Heart Failure

Robert Hobbs

Andrew Boyle

CHAPTER SECTION LINKS

• Definition and causes

• Prevalence and risk factors
• Pathophysiology and natural history
• Signs and symptoms
• Diagnosis
• Treatment

• Prevention and screening

• Considerations in special populations
• Summary
• References

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Definition and causes

Heart failure is a clinical syndrome characterized by systemic perfusion inadequate to meet the
body's metabolic demands as a result of impaired cardiac pump function. This may be further
subdivided into systolic or diastolic heart failure. In systolic heart failure, there is reduced
cardiac contractility, whereas in diastolic heart failure there is impaired cardiac relaxation and
abnormal ventricular filling (Fig. 1).

Figure 1: Click to Enlarge

The most common cause of heart failure is left ventricular systolic dysfunction (about 60% of
patients). In this category, most cases are a result of end-stage coronary artery disease, either
with a history of myocardial infarction(s) or chronically underperfused, yet viable, myocardium.
In many patients, both processes are present simultaneously (Fig. 2A). Other common causes of
left ventricular systolic dysfunction include idiopathic dilated cardiomyopathy, valvular heart
disease, hypertensive heart disease, toxin-induced cardiomyopathies (e.g., doxorubicin,
herceptin, alcohol), and congenital heart disease (see Fig. 2B).

Figure 2: Click to Enlarge

Right ventricular systolic dysfunction is usually a consequence of left ventricular systolic

dysfunction. It may also develop as a result of right ventricular infarction, pulmonary
hypertension, chronic severe tricuspid regurgitation, or arrhythmogenic right ventricular
dysplasia. A less common cause of heart failure is high-output failure caused by thyrotoxicosis,
arteriovenous fistulae, Paget's disease, pregnancy, or severe chronic anemia.

Diastolic left ventricular dysfunction (impaired relaxation) usually is related to chronic

hypertension or ischemic heart disease. Other causes include restrictive, infiltrative, and
hypertrophic cardiomyopathies. Inadequate filling of the right ventricle may result from
pericardial constriction or cardiac tamponade.

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Prevalence and risk factors

Heart failure is a common syndrome, especially in older adults. Although more patients survive
acute myocardial infarction because of reperfusion therapy, most have at least some residual left
ventricular systolic dysfunction, which may lead to heart failure. Currently, 5 million Americans
are afflicted with heart failure, approximately 2% of the population. 1 Patients with heart failure
account for about 1 million hospital admissions annually, with another 2 million patients having
heart failure as a secondary diagnosis. One third of these patients are readmitted within 90 days
for recurrent decompensation.

Patients at high risk for developing heart failure are those with hypertension, coronary artery
disease, diabetes mellitus, familial history of cardiomyopathy, use of cardiotoxins, and obesity.

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Pathophysiology and natural history

Although much progress has been made in the treatment of heart failure, there is a high overall
annual mortality (5% to 20%), particularly in patients with New York Heart Association
(NYHA) Class IV symptoms. 2 Many patients succumb to progressive pump failure and
congestion, although one half die from sudden cardiac death. Some patients die from end-organ
failure resulting from inadequate systemic organ perfusion, particularly to the kidneys. Indicators
of poor cardiac prognosis include renal dysfunction, cachexia, valvular regurgitation, ventricular
arrhythmias, higher NYHA heart failure class, lower left ventricular ejection fraction, high
catecholamine and B-type natriuretic peptide levels, low serum sodium level,
hypocholesterolemia, and marked left ventricular dilation. Patients with combined systolic and
diastolic left ventricular dysfunction also have a worse prognosis than patients with either in
isolation. 3

In left ventricular systolic dysfunction, regardless of the cause, cardiac output is low and
pulmonary pressures are high, leading to pulmonary congestion. Initially, as a direct result of
inadequate cardiac output and systemic perfusion, the body activates several neurohormonal
pathways to increase circulating blood volume. The sympathetic nervous system increases heart
rate and contractility, both of which increase cardiac output. Circulating catecholamines also
cause arteriolar vasoconstriction in nonessential vascular beds and stimulate secretion of renin
from the juxtaglomerular apparatus of the kidney.

Unfortunately, catecholamines aggravate ischemia, potentiate arrhythmias, promote cardiac

remodeling, and are directly toxic to myocytes. Stimulation of the renin-angiotensin system as a
result of increased sympathetic stimulation and decreased renal perfusion results in further
arteriolar vasoconstriction, sodium and water retention, and release of aldosterone. An increased
aldosterone level, in turn, leads to sodium and water retention, endothelial dysfunction, and
organ fibrosis.

In heart failure, baroreceptor and osmotic stimuli lead to vasopressin release from the
hypothalamus, causing reabsorption of water in the renal collecting duct. Endothelin levels are
elevated in heart failure and correlate with the severity of disease and prognosis. Endothelin is an
endogenous vasoconstrictor and growth factor. Levels of the proinflammatory cytokines also are
elevated in heart failure, and contribute to cardiac cachexia and apoptosis. Although these
neurohormonal pathways initially are compensatory and beneficial, eventually they are
deleterious, and neurohormonal modulation is the basis for modern treatment of heart failure.

In contrast, natriuretic peptides are hormones released by secretory granules in cardiac myocytes.
They have a beneficial influence in heart failure, including systemic and pulmonary vasodilation,
enhanced sodium and water excretion, and suppression of other neurohormones.

With continuous neurohormonal stimulation, the left ventricle undergoes remodeling consisting
of left ventricular dilation and hypertrophy, such that stroke volume is increased without an
actual increase in ejection fraction. This is achieved by myocyte hypertrophy and elongation.

Left ventricular chamber dilation causes increased wall tension, worsens subendocardial
myocardial perfusion, and may provoke ischemia in patients with coronary atherosclerosis.
Furthermore, left ventricular chamber dilation may cause separation of the mitral leaflets and
mitral regurgitation, leading to pulmonary congestion. Enhanced neurohormonal stimulation of
the myocardium also causes apoptosis or programmed cell death, worsening of ventricular
contractility, and death.
In diastolic dysfunction, the primary abnormality is impaired left ventricular relaxation, causing
high diastolic pressures and poor filling of the ventricles. To increase diastolic filling, left atrial
pressure increases until it exceeds the hydrostatic and oncotic pressures in the pulmonary
capillaries and pulmonary edema ensues. As a result, patients are often symptomatic with
exertion when increased heart rate reduces left ventricular filling time and circulating
catecholamines worsen diastolic dysfunction.

The American College of Cardiology and American Heart Association have developed a
classification of heart failure based on stages of the syndrome ( Table 1 ). 4 Stage A includes
patients at risk of developing heart failure but who have no structural heart disease at present.
The management strategy in this group is prevention of heart failure. Stage B includes patients
with structural heart disease but no symptoms. The management goal is prevention of left
ventricular remodeling leading to heart failure. Stage C includes patients with structural heart
disease with current or prior symptomatic heart failure. Diuretics, digoxin, and aldosterone
antagonists may be added to angiotensin-converting enzyme (ACE) inhibitors and beta blockers,
depending on the severity of symptoms. Cardiac resynchronization therapy also may be
considered. Stage D includes patients with severe refractory heart failure. Physicians should
consider either end-of-life care or high-technology therapies such as cardiac transplantation,
based on individual cases.
Table 1: American College of Cardiology–American Heart Association Classification of Chronic Heart Failure

Stage
A—high risk for developing heart Hypertension, diabetes mellitus, CAD, family history of
failure
B—asymptomatic heart failure
C—symptomatic heart failure
D—refractory end-stage heart
failure
Description
cardiomyopathy
Previous MI, LV dysfunction, valvular heart disease
Structural heart disease, dyspnea and fatigue, impaired
exercise tolerance
Marked symptoms at rest despite maximal medical therapy

CAD, coronary artery disease; MI, myocardial infarction; LV, left ventricular.

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Signs and symptoms

There is a wide spectrum of potential clinical manifestations of heart failure. 5 Most patients have
signs and symptoms of fluid overload and pulmonary congestion, including dyspnea, orthopnea,
and paroxysmal nocturnal dyspnea. Patients with right ventricular failure have jugular venous
distention, peripheral edema, hepatosplenomegaly, and ascites. Others, however, do not have
congestive symptoms but have signs and symptoms of low cardiac output, including fatigue,
effort intolerance, cachexia, and renal hypoperfusion. The NYHA functional classification
scheme is used to assess the severity of functional limitations and correlates fairly well with
prognosis ( Table 2 ).
Table 2: New York Heart Association (NYHA) Heart Failure Symptom Classification System
 NYHA
Level of Impairment
Class
I No symptom limitation with ordinary physical activity
Ordinary physical activity somewhat limited by dyspnea (e.g., long-distance walking,
II
climbing two flights of stairs)
Exercise limited by dyspnea with moderate workload (e.g., short-distance walking,
III
climbing one flight of stairs)
IV Dyspnea at rest or with very little exertion

On physical examination, patients with decompensated heart failure may be tachycardic and
tachypneic, with bilateral inspiratory rales, jugular venous distention, and edema. They often are
pale and diaphoretic. The first heart sound usually is relatively soft if the patient is not
tachycardic. An S3 and often an S4 gallop will be present. Murmurs of mitral or tricuspid
regurgitation may be heard. Paradoxical splitting of S2 may be present because of delayed
mechanical or electrical activation of the left ventricle. Patients with compensated heart failure
will likely have clear lungs but a displaced cardiac apex. Patients with decompensated diastolic
dysfunction usually have a loud S4, which may be palpable, rales, and often systemic
hypertension.

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Diagnosis

The initial evaluation of new-onset heart failure should include an electrocardiogram, chest
radiograph, and B-type natriuretic peptide assay. The cardiac rhythm may be normal sinus
rhythm, sinus tachycardia, or atrial fibrillation. Left ventricular hypertrophy, left bundle branch
block, intraventricular conduction delay, and nonspecific ST-segment and T wave changes
support a diagnosis of heart failure. Q waves in contiguous leads strongly implicate a previous
myocardial infarction and coronary atherosclerosis as the cause. Chest radiographic findings of
heart failure include cardiomegaly, pulmonary vascular redistribution, pulmonary venous
congestion, Kerley B lines, alveolar edema, and pleural effusions.

The single most useful diagnostic test is the echocardiogram, which can distinguish between
systolic and diastolic dysfunction. If systolic dysfunction is present, regional wall motion
abnormalities or left ventricular aneurysm suggest an ischemic basis for heart failure, whereas
global dysfunction suggests a nonischemic cause. Echocardiography is helpful in determining
other causes, such as valvular heart disease, cardiac tamponade, and pericardial constriction, and
provides useful clues about infiltrative and restrictive cardiomyopathies. Echocardiography can
also provide meaningful prognostic information about diastolic function, severity of hypertrophy,
chamber size, and valvular abnormalities. In many cases, however, the exact cause of the heart
failure cannot be discerned from the echocardiogram.

Cardiac catheterization may detect coronary atherosclerosis as the cause of heart failure. Left
ventriculography documents the severity of left ventricular systolic dysfunction and mitral valve
regurgitation. Severe coronary artery disease is so prevalent that coronary angiography routinely
should be performed to exclude this cause and, if found, should lead to an assessment of
myocardial viability, with a goal of revascularization.

Radionuclide ventriculography provides objective data about right and left ventricular systolic
function. Because no assessment of diastolic function or valvular function can be obtained, this
test is performed less frequently than echocardiography. Magnetic resonance imaging (MRI) is
useful in assessing for arrhythmogenic right ventricular dysplasia, myocardial viability, and
infiltrative cardiomyopathies.

Objective information about functional capacity can be obtained from metabolic

(cardiopulmonary) exercise testing, usually performed at larger centers. This test can distinguish
ventilatory from cardiac limitations in patients with exertional dyspnea. A peak oxygen
consumption higher than 25 mL/kg/min is normal for middle-age adults, but a value lower than
14 mL/kg/min is indicative of severe cardiac limitation and poor prognosis.

A useful diagnostic test for the detection of heart failure is the B-type natriuretic peptide (BNP)
assay. 6,7 BNP levels correlate with severity of heart failure and decrease as a patient reaches a
compensated state. This blood test may be useful for distinguishing heart failure from pulmonary
disease. Because smokers often have both these clinical diagnoses, differentiating between them
may be challenging.

Summary

• Jugular venous distention is a useful physical sign of heart failure.

• The lungs usually are clear in chronic heart failure.
• The BNP assay improves the accuracy of diagnosing heart failure.
• Echocardiography is the single most useful diagnostic modality.
• Coronary angiography confirms or excludes coronary artery disease as the cause.

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Treatment

Lifestyle Modifications

Dietary sodium and fluid restrictions should be implemented in all patients with congestive heart
failure. Limiting patients to 2 g/day of dietary sodium and 2 L/day of fluid will lessen congestion
and lower the need for diuretics. Patient education guidelines are listed in Box 1.

Box 1: Patient Education Guidelines

2-g sodium diet
Monitoring weight daily
2-L fluid restriction
Monitoring blood pressure
Medications
Smoking cessation
Light aerobic exercise
Knowing who to call
Achieving ideal weight
Follow-up visits

Cardiac rehabilitation may improve symptoms and exercise tolerance in patients with heart
failure. This will also reduce or prevent skeletal muscle atrophy that could worsen exercise
tolerance. Weight loss is encouraged in obese patients. Patients should be counseled about
smoking cessation.

Medical Options

Angiotensin-Converting Enzyme Inhibitors

All patients with left ventricular (LV) systolic dysfunction should be treated with an ACE
inhibitor unless they have a contraindication or intolerance to the drug (stages B to D). ACE
inhibitors are useful in preventing heart failure in patients at high risk who have atherosclerotic
cardiovascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk
factors (stage A). ACE inhibitors and beta blockers should be used for all patients with a history
of myocardial infarction, regardless of left ventricular ejection fraction. Vasodilation and
neurohormonal modulation with ACE inhibitors improve mortality, heart failure symptoms,
exercise tolerance, and left ventricular ejection fraction as well as reduce emergency room visits
and hospitalizations. 8–10 The dose of ACE inhibitors should be titrated to the maximum tolerated
dose 11 or the target dose as listed in Table 3 . Approximately 10% to 20% of patients are ACE
inhibitor–intolerant. The main side effect from ACE inhibition is cough, which may necessitate
change to an angiotensin II receptor blocker (ARB) or to a combination of hydralazine and
nitrate. Of note, most patients who cough on ACE inhibitors have this symptom because of
congestive heart failure rather than ACE inhibitor intolerance, and may improve with further
diuresis. Two uncommon side effects of ACE inhibitors are angioedema and acute renal failure
(caused by bilateral renal artery stenosis); both necessitate immediate cessation of the drug. ACE
inhibitors should be used in combination with beta blockers in most patients. Either agent may be
started first.
Table 3: Angiotensin-Converting Enzyme Inhibitor Dosing Table

Agent Target Dose (mg) Frequency

Captopril * 50 tid
Enalapril * 20 bid
Lisinopril * 40 qd
Ramipril * 5 bid
Quinapril * 20 bid
Fosinopril * 20 bid
Benazepril * 20 qd
Trandolapril † 4 qd

* FDA-approved for treatment of heart failure.

†FDA-approved for treatment of postmyocardial infarction heart failure.

Angiotensin Receptor Blockers

These agents block the effects of angiotensin II at the receptor level ( Table 4 ). In clinical trials,
these agents were found to be superior to placebo but no better than ACE inhibitors in improving
mortality. They improve morbidity when added to ACE inhibitors and have fewer side effects. 12
ARBs are recommended as second-line therapy in patients who are intolerant to ACE inhibitors
because of cough or angioedema (stages B to D). ARBs are also useful in preventing heart
failure in high-risk patients with a history of atherosclerotic cardiovascular disease, diabetes
mellitus, hypertension, and associated cardiovascular risk factors (stage A). The addition of an
ARB may be considered for persistently symptomatic patients with reduced ejection fraction
who are being treated with conventional therapy. ARBs should not be substituted for ACE
inhibitors in cases of hyperkalemia or renal dysfunction. ARBs may have morbidity benefits for
patients with diastolic heart failure. 13
Table 4: Angiotensin Receptor Blocker Dosing Table

Agent Initial Dose (mg) Maximal Dose (mg)

Valsartan * 80 320
Candesartan * 16 32
Losartan 25 100
Irbesartan 75 300
Telmisartan 40 80
Eprosartan 400 800
Olmesartan 20 40

* FDA-approved for treatment of heart failure.

Beta Blockers

Three beta blockers—carvedilol, metoprolol succinate (Toprol XL), and bisoprolol—have been
shown to improve survival in patients with heart failure ( Table 5 ). 14–16 Metoprolol tartrate is not
U.S Food and Drug Administration (FDA)–approved for heart failure and was less effective than
carvedilol in preventing sudden death in the COMET Trial. 17 The exact mechanism of beta
blocker action is unclear, but likely involves antiarrhythmic, anti-ischemic, antiremodeling, and
antiapoptotic properties, as well as improved beta receptor pathway function. Myocardial oxygen
consumption is reduced with beta blockers, primarily because of a reduction in heart rate.
Table 5: Beta Blocker Dosing Table

Beta Blocker Initial Dose (mg) Target Dose

Carvedilol * 3.125 mg bid 50 mg bid if >75 kg
25 mg bid if <75 kg
Metoprolol succinate * 12.5 mg qd 200 mg qd
Metoprolol tartrate 12.5 mg bid 50 mg tid
Bisoprolol 2.5 mg qd 10 mg qd
*FDA-approved for treatment of heart failure.

All stable patients with current or prior symptoms of heart failure and reduced left ventricular
ejection fraction should receive a beta blocker unless contraindicated (stages C and D). All
patients with reduced left ventricular ejection fraction with no symptoms of heart failure should
be given a beta blocker (stage B). Diabetes mellitus, chronic obstructive pulmonary disease, and
peripheral arterial disease are not contraindications to beta blocker use, although patients with
severe bronchospasm and hypotension may not tolerate the drug. Beta blockers may be used in
stable NYHA Class IV patients who are euvolemic. 2 In heart failure patients, a beta blocker
should be initiated before hospital discharge or on an outpatient basis at a low dose and titrated
slowly to target levels or maximally tolerated doses. Beta blockers usually are given in
combination with an ACE inhibitor, but either agent may be initiated first.

Digoxin

Digoxin is a neurohormonal modulating agent that inhibits the enzyme Na+,K+-ATPase in

various organs. In cardiac cells, this inhibition increases myocardial contractility. In the central
nervous system, it reduces sympathetic outflow and, in the kidney, it inhibits renin release. A
large, randomized, controlled trial has shown that the use of digoxin reduces the rate of
hospitalization for heart failure, but does not reduce mortality. 18 Digoxin is excreted by the
kidneys, so dose adjustment is necessary in cases of renal failure ( Table 6 ). A low dose of
digoxin (0.125 mg daily) should be prescribed to most patients, especially women, and serum
digoxin levels maintained at lower than 1 ng/mL. Digoxin may be prescribed for patients with
left ventricular systolic dysfunction who remain symptomatic while receiving standard medical
therapy, particularly if they are in atrial fibrillation.
Table 6: Other Heart Failure Drugs

Initial Maximal
Agent Guidelines
Dose Dose
0.125 mg Reduce dose in women with renal dysfunction, with
Digoxin 0.25 mg qd
qd amiodarone
Hydralazine 25 mg qid 100 mg qid Use concurrently with nitrates to prevent coronary steal
Isosorbide
20 mg tid 80 mg tid Also useful for angina pectoris
dinitrate
12.5 mg Weak diuretic, risk of hyperkalemia, avoid in renal
Spironolactone 25 mg qd
qd dysfunction; gynecomastia
Risk of hyperkalemia, avoid in renal dysfunction; no
Eplerenone 25 mg qd 50 mg qd
gynecomastia

Diuretics

Diuretics should be used in combination with an ACE inhibitor (or ARB) and a beta blocker.
Most patients with heart failure have some degree of symptomatic congestion and will benefit
from diuretic therapy. 19 Usually, a loop diuretic is required, with the addition of a thiazide
diuretic in patients refractory to the loop diuretic alone (diuretic resistance or cardiorenal
syndrome). Although useful for symptomatic relief, diuretics have not been shown to improve
survival, and may cause azotemia, hypokalemia, metabolic alkalosis, and elevation of
neurohormone levels ( Table 7 ).
Table 7: Diuretic Dosing Table

Initial Dose
Generic Name Class Special Considerations
(mg)
Can be given intravenously; PO equivalent twice IV
Furosemide Loop 20
dose
Good oral bioavailability; can be given intravenously;
Bumetanide Loop 0.5
oral and IV doses the same
Torsemide Loop 5-10 Best oral availability
Only diuretic with no sulfhydryl group; used if
Ethacrynic acid Loop 50
allergic to furosemide
HydrochlorothiazideThiazide12.5 Weak diuretic; used mainly for hypertension
Give ½ hr before furosemide; only available orally;
Metolazone Thiazide2.5
high risk of hypokalemia

Aldosterone Antagonists

Two aldosterone antagonists have been approved for patients with heart failure, spironolactone
and eplerenone. The RALES trial has reported a 30% reduction in mortality and hospitalizations
when spironolactone is added to standard therapy for patients with advanced heart failure. 20 The
EPHESUS study has reported a 15% reduction in the risk of death and hospitalization in patients
with heart failure and a left ventricular ejection fraction (LVEF) lower than 40% after a
myocardial infarction who were treated with eplerenone. 21

Aldosterone inhibition may prevent sodium and water retention, endothelial dysfunction, and
myocardial fibrosis. With aldosterone antagonists, diligent monitoring of serum potassium levels
is mandatory, because patients may develop hyperkalemia (see Table 6 ). These drugs should be
avoided in patients with a creatinine level higher than 2.5 mg/dL. Eight percent of men develop
gynecomastia with spironolactone, but not with eplerenone. Data from studies of mild heart
failure are lacking, and so these drugs should be reserved for patients with moderately severe to
severe heart failure. Therefore, the addition of an aldosterone antagonist is reasonable for select
patients with moderately severe to severe symptoms of heart failure and reduced LVEF who can
be carefully monitored for preserved renal function and normal potassium concentration.

Hydralazine and Nitrates

Hydralazine, an arterial dilator, and a nitrate, a venous dilator, increase nitric oxide
bioavailability, leading to increased intracellular concentrations of cyclic guanosine
monophosphate (cGMP) and vasodilation. Hydralazine also prevents nitrate tachyphylaxis (loss
of effect). The combination of hydralazine and nitrate is inferior to an ACE inhibitor in
improving survival, but better than the ACE inhibitor in improving hemodynamics. 22 Once-daily
dosing of ACE inhibitors is easier than giving nitrates three times daily and giving hydralazine
four times daily (see Table 6 ). The combination of hydralazine and nitrate is reasonable for
patients with current or prior symptoms of heart failure and reduced LVEF who cannot be given
an ACE or ARB because of drug intolerance, hyperkalemia, or renal insufficiency. Hydralazine
and nitrate also may be added to ACE inhibitors and beta blockers when additional afterload
reduction is needed or pulmonary hypertension is present. A fixed-dose combination tablet has
been approved for treating heart failure in blacks.

Other Medical Therapies

Patients with known coronary artery disease should be treated with aspirin and a statin to lower
the low-density lipoprotein (LDL) level to 70 mg/dL. Calcium channel antagonists have not been
proven to be beneficial in heart failure patients. Short-acting calcium channel antagonists such as
nifedipine are contraindicated because they increase mortality, elevate neurohormone levels, and
worsen heart failure. Dihydropyridines such as amlodipine have a neutral effect on heart failure
and may be useful for treating concomitant hypertension or angina pectoris. 23

The use of warfarin to prevent cardioembolic strokes remains controversial in the absence of
atrial arrhythmias, because the risk appears to be relatively low (1% to 3%/year). Warfarin
therapy is recommended for patients with atrial arrhythmias, previous embolic event, cardiac
thrombi, or left ventricular aneurysms.

Specific therapies for treating atrial fibrillation, sleep apnea, anemia, obesity, and thyroid disease
may improve the symptoms and functional limitations of heart failure.

Intravenous Inotropes and Vasodilators

Dobutamine

Dobutamine ( Table 8 ) enhances contractility by directly stimulating cardiac 1 receptors. 24

Intravenous (IV) dobutamine infusions, sometimes guided by hemodynamic monitoring, may be
useful for select patients with acute hypotensive heart failure or shock. The dose of dobutamine
should always be titrated to the lowest dose compatible with hemodynamic stability to minimize
adverse events. As with many inotropes, long-term infusions of dobutamine may increase
mortality, principally because of its arrhythmogenic effect. As a result, chronic dobutamine
infusions are reserved for palliative symptom relief or for patients with an implantable
cardioverter-defibrillator (ICD) awaiting heart transplantation. Intermittent outpatient infusions
of dobutamine are not recommended for routine management of heart failure.
Table 8: Intravenous Agents Used for Treatment of Heart Failure

Drug Dose Special Considerations

Dobutamine 2-20 mcg/kg/min ß receptor agonist; proarrhythmic; heart rate; ischemia
Phosphodiesterase inhibitor; vasodilator; may improve
0.375-0.75
Milrinone pulmonary hypertension; used for patients taking beta
mcg/kg/min
blockers; proarrhythmic
Anti-ischemic; vasodilator; limited by vascular headache;
Nitroglycerin 10-500 mcg/min
hypotension, tolerance develops rapidly
Thiocyanate accumulation in renal failure; may provoke
Nitroprusside10-500 mcg/min
ischemia by coronary steal; vasodilator; should be given only
 in intensive care unit
2-mcg/kg bolus; then
Nesiritide Fixed weight-based dose; vasodilator; occasional hypotension
0.01 mcg/kg/min

Milrinone

Milrinone (see Table 8 ) is a phosphodiesterase inhibitor that increases the intracellular cyclic
adenosine monophosphate (cAMP) level and enhances contractility. Milrinone is useful for
patients with hypotensive low-output heart failure and pulmonary hypertension, because it is a
more potent pulmonary vasodilator than dobutamine. Milrinone, in contrast to dobutamine, is
also useful for patients on chronic oral beta blocker therapy who develop acute hypotensive heart
failure. The OPTIME study, involving the routine intravenous infusion of milrinone for 48 hours
during hospitalization for decompensated heart failure, has failed to show symptomatic benefit,
and was associated with an increased risk of atrial arrhythmias and hypotension. 25 Similar to
dobutamine, intermittent outpatient milrinone infusions are not recommended for routine
management of heart failure.

Nitroglycerin

Nitroglycerin (see Table 8 ) is a nitric oxide donor that increases intracellular concentrations of
cGMP in endothelial and smooth muscle cells, causing vasodilation. It is a venodilator at low
doses and an arterial dilator at higher doses, lowering intracardiac pressures and alleviating
pulmonary congestion.

Nitroglycerin also dilates coronary arteries, making it useful for patients with heart failure and
myocardial ischemia. IV nitroglycerin requires dose titration to achieve therapeutic goals. The
effectiveness of prolonged infusions is limited by the development of tachyphylaxis (loss of
effect) within the first 24 hours.

Sodium Nitroprusside

Sodium nitroprusside (see Table 8 ) is a nitric oxide donor and a potent short-acting arterial and
venous dilator. Nitroprusside infusions generally are reserved for patients in an intensive care
unit and require invasive hemodynamic monitoring. During nitroprusside infusions, patients
should be converted to oral vasodilators such as ACE inhibitors, ARBs, or hydralazine and a
nitrate.

Sodium nitroprusside should be infused for a short duration in patients with severe renal disease
to avoid accumulation of thiocyanate, the by-product of hepatic metabolism of nitroprusside,
which is excreted by the kidney. Nitroprusside should be avoided in patients with active
ischemia because of its potential for coronary steal syndrome, which shunts blood away from the
ischemic myocardium to well-perfused muscle.

Nesiritide

Nesiritide (see Table 8 ), synthetic BNP, is an arterial and venous vasodilator with modest
diuretic and natriuretic properties. 26 Nesiritide increases cardiac output by reflex vasodilation
without increasing heart rate or oxygen consumption. It modulates the vasoconstrictor and
sodium-retaining effects of other neurohormones. Nesiritide is administered as a weight-based
bolus followed by continuous IV infusion in patients with acutely decompensated heart failure
who have dyspnea at rest or with minimal activity. It may be started in the emergency
department and does not require invasive hemodynamic monitoring or frequent titration.
Tolerance to the drug does not occur and it is not arrhythmogenic.

Electronic Therapies for Heart Failure

Figure 3: Click to Enlarge

Cardiac Resynchronization Therapy

Multiple clinical trials have shown the potential benefit of cardiac resynchronization therapy
(CRT) for patients with severe symptomatic heart failure and a wide QRS complex. 27,28
Symptomatic improvement is achieved in approximately 70% of patients because of improved
ventricular contraction and reduction of mitral regurgitation. With cardiac resynchronization
therapy (biventricular pacing), a third electrode is implanted in a left cardiac vein via the
coronary sinus so that the right and left ventricles are activated simultaneously (Fig. 3). Optimal
synchronization of atrial and ventricular contraction is achieved with echocardiographic
guidance. Guidelines for resynchronization therapy are listed in Box 2.

Box 2: Guidelines for Resynchronization Therapy

NYHA Class III or IV heart failure symptoms
Symptomatic despite medications
Left ventricular ejection fraction 35% (consider CRT-D)
Wide QRS (>120 ms; left bundle branch block, IVCD)
Evidence of dyssynchrony

Defibrillator Therapy
Approximately 50% of patients with heart failure die suddenly. Implantation of an ICD may
improve survival in certain subsets of heart failure patients and has been shown to be superior to
antiarrhythmic drug therapy in preventing sudden death. 29–32 Current indications for defibrillator
therapy are listed in Box 3. Cardiac resynchronization therapy can be combined with an ICD as a
single device if the patient meets criteria for both therapies, as is often the case.

Box 3: Indications for an Implantable Cardioverter-Defibrillator

Cardiac arrest survivor
Sustained ventricular tachycardia
Inducible ventricular tachycardia
Ischemic cardiomyopathy,* LVEF 35%
Dilated cardiomyopathy†, LVEF 35%
*40-day waiting period after myocardial infarction, stenting, bypass surgery.

†9-month waiting period after diagnosis. Excludes NYHA Class I. NYHA Class IV patients should be CRT eligible.
LVEF, left ventricular ejection fraction.

Surgical Options

Figure 4: Click to Enlarge

Left Ventricular Assist Devices (LVADs)

Certain patients with cardiogenic shock unresponsive to intra-aortic balloon counterpulsation and
intravenous inotrope therapy are referred to a tertiary care center for mechanical circulatory
support. 33,34 At present, left ventricular assist devices (LVADs) are best used as a bridge to
cardiac transplantation in patients who are appropriate transplantation candidates. The inflow
cannula of an LVAD is connected to the apex of the left ventricle. Blood is mechanically
pumped by the device via the outflow cannula to the aorta (Fig. 4). FDA-approved LVADs
include the HeartMate, Novacor, Thoratec, and Abiomed devices. Complications following
LVAD implantation are common and often life threatening; these include stroke, infection,
perioperative coagulopathy and bleeding, multisystem organ failure, and bioprosthetic valve
insufficiency. LVADs may be used as permanent implants (destination therapy), but many
obstacles currently prevent widespread implementation.

Ventricular Reconstruction Surgery

Ventricular reconstruction surgery, also called ventricular remodeling surgery or a Dor

procedure, is performed for heart failure secondary to ischemic cardiomyopathy. 35 It consists of
several components—coronary artery bypass grafting, mitral and tricuspid valve repair, resection
of left ventricular scar or aneurysm, reshaping the left ventricle from a spherical to an elliptic
shape, and epicardial left ventricular pacing lead placement (Fig. 5). Patients suitable for this
procedure have coronary artery disease, extensive ischemia or hibernating myocardium, severe
left ventricular dysfunction with akinetic or dyskinetic ventricular segments, and mitral or
tricuspid regurgitation.

Figure 5: Click to Enlarge

Cardiac Transplantation

Cardiac transplantation is reserved for otherwise healthy patients who have end-stage heart
failure with severely impaired functional capacity despite optimal medical therapy (Fig. 6). 36
Patients are excluded from transplantation if they have chronic medical comorbidities,
pulmonary hypertension, active infection, psychosocial contraindications, or medical
noncompliance. Survival after cardiac transplantation is about 85% at 1 year and then declines
by 4% annually thereafter. Complications limiting survival include rejection, infection,
transplant coronary vasculopathy, and malignancy. Following cardiac transplantation, patients
are subjected to lifelong immunosuppression to prevent rejection, which in turn renders them
susceptible to various opportunistic infections and malignancies.

Summary

• All heart failure patients should receive an ACE inhibitor and a beta blocker.
• Diuretics are needed in most patients to manage fluid retention.
• Digoxin is reserved for patients with signs and symptoms of heart failure.
• Aldosterone antagonists are used in patients with Class III or IV heart failure.
• ARBs or a hydralazine plus nitrate may be added to standard therapy for additional
benefit.

Figure 6: Click to Enlarge

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Prevention and screening

Patients who classified as stage A are at high risk for heart failure but without structural heart
disease or heart failure symptoms. They include individuals with hypertension, diabetes mellitus,
obesity, coronary artery disease, or use of cardiotoxins or those with a familial history of
cardiomyopathy. Preventive therapies include treatment of lipid disorders and hypertension,
smoking cessation, regular exercise, avoidance of alcohol, excess or illicit drugs, and ACE
inhibitors in appropriate patients. Patients with stage B heart failure have structural heart disease,
but no symptoms of heart failure. These include patients with previous myocardial infarction, left
ventricular systolic dysfunction, and asymptomatic valvular disease. Therapies are prescribed to
prevent left ventricular remodeling. These include all preventive strategies for stage A, as well as
ACE inhibitors and beta blockers for appropriate patients.

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Considerations in special populations

Heart failure is slightly more common in women than men. In women, heart failure occurs later
in life, is often related to hypertension, and frequently is associated with preserved left
ventricular systolic function. Women tend to have more prominent heart failure manifestations
and more hospitalizations, but better overall survival (except with coronary artery disease) than
men. They have lower peak V.o2 and higher BNP levels. Although heart failure agents are not
gender specific, women benefit less from ACE inhibitors (based on meta-analyses), but respond
equally to other heart failure therapies.

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References

1. American Heart Association. Heart Disease and Stroke Statistics—2008 Update. 2008;
Dallas. American Heart Association, 2008.
2. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 344: 2001;
1651-1658.
3. Prognostic value of Doppler echocardiographic mitral inflow patterns: Implications for
risk stratification in patients with chronic congestive heart failure. J Am Coll Cardiol. 37:
2001; 1049-1055.
4. American College of Cardiology; American Heart Association Task Force on Practice
Guidelines; American College of Chest Physicians; International Society for Heart and
Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the
Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the
American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and
Management of Heart Failure): Developed in collaboration with the American College of
Chest Physicians and the International Society for Heart and Lung Transplantation:
Endorsed by the Heart Rhythm Society. Circulation. 112: 2005; e154-e235.
5. Guidelines for the diagnosis and treatment of chronic heart failure: Executive summary
(Update 2005). Eur Heart J. 26: 2005; 1115-1140.
6. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an
urgent-care setting. J Am Coll Cardiol. 37: 2001; 379-385.
7. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N
Engl J Med. 350: 2004; 647-654.
8. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left
ventricular ejection fractions and congestive heart failure (SOLVD). N Engl J Med. 325:
1991; 293-302.
9. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a
Veterans Administration Cooperative Study. N Engl J Med. 314: 1986; 1547-1552.
10. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events
in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N
Engl J Med. 342: 2000; 145-153.
11. Comparative effects of low and high doses of the angiotensin-converting enzyme
inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study
Group. Circulation. 100: 1999; 2312-2318.
12. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
N Engl J Med. 345: 2001; 1667-1675.
13. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular
ejection fraction: The CHARM-Preserved Trial. Lancet. 362: 2003; 777-781.
14. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 334: 1996; 1349-1355.
15. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-
being in patients with heart failure: The Metoprolol CR/XL Randomized Intervention
Trial in congestive heart failure (MERIT-HF). JAMA. 283: 2000; 1295-1302.
16. Cardiac Insufficiency Bisoprolol Study Group. The Cardiac Insufficiency Bisoprolol
Study II (CIBIS-II): A randomised trial. Lancet. 353: 1999; 9-13.
17. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic
heart failure in the Carvedilol or Metoprolol European Trial (COMET): Randomized
controlled trial. Lancet. 362: 2003; 7-13.
18. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in
patients with heart failure. N Engl J Med.. 336: 1997; 525-533.
19. Diuretic therapy. N Engl J Med. 339: 1998; 387-395.
20. The effect of spironolactone on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 341: 1999;
709-717.
21. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction
after myocardial infarction. N Engl J Med. 348: 2003; 1309-1321.
22. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of
chronic congestive heart failure. N Engl J Med. 325: 1991; 303-310.
23. Effect of amlodipine on morbidity and mortality in severe chronic heart failure.
Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med.
335: 1996; 1107-1114.
24. Inotropic therapy for heart failure: An evidence-based approach. Am Heart J. 142: 2001;
393-401.
25. Short-term intravenous milrinone for acute exacerbation of chronic heart failure. A
randomized controlled trial. JAMA. 287: 2002; 1541-1547.
26. Nesiritide for the treatment of congestive heart failure. Expert Opin Pharmacother. 5:
2004; 901-907.
27. Cardiac resynchronization in chronic heart failure. N Engl J Med. 346: 2002; 1845-1853.
28. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N
Engl J Med. 352: 2005; 1539-1549.
29. Current status of the implantable cardioverter-defibrillator. Chest. 119: 2002; 1210-1221.
30. Prophylactic implantation of a defibrillator in patients with myocardial infarction and
reduced ejection fraction. N Engl J Med. 346: 2002; 877-883.
31. Prophylactic defibrillator implantation in patients with nonischemic dilated
cardiomyopathy. N Engl J Med. 350: 2004; 2151-2158.
32. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N
Engl J Med. 352: 2005; 225-237.
33. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J
Med. 345: 2001; 1435-1443.
34. Mechanical circulatory assistance: State of the art. Circulation. 106: 2002; 2046-2050.
35. Left ventricular reconstruction: Early and late results. J Thorac Cardiovasc Surg. 128:
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36. Current status of cardiac transplantation. JAMA. 280: 1998; 1692-1698.
Back to Top

Suggested Readings

• Executive summary: HFSA 2006 comprehensive heart failure practice guideline. J

Cardiac Failure. 12: 2006; 10-38.
• Heart Disease and Stroke Statistics—2008 Update. 2008; Dallas. Dallas. American Heart
Association, 2008.
• Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N
Engl J Med. 352: 2005; 225-237.
• Diuretic therapy. N Engl J Med. 339: 1998; 387-395.
• The effect of cardiac resynchronization on morbidity and mortality in heart failure. N
Engl J Med. 352: 2005; 1539-1549.
• The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J
Med. 336: 1997; 525-533.
• Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-
being in patients with heart failure: The Metoprolol CR/XL Randomized Intervention
Trial in congestive heart failure (MERIT-HF). JAMA. 283: 2000; 1295-1302.
• American College of Cardiology; American Heart Association Task Force on Practice
Guidelines; American College of Chest Physicians; International Society for Heart and
Lung Transplantation; Heart Rhythm Society: ACC/AHA 2005 Guideline Update for the
Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the
American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and
Management of Heart Failure): Developed in collaboration with the American College of
Chest Physicians and the International Society for Heart and Lung Transplantation:
Endorsed by the Heart Rhythm Society. Circulation. 112: 2005; e154-e235.
• Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N
Engl J Med. 350: 2004; 647-654.
• Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction
after myocardial infarction. N Engl J Med. 348: 2003; 1309-1321.
• The effect of spironolactone on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 341: 1999;
709-717.
• Guidelines for the diagnosis and treatment of chronic heart failure: Executive summary
(Update 2005). Eur Heart J. 26: 2005; 1115-1140.