Approach to the Patient with Heart Failure

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Heart Failure Definition and Epidemiology

Heart failure (HF) is a complex clinical syndrome resulting from structural and functional impairment of ventricular filling or ejection of blood. While the clinical syndrome of HF may arise due to abnormalities or disorders involving all aspects of cardiac structure and function, most patients have impairment of myocardial function, ranging from normal ventricular size and function to marked dilation and reduced function. While symptoms of HF frequently depend on the presence of elevated left or right heart filling pressures, the term “congestive” HF is no longer preferred, as many patients do not have overt congestion at the time of evaluation, and their symptoms may be due to reduction in cardiac output, for example.

The global incidence and prevalence rates of HF have reached epidemic proportions, as evidenced by the relentless increase in the number of HF hospitalizations, the growing number of HF deaths, and the spiraling costs associated with the care of HF patients. The overall prevalence of HF is increasing in part because our current therapies of cardiac disorders (such as myocardial infarction, valvular heart disease, and arrhythmias) are allowing patients to survive longer. Worldwide, HF affects nearly 23 million people. In the United States, the most recent epidemiologic data suggest that 6.2 million adult Americans have HF, and it is estimated that by 2030 the prevalence will increase 46% from current estimates. Estimates of the prevalence of symptomatic HF in the general European population is similar to that in the United States, and ranges from 0.4% to 2%. The prevalence of HF rises exponentially with age, and affects 4% to 8% of people over the age of 65 years ( Fig. 48.1A ). Although the relative incidence of HF is lower in women than men for all age groups, women constitute at least half of the cases of HF because of their longer life expectancy and the overall prevalence of HF is greater in women than men ≥80 years of age. The age-adjusted incidence of HF appears greatest in black men, followed by black women, white men, and white women; the higher incidence of HF in blacks was attributed to the greater levels of atherosclerotic risk factors in this population ( Fig. 48.1B ). In North America and Europe, the lifetime risk of developing HF is approximately one in five for a 40-year-old. Risk factors for HF include ischemic heart disease, incident or prevalent myocardial infarction, myocarditis, valvular heart disease, tachycardia, diabetes mellitus, structural heart disease related to congenital heart disease, sleep apnea, excessive drug or alcohol use, as well as obesity. A significant percentage (approximately 30% to 40%) of nonischemic HF is thought to be due to genetic factors (see Chapter 52 ). In addition certain medications may increase the risk for HF, including nonsteroidal antiinflammatory medications and cancer chemotherapy.

FIGURE 48.1, Prevalence and outcomes of heart failure in the United States. A, Prevalence of heart failure by gender and age. B, Prevalence of heart failure by age and racial or ethnic group.

The distribution of ejection fraction (EF) across unselected populations of HF patients is bimodal with peaks centered around 35% and 55%. Approximately half of patients have HF with preserved EF (HFpEF [see Chapter 51 ]), while the balance have HF with reduced EF (HFrEF [see Chapter 50 ]) ; HFpEF is generally defined as a left ventricular EF ≥50%, whereas HFrEF is generally defined as an EF less than 40%. Insofar as treatment strategies for treating HF are based on these two categories, these distinctions are critical and consensus is not present regarding this classification or how to consider those with HF and an EF between 40% and 50% ; this latter category of patients is often excluded from clinical trials, although recent HFpEF trials have included patients down to an EF of 45%.

The prevalence of HFpEF increases dramatically with age and is much more common in women than in men at any age. The prevalence of HFpEF appears to be increasing, perhaps as a function of the aging population and increased recognition of the diagnosis.

An increasingly important population of patients are those with HF and “recovered” EF (HFrecEF). ^, Although increases in left ventricular ejection fraction (LVEF) may occur “spontaneously” in some forms of dilated cardiomyopathy (DCM), the changes generally occur in the setting of the use of guideline-directed medical and device therapy. Moreover, it is usually not possible to clearly discern the “spontaneous” component to the improvement in myocardial function, because most patients are treated with guideline-directed medical therapy (GDMT). It is important to recognize that the subgroup of HFrEF patients with a recovered LVEF are clinically distinct from patients with HF with a preserved EF (HFpEF), who also have an LVEF greater than 50% along with the presence of HF signs and symptoms. Improvements in LVEF with GDMT can lead to a complete normalization of LVEF (i.e., >50%) or a partial normalization of LVEF (40% to 50%) ( Fig. 48.2 ). Estimates of the proportion of patients with improved LVEF range widely (e.g., 10% to 40%) due to variable definitions, and the use of both observational and clinical trial datasets. Patients in this category have somewhat characteristic demographics, in that they are more likely to be younger, female, to have nonischemic HF, shorter duration of HF, and to have less remodeling of their left ventricle at the time of diagnosis. Genetic factors may play a role in recovery of EF, as certain mutations (such as those involving the titin gene) may be associated with more robust improvement in LVEF after therapy. A recent consensus statement suggested that patients with a recovered LVEF should be referred to as HFrecEF, to denote that they were initially HF patients with a remodeled (e.g., dilated) LV. This terminology also avoids confusing these patients with patients with HFpEF who have an LVEF greater than 50%, as well as with patients with an intermediate LVEF (40% to 50%) that may represent HFpEF patients with deteriorating LVEF.

$FIGURE 48.2, Changes in left ventricular (LV) ejection fraction (EF) with guideline-directed medical or device therapies (GDMT) in patients with heart failure with a reduced EF (HFrEF). HF and “recovered” EF (HFrecEF) patients treated with GDMT may have a complete recovery of left ventricular (LV) ejection fraction (EF) greater than 50%, partial recovery of LVEF (EF 40% to 50%), or no functional recovery of LVEF (EF <40%).$

As noted above, one of the major hurdles toward our understanding of this unique group of patients is the lack of standardization with regard to the definition of HFrecEF. A working definition of HFrecEF that is consistent with the majority of studies in the literature includes: (1) documentation of a decreased LVEF less than 40% at baseline, (2) ≥10% absolute improvement in LVEF, and (3) a second measurement of LVEF greater than 40%. These improvements in LVEF are typically accompanied by a reduction in LV volumes.

Patients with HF and improved EF represent a therapeutic conundrum. Although demonstrating improvement in LVEF, many of these patients may have persistent biochemical signs of HF pathophysiology with abnormal concentrations of natriuretic peptides, and a recent study suggested that discontinuation of GDMT for HF was accompanied by an unacceptably high rate (44%) of recrudescent HFrEF. Further, many patients with HF and improved EF remain at risk of adverse outcomes including return of depressed left ventricular function or hospitalization for HF. Although more studies are needed, the existing data suggest that HFrecEF patients should continue receiving GDMT despite normalization of LVEF, because of the concern for recurrence of HF, as well as the clinical observation that, among patients who experience a relapse and recurrent decline in LVEF, there is a higher likelihood of recurring myocyte injury and a diminished ability to recover LVEF the second time around.

Classification of Heart Failure

Patients with HF are classified according to symptomatology and the stage of the disease. The American College of Cardiology/American Heart Association (ACC/AHA) HF staging approach ( Table 48.1 ) emphasizes the importance of development and progression of disease, whereas the New York Heart Association (NYHA) functional classification focuses more on exercise tolerance in those with established HF (see Table 48.1 ). While suffering from considerable subjectivity, the NYHA functional classification is widely used. Use of both systems in conjunction provides a reasonable framework for clinician communication and patient prognostication; the NYHA functional classification is also used to determine eligibility for certain therapies, such as mineralocorticoid receptor antagonists, or cardiac resynchronization therapy.

TABLE 48.1

American College of Cardiology/American Heart Association (ACC/AHA) Stages of Heart Failure (HF) Compared to the New York Heart Association (NYHA) Functional Classification

ACC/AHA Stages of Heart Failure		NYHA Functional Classification
A	At high risk for HF but without structural heart disease or symptoms of heart failure.	None
B	Structural heart disease but without signs or symptoms of heart failure.	I	No limitation of physical activity. Ordinary physical activity does not cause symptoms of heart failure.
C	Structural heart disease with prior or current symptoms of heart failure.	I	No limitation of physical activity. Ordinary physical activity does not cause symptoms of heart failure.
		II	Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of heart failure.
		III	Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of heart failure.
D	Refractory heart failure requiring specialized interventions.	IV	Unable to carry on any physical activity without symptoms of heart failure, or symptoms of heart failure at rest.

HF , Heart failure.

When the diagnosis of HF is suspected, the goals of the clinical assessment are to determine whether HF is present, define the underlying cause and the type of HF (HFrEF vs. HFpEF), assess the severity of HF, as well as identify comorbidities that can influence the clinical course and response to treatment. While the diagnosis of HF can be straightforward when the patient presents with a constellation of the classic signs and symptoms in the appropriate clinical setting ( Tables 48.2 and 48.3 ), no sign or symptom alone can define the presence or severity of HF. Furthermore, detection of diagnostic physical findings of HF is imprecise, often requiring other diagnostic tools. Thus, as depicted in Figure 48.3 , the clinical assessment of HF most often depends on information that is gleaned from a variety of sources including the history (both past and present), physical examination, laboratory tests, cardiac imaging, and functional studies.

TABLE 48.2

Using the Medical History to Assess the Heart Failure Patient

Symptoms associated with heart failure include:

1.
Fatigue

2.
Shortness of breath at rest or during exercise

3.
Dyspnea

4.
Tachypnea

5.
Cough

6.
Diminished exercise capacity

7.
Orthopnea

8.
Paroxysmal nocturnal dyspnea

9.
Nocturia

10.
Weight gain/Weight loss

11.
Edema (of the extremities, scrotum, or elsewhere)

12.
Increasing abdominal girth or bloating

13.
Abdominal pain (particularly if confined to the right upper quadrant)

14.
Loss of appetite or early satiety

15.
Cheyne-Stokes respirations (often reported by the family rather than the patient)

16.
Somnolence or diminished mental acuity

Historical information that is helpful in determining if symptoms are due to heart failure include:

1.
A past history of heart failure

2.
Cardiac disease (e.g., coronary artery, valvular or congenital disease, previous myocardial infarction)

3.
Risk factors for heart failure (e.g., diabetes, hypertension, obesity)

4.
Systemic illnesses that can involve the heart (e.g., amyloidosis, sarcoidosis, inherited neuromuscular diseases)

5.
Recent viral illness or history of HIV or Chagas disease

6.
Family history of heart failure or sudden cardiac death

7.
Environmental and/or medical exposure to cardiotoxic substances

8.
Substance abuse

9.
Noncardiac illnesses that could affect the heart indirectly (including high output states such as anemia, hyperthyroidism, arteriovenous fistulae)

TABLE 48.3

Physical Findings of Heart Failure

1.
Tachycardia

2.
Extra beats or irregular rhythm

3.
Narrow pulse pressure or thready pulse ∗

4.
Pulses alternans ∗

5.
Tachypnea

6.
Cool and/or mottled extremities ∗

7.
Elevated jugular venous pressure

8.
Dullness and diminished breath sounds at one or both lung bases

9.
Rales, rhonchi, and/or wheezes

10.
Apical impulse displaced leftward and/or inferiorly

11.
Sustained apical impulse

12.
Parasternal lift

13.
S3 and/or S4 (either palpable and/or audible)

14.
Tricuspid or mitral regurgitant murmur

15.
Hepatomegaly (often accompanied by right upper quadrant discomfort)

16.
Ascites

17.
Pre-sacral edema

18.
Anasarca ∗

19.
Pedal edema

20.
Chronic venous stasis changes

∗ Indicative of more severe disease.

FIGURE 48.3, Flow chart for the evaluation of patients with heart failure (HF). Appropriate cut points for natriuretic peptide testing to identify or exclude HF are discussed in eTable 48.1 . The diagnosis of HF is made using a combination of clinical judgment and initial and subsequent testing. Following thorough history and physical examination together with initial diagnostic testing, imaging (such as with echocardiography [ECG]) may still be necessary in ambiguous cases to definitively identify or exclude the diagnosis.

The Medical History and Physical Examination

A complete medical history and carefully focused physical examination are the foundation of the assessment in HF patients, providing important information regarding etiology of HF, identifying possible exacerbating factors, and lending pivotal data for proper management (see Chapter 13 ). The information obtained guides the further direction of the patient’s evaluation and enables the clinician to make the most judicious use of additional tests. Further, the history helps to evaluate incongruent results that may emerge during the diagnostic process, and it can obviate the need for needless further testing.

Heart Failure Symptoms and Signs

Patients with HF may complain of a vast array of symptoms, the most common of which are listed in Table 48.2 . While none of these are entirely sensitive or specific for identifying the presence of congestion (see Table 48.4 ), some are more reliable than others for this indication. Importantly, none are specific to HFpEF versus HFrEF. Worsening dyspnea is a cardinal symptom of HF, and is typically related to increases in cardiac filling pressures but also may represent restricted cardiac output. The absence of worsening dyspnea, however, does not necessarily exclude the diagnosis of HF, because patients may accommodate symptoms by substantially modifying their lifestyle. Probing more deeply into the current level of activity may uncover a decline in exercise capacity that is not immediately apparent. Dyspnea at rest is often mentioned by patients hospitalized with HF and has a high-diagnostic sensitivity and significant prognostic ramifications in this population. However, it is also cited by patients with many other medical conditions, so that the specificity and positive predictive value of dyspnea at rest alone are low. Patients may sleep with their heads elevated to relieve dyspnea while recumbent (orthopnea); additionally, dyspnea while lying on the left side (trepopnea) may occur. Paroxysmal nocturnal dyspnea, shortness of breath developing while recumbent, is one of the most highly reliable indicators of HF. Cheyne-Stokes respiration (also referred to as periodic or cyclic respiration) is common in advanced HF and is usually associated with low cardiac output and sleep-disordered breathing (see also Chapter 50, Chapter 89 ). The presence of Cheyne-Stokes respiration is generally indicative of an adverse prognosis. Nocturnal cough is a frequently overlooked symptom of HF. These symptoms all typically reflect pulmonary congestion, whereas a history of weight gain, increasing abdominal girth, early satiety, and the onset of edema in dependent organs (extremities or scrotum) indicate right heart congestion; while nonspecific, right upper quadrant pain due to congestion of the liver is common in those with significant right HF, and may be incorrectly attributed to other conditions. Another cardinal symptom of HF is fatigue, generally held to be reflective of reduction in cardiac output as well as abnormal skeletal muscle metabolic responses to exercise. Other causes of fatigue in HF may include major depression, anemia, renal dysfunction, endocrinologic abnormalities, as well as side effects to medications. Unintended weight loss, often leading to cachexia, may be prominent and is a major prognostic indicator.

Other Historical Information

Information about a patient’s past and current medical problems and a multigenerational family history as well as social history provides the background upon which symptoms are interpreted and a management plan is designed.

The presence of hypertension, coronary artery disease, and/or diabetes is particularly helpful because these conditions account for approximately 90% of the population attributable risk for HF in the United States. The medical history should also focus on what drugs are taken by the patient; notable agents associated with incident HF include cancer chemotherapy, diabetes drugs (e.g., thiazolidinediones), ergot-based antimigraine drugs, appetite suppressants, certain antidepressants and antipsychotic agents (notably including clozapine), decongestants such as pseudoephedrine (due to its ability to trigger severe hypertension), as well as antiinflammatory agents such as the antimalarial drug hydroxychloroquine (uncommonly associated with an infiltrative cardiomyopathy) or nonsteroidal antiinflammatory drugs. The latter class of agents is well recognized to lead to HF through their ability to worsen renal function, trigger hypertension, and lead to fluid retention, particularly in older adults. A history of use of herbal remedies and dietary supplements should be obtained. Environmental or toxic exposures including alcohol or drug abuse should be carefully sought. A multigenerational family history should be taken for prior HF or sudden cardiac death. Information about the presence of comorbidities (as described later in the chapter) is essential in devising management plans. While most etiologies of HF are cardiac, it is worth remembering that some systemic illnesses (e.g., anemia, hyperthyroidism) can cause this syndrome without direct cardiac involvement (see Chapter 96 ).

TABLE 48.4

Sensitivity and Specificity of History and Physical Exam Components for the Diagnosis of Elevated Filling Pressures in Patients with Heart Failure

H&P Finding	Frequency	Sensitivity	Specificity	Predictive Value		LR		OR (95% CI)
H&P Finding	Frequency	Sensitivity	Specificity	Positive	Negative	Positive	Negative	OR (95% CI)
Values expressed as percentages unless otherwise indicated. LR indicates likelihood ratio; OR, odds ratio.
Rales (≥1/3 lung fields)	26/192	15	89	69	38	1.32	1.04	1.4 (0.6, 3.4)
S3	123/192	62	32	61	33	0.92	0.85	0.8 (0.4, 1.5)
Ascites (moderate/massive)	31/192	21	92	81	40	2.44	1.15	2.8 (1.1, 7.3)
Edema (≥2+)	73/192	41	66	67	40	1.20	1.11	1.3 (0.7, 2.5)
Orthopnea (≥2 pillows)	157/192	86	25	66	51	1.15	1.80	2.1 (1, 4.4)
Hepatomegaly (>4 finger breadths)	23/191	15	93	78	39	2.13	1.09	2.3 (0.8, 6.6)
Hepatojugular reflux	147/186	83	27	65	49	1.13	1.54	1.7 (0.9, 3.5)
JVP ≥12 mm Hg	101/186	65	64	75	52	1.79	1.82	3.3 (1.8, 6.1)
JVP <8 mm Hg	18/186	4.3	81	28	33	0.23	0.85	0.2

JVP , Jugular venous pressure.

The Physical Examination

The physical findings listed in Table 48.2 complement information from the medical history in defining the presence and severity of HF (see also Chapter 13 ). The signs of HF have been extensively described, and much as with the history of patients with HF, components of the physical exam have variable sensitivity and specificity for the diagnosis (see Table 48.4 ), in part due to the subtlety of some physical findings as well as variability in the physical diagnostic skills of the examiner. No physical finding in HF is absolutely pathognomonic for HFpEF versus HFrEF.

An evaluation for the presence and severity of HF should include consideration of the patient’s general appearance, measurement of vital signs in the seated and standing position, examination of the heart and pulses, and assessment of other organs for evidence of congestion, hypoperfusion, or indications of comorbid conditions. The patient’s general appearance conveys vital information. The examiner should assess the patient’s body habitus and state of alertness, as well as whether the patient is comfortable, short of breath, coughing, or in pain. The skin exam may show pallor or cyanosis due to under-perfusion, stigmata of alcohol abuse (such as spider angiomata or palmar erythema), erythema nodosum due to sarcoidosis, bronzing due to hemachromatosis, or easy bruising from amyloidosis; additional findings supporting amyloidosis include deltoid muscle infiltration (leading to the “shoulder pad sign”), tongue hypertrophy, and bilateral thenar wasting from carpal tunnel syndrome. The details of inspection and palpation of the heart are discussed in Chapter 13 . By observing or palpating the apical impulse, the examiner can rapidly determine heart size and quality of the point of maximal impulse. In cases of severe HF, a palpable impulse corresponding to a third heart sound may be present. Cardiac auscultation ( Chapter 13 ) is a crucial part of HF evaluation.

A characteristic holosystolic murmur of mitral insufficiency is heard in many HF patients. Tricuspid insufficiency, which is also common, can be differentiated from mitral insufficiency by the location of the murmur at the left sternal border, an increased intensity of the murmur during inspiration, and the presence of prominent “V” waves in the jugular venous waveform. Both mitral and tricuspid insufficiency murmurs may become softer as volume overload is treated, and a reduction in ventricular size (with corresponding reduction in annular diameter) improves valve coaptation and competency. Aortic stenosis is an important cause of HF because its presence greatly alters management. The presentation of aortic stenosis may be subtle, however, because the intensity of the murmur depends on blood flow across the valve and this may be reduced as HF develops. The presence of a third heart sound is a crucially important finding and suggests increased ventricular filling volume; while difficult to identify, a third heart sound is highly specific for HF, and carries a substantial prognostic meaning. A fourth heart sound usually indicates reduced ventricular compliance. In advanced HF, the third and fourth heart sounds may be superimposed, resulting in a summation gallop.

A key objective of the examination in HF patients is to detect and quantify the presence of volume retention, with or without pulmonary and/or systemic congestion. As with symptoms, evidence of congestion does not always indicate with certainty that HF is present, nor does absence of manifest congestion definitively exclude the diagnosis. Patients with HFpEF and HFrEF do not generally show significant differences in frequency or significance of the stigmata of volume overload.

The most definitive method for assessing a patient’s volume status by physical examination is by the measurement of jugular venous pressure (JVP), which is discussed in detail in Chapter 13 . An elevated JVP has good sensitivity (70%) and specificity (79%) for elevated left-sided filling pressure (see Table 48.4 ). The sensitivity and specificity of the JVP in detecting congestion can be considerably improved by exerting pressure on the right upper quadrant of the abdomen while assessing venous pulsations in the neck (hepatojugular reflux). Changes in JVP with therapy usually parallel changes in left-sided filling pressure. Limitations of JVP assessment include difficulties in its evaluation due to body habitus as well as significant interobserver variability in its estimation. Increase in the JVP may lag behind left heart filling pressures or may not rise at all if pulmonary artery pressure is increased to the extent that right ventricular failure or tricuspid insufficiency occur. Conversely, the JVP may be elevated without an increase in left ventricular filling pressures in patients with pulmonary arterial hypertension, in those with isolated right ventricular pressure, or when isolated severe tricuspid regurgitation is present.

While pulmonary congestion is exceedingly common in HF, physical findings indicating its presence are variable, and many are nonspecific. Dullness to percussion and diminished breath sounds at one or both lung bases suggests the presence of a pleural effusion. Bilateral pleural effusions are most common but when an effusion is present unilaterally, it is usually right sided with only approximately 10% occurring exclusively on the left side. Leakage of fluid from pulmonary capillaries into the alveoli can be manifest as rales or rhonchi, while wheezing may occur due to reactive bronchoconstriction. Pulmonary rales due to HF are usually fine in nature and extend from the base upward while those due to other causes (e.g., pulmonary fibrosis) tend to be coarser. Importantly, rales or rhonchi may be absent in congested patients with advanced HF; this may reflect compensatory increase in local lymphatic drainage. The occurrence of so-called “cardiac asthma” is due to the physical presence of fluid in the bronchial wall as well as secondary bronchospasm, and can commonly result in an incorrect diagnosis of obstructive airways disease exacerbation, with consequent mis-triage and incorrect therapy with bronchodilators; such incorrect management may be associated with increased risk for mortality.

Lower-extremity edema is a common finding in volume-overloaded HF patients but may commonly be the result of venous insufficiency (particularly after saphenous veins have been harvested for coronary artery bypass grafts) or as a side effect of medications (e.g., calcium channel blockers). Careful inspection of the JVP helps improve the specificity of pedal edema for HF.

Detecting reduced cardiac output and systemic hypoperfusion are key components of the examination. While patients with poor systemic perfusion usually have low systolic and narrow pulse pressures as well as weak and thready pulses, this relationship is not exact. Many patients with systolic blood pressure in the range of 80 mm Hg (or even lower) may have adequate perfusion while others with reduced cardiac output may maintain blood pressure in the normal range at the expense of tissue perfusion by greatly increasing systemic vascular resistance. Findings suggesting reduced cardiac output include poor mentation, reduced urine output, mottled skin, and cool extremities. Of these, cool extremities are the most broadly useful.

Assessment for systemic congestion taken together with evaluation for reduced cardiac output may be useful to categorize patients ( Fig. 48.4 ) into “dry/warm” (uncongested with normal perfusion), “wet/warm” (congested with normal perfusion, the most common combination found in decompensated HF), “dry/cold” (uncongested but hypoperfused), and “wet/cold” (cardiogenic shock), as discussed in Chapter 49 . These categories are not only prognostic, but also inform treatment decision making.

FIGURE 48.4, Schema for categorizing patients with heart failure (HF) on the basis of perfusion (warm versus cold) and presence of congestion (dry versus wet). In doing so, four categories may be identified, which have different treatment strategies. The four categories of HF identified in this schema have different treatment strategies.

Routine Laboratory Assessment

A suggested algorithm for the diagnostic evaluation of HF is presented in Figure 48.3 . The laboratory testing and imaging modalities described below provide important information for the diagnosis and management of patients with suspected or proven HF.

Chest Radiography

Despite advances in other imaging technologies the chest X-ray remains a very useful component of the assessment, particularly when the clinical presentation is ambiguous. Results of chest radiography are additive to clinical variables from history and physical examination, and similarly complement the results of biomarker testing. Accordingly, chest radiography should be a routine part of the early evaluation of patients presenting with symptoms suggestive of acutely decompensated HF (see also Chapter 17 ).

The classical chest X-ray pattern in patients with pulmonary edema is a “butterfly” pattern of interstitial and alveolar opacities bilaterally fanning out to the periphery of the lungs. Many patients, however, present with more subtle findings, in which increased interstitial markings including Kerley B lines (thin horizontal linear opacities extending to the pleural surface caused by accumulation of fluid in the interstitial space), peri-bronchial cuffing, and evidence of prominent upper lobe vasculature (indicating pulmonary venous hypertension) are the most prominent findings. Pleural effusions and/or fluid in the right minor fissure may also be seen. In many cases, particularly in those with very advanced HF, the chest X-ray may be entirely clear, despite significant symptoms of dyspnea; the negative predictive value of chest radiography is too low to definitively exclude HF.

The Electrocardiogram

The electrocardiogram (ECG) is a standard part of the initial evaluation of a patient with suspected HF, as it may provide important clues regarding incident HF, while also assisting in understanding when previously diagnosed patients experience an episode of decompensation (see also Chapter 14 ). In patients with HF, the ECG is infrequently normal, but may only show nonspecific findings; thus, much like the chest radiography, the positive predictive value of ECG far surpasses the negative predictive value in this setting.

Sinus tachycardia due to sympathetic nervous system activation is seen with advanced HF or during episodes of acute decompensation; beside increasing the likelihood for the diagnosis finding of elevated heart rate it is a prognostic finding in HF as well. The presence of atrial arrhythmia on the ECG as well as the ventricular response may provide clues as to the cause of HF, as well as explain why a patient may have developed decompensated symptoms; identifying atrial arrhythmia with a rapid ventricular response also provides a target for therapeutic interventions. Increased ventricular ectopy identifies a patient at risk for sudden death, particularly when the EF is very low (e.g., <30%).

The presence of increased QRS voltage may suggest left ventricular hypertrophy; in the absence of a prior history of hypertension, such a finding might be caused by valvular heart disease or by hypertrophic cardiomyopathy, particularly if bizarre repolarization patterns are noted. If right ventricular hypertrophy is present, primary or secondary pulmonary hypertension should be considered. Low QRS voltage suggests the presence of an infiltrative disease or pericardial effusion. The presence of Q waves suggests that HF may be due to ischemic heart disease, while new or reversible ST changes identify acute coronary ischemia is present even when chest pain is absent. Indeed, as acute coronary ischemia is a leading cause of acutely decompensated HF, a 12-lead ECG should be immediately obtained in this setting, to exclude acute MI.

The intervals on the ECG may provide important information regarding causes of HF, as well as yielding information with respect to treatment strategy. Prolongation of the PR interval is common in patients in this setting, and may be due to intrinsic conduction disease, but may also be seen in patients with infiltrative cardiomyopathy such as amyloidosis. With the advent of cardiac resynchronization therapy (see Chapter 58 ) evaluation the QRS complex has become a critical part of the clinical assessment, in that it provides important information regarding the cause of HF, as well as providing pivotal information regarding the therapeutic approach. The QT interval is often prolonged in patients with HF, and may be due to electrolyte abnormalities, myocardial disease, or from effects of commonly used drugs, such as antiarrhythmics. A lengthened QT interval may identify patients at risk for torsades de pointes and is thus an important variable to consider when utilizing therapeutic agents with effects on ventricular repolarization.

Measurement of Blood Chemistry and Hematologic Variables

Patients with new-onset HF and those with acute decompensation of chronic HF should have a panel of electrolytes, blood urea nitrogen, serum creatinine, hepatic enzymes, fasting lipid profile, thyroid stimulating hormone, transferrin saturation, uric acid, a complete blood count, and a urinalysis measured. As discussed below, the natriuretic peptides may be useful for diagnosis as well as for prognostication. A test for human immunodeficiency virus or further screening for hemachromatosis is reasonable in selected patients, while diagnostic tests for rheumatologic diseases or pheochromocytoma are reasonable when suspicion exists for these diseases. When the diagnosis of cardiac amyloidosis is entertained (see also Chapter 53 ), serum-free light chains may be measured to screen for the AL form of the diagnosis, however no reliable blood tests exist for diagnosis of the transthyretin form of cardiac amyloidosis, which typically requires imaging for its evaluation (see also Chapter 53 ).

Abnormalities of sodium are common in HF patients, particularly during periods of acute decompensation, and have substantial prognostic meaning. Studies have shown that hyponatremia (defined as serum sodium values below 135 mmol/L) may be found in up to 25% of patients with acute HF, and hyponatremia may also be seen in patients with indolently worsening HF without obvious decompensation. Low-sodium concentrations in HF may be due to worsening volume retention or may be related to the use of diuretics, including thiazides. Hyponatremia is associated with impaired cognitive and neuromuscular function, and when present and persistent, low sodium is strongly prognostic for longer hospital stay, as well as a high risk for mortality. Despite this fact, strategies to correct serum-sodium levels have not been shown to clearly improve the clinical course (see Chapter 50 ). Hypernatremia, although uncommon, is also prognostic for mortality in patients with HF. Hypokalemia occurs commonly in HF patients who are treated with diuretics. Besides increasing the risk of cardiac arrhythmias, low potassium may also lead to leg cramps and muscle weakness. Conversely, hyperkalemia is less common, and most often is due to effects of medications such as angiotensin-converting enzyme inhibitors or mineralocorticoid inhibition.

Abnormalities of renal function are common in patients with HF, and occur due to renal congestion, inadequate cardiac output, or as a consequence of comorbid conditions. In addition, HF therapies such as diuretics and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can increase blood urea nitrogen and creatinine. In this regard, abnormalities of renal function may have substantial effects on the ability to aggressively treat HF patients. Furthermore, abnormal renal function represents one of the more powerful prognostic variables gleaned from routine laboratory testing in HF. For these reasons, assessment of renal function should be performed as part of the initial evaluation of HF, and then periodically repeated during follow-up.

In patients hospitalized with acutely decompensated HF (see Chapter 49 ), registry data suggest that 60% to 70% have a reduced estimated glomerular filtration rate ; among such patients, the initial blood urea nitrogen and serum creatinine concentrations are both independently predictive of death. Following admission, approximately 30% of patients with acute HF may also develop an increase in serum creatinine by ≥0.3 mg/dL, which is similarly prognostic for mortality. ^, The causes of this so-called “cardiorenal” syndrome are complex, but include the severity of right heart congestion, increased intraabdominal pressure, as well as renal hypoperfusion from inadequate cardiac output. On the other hand, worsening renal function may also occur from aggressive decongestion strategies; such decline in renal function has been linked to improved (rather than worse) prognosis, as it presumably indicates a more thorough treatment for congestion, the trigger for acute HF hospitalization. Accordingly, when faced with worsening renal function, the clinician must perform a careful examination to assess volume status and tissue perfusion to decide on appropriate therapies to manage the situation. Lastly, improvement in renal function may follow therapies improving the severity of congestion, although such a finding is still associated with poor long-term prognosis.

Diabetes mellitus is common in HF patients and hyperglycemia has emerged as a possible risk factor for adverse outcome in affected patients. Because diuretics can cause gout, measuring uric acid levels can help in patient management; elevated serum uric acid levels have been noted to be prognostic, and therapies to lower their concentration are now being studied to improve HF outcomes. Abnormalities in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, or lactate dehydrogenase may occur in HF patients as a consequence of either hemodynamic derangements leading to hepatic congestion, or may be due to medications, and it is important to follow levels periodically. An unexpected increase in prothrombin time in patients receiving warfarin therapy may be an early harbinger of decompensation as it may reflect impaired synthetic capacity of a congested liver. Albumin levels are an indication of the patient’s nutritional status and they may be depressed due to poor appetite or impaired absorption across an engorged bowel wall; hypoalbuminemia is prognostic for mortality in acute and chronic HF.

Hematologic abnormalities are exceedingly common in HF, affecting nearly 40% of affected patients. Low hemoglobin levels have been associated with more severe HF symptoms, reduced exercise capacity and quality of life, and increased mortality. While anemia may be a consequence of chronic disease in HF patients, a low hemoglobin level should trigger an evaluation to detect treatable causes, particularly iron deficiency. Increasing attention has also been given to the red cell distribution width as a prognostic variable in both acutely decompensated and chronic HF. The white blood cell count and differential is helpful in detecting the presence of infection that is responsible for destabilizing a previously well-compensated patient and could provide a clue that HF is due to uncommon cause such as eosinophilic infiltration of the myocardium.

Beyond standard laboratory testing, the measurement of biomarkers has emerged over the past decade as important adjunct to the initial and subsequent evaluation of patients with suspected or proven HF. Biomarkers are now routinely used for distinguishing HF from other conditions and to establish severity of the diagnosis, and also to provide useful prognostic information in HF patients. Lastly, there is considerable interest in determining the ability of biomarkers to guide therapy both in the acute and chronic settings. As shown in Table 48.5 , Braunwald has proposed that HF biomarkers be divided into six distinct categories with an additional one reserved for biomarkers that have not yet been classified (see also Chapter 8 and 10 ).

TABLE 48.5

Biomarkers Used in Assessing Patients with Heart Failure

Inflammation ∗ ^, ^† ^, ^‡

C-reactive protein
Tumor necrosis factor
Fas (APO-1)
Interleukins 1, 6, and 18

Oxidative stress ∗ ^, ^† ^, ^§ ^,

Oxidized low-density lipoproteins
Myeloperoxidase
Urinary biopyrrins
Urinary and plasma isoprostanes
Plasma malondialdehyde

Extracellular-matrix remodeling ∗ ^, ^§

Matrix metalloproteinases
Tissue inhibitors of metalloproteinases
Collagen propeptides
Propeptide procollagen type I
Plasma procollagen type III

Neurohormones ∗ ^, ^† ^, ^§

Norepinephrine
Renin
Angiotensin II
Aldosterone
Arginine vasopressin
Endothelin

Myocyte injury ∗ ^, ^† ^, ^§

Cardiac-specific troponins I and T
Myosin light-chain kinase I
Heart-type fatty-acid protein
Creatine kinase MB fraction

Myocyte stress ^† ^, ^‡ ^, ^§ ^, ^¶

B-type natriuretic peptide/N-terminal pro-B type natriuretic peptide
Midregional proadrenomedullin
ST2

New Biomarkers ^†

Chromogranin
Galectin 3
Osteoprotegerin
Adiponectin
Growth differentiation factor 15
Insulin-like growth factor binding protein 7

∗ Biomarkers in this category aid in elucidating the pathogenesis of heart failure.

† Biomarkers in this category provide prognostic information and enhance risk stratification.

‡ Biomarkers in this category can be used to identify subjects at risk for heart failure.

§ Biomarkers in this category are potential targets of therapy.

¶ Biomarkers in this category are useful in the diagnosis of heart failure and in monitoring therapy.

As articulated, clinically useful biomarkers of HF should be easily measured with high analytical precision, should reflect important processes involved in HF presence and progression, should not recapitulate clinical information already available at the bedside, and must provide clinically useful information for caregivers to more swiftly and reliably establish/reject a diagnosis, to more accurately estimate prognosis, or to inform more successful therapeutic strategies. Only the natriuretic peptides have met these requirements, although other promising biomarkers exist for use in HF assessment.

Natriuretic Peptides

The natriuretic peptides are useful biomarkers for HF diagnosis, estimation of HF severity and prognosis, and possibly for management of HF as well. The most commonly measured natriuretic peptides are B-type natriuretic peptide (BNP) and its amino-terminal cleavage pro-peptide equivalent, NT-proBNP; these two biomarkers are released from cardiomyocytes in response to stretch, and highly precise assays exist for their detection in blood (see also Chapter 47 ). Given the preponderance of myocardium in the ventricles, BNP and NT-proBNP mainly reflect ventricular stretch and are synthesized in response to wall stress. Atrial natriuretic peptide (ANP) is another member of the class of natriuretic peptides and is synthesized and secreted from atrial tissue; a mid-regional pro-ANP assay is now available and appears to deliver comparable results to BNP and NT-proBNP when tested in HF patients.

Due to the differences in their clearance BNP and NT-proBNP have considerably different half-lives (BNP: 20 minutes; NT-proBNP: 90 minutes), and thus they circulate with very different concentrations. Both natriuretic peptides have become an important part of the HF assessment, however much like any diagnostic test, clinicians must always remember the broad array of structural and functional reasons for BNP or NT-proBNP release to correctly interpret their values. Natriuretic peptide levels tend to increase progressively with worsening NYHA functional class, and tend to be higher in HFrEF, compared to HFpEF, despite independent contributions of diastolic function to their concentrations. Patients with acute HF most often have higher values for BNP and NT-proBNP, compared to chronic stable patients, however this is by no means a universal finding, and knowledge of an individual’s natriuretic peptide value when stable may be useful to better interpret a change when a change in symptoms occurs.

When using BNP or NT-proBNP, the clinician should remember that beyond left ventricular systolic and diastolic dysfunction, concentrations of both peptides are higher in patients with valvular heart disease, pulmonary hypertension, ischemic heart disease, atrial arrhythmias, and even pericardial processes such as constriction. Elevation of BNP or NT-proBNP—often marked—is nearly ubiquitous in infiltrative cardiomyopathies such as cardiac amyloidosis; these elusive diagnoses should be considered in a patient with significant elevation of natriuretic peptide but without obvious congestion. Additionally, numerous relevant medical covariates with effects on natriuretic peptide values must also be kept in mind. For example, both BNP and NT-proBNP concentrations increase with age, thought to identify accumulating structural heart disease in older patients. Both natriuretic peptides are higher in patients with renal failure, partially reflective of slower clearance, but also similarly identifying heart disease in this population of patients with prevalent cardiovascular risk factors. Elevated natriuretic peptide values can also be seen in hyperdynamic states, including sepsis. Patients who have right ventricular dysfunction as a result of pulmonary embolus may have elevated natriuretic peptide concentrations. It is also important to recognize that angiotensin receptor neprilysin inhibitors (ARNIs [see Chapter 50 ]) may modestly increase levels of BNP, but this finding is not universal and may be transient. As NT-proBNP is not a substrate for neprilysin, its concentrations remain reflective of the clinical picture; in patients under treatment with ARNI, changes in NT-proBNP are associated with LV remodeling parameters (such as change in LVEF) and strongly predict outcomes. ^,

Obesity is strongly linked to lower-than-expected BNP or NT-proBNP values, despite comparable or higher wall stress in heavier patients. Given the common effect on BNP, NT-proBNP, and MR-proANP, this is not likely to be a clearance effect (as each are cleared differently), rather more likely to represent suppression of natriuretic peptide gene expression or post-translational modification.

Results of BNP or NT-proBNP, although useful, should always be interpreted in the context of sound clinical judgment, integrated with results of history, physical examination, and other testing; these important biomarkers strongly supplement clinical judgment, but should not replace it. Keeping this in mind, the natriuretic peptides have been shown to be useful to identify and exclude acute HF in the emergency department, as well as more indolent HF in the outpatient setting. Suggested cutoffs for use of natriuretic peptides are shown in eTable 48.1 .

ETABLE 48.1

Suggested Cutoffs for Clinical Applications of the Natriuretic Peptides

	Cutoff value	Sensitivity	Specificity	Positive predictive value	Negative predictive value
To exclude acutely decompensated HF: BNP NT-proBNP MR-proANP	<30–50 pg/mL <300 pg/mL <57 pmol/L	97% 99% 98%	∗ ∗ ∗	∗ ∗ ∗	96% 99% 97%
To identify acutely decompensated HF: Single cutoff point strategy BNP NT-proBNP MR-proANP Multiple cut point strategy BNP, “grey zone” approach NT-proBNP, “age-stratified” approach MR-proANP, “age-stratified” approach	<100 pg/mL <900 pg/mL <127 pmol/L <100 pg/mL to exclude 100–400 pg/mL, “grey zone” >400 pg/mL, to rule in <450 pg/mL for age <50 yr <900 pg/mL for age 50–75 yr <1800 pg/mL for age >75 yr <104 pmol/L for age <65 yr 214 pmol/L for age ≥65 yr	90% 90% 87% 90% ∗ 63% 90% 82%	76% 85% 79% 73% ∗ 91% 84% 86%	79% 76% 67% 75% ∗ 86% 88% 75%	89% 94% 93% 90% ∗ 74% 66% 91%
Outpatient Application BNP NT-proBNP, “age stratified” approaches MR-proANP	20 pg/mL (asymptomatic) or 40 pg/mL (symptomatic) <125 pg/mL for age <75 yr <450 pg/mL for age ≥75 yr or <50 pg/mL for age <50 yr <75 pg/mL for age 50–75 yr <250 pg/mL for age >75 yr Unknown	∗ ∗ ∗ ∗ ∗ ∗ ∗ Unknown	∗ ∗ ∗ ∗ ∗ ∗ ∗ Unknown	∗ ∗ ∗ ∗ ∗ ∗ ∗ Unknown	96% 98% 91% 98% 98% 93% Unknown

BNP , B-type natriuretic peptide; HF , heart failure.

Pivotal data for BNP and NT-proBNP testing to diagnose acute HF came from the Breathing Not Properly and ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) studies respectively. In the Breathing Not Properly, a BNP concentration of 100 pg/mL was highly accurate for the diagnosis of acutely decompensated HF; in PRIDE, an NT-proBNP cutoff of 900 pg/mL provided comparable performance to a BNP of 100 pg/mL. Subsequently, the International Collaborative of NT-proBNP (ICON) investigators showed that age stratification improved positive predictive value of NT-proBNP in acutely dyspneic patients; as well, an NT-proBNP concentration below 300 pg/mL was useful to exclude acutely decompensated HF. These data were more recently affirmed in the ICON: Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study, where performance of NT-proBNP to detect or exclude acute HF remained robust in a more contemporary population of patients with acute dyspnea.

Knowledge of natriuretic peptide levels in the emergency department is associated with more rapid diagnosis, lower admission rate, shorter length of hospital stay, and reduced cost. As clinical uncertainty in acute dyspnea is associated with worse prognosis, it is reassuring to note that natriuretic peptide testing is particularly useful in this complex situation.

For patients with less acute presentations of dyspnea in settings other than the ED, values of BNP or NT-proBNP are most often considerably lower; when used for evaluation of the dyspneic ambulatory patient, therefore, the optimized cutoffs from emergency department studies should not be used: lower values are mandatory, and optimized for their negative predictive value to exclude (rather than identify) HF (see eTable 48.1 ). Age stratification again improves diagnostic accuracy in this setting, as older patients are expected to have generally higher concentrations of BNP or NT-proBNP in the absence of clinical HF. If a patient is found to be above such cutoffs, further diagnostic testing such as echocardiography is likely needed. Causes of falsely low BNP or NT-proBNP in the outpatient setting are comparable to those with acute dyspnea.

Natriuretic peptide levels provide useful prognostic information across all ACC/AHA stages of HF even when adjusted for important variables from history, physical examination, echocardiography, or even cardiopulmonary exercise testing ( Fig. 48.5 ). While one natriuretic peptide measurement is prognostically meaningful, serial follow up measurements add incrementally important prognostic information. For example, in patients with acute HF, those who do not show a robust reduction in BNP or NT-proBNP by the time of hospital discharge tend to have considerably higher rates of morbidity and mortality. It has thus been suggested that a BNP or NT-proBNP decrease of 30% or more by hospital discharge is desirable. Similarly, in ambulatory HF, chronically elevated or rising natriuretic peptide values identify a particularly high-risk patient population. HF therapies may lower concentrations of BNP and NT-proBNP; when this finding occurs, prognosis is improved.

FIGURE 48.5, Indications for the use of biomarkers in heart failure. Key: ∗Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and high-sensitivity troponin. ACC , American College of Cardiology; ADHF , acute decompensated heart failure; AHA , American Heart Association; BNP , B-type natriuretic peptide; COR , Class of Recommendation; ED , emergency department; HF , heart failure; NT-proBNP , N-terminal pro-B-type natriuretic peptide; NYHA , New York Heart Association; pts , patients.

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