Heart Failure: Pathophysiology and Diagnosis

1931CHAPTER 257

characterized by elevated cardiac filling pressure and/or inadequate

peripheral oxygen delivery, at rest or during stress, caused by cardiac

dysfunction.

Chronic heart failure describes patients with longstanding (e.g.,

months to years) symptoms and/or signs of HF typically treated with

medical and device therapy as described in Chap. 258. Acute heart

failure, previously termed acute decompensated HF, refers to the rapid

onset or worsening of symptoms of HF. Most episodes of acute HF

result from worsening of chronic HF, but ~20% are due to new-onset

HF that can occur in the setting of acute coronary syndrome, acute valvular dysfunction, hypertensive urgency, or postcardiotomy syndrome.

Similarly, acute pulmonary edema in HF describes a clinical scenario in

which a patient presents with rapidly worsening signs and symptoms

of pulmonary congestion, typically due to severe elevation of left heart

filling pressure.

■ EPIDEMIOLOGY

Global Incidence and Prevalence HF is a major cause of morbidity and mortality worldwide. An estimated 6.2 million American

adults are being treated for HF, with >600,000 new cases diagnosed

each year. Globally, >26 million people are affected by HF. The prevalence of HF increases significantly with

age, occurring in 1–2% of the population

aged 40–59 years and up to 12% of adults

>80 years old (Fig. 257-1). The lifetime

risk of HF at age 55 years is 33% for men

and 28% for women. Projections show

that the prevalence of HF in the United

States will increase by 46% from 2012 to

2030. Between 1980 and 2000, the number of HF hospitalizations rose steadily

in both men and women to ~1 million

per year. However, according to the most

recent AHA statistics, hospitalizations

decreased from 1,020,000 in 2006 to

809,000 in 2016. While prevalence of

HF continues to rise, incidence may be

decreasing due to improved recognition

and treatment of cardiovascular disease

and its comorbidities as well as disease

prevention. However, as rates of obesity

rise globally, these favorable trends in

HF incidence may reverse.

There are distinct racial and ethnic differences in HF epidemiology

(Fig. 257-2). In community-based

14

10

12

8

6

Percentage of population

4

2

0

20–39

0.3 0.2

1.2 1.7

6.9

4.8

12.8

12.0

40–59

Age (years)

60–79 ≥80

Males Females

FIGURE 257-1 Prevalence of heart failure. Prevalence of heart failure among U.S.

adults ≥20 years of age by sex and age, from the National Health and Nutrition

Examination Survey (NHANES), 2013–2016. (Source: SS Virani et al: Circulation

141:e139, 2020.)

40.0

25.0

30.0

35.0

20.0

Per

15.0

1000 Person-Years

10.0

5.0 3.9

11.2

2.7

8.2

11.0

17.9

7.6

16.3

32.0

34.7

26.2

31.4

0.0

Black males

White males White females

Black females

55–64

Age (years)

65–74 >75

FIGURE 257-2 Incidence of heart failure. First acute heart failure annual event rates per 1000 from Atherosclerosis

Risk in Communities (ARIC) Community Surveillance by sex and race in the United States from 2005 to 2014. (Source:

SS Virani et al: Circulation 141:e139, 2020.)

studies, blacks have the highest risk of developing HF, followed by Hispanic, white, and Chinese Americans. These differences are attributed

to disparities in risk factors (e.g., obesity, hypertension, diabetes),

socioeconomic status, and access to health care. Similarly, studies have

shown that age-adjusted rates of HF hospitalization are highest for

black men, followed by black women, white men, and white women.

Accurate data on HF prevalence from emerging nations are lacking. As

developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North

America, with coronary artery disease emerging as the most common

cause of HF.

Morbidity and Mortality In primary care, the overall 5-year survival following the diagnosis of HF is ~50%. For patients with severe

HF, the 1-year mortality may be as high as 40%. In the United States,

1 in 8 deaths list HF on the death certificate. The majority of these

patients die of cardiovascular causes, most commonly progressive

HF or sudden cardiac death. A number of clinical and laboratory

parameters are independent predictors of mortality (Table 257-1). In a

population-based study, hospitalizations were common after an HF

diagnosis, with 83% hospitalized at least once, and 67%, 54%, and 43%

hospitalized at least two, three, and four times, respectively. Following

an HF admission, mortality rates range from 8–14% at 30 days to

26–37% at 1 year to up to 75% at 5 years. Readmission with HF is also

common, ranging from 20–25% at 60 days to nearly 50% at 6 months.

With each subsequent admission, the risk of death rises. There are

racial disparities in outcomes with blacks having higher case–fatality

rates compared to whites. Despite these statistics, the overall prognosis

for patients with HF is improving due to treatment of risk factors and

increased use of guideline-directed therapies.

Costs The overall cost of HF care is high (estimated $30.7 billion

in the United States in 2012) and rising. Projections for 2030 are that

hospitalization costs for HF in the United States will increase to $70

billion. Indirect costs due to lost work and productivity may equal or

exceed this amount. The global economic burden of HF in 2012 was

estimated at $108 billion, with direct costs accounting for 60%. For

pediatric patients with acute HF, inpatient costs are estimated at nearly

$1 billion annually and rising.

■ PHENOTYPES AND CAUSES

HF with Reduced Versus Preserved Ejection Fraction

Epidemiologic studies have shown that approximately one-half of patients

who develop HF have reduced left ventricular ejection fraction (EF;

1932 PART 6 Disorders of the Cardiovascular System

≤40%) while the other half have near-normal or preserved EF (≥50%).

Because most patients with HF (regardless of EF) have abnormalities

in both systolic and diastolic function, the older terms of systolic heart

failure and diastolic heart failure have fallen out of favor. Classifying

patients based on their EF (HF with reduced EF [HFrEF] vs HF with

preserved EF [HFpEF]) is important due to differences in demographics, comorbidities, and response to therapies (Chap. 258). Underlying

causes of HF may be associated with reduced or preserved EF and

include disorders of the coronary arteries, myocardium, pericardium,

heart valves and great vessels (Table 257-2). The diagnosis of HFpEF

is often more challenging due to the need to rule out noncardiac causes

of shortness of breath and/or fluid retention.

HF with Recovered EF A subgroup of patients who are diagnosed with HFrEF and treated with guideline-directed therapy have

rapid or gradual improvement in EF to the normal range and are

referred to as having HF with recovered EF (HFrecEF). Predictors of

HFrecEF include younger age, shorter duration of HF, nonischemic

etiology, smaller ventricular volumes, and absence of myocardial fibrosis. Specific clinical examples include fulminant myocarditis, stress

cardiomyopathy, peripartum cardiomyopathy, and tachycardia-induced cardiomyopathy, as well as reversible toxin exposures such as

chemotherapy, immunotherapy, or alcohol. Despite recovery of EF,

patients may remain symptomatic due to persistent abnormalities in

diastolic function or exercise-induced pulmonary hypertension. For

patients who become asymptomatic, withdrawal of therapy can lead to

recurrence of HF symptoms and decrease in EF. In general, prognosis

of patients with HFrecEF is superior to that of patients with either

HFrEF or HFpEF.

Heart Failure with Mildly Reduced EF (HFmrEF) Patients

with HF and an EF between 40 and 50% represent an intermediate

group that are often treated for risk factors and comorbidities and with

guideline-directed medical therapy similar to patients with HFrEF. They

are felt to have primarily mild systolic dysfunction, but with features

of diastolic dysfunction. They may also include either patients with

reduced EF who experience improvement in their EF or those with

initially preserved EF who suffer a mild decline in their systolic performance. Unlike the ACCF/AHA and HFSA guidelines, the ESC guideline

has identified HFmrEF as a separate group in order to stimulate research

into underlying characteristics, pathophysiology, and treatment.

Acquired Versus Familial, Congenital, and Other Disorders In

developed countries, coronary artery disease is responsible for approximately two-thirds of the cases of HF, with hypertension as a principal

contributor in up to 75% and diabetes mellitus in 10–40% (Fig. 257-3).

While most cardiovascular disease underlying HF is acquired in mid

and later life (Chaps. 261, 273, and 277), a wide range of congenital

and inherited disorders leading to HF may be diagnosed in children

and younger adults. It is currently estimated that >1.4 million U.S.

adults are living with congenital heart disease (CHD), which surpasses

the number of children with CHD. In general, adults with CHD who

develop HF can be divided into one of three pathophysiologic groups:

uncorrected defects with late presentation due to missed diagnosis,

nonintervention, or lack of access to care; repaired or palliated defects

with late valvular and/or ventricular failure; or failing single-ventricle

physiology. In addition, each adult with CHD often presents with

unique anatomic and physiologic challenges that affect HF and its

treatment.

TABLE 257-1 Independent Predictors of Adverse Outcomes

in Heart Failure

Clinical Male sex

Increasing age

Diabetes mellitus

Chronic kidney disease

Coronary artery disease

Advanced NYHA classa

Presence of third heart sound or elevated JVP

Decreased exercise capacity

Cardiac cachexia

Depression

Structural Reduced left ventricular ejection fraction

Reduced right ventricular ejection fraction

Increased ventricular volumes and mass

Secondary mitral or tricuspid regurgitation

Hemodynamic Elevated pulmonary capillary wedge pressure

Reduced cardiac index

Reduced peak oxygen consumption

Pulmonary hypertension

Diastolic dysfunction

Biochemical Worsening renal function

Hyponatremia

Hyperuricemia

Elevated cardiac biomarkers (troponin and natriuretic

peptides)

Elevated plasma neurohormones (norepinephrine, renin,

aldosterone, and endothelin-1)

Electrophysiologic Tachycardia

Widened QRS interval or LBBB

Atrial fibrillation

Ventricular ectopic activity

Ventricular tachycardia and sudden death

a

See Table 257-4.

Abbreviations: JVP, jugular venous pressure; LBBB, left bundle branch block; NYHA,

New York Heart Association.

TABLE 257-2 Selected Causes of Heart Failure

Heart Failure with Reduced Ejection Fraction

Coronary artery disease

Myocardial infarction

Myocardial ischemia

Nonischemic cardiomyopathy

Infiltrative disorders

Familial disorders

Tachycardia induced

Valvular heart disease

Aortic stenosis or regurgitation

Mitral or tricuspid regurgitation

Toxic cardiomyopathy

Chemotherapy, immunotherapy

Drugs such as hydroxychloroquine

Alcohol, cocaine

Congenital heart disease

Intracardiac shunts

Repaired defects

Systemic right ventricular failure

Chronic lung/pulmonary vascular disease

Cor pulmonale

Pulmonary arterial hypertension

Infectious

Chagas

HIV

Autoimmune disease

Giant cell myocarditis

Lupus myocarditis

Heart Failure with Preserved Ejection Fraction

Hypertension Coronary artery disease

Valvular heart disease

Aortic stenosis

Mitral stenosis

Restrictive cardiomyopathy

Amyloidosis

Sarcoidosis

Hemochromatosis

Glycogen storage disease

Hypertrophic cardiomyopathy Radiation therapy

Constrictive pericarditis Aging

Myocarditis Endomyocardial fibroelastosis

Obesity

High-Output Heart Failure

Thyrotoxicosis Arteriovenous shunt

Obesity Cirrhosis

Anemia Vitamin B deficiency (beriberi)

Chronic lung disease Myeloproliferative disorder

Abbreviation: HIV, human immunodeficiency virus.

Heart Failure: Pathophysiology and Diagnosis

1933CHAPTER 257

34%

39%

7%

Valvular disease

LVH

Diabetes

Angina

pectoris

Myocardial

infarction

Hypertension

Men Women

4%

5%

6%

59%

13%

5%

5%

8%

12%

Valvular disease

LVH

Diabetes

Angina

pectoris

Myocardial

infarction

Hypertension

FIGURE 257-3 Population attributable risk of heart failure (HF) incidence. Based on longitudinal data from the

Framingham Heart Study, the risk factors contributing most significantly to the population attributable risk (PAR) of HF

in men were previous myocardial infarction and hypertension (in men, both represented equal contributions to HF PAR).

In contrast, hypertension was the risk factor accounting for the majority of total PAR in women. In women, previous

myocardial infarction accounted for only 13% of the PAR of HF compared with 34% in men. PAR values are developed

based on individual calculations for each variable using hazard ratio and prevalence statistics. Thus, they may not, in

aggregate equal 100%. LVH, left ventricular hypertrophy. (From MM Givertz, WS Colucci: Heart failure. In Peter Libby,

Essential Atlas of Cardiovascular Disease, 2009, Current Medicine Group. Reproduced with permission of SNCSC.)

Inherited cardiomyopathies are also increasingly recognized in

adults presenting with HF. These include more common disorders,

such as hypertrophic and arrhythmogenic cardiomyopathies, and

lesser known heart muscle disease related to pathogenic variants in

genes encoding lamin and titin, muscular dystrophies, and mitochondrial disease. Most forms of familial cardiomyopathy are inherited in

an autosomal dominant fashion. Society guidelines have been published documenting the importance of taking a detailed family history

and indications for (and limitations of) clinical genetic testing.

A myriad of systemic diseases with cardiac and extracardiac manifestations (e.g., amyloidosis, sarcoidosis), autoimmune disorders (e.g.,

systemic lupus erythematosus, rheumatoid arthritis), infectious diseases

(e.g., Chagas, HIV), and drug toxicities (chemotherapy, other prescribed

or illicit agents) can result in HF with either reduced or preserved EF. In

Africa and Asia, rheumatic heart disease remains a major cause of HF,

especially in the young. Finally, disorders associated with a high cardiac

output state (e.g., anemia, thyrotoxicosis) are seldom associated with HF

in the absence of underling structural heart disease. However, diagnosis

and treatment of high-output HF will be missed if not considered in

the differential diagnosis of patients with predisposing conditions (e.g.,

cirrhosis, end-stage renal disease with arteriovenous fistula, Paget’s disease, or nutritional deficiency such as beriberi).

PATHOPHYSIOLOGY

■ PROGRESSIVE DISEASE

HFrEF is a progressive disease that typically involves an index event

followed by months to years of structural and functional cardiovascular

remodeling (Fig. 257-4). The primary event may be sudden in onset,

such as an acute myocardial infarction; more gradual, as occurs in the

setting of chronic pressure or volume overload; inherited, as seen with

genetic cardiomyopathies; or congenital disease. Despite an initial

reduction in cardiac performance, patients may be asymptomatic or

mildly symptomatic for prolonged periods due to the activation of

compensatory mechanisms (described below) that ultimately contribute to disease progression.

Ventricular Remodeling As demonstrated in both animal and

human studies, different patterns of ventricular remodeling occur

in response to excess cardiac workload. Concentric hypertrophy,

in which increased mass is out of proportion to chamber volume,

effectively reduces wall stress under conditions of pressure overload

(e.g., hypertension, aortic stenosis). By contrast, an increase in cavity

size or volume (eccentric hypertrophy) occurs in volume overload

conditions (e.g., aortic regurgitation, mitral regurgitation). In both

forms of remodeling, an increase in ventricular mass is accompanied at the cellular level by myocyte hypertrophy and interstitial

fibrosis, at the protein level by alteration in

calcium-handling and cytoskeletal function, and at the molecular level by reexpression of fetal genes (Table 257-3). In

addition to cell loss from necrosis, myocytes that are unable to adapt to remodeling stimuli may be triggered to undergo

apoptosis or programmed cell death. Further impairment in pump function and

increased wall stress in the face of systemic

vasoconstriction and loss of neurohormonal adaptation (discussed below) can

lead to afterload mismatch. These events

feed back on remodeling stimuli, setting

up a cycle of deleterious processes resulting

in clinical HF.

While our understanding of ventricular

remodeling in HFrEF is well supported

by animal and human studies, the mechanisms underlying HFpEF are less clear. The

original descriptions of HFpEF focused on

diastolic dysfunction as the primary mediator of HF signs and symptoms as exemplified in older women with hypertension. At the myocyte level, impaired

uptake of cytosolic calcium into the sarcoplasmic reticulum by reductions in adenosine triphosphate explained abnormalities in myocardial

relaxation. As different phenotypes of HFpEF have emerged, many

pathophysiologic processes other than diastolic dysfunction have been

implicated in disease progression, including vascular stiffness, renal

dysfunction, sodium avidity, and metabolic inflammation related to

regional adiposity. Furthermore, biologic alterations including oxidative stress and impaired nitric oxide signaling leading to nitrosative

stress may play a role in disease activity and inform future therapies.

■ MECHANISMS OF DISEASE PROGRESSION

A number of compensatory mechanisms become activated during

the development of HF and contribute to disease progression. Our

Increased wall stress

Myocyte hypertrophy

Myocyte death

Altered intestinal matrix

Ventricular

enlargement

Systolic or

diastolic

dysfunction

Fetal gene expression

Altered calcium-handling

proteins

Remodeling stimuli

 Wall stress

 Cytokines

 Neurohormonal

 Oxidative stress

FIGURE 257-4 Remodeling stimuli in heart failure. Chronic hemodynamic stimuli

such as pressure and volume overload lead to ventricular remodeling through

increases in myocardial wall stress, inflammatory cytokines, signaling peptides,

neuroendocrine signals, and oxidative stress. The myocardium responds with

adaptive as well as maladaptive changes. Reexpression of fetal contractile

proteins and calcium handling proteins may contribute to impaired contraction and

relaxation. Myocytes unable to adapt might be triggered to undergo programmed

cell death (apoptosis). The net result of these changes is further impairment in

pump function and increased wall stress, thus completing a vicious cycle that leads

to further progression of myocardial dysfunction. (From MM Givertz, WS Colucci:

Heart failure. In Peter Libby, Essential Atlas of Cardiovascular Disease, 2009, Current

Medicine Group. Reproduced with permission of SNCSC.)

1934 PART 6 Disorders of the Cardiovascular System

understanding of these mechanisms derives from preclinical studies,

in vivo human studies, and randomized clinical trials demonstrating

benefit of therapies targeted to attenuating or reversing these biologic

processes.

Neurohormonal Activation Activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS)

plays a critical role in the development and progression of HF. Initially, neurohormonal activation leads to increases in heart rate, blood

pressure, and cardiac contractility and retention of sodium and water

to augment preload and maintain cardiac output at rest and during

exercise. Over time, these unchecked compensatory responses lead

to excessive vasoconstriction and volume

retention, electrolyte and renal abnormalities,

baroreceptor dysfunction, direct myocardial

toxicity, and cardiac arrhythmias. At the tissue

level, neurohormonal activation contributes

to remodeling of the heart, blood vessels

(atherosclerosis), kidneys, and other organs

(Fig. 257-5) and the development of symptomatic HF. Landmark clinical trials in HF

have demonstrated that antagonism of the

RAAS and SNS with renin-angiotensin system

inhibitors, mineralocorticoid receptor antagonists, and beta blockers attenuates or reverses

ventricular and vascular remodeling and

reduces morbidity and mortality (Chap. 258).

Vasodilatory Hormones While RAAS

and SNS activation contributes to disease

progression in HF, a number of counterregulatory hormones are upregulated and exert

beneficial effects on the heart, kidney, and

vasculature. These include the natriuretic

peptides (atrial natriuretic peptide [ANP]

and B-type natriuretic peptide [BNP]),

prostaglandins (prostaglandin E1

 [PGE1

]

and prostacyclin [PGI2

]), bradykinin, adrenomedullin, and nitric oxide. ANP and BNP

are stored and released primarily from the

atria and ventricles, respectively, in response

to increased stretch or pressure. Beneficial

actions are mediated through stimulation of

guanylate cyclase and include systemic and

pulmonary vasodilation, increased sodium

and water excretion, inhibition of renin and

aldosterone, and baroreceptor modulation.

Bradykinin and natriuretic peptides are inactivated by neprilysin, a membrane bound

peptidase, which explains in part the beneficial clinical impact of

angiotensin receptor–neprilysin inhibition in HF (Chap. 258). As

described below, natriuretic peptide levels can be used to assist in the

diagnosis and risk stratification of patients with HF.

Endothelin, Inflammatory Cytokines, and Oxidative Stress

Endothelin is a potent vasoconstrictor peptide with growth-promoting

effects that may play an important role in pulmonary hypertension

and right ventricular failure. Endothelin is released from a variety of

vascular and inflammatory cells within the pulmonary circulation

and myocardium in response to increased pressure and has direct

deleterious effects on the heart, leading to myocyte hypertrophy and

interstitial fibrosis. Unlike RAAS and SNS inhibition, however, endothelin blockade has not been shown to slow the progression of clinical

HF but is beneficial for treatment of pulmonary arterial hypertension

(Chap. 283). Other factors that have the potential to cause or contribute to ventricular remodeling in HF include inflammatory cytokines

such as tumor necrosis factor (TNF) α and interleukin (IL) 1β and

reactive oxygen species such as superoxide. Potential sources of these

biologically active substances are the liver and gastrointestinal tract, as

described below. The role of anti-inflammatory and antioxidant therapies remains unproven.

Novel Biologic Targets Sodium-glucose cotransporter-2 (SGLT-2)

is a protein located on the proximal tubule of the kidney that is

responsible for reabsorption of up to 90% of filtered glucose. In

patients with HF, activity of SGLT-2 contributes to sodium and water

retention, endothelial dysfunction, abnormal myocardial metabolism,

and impaired calcium handling. Inhibitors of SGLT-2 were developed

for the treatment of type 2 diabetes mellitus to take advantage of their

glycosuric and metabolic effects (Chap. 404). Subsequent large clinical

trials in cardiovascular disease including HF (with or without overt

diabetes mellitus) have demonstrated not only safety of these agents

TABLE 257-3 Mechanisms of Ventricular Remodeling

Changes in Myocyte Biology

Abnormal excitation-contraction coupling and crossbridge interaction

Fetal gene expression (e.g., β-myosin heavy chain)

β-Adrenergic receptor desensitization

Myocyte hypertrophy

Impaired cytoskeletal proteins

Changes in Myocardial Makeup

Myocyte necrosis, apoptosis, and autophagy

Interstitial and perivascular fibrosis

Matrix degradation

Changes in Ventricular Geometry

Ventricular dilation and wall thinning

Increased sphericity and displacement of papillary muscles

Atrioventricular valve regurgitation

↑ Sympathetic nervous

 system activity

↑ Vasopressin

 secretion

Baroreceptor

dysfunction ↓ Afferent

inhibitory signals

↓ Limb blood flow

Vasomotor center

↑ Renin secretion

↑ Angiotensin II

↓ Renal blood flow

↑ Aldosterone secretion

↑ Sodium reabsorption

↑ Water reabsorption

↑

dium reabso

dosterone se

nal bloodflo

Vasomotor cente tor

mb bloo

FIGURE 257-5 Activation of neurohormonal systems in heart failure. Decreased cardiac output in heart failure

(HF) results in an “unloading” of high-pressure baroreceptors (circles) in the left ventricle, carotid sinus, and

aortic arch, which in turn causes reduced parasympathetic tone. This decrease in afferent inhibition results in

a generalized increase in efferent sympathetic tone and nonosmotic release of arginine vasopressin from the

pituitary. Vasopressin is a powerful vasoconstrictor that also leads to reabsorption of free water by the kidney.

Afferent signals to the central nervous system also activate sympathetic innervation of the heart, kidney, peripheral

vasculature, and skeletal muscles. Sympathetic stimulation of the kidney leads to the release of renin, with a

resultant increase in circulating levels of angiotensin II and aldosterone. The activation of the renin-angiotensinaldosterone system promotes salt and water retention, peripheral vasoconstriction, myocyte hypertrophy, cell

death, and myocardial fibrosis. Although these neurohormonal mechanisms facilitate short-term adaptation by

maintaining blood pressure, they also result in end-organ changes in the heart and circulation. (Modified from

A Nohria et al: Atlas of Heart Failure: Cardiac Function and Dysfunction, 4th ed, WS Colucci [ed]. Philadelphia,

Current Medicine Group, 2002, p. 104, and J Hartupee, DL Mann: Nat Rev Cardiol 14:30, 2017.)

Heart Failure: Pathophysiology and Diagnosis

1935CHAPTER 257

(as required by the U.S. Food and Drug Administration) but also, more

importantly, beneficial effects on morbidity and mortality. Whether

benefits of SGLT-2 inhibitors in HF are due primarily to diuretic effects

or to effects on cardiac and vascular remodeling, proarrhythmia, renal

function, and/or metabolic function or inflammation remains to be

determined. Another pathway that is downregulated in HF and contributes to endothelial dysfunction involves cyclic guanosine monophosphate (cGMP). Oral soluble guanylate cyclase stimulators enhance

the cGMP pathway and exert beneficial myocardial and vascular effects

in experimental and clinical HF.

Dyssynchrony and Electrical Instability In up to one-third of

patients with HF, disease progression is associated with prolongation

of the QRS interval. Electrical dyssynchrony in the form of left bundle

branch block (LBBB) or intraventricular conduction delay results in

abnormal ventricular contraction. As discussed in Chap. 258, correction of electrical dyssynchrony with left or biventricular pacing

can improve contractile function, decrease mitral regurgitation, and

reverse ventricular remodeling. In patients with symptomatic HFrEF

and LBBB on guideline-directed medical therapy, cardiac resynchronization therapy is indicated to reduce morbidity and mortality.

Other forms of electrical instability, including atrial fibrillation with

inadequate rate control and frequent premature ventricular complexes,

can also contribute to worsening HF. In addition to the direct impact

of tachycardia and irregular rhythm on disease progression, the link

between these arrhythmias and cardiac remodeling (atrial and ventricular) involves increased wall stress, neurohormonal activation, and

inflammation.

Secondary Mitral Regurgitation A large number of patients

with HFrEF demonstrate evidence of mitral regurgitation. This occurs

due to a distortion in the mitral valve apparatus and includes the effects

of various pathophysiologic mechanisms including reduced contractile

force, which leads to decreased coaptation of the leaflets, a spherical shape of the ventricle that influences length and function of the

chordal-papillary muscle structure, increased dimension of the mitral

annulus (and inability of the annulus to contract during systole) with

reduced leaflet alignment, and dilation of the posterior wall of the left

atrium, which distorts the posterior leaflet of the valve. This worsening

in regurgitant volume contributes to progression in HF and adversely

influences prognosis. Ensuring that this vicious cycle is interrupted

is now a therapeutic target in HF. Some success has been noted by

treating the mitral valve using transcatheter techniques when patients

are carefully selected after exposure to optimal medical therapy when

residual and significant secondary mitral regurgitation persists.

■ CARDIORENAL AND ABDOMINAL INTERACTIONS

An important concept underlying the pathophysiology of HF recognizes the systemic nature of disease. Thus, while the primary hemodynamic problem in HF is related to abnormalities in myocardial

function (preload, afterload, and contractility), many of the presenting

signs and symptoms are related to end-organ failure, including dysfunction of the kidneys, liver, and lungs. The heart and kidney interaction increases circulating volume, worsens symptoms of HF, and

results in disease progression, referred to as the cardiorenal syndrome.

Traditionally, this relationship was deemed to be a consequence of an

impairment in forward flow (cardiac output) leading to a decrease in

renal arterial perfusion, worsening renal function, and neurohormonal

activation with release of arginine vasopressin, resulting in water and

sodium retention. However, evidence has emerged that renal dysfunction may not be adequately explained simply by arterial underfilling

and a decline in cardiac output. Systemic venous congestion in HF

with increased backward pressure may be operative in determining the

development of the cardiorenal syndrome, and relief of venous congestion is associated with significant improvement in renal function

in HF. Increased intraabdominal pressure, as noted in right-sided HF,

and a rise in abdominal congestion are correlated with renal dysfunction in worsening HF. The interaction is not only confined to the renal

component of the abdominal compartment but also involves the liver

and spleen. The splanchnic veins serve as a blood reservoir and actively

function in regulation of cardiac preload during changes in volume

status, regulated by transmural pressure changes or mechanisms of

systemic sympathetic activation. The liver and spleen participate in

determining volume regulation in HF in addition to several additional

interactive pathways. Splanchnic congestion results in portal vein distension and activation of the hepatorenal reflex as well as the splenorenal reflex, which induces renal vasoconstriction. Thus, decongestion

in HF by diuretic therapy or mechanical means such as ultrafiltration

reduces volume, but also facilitates a decrease in pressure within the

abdominal compartment, and this combination of therapeutic effect

may serve to improve renal function in HF.

■ GUT CONGESTION, THE MICROBIOME, AND

INFLAMMATION

As noted above, circulating levels of proinflammatory cytokines are

elevated in a number of cardiovascular disease states, including HF,

and have been associated with disease progression. While the primary

source of inflammation is unknown, emerging evidence suggests that

an alteration in gut microbial composition and loss of microbial diversity may play an important role. The potential role of gut congestion and

also altered gut microbial composition may propagate the chronic state

of inflammation and immune system dysregulation, eventually leading

to progression of HFrEF. Lipopolysaccharide (LPS) is a gram-negative

bacterial cell wall product whose levels are increased in patients with

HF and increased intestinal permeability during periods of congestion,

and reduced with diuretic treatment. LPS is a strong stimulator of the

immune system and can lead to dysregulated systemic inflammation

via macrophage activation. Resulting increases in cytokines such as

TNF-α, IL-1, and IL-6 in these pathways can cause progressive loss of

cardiac function and also contribute to cardiac cachexia. A mechanistic

link has been shown between gut microbe–dependent generation of

trimethylamine N-oxide derived from specific dietary nutrients such

as choline and carnitine and poor outcomes in patients with both acute

and chronic HF. Microbe-generated uremic toxins, such as indoxyl sulfate, may play an important role in the development of HF, particularly

in interaction with renal insufficiency. Thus, bowel ischemia and/or

congestion depending on HF severity may be associated with morphologic and functional alterations in the intestines and result in bacterial

endotoxemia and a proinflammatory state.

■ HIGH-OUTPUT STATES

Although most patients with HF, with either reduced or preserved EF,

have low or normal cardiac output (CO) accompanied by elevated systemic vascular resistance (SVR), a minority of patients with HF present

with a high-output state with low SVR (Table 257-2). High-output

states by themselves are seldom responsible for HF, but their development in the presence of underlying cardiovascular disease can precipitate HF. For example, chronic anemia is associated with high CO when

hemoglobin reduces significantly, for example, to a level that is ≤8 g/dL.

An increase in vasodilatory metabolites and arteriolar vasodilation

in response to decreased oxygen-carrying capacity of the blood in

addition to a decrease in blood viscosity contributes to low SVR. Even

when severe, anemia rarely causes high-output HF in the absence of a

specific cardiac abnormality such as ischemic or valvular heart disease.

Patients with end-stage renal disease (Chap. 312) are at particular risk

of developing high-output HF when chronic anemia is exacerbated by

increased flow through an arteriovenous fistula. In a contemporary

series of patients with high-output HF, the most common causes were

obesity (31%), liver disease (23%), arteriovenous shunts (23%), lung

disease (16%), and myeloproliferative disorders (8%).

EVALUATION

■ HISTORY

Symptoms of Congestion: Pulmonary Versus Systemic The

most common symptoms of HF are related to volume overload with

elevation in pulmonary and/or systemic venous pressures. Shortness of

breath is a cardinal manifestation of left HF and may arise with increasing severity as exertional dyspnea, orthopnea, paroxysmal nocturnal

1936 PART 6 Disorders of the Cardiovascular System

dyspnea, and dyspnea at rest. Mechanisms of dyspnea include pulmonary venous congestion and transudation of fluid into the interstitium

and/or alveoli, leading to decreased lung compliance, increased airway

resistance, hypoxemia, and ventilation/perfusion mismatch. Stimulation of juxtacapillary J receptors leading to an increased ventilatory

drive and reduced blood flow to respiratory muscles may cause lactic

acidosis and a sensation of dyspnea. The New York Heart Association

(NYHA) functional classification (Table 257-4) may be used to categorize patients based on the amount of effort required to provoke

breathlessness. Notably, however, NYHA class does not correlate well

with other objective measures of cardiac structure (e.g., left ventricular

size, EF) or function (e.g., peak oxygen consumption).

Orthopnea refers to dyspnea that occurs in the recumbent position

and is due to redistribution of fluid from the abdomen and lower body

into the chest, increased work of breathing due to decreased lung compliance, and, in patients with ascites or hepatomegaly, elevation of the

diaphragm. Orthopnea typically occurs in the awake patient within 1–2

min of lying down and may be relieved by raising the head and chest

with pillows or an adjustable bed. With more severe HF, patients may

end up sleeping in a recliner chair or sitting up, although for some,

orthopnea may diminish as symptoms of right HF appear. Orthopnea may be accompanied by nocturnal cough related to pulmonary

congestion.

Paroxysmal nocturnal dyspnea (PND) refers to episodes of shortness of breath that awaken a patient suddenly from sleep with feelings

of anxiety and suffocation and require sitting upright for relief. In contrast to orthopnea, PND usually occurs after prolonged recumbency,

is less predictable in occurrence, and may require 30 min or longer

in the upright position for relief. Episodes are often accompanied by

coughing and wheezing (so-called cardiac asthma) thought to be due

to increased bronchial arterial pressure leading to airway compression

and interstitial pulmonary edema causing increased airway resistance.

Acute pulmonary edema, due to marked elevation of the pulmonary

capillary wedge pressure, is manifested by severe shortness of breath

and pink, frothy sputum (Chap. 305). Cheyne-Stokes respiration and

central sleep apnea may precipitate episodes of PND in HF and are

related to increased sensitivity of the respiratory center to arterial

PCO2 and a prolonged circulatory time. Unlike obstructive sleep apnea,

which can be treated with positive airway pressure therapy, central

sleep apnea has no proven therapy beyond the directed treatment of

HF (Chap. 297).

In contrast to symptoms of left HF due to pulmonary venous congestion, symptoms of right HF are typically related to systemic venous

congestion. Weight gain and lower extremity edema may be the initial

manifestations followed by a range of gastrointestinal symptoms due

to edema of the bowel wall and hepatic congestion. Abdominal bloating, anorexia, and early satiety are common. Some patients develop

right upper quadrant pain related to stretching of the hepatic capsule

with nausea and vomiting. When these symptoms are associated with

abnormal liver function tests (see below), misdiagnosis of biliary tract

disease may occur. For patients with refractory right HF, the development of massive edema involving the entire body with recurrent

pleural effusions and/or ascites is termed anasarca.

Symptoms of Reduced Perfusion Some patients with advanced

HF present with symptoms related to decreased CO, sometimes

referred to as low-output syndrome. Fatigue and weakness, particularly

of the lower extremities, are nonspecific symptoms that can occur with

exertion or at rest. Pathophysiology includes reduced blood flow to

exercising muscles due to endothelial dysfunction and increased SVR

from neurohormonal activation. Chronic alterations in skeletal muscle structure and metabolism have also been demonstrated. In older

patients with HF and cerebrovascular disease, reduced systemic perfusion may result in mental dullness, depressed affect, and confusion.

In addition to low CO, fatigue may be caused by volume depletion,

hyponatremia, iron deficiency, and medications (e.g., beta blockers).

Other Symptoms Patients with HF may present with mood disturbances and poor sleep, both of which may be exacerbated by nocturnal

dyspnea and obstructive and/or central sleep apnea. Nocturia due to

improved CO and renal perfusion in the supine position, in addition

to delayed diuretic effects, can also contribute to sleep disturbances.

Oliguria due to severe reductions in renal blood flow may be a sign of

advanced-stage HF.

Precipitating Factors Patients with HF may be asymptomatic

or mildly symptomatic either because the cardiac impairment is mild

or because compensatory mechanisms help to balance or normalize

cardiac function. Symptoms of HF may develop when one or more precipitating factors increase cardiac workload and disrupt the balance in

favor of decompensation. Specific factors may be identified in 50–90%

of admissions and can be divided into patient-related factors, providerrelated factors, HF-related disease states, and other causes (Table 257-5).

Inability to recognize and correct these factors promptly may lead to

persistent HF despite adequate treatment.

■ PHYSICAL EXAMINATION

General Appearance Most patients with mild-moderate HF will

appear well nourished and comfortable at rest. Even patients with more

advanced disease may be in no distress after resting for a few minutes

but may demonstrate dyspnea with minimal exertion such as walking

across the room. In contrast, patients with severe HF may need to sit

upright and appear anxious, diaphoretic, and dyspneic at rest with

TABLE 257-4 New York Heart Association Functional Classification

FUNCTIONAL

CLASS LIMITATION CLINICAL ASSESSMENT

Class 1 None Ordinary physical activity does not cause

undue fatigue, dyspnea, palpitations, or angina.

Class II Slight Comfortable at rest. Ordinary physical activity

(e.g., carrying heavy packages) may result in

fatigue, dyspnea, palpitations, or angina.

Class III Marked Comfortable at rest. Less than ordinary

physical activity (e.g., getting dressed) leads to

symptoms.

Class IV Severe Symptoms of heart failure or angina are

present at rest and worsened with any activity.

TABLE 257-5 Precipitating Factors in Heart Failure

Patient-Related

Excess exertion or emotional stress

Excess fluid and/or sodium intake

Nonadherence with medications

Heavy alcohol use

Provider-Related

 Recommended use of mediations that cause salt and water retention

(e.g., NSAIDs)

Prescribed use of medications with negative inotropic properties (e.g., CCBs)

Unrecognized congestion and inadequate use of diuretics

Heart Failure–Related

Uncontrolled hypertension

Myocardial ischemia or infarction

Atrial or ventricular arrhythmias

Pulmonary embolism

Other Disease States

Systemic infection

Worsening renal or hepatic failure

Hyperthyroidism

Untreated sleep apnea

Anemia

Abbreviations: CCB, calcium channel blocker; NSAID, nonsteroidal antiinflammatory drug.

Heart Failure: Pathophysiology and Diagnosis

1937CHAPTER 257

pallor due to anemia or duskiness due to low output. Other signs of

severe HF include cool extremities and peripheral cyanosis. Cardiac

cachexia (Table 257-6), defined partially as unintentional edema-free

weight loss of >5% over 12 months, may be observed in patients with

longstanding, severe HF as bitemporal or upper body muscle wasting. Contributing factors include poor oral intake due to anorexia,

decreased fat absorption due to bowel wall edema, and catabolic/

metabolic imbalance from activation of inflammatory cytokines (see

above) and dysregulation of the growth hormone–insulin-like growth

factor 1 pathway. Rarely, scleral icterus and jaundice may result from

severe right HF.

Vital Signs With new-onset HF, heart rate rises and blood pressure

may initially be increased due to sympathetic activation. In patients

with chronic HF on guideline-directed medical therapy, resting heart

rate ideally should be <70–75 beats/min, and blood pressure should be

in the normal to low-normal range. An irregular rhythm may be due

to atrial fibrillation or flutter or frequent premature atrial or ventricular

complexes. Severe HF may be associated with hypotension and narrow

pulse pressure along with a rapid, thready pulse. An alternatingly

strong and weak pulse, known as pulsus alternans, is attributed to

reduced left ventricular contraction in every other cardiac cycle due to

incomplete recovery causing alternation in the left ventricular stroke

volume. Respiratory rate may be normal at rest but may increase on

lying down or on minimal exertion. Advanced HF may be associated

with periodic breathing or Cheyne-Stokes respirations. The patient is

usually unaware of the altered breathing pattern, but family members

or friends may become alarmed or attribute this incorrectly to anxiety.

Oxygen saturation is typically normal on room air unless there is acute

pulmonary edema, underlying CHD with shunting, severe pulmonary

arterial hypertension, or concomitant acute or chronic lung disease. A

low-grade fever resulting from cytokine activation may occur in severe

HF and subside when compensation is restored.

Jugular Venous Pulse Examination of the jugular veins provides

an estimate of the right atrial pressure. Typically, the patient is examined at a 45° angle, and jugular venous pressure (JVP) is quantified in

centimeters of water by estimating the height of the venous column

of blood above the sternal angle in centimeters and then adding 5. In

patients with mild right HF, JVP may be normal at rest (≤8 cmH2

O) but

increase with compression of the right upper quadrant. Hepatojugular

reflux is elicited by applying firm continuous pressure over the liver

for 15–30 s while observing the neck veins. The patient must breathe

normally and not strain during the maneuver. Higher levels of venous

pressure approaching the angle of the jaw are common in chronic right

HF. If significant tricuspid regurgitation is present, prominent V waves

and Y descents may be noted. The abdominojugular test, defined as

an increase in right atrial pressure during 10 s of firm midabdominal

compression followed by an abrupt drop on pressure release, suggests

elevated left-sided filling pressure. A rise in JVP with inspiration or

Kussmaul’s sign may be due to severe biventricular HF and is a marker

of poor outcome.

Lung Examination Pulmonary rales result from transudation of

fluid from the intravascular space into the alveoli and airways. In general, rales are heard at the lung bases, but in severe HF or acute pulmonary edema, they may be heard throughout the lung fields. Wheezing

and rhonchi can occur with congestion of the bronchial mucosa and

sometimes lead to a misdiagnosis (and inappropriate treatment) of

asthma or chronic obstructive pulmonary disease (COPD). Rales may

be absent in patients with longstanding HF and chronically elevated

pulmonary capillary wedge pressures due to increased lymphatic

drainage, which prevents spillage from the interstitium into the alveoli.

In biventricular or predominant right HF, bilateral pleural effusions are

recognized as dullness to percussion and decreased breath sounds at

the bases. When pleural effusions are unilateral, they typically involve

the right side.

Cardiac Examination As discussed above, chronic HF with

ventricular remodeling is accompanied by cardiac enlargement. The

apical impulse is displaced downward and to the left and may be diffuse in dilated cardiomyopathy or sustained in pressure overloaded

states such as aortic stenosis. In biventricular or severe right HF, a

right ventricular heave or parasternal lift may be palpated along the

left sternal border. Uncommonly, a palpable third heart sound may be

present. In patients with HFpEF, precordial palpation is often normal.

On auscultation, an S3

 gallop is most commonly present in patients

with volume overload and tachycardia, suggests severe hemodynamic

compromise, and carries negative prognostic significance. An S4

 gallop is not specific to HF but may be present in patients with HFpEF

due to hypertension. Holosystolic murmurs of mitral and tricuspid

regurgitation are present in the setting of advanced HF, often in the

absence of structural valvular abnormalities. In patients with secondary pulmonary hypertension, a loud pulmonary component of the

second heart sound may be heard.

Abdomen and Extremities Hepatomegaly is an early sign of systemic venous congestion. The liver edge may be tender due to stretching of the capsule, but with progression of right HF, tenderness may

disappear. The liver edge may be pulsatile in patients with tricuspid

regurgitation. Longstanding hepatic congestion may result in cardiac

cirrhosis with congestive splenomegaly and mild-moderate ascites.

The presence of massive ascites should lead to a search for other causes

such as constrictive pericarditis or primary liver failure. Dependent

lower extremity edema is common in chronic HF and is typically

symmetric and pitting. Over time, chronic edema may cause reddening and induration of the skin, become weeping, or lead to cellulitis.

Anasarca is used to describe massive, generalized edema involving the

legs, sacrum, and abdominal wall. In patients with acute HF or younger

adults with chronic HF, lower extremity edema may be absent despite

marked systemic venous hypertension. Unilateral lower extremity

edema may be due to deep venous thrombosis, prior trauma, or history

of vein harvest for bypass surgery. Nonpitting edema that does not

respond to increasing doses of diuretics may represent lymphedema

that requires alternative diagnostic workup and treatment.

■ DIAGNOSIS

The diagnosis of HF is relatively straightforward when the patient

presents with typical signs and symptoms; however, the signs and

symptoms of HF are neither specific nor sensitive. It is therefore

important for clinicians to have a high index of suspicion for HF,

particularly in patients who are at increased risk, including older patients

with underlying cardiovascular disease and those with comorbidities such

hypertension, diabetes, and chronic kidney disease. In this setting, additional laboratory testing and imaging should be performed (Fig. 257-6).

Routine Laboratories Standard laboratory testing in patients

with HF includes a comprehensive metabolic panel, complete blood

count, coagulation studies, and urinalysis. Selected patients should

have assessment for diabetes, dyslipidemia, and thyroid function. Blood

urea nitrogen and creatinine levels are often elevated in moderate-severe

HF due to reduced renal blood flow and/or increased renal venous

pressure. Worsening renal function (Chaps. 310 and 311) due to

TABLE 257-6 Definition of Cardiac Cachexia

Edema-free weight loss of at least 5% in 12 months or less in the presence of

underlying illness (or a BMI <20 kg/m2

) and at least three of the following criteria:

• Decreased muscle strength (lowest tertile)

• Fatigue (physical and/or mental weariness resulting from exertion)

• Anorexia (limited food intake [<70% of usual] or poor appetite)

• Low fat-free BMI (lean tissue depletion by DEXA <5.45 in women and <7.25 in

men)

• Abnormal biochemistry:

• Increased inflammatory markers (CRP >5.0 mg/L, IL-6 >4.0 pg/mL)

• Anemia (hemoglobin <12 g/dL)

• Low serum albumin (<3.2 g/dL)

Abbreviations: BMI, body mass index; CRP, C-reactive protein; DEXA, dual-energy

x-ray absorptiometry; IL, interleukin.

Source: Modified from WJ Evans et al: Clin Nutr 27:793, 2008.

1938 PART 6 Disorders of the Cardiovascular System

diuretics, RAAS inhibitors, and noncardiac medications (e.g., nonsteroidal anti-inflammatory drugs) is also common. Proteinuria may

be present in the setting of longstanding hypertension or diabetes or

suggest an underlying systemic disease. Chronic right HF with congestive hepatomegaly can lead to modest elevations in transaminases,

alkaline phosphatase, and bilirubin that should not be confused with

biliary tract disease. Marked elevation in transaminases and lactic acid

suggest cardiogenic shock with severe low output. In patients with cardiac cirrhosis, hypoalbuminemia may exacerbate fluid accumulation,

whereas hyperammonemia contributes to altered mental status. In

general, inflammatory markers such as erythrocyte sedimentation rate,

C-reactive protein, and uric acid are nonspecific and do not aid in the

diagnosis of HF. Other laboratories, including antinuclear antibodies,

rheumatoid factor, serum free light chains, serum protein electrophoresis, ferritin, ceruloplasmin, hepatitis C, and HIV, are reserved for

targeted testing.

Electrolyte abnormalities seen in HF include hyponatremia due to

sodium restriction, diuretic therapy, and vasopressin-mediated free

water retention. Hyponatremia is a negative prognostic indicator at

the time of HF hospitalization and predicts decreased long-term survival (Table 257-1). Hypokalemia is most often due to thiazide or loop

diuretics given without oral potassium supplementation but may also

result from increased aldosterone levels. Hyperkalemia may result from

marked reductions in glomerular filtration rate and is exacerbated by

use of RAAS inhibitors and potassium-sparing diuretics (Chap. 258).

Hypo- or hyperkalemia may lead to atrial or ventricular arrhythmias.

Hypophosphatemia and hypomagnesemia are commonly associated

with chronic alcohol use.

Anemia is not diagnostic of HF, but when present, it may exacerbate

underlying ischemic heart disease and should be corrected. Rarely,

severe anemia may cause high-output HF typically in the presence

of underlying cardiovascular disease. The presence of iron deficiency

(with or without anemia) is increasingly recognized in patients with

chronic HF and has been attributed to decreased gut absorption,

impaired hepatic storage, and chronic blood loss. Repletion with IV

iron results in improved symptoms and exercise capacity and reduced

HF hospitalizations, but its effect on survival remains uncertain.

Chest X-Ray Major abnormalities on chest imaging associated with

left HF include enlarged cardiac silhouette (cardiothoracic ratio >0.5)

and pulmonary venous congestion. Early radiologic signs of acute HF

include upper zone venous redistribution and thickening of interlobular septa. When the pulmonary capillary wedge pressure is moderate

to severely elevated, alveolar edema can present as diffuse haziness

extending downward toward the lower lung fields. The absence of these

findings in patients with chronic HF reflects the increased capacity of

the lymphatics to remove interstitial and/or pulmonary fluid. Pleural

effusions of varying size and distribution are common in biventricular

HF. Chest x-ray can also be used to identify noncardiac causes of dyspnea (e.g., pneumonia, COPD).

Electrocardiogram No specific electrocardiographic (ECG) pattern is diagnostic of HF. Rather, the ECG may provide important information regarding presence of underlying cardiac disease. For example,

left ventricular hypertrophy and left atrial enlargement suggest HFpEF

due to hypertension, aortic stenosis, or hypertrophic cardiomyopathy.

The presence of Q waves or infarction is suggestive of ischemic heart

disease, whereas Q waves with reduced QRS voltage (pseudo-infarct

pattern) may be seen with restrictive or infiltrative cardiomyopathies

(e.g., amyloid). Conduction system disease should raise concern for

cardiac sarcoid or Chagas cardiomyopathy in the right clinical setting.

Paroxysmal or persistent atrial fibrillation is present in up to 40%

of patients with chronic HF and is an indication for anticoagulation.

Premature ventricular complexes (PVCs) and nonsustained ventricular

tachycardia can reflect worsening HF and are markers of increased

risk. Conversely, frequent PVCs can cause cardiomyopathy that may be

treated successfully with ablation (Chap. 253). Finally, determination

of the QRS width and presence of LBBB is used to ascertain whether

the patient may benefit from cardiac resynchronization therapy.

Noninvasive Imaging Noninvasive cardiac imaging (Chap. 241)

is essential for the diagnosis, evaluation, and management of HF.

Two-dimensional echocardiography provides an accurate and rapid

determination of ventricular size and function and valvular morphology and function and can detect intracavitary thrombi and pericardial

effusions. When left ventricular ejection fraction (LVEF) is ≥50%, systolic function is deemed to be normal. Myocardial strain rate imaging

using speckle tracking can add incremental value to LVEF and carries

prognostic value. Doppler techniques can be used to estimate CO, pulmonary artery pressures, and valve areas, and may detect abnormalities

in left ventricular diastolic filling in patients with HFpEF. For patients

with end-stage HF, echocardiography is critical for assessment of right

ventricular function before and after mechanical circulatory support

and heart transplant. Transesophageal echocardiogram is indicated to

rule out atrial thrombi prior to cardioversion and can assess aortic or

mitral valve pathology in planning for transcatheter valvular replacement or repair.

Cardiac magnetic resonance imaging (CMR) has emerged as a

highly accurate and quantitative tool for evaluation of left ventricular

mass, volumes, and function and for determining specific causes of HF

(e.g., ischemic cardiomyopathy, myocarditis, amyloidosis, hemochromatosis). CMR is particularly helpful in defining multiple anatomic

and functional abnormalities in adults with CHD. Serial CMR studies

can assess ventricular remodeling in response to therapy and are useful

History and physical examination

Laboratories

Chest x-ray

Electrocardiogram

Echocardiogram

Determine cause

CMR/CT/PET

 Ischemia/viability imaging

 Tissue characterization

Coronary angiography

 Angina or ischemia

 Chest pain or risk factors

Screening for:

 Hemochromatosis

 Amyloidosis

 Sarcoidosis

Endomyocardial biopsy

NYHA functional class

Cardiopulmonary exercise test

Natriuretic peptide level

Ambulatory rhythm monitor

Hemodynamics

Family history

Risk stratification

FIGURE 257-6 Initial assessment of patients presenting with heart failure. The

initial evaluation starts with a thorough history and physical examination, focusing

on detection of comorbidities including hypertension, diabetes, and dyslipidemia.

In addition, identification of valvular heart disease, vascular disease, history of

mediastinal radiation, or exposure to cardiotoxins (e.g., chemotherapy, alcohol, or

illicit drugs) may help determine underlying cause. A family history of sudden death,

heart failure, arrhythmias, or cardiomyopathy is also useful. Routine laboratory

evaluation (see text) should also be performed. Chest x-ray is useful to detect

cardiomegaly and fluid overload and to rule out pulmonary disease. A 12-lead

electrocardiogram should be performed to detect abnormalities of cardiac rhythm

and conduction, left ventricular hypertrophy, and evidence of myocardial ischemia

or infarction. Two-dimensional echocardiography with Doppler imaging is indicated

to assess cardiovascular structure and function and detect abnormalities of the

myocardium, heart valves, or pericardium. Further imaging and laboratory studies

aimed at identifying a specific cause of cardiomyopathy depend on information

obtained from the history and physical examination. In all patients, risk stratification

should be performed to assess severity of illness, guide therapy, and provide

prognosis to patient and family. CMR, cardiac magnetic resonance imaging; CT,

computed tomography; NYHA, New York Heart Association; PET, positron emission

tomography.

Heart Failure: Pathophysiology and Diagnosis

1939CHAPTER 257

in clinic research. For patients who cannot undergo CMR (e.g., due to

implantable devices), cardiac computed tomography (CT) is particularly helpful to rule out pericardial disease or left ventricular apical

thrombus. While limited by availability and cost, cardiac positron

emission tomography (PET) plays a role in evaluating the extent of

ischemia or infarction in patients with coronary artery disease and, in

the case of sarcoid, can reliably determine the severity and distribution

of cardiac inflammation.

Cardiopulmonary Exercise Testing While not routinely performed in HF, cardiopulmonary exercise testing using a symptomlimited, ramp protocol can provide an objective assessment of peak

functional capacity in patients being evaluated for mechanical circulatory support or heart transplant (Chap. 260). Several parameters

including absolute and percent-predicted peak oxygen consumption

(VO2

) and ventilatory efficiency (assessed by the VE/VCO2

 slope) are

independent predictors of survival. Additional data including heart

rate and blood pressure response to exercise and exercise-induced

arrhythmias can also be assessed. This test may also be useful in defining the cause of dyspnea when the diagnosis is uncertain.

Biomarkers Circulating levels of natriuretic peptides are useful,

adjunctive tools in the diagnosis of HF. BNP and N-terminal pro-BNP

(NT-proBNP) are released from the atria and ventricles in response to

increased wall stress. Patients with HFrEF tend to have higher levels

than patients with HFpEF, whereas levels may be falsely low in obesity.

In ambulatory patients with dyspnea, the measurement of BNP or

NT-proBNP is useful to support clinical decision-making regarding

the diagnosis of HF, especially in the setting of clinical uncertainty or

with concomitant lung disease. Moreover, natriuretic peptide levels

can be used to establish disease severity and prognosis in chronic HF

and may help to guide optimal dosing of medical therapy in stable outpatients. Importantly, many noncardiac factors, including age, female

sex, and chronic kidney disease, increase natriuretic peptide levels.

Other cardiovascular diseases including atrial fibrillation, pulmonary

embolism, and pulmonary arterial hypertension can also increase BNP

levels. Galectin-3 and soluble ST2 are newer biomarkers that have been

approved for assessment of prognosis in HF but are not widely used.

Biomarkers of renal injury require further study in HF.

Invasive Studies In the intensive care setting, assessment of

cardiac filling pressures and CO may be necessary to differentiate

cardiogenic from noncardiogenic pulmonary edema and manage

hemodynamic instability. Placement of a pulmonary artery catheter

can be performed safely at the bedside and used to determine response

to intravenous vasoactive and diuretic therapy in severe HF. Simultaneous measurement of right and left heart filling pressures in the

cardiac catheterization laboratory can be used to distinguish restrictive

cardiomyopathy from constrictive pericarditis. Coronary angiography

is indicated to exclude ischemic heart disease as an underlying, potentially reversible cause of left ventricular dysfunction. The management

of coronary artery disease in the setting of chronic HF is discussed in

Chaps. 274–276. If echocardiographic windows are suboptimal, left

ventriculography can provide an assessment of left ventricular size

and function and severity of mitral regurgitation. The role of right

ventricular endomyocardial biopsy in the management of HF and

cardiomyopathy remains controversial. Indications include detection

of myocarditis, diagnosis of cardiac amyloidosis and chemotherapyrelated left ventricular failure, and screening for cardiac allograft rejection following heart transplant.

COMORBIDITIES

■ DIABETES

Type 2 diabetes mellitus is a risk factor for the development of HF

(Table 257-7) and increases the risk of morbidity and mortality in

patients with established disease. In ambulatory HF cohorts, the prevalence of diabetes ranges from 10 to 40%, with prevalence even higher in

patients hospitalized with HF. When the two diseases coexist, patients

are at increased risk for adverse outcomes, worse quality of life, and

higher costs of care. Recent data from cardiovascular outcomes trials

demonstrate that HF is a critical outcome in patients with diabetes and

that glucose-lowering therapies can impact morbidity and mortality.

As discussed above, SGLT-2 inhibitors in particular have not only been

shown to be safe in patients with HF but can also improve renal function and decrease the risk of hospitalization and death. Use of other

guideline-directed medical therapy is indicated in patients with HF

regardless of diabetes status.

■ SLEEP APNEA

Sleep-disordered breathing is common in HF, with increased incidence

of both obstructive sleep apnea and central sleep apnea (Chap. 297).

The pathophysiologic link between these disorders has been studied

in both animal models and humans and includes increased afterload,

decreased preload, intermittent hypoxia, and sympathetic activation.

Increase in sympathetic tone can provoke ischemia and arrhythmias

and complicate blood pressure management. Approximately one-third

of patients with HF and sleep-disordered breathing have central sleep

apnea, which is associated with increased mortality independent of other

known risk factors. In patients with HFrEF and obstructive sleep apnea,

continuous positive airway pressure has been shown to improve quality

of life, decrease blood pressure and arrhythmias, and increase EF. Unlike

obstructive sleep apnea, there is no proven therapy for central sleep

apnea, although the role of nocturnal oxygen is currently being tested.

■ OBESITY

Similar to diabetes, obesity is both a risk factor for the development

of HF and highly prevalent in patients with HF. In particular, obesity

is common in patients with HFpEF and complicates the assessment

of volume status in both ambulatory and inpatient settings. Unlike

diabetes, the risk of morbidity and mortality in obese patients with HF

is complex. The obesity paradox refers to the observation that obese

patients diagnosed with HF have a more favorable prognosis than

patients with low or even normal body mass index. While weight loss

has been shown to improve quality of life and exercise capacity and

may contribute to reverse ventricular remodeling in patients with HF,

the impact on survival is unknown.

■ DEPRESSION

Depression is an independent risk factor for adverse outcomes in HF

(Table 257-1), especially in older women. The mechanisms underlying

this risk remain unknown but may involve neuroendocrine dysfunction and systemic inflammation, as well as contributions from poor

sleep, decreased appetite, and adverse effects of medications and alcohol. The AHA recommends screening for depression among patients

with cardiovascular disease including HF using validated patient

health questionnaires. Selective serotonin reuptake inhibitors are safe

for treating depression in HF but do not appear to affect the natural

history of disease. The effect of cognitive behavioral therapy and the

collaborative care model, as well as newer therapies such as transcranial

TABLE 257-7 Mechanisms That Contribute to Development of Heart

Failure in Patients with Type 2 Diabetes Mellitus

Altered myocardial substrate

Abnormal mitochondrial bioenergetics

Oxidative stress and inflammation

Lipotoxicity

Endoplasmic reticulum stress

Impaired insulin signaling

β2

-Adrenergic receptor signaling

G protein–coupled receptor kinase 2 signaling

RAAS activation

Advanced glycation end products

Autophagy

Abbreviation: RAAS, renin-angiotensin-aldosterone system.

Source: Reproduced with permission from TA Zelniker: Mechanisms of cardiorenal

effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review.

J Am Coll Cardiol 75:422, 2020.