population growth will be fueled by immigration

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 1.1%

between 2010 and 2017, whereas it was 11% in South Asia. 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.

■ RISK FACTORS

Global variation in CVD rates is related to temporal and regional

variations in known risk factors and behaviors. Ecologic 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

that many regional variations are based on differences in conventional

risk factors.

Behavioral Risk Factors •  TOBACCO Over 1.4 billion people

use tobacco worldwide. Tobacco use currently causes about 7.1 million

deaths annually (12.7% of all deaths), 2.6 million of which are CVDrelated. The population of the high-income country group smokes

(21.6%) at almost double the rate of the low-income countries (11.2%),

whereas the middle-income country group’s smoking rate (19.5%)

approximates the global average (19.2%). From 2007 to 2017, smoking

rates decreased across low-, middle-, and high-income country groups,

with relative reductions of 19%, 12%, and 20%, respectively. By 2030,

the global average smoking rate is expected to decline from 19% to

16% (women, 4%; men, 28%); however, the number of tobacco users

is expected to rise owing to population growth. Secondhand smoke is

another well-established cause of CVD, responsible for 575,000 deaths of

nonsmokers in 2017. Although smoking bans have both immediate and

long-term benefits, implementation varies greatly between countries.

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 <20% of calories in rural China and India, <30% in Japan, and well

above 30% in the United States. Caloric contributions from fat appear

to be falling in the HICs.

PHYSICAL INACTIVITY The increased mechanization that accompanies the economic transition leads to a shift from physically demanding,

agriculture-based work to largely sedentary industry- and office-based

work. Physical inactivity is responsible for 1.3 million global deaths

annually. The global prevalence of physical inactivity has remained

steady between 2001 and 2016 (28.5% to 27.5%). In the United States,

approximately one-quarter of the adult population does not participate

1814 PART 6 Disorders of the Cardiovascular System

in any leisure-time physical activity, and only 24.3% of adults reported

participating in adequate leisure-time aerobic and muscle-strengthening

activity to meet federal guidelines. 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. Mortality rates

attributable to inactivity are highest in North Africa and the Middle

East and in Central and Eastern Europe. In urban China, for example,

the proportion of adults who participate in moderate- or high-level

activity has decreased significantly, whereas the proportion of those

who participate in low-level activity has increased.

■ METABOLIC RISK FACTORS

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 2017). The GBD project identified and compiled

mortality and morbidity data from 195 countries from 1980 to 2017.

Lipid Levels Worldwide, high cholesterol levels are estimated to

play a role in 42% of ischemic heart disease deaths and 9% of stroke

deaths, amounting to 4.3 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. 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 >0.08 mmol/L in both men and women.

More recent research including Mendelian studies suggests that lipoprotein(a) may act as an individual predictor of CVD risk beyond traditional total or low-density lipoprotein cholesterol through increased

cellular lipid accumulation, endothelial dysfunction, and impacts on

coagulation. It appears to be elevated in ~20% of the global population, although fewer data are available from LMICs. Nonrandomized

data suggest higher rates among those of African descent with twice

the levels of Caucasians, with East Asians and South Asians having

intermediate levels. There are limited data on clinical agents that target

lipoprotein(a), although PCSK9 inhibitors lower it or other specific

targets, so this remains an area of intense research.

Hypertension Elevated blood pressure is an early indicator of the

epidemiologic transition. Observational studies show increased risk of

CVD beginning with systolic blood pressures (SBPs) >110–115 mmHg.

Between 1990 and 2015, the global prevalence of SBP ≥110–115 mmHg

increased from 73,119 to 81,373 per 100,000, whereas the prevalence

of SBP ≥140 mmHg rose from 17,307 to 20,526 per 100,000. In 2015,

of the estimated 3.47 billion adults with SBP ≥110–115 mmHg, 874

million (25%) had SBP ≥140 mmHg. While SBP ≥140 mmHg accounts

for only 25% of those with elevated blood pressure, it accounted for

73% (7.8 million) of deaths due to SBP of ≥110–115 mmHg in 2015.

Worldwide, 55% of stroke deaths (3.36 of 6.17 million) and 55% of

CHD deaths (4.89 of 8.93 million) are attributable to high blood pressure, accounting for 8.25 million deaths in 2017. From 1990 to 2015,

the number of deaths related to SBP ≥140 mmHg increased in all LMIC

groups but fell in HICs. Between 1980 and 2008, the age-standardized

prevalence of uncontrolled hypertension decreased even as the number

of people with uncontrolled hypertension increased due to 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 33.8%, but

varies between 14.5 and 31.7% in rural regions. 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 SBP has

decreased for both sexes (0.8 mmHg per decade for men; 1.0 mmHg

per decade for women).

Obesity In 2015, an estimated 603.4 million adults and 107.7 million

children were obese. Global obesity prevalence was 12.0% among

adults (5.0% among children) and is increasing throughout the world,

particularly in developing countries where the trajectories are steeper

than those experienced by the developed countries. High body mass

index (BMI) contributed to 4.0 million deaths worldwide (7.1% deaths

from any cause); CVD was the leading cause of these deaths (2.7 million)

and also of associated DALYs (66.3 of 120 million) followed by diabetes

(0.6 million deaths, 30.4 million DALYs). Women are more affected by

obesity than men; from 1975 to 2014, global mean age-standardized

BMI increased from 22.1 to 24.4 kg/m2

 in females and from 21.7 to 24.2

kg/m2

 in males, whereas the prevalence of obesity increased from 6.4%

to 14.9% in females and 3.2% to 10.8% in males. The proportion of

the world’s adult women who are either overweight or obese rose from

29.8% to 38.0% between 1980 and 2013, while an increase from 28.8%

to 36.9% was observed for men. Country and regional differences

are observed. The highest prevalence of male obesity is in the United

States, Southern and Central Latin America, Australasia, and Central

and Western Europe. For females, the highest prevalence of obesity is

in Southern and North Africa, the Middle East, Central and Southern

Latin America, and the United States. The lowest prevalence for both

males and females was observed in South and Southeast Asia and in

East, Central, and West Africa. Generally, the prevalence of obesity

for both sexes increased with the increase in sociodemographic index;

however, the rise in adult obesity in developed countries has slowed

since 2006. In many of the LMICs, obesity appears to coexist with

undernutrition and malnutrition. Adolescents are at particular risk.

Diabetes Mellitus As a consequence of, or in addition to, increasing BMI 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, the prevalence of diabetes increased 129.7% for males and 120.9% for females between 1990

and 2017. An estimated 476 million people worldwide have diabetes,

and the International Diabetes Foundation predicts this number will

reach 693 million by 2045. Nearly 50% of people with diabetes are

undiagnosed, and 80% live in LMICs. The Middle East and North

Africa have the highest regional age-standardized prevalence (8.7%

of the population) and incidence rates (400 per 100,000) of diabetes, whereas East Asia and the Pacific has the lowest (5.8%; 249 per

100,000). Future growth will also largely occur in the Middle East and

Africa, along with other LMICs in South Asia and sub-Saharan Africa.

■ GENETIC RISK FACTORS

A great deal of effort has recently been invested in understanding how

genes affect cardiovascular health in populations. These efforts have

focused on germline genetic variants that are related to specific CVDs as

well as those that are associated with cardiovascular risk factors. In both

cases, every year, the number of associated variants has increased meaningfully to the point that it appears that hundreds or even thousands of

variants are associated with these conditions, each explaining a small

amount of the population variability in disease and risk factors. Collections of variants have been combined in polygenomic risk scores, but

these too explain only a small amount of the variability of the disease

in the population. Much more data will emerge in the coming years

about these associations, the mechanisms that explain these associations, the relationships of variants that are specific to certain tissues

such as the heart or the brain, and the interactions between genetic

and lifestyle factors in causing disease. Currently, most of the data are

among those with European ancestry; however, large-scale efforts are

underway to understand the relationships between genes and diseases

and their risk factors around the world. The early data suggest nontrivial differences among various world populations. Beyond germline

risk, there appears to be increased cardiovascular risk associated with

age-related expansion of hematopoietic clones with somatic mutations,

including loss-of-function alleles of certain genes. Individuals with

these mutations without other hematologic abnormalities are defined

as having clonal hematopoiesis of indeterminate potential (CHIP).

Physical Examination of the Cardiovascular System

1815CHAPTER 239

Recent studies suggest those with CHIP have up to a twofold increased

risk of developing CHD.

SUMMARY

Although CVD rates are declining in the HICs, they are increasing in

many other regions 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

against cigarette smoking, unhealthy diets, and physical inactivity. Second,

it is important to identify higher risk subgroups of the population who

stand to benefit the most from specific, low-cost prevention interventions, including screening for and treatment of hypertension and elevated

cholesterol. Simple, low-cost interventions, such as the “polypill”—a

regimen of aspirin, a statin, and an antihypertensive agent—also need

to be explored. Third, resources should be allocated to acute, as well

as secondary, prevention interventions. For countries with limited

resources, a critical first step in developing a comprehensive plan is

better assessment of cause-specific mortality and morbidity, as well as

the prevalence, of the major preventable risk factors.

In the meantime, the HICs must continue to bear the burden of

research and development aimed at prevention and treatment, being

mindful of the economic limitations of many countries. The concept

of the epidemiologic transition provides insight into how to alter the

course of the CVD epidemic. The efficient transfer of low-cost preventive and therapeutic strategies could alter the natural course of this

epidemic and thereby reduce the excess global burden of preventable

CVD.

■ FURTHER READING

Gaziano T, Gaziano JM: Global burden of cardiovascular disease,

in Heart Disease: A Textbook of Cardiovascular Medicine, 11th ed,

E Braunwald (ed). Philadelphia, Elsevier/Saunders, 2018.

Jaiswal S et al: Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377:111 2017.

Murray C et al: Population and fertility by age and sex for 195 countries and territories, 1950-2017: A systematic analysis for the Global

Burden of Disease Study 2017. Lancet 392:1995, 2018.

Roth G et al: Global, regional, and national age-sex-specific mortality

for 282 causes of death in 195 countries and territories, 1980-2017:

A systematic analysis for the Global Burden of Disease Study 2017.

Lancet 392:1736, 2018.

Virani S et al: Heart disease and stroke statistics – 2020 update: A

report from the American Heart Association. Circulation 141:e139,

2020.

Section 2 Diagnosis of Cardiovascular Disorders

239 Physical 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, ranging

from an elective ambulatory follow-up visit to a more urgent emergency department encounter. There has been a gradual decline in

physical examination skills over the past few 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 acquisition of new examination skills may become more difficult for a busy

individual practitioner. Less time is now devoted to mentored cardiovascular 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 presence and

severity of cardiovascular disease even when the examination findings

imply a low pretest probability of significant pathology. Proponents of

the use of hand-held ultrasound devices to identify and characterize

structural cardiac disease have called for its incorporation into educational curricula. Techniques to improve bedside examination skills

include repetition, patient-centered teaching conferences, visual display feedback of auscultatory events using Doppler echocardiographic

imaging, and simulation-based training.

The evidence base that links the findings from the history and

physical examination to the presence, severity, and prognosis of cardiovascular disease has been established most rigorously for coronary

artery disease, heart failure, and valvular heart disease. For example,

observations 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 setting can inform clinical decision-making before the results of cardiac

biomarker 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 important role played by the physical examination

in enhancing the clinician-patient relationship cannot be overstated.

■ THE GENERAL PHYSICAL EXAMINATION

Any examination begins with an assessment of the general appearance

of the patient, with notation of age, posture, demeanor, and 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 appreciated readily and provide

additional clues. The appearance of 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 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.

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 vasoconstriction.

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 rightto-left to shunting at the great vessel level. Telangiectasias on the lips,

1816 PART 6 Disorders of the Cardiovascular System

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 telangiectasias also are seen in patients with

advanced mitral stenosis (MS) or 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. Various hereditary 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.

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 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 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.

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 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.

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 ultrasound examination is advised when

appropriate. The presence of an arterial bruit over the abdomen suggests high-grade atherosclerotic disease, although precise localization

is difficult.

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 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 lesions of endocarditis are nontender, 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.

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 profound hypoalbuminemia as seen in nephrotic syndrome or liver failure. Other causes

include lymphatic or venous obstruction or, more commonly, venous

insufficiency, as would be 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.

■ CARDIOVASCULAR EXAMINATION

Jugular Venous Pressure and Waveform The 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

Physical Examination of the Cardiovascular System

1817CHAPTER 239

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 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 must be converted to

millimeters of mercury to provide correlation with accepted hemodynamic norms (1.36 cmH2

O = 1.0 mmHg).

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. 239-1). 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 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, which occurs as the closed tricuspid valve is pushed

into the right atrium during early ventricular systole, 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 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 (LV)

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 passive leg elevation or performance of the abdominojugular reflux maneuver. When

these signs are positive, a volume-overloaded state with limited compliance of an overly distended or constricted venous system is present.

Abdominojugular reflux is produced with firm and consistent pressure

over the upper portion of the abdomen, preferably over the right upper

quadrant, for >15 s. A positive response is defined by a sustained rise

of >3 cm in the JVP during the application of firm abdominal pressure.

The response should be assessed after 10 s of continuous pressure to

allow for respiratory artifacts and tensing of the abdominal muscles to

subside. Patients must be coached to refrain from breath holding or

a Valsalva-like maneuver during the procedure. Performance of the

abdominojugular reflux maneuver is useful in predicting a pulmonary

artery wedge pressure >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.

A

B

C

Severe

ECG

JVP

Mild

Normal

A

A

A

A

A

IV III

I II III

I II K

C

C

C

V

V

V

P

V

V

V

X

X

X

X

Y

Y

Y

Y

Y

FIGURE 239-1 A. Jugular venous pulse wave tracing (top) with heart sounds (bottom)

in a patient with reduced right ventricular compliance. 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 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). (Reproduced with permission from J Abrams: Synopsis of Cardiac Physical

Diagnosis, 2nd ed. Boston, Butterworth Heinemann, 2001.)