All About Heart Failure

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. Back to Top

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. Back to Top

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

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 Class I II III IV

Level of Impairment No symptom limitation with ordinary physical activity Ordinary physical activity somewhat limited by dyspnea (e.g., long-distance walking, climbing two flights of stairs) Exercise limited by dyspnea with moderate workload (e.g., short-distance walking, climbing one flight of stairs) 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. Back to Top

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 Captopril * Enalapril * Lisinopril * Ramipril * Quinapril * Fosinopril * Benazepril * Trandolapril †

Target Dose (mg) 50 20 40 5 20 20 20 4

* FDA-approved for treatment of heart failure.

Frequency tid bid qd bid bid bid qd qd

†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 Valsartan * Candesartan * Losartan Irbesartan Telmisartan Eprosartan Olmesartan

Initial Dose (mg) 80 16 25 75 40 400 20

Maximal Dose (mg) 320 32 100 300 80 800 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 Carvedilol *

Initial Dose (mg) 3.125 mg bid

Metoprolol succinate * Metoprolol tartrate Bisoprolol

12.5 mg qd 12.5 mg bid 2.5 mg qd

Target Dose 50 mg bid if >75 kg 25 mg bid if <75 kg 200 mg qd 50 mg tid 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

Agent Digoxin Hydralazine Isosorbide dinitrate

Initial Maximal Guidelines Dose Dose 0.125 mg Reduce dose in women with renal dysfunction, with 0.25 mg qd qd amiodarone 25 mg qid 100 mg qid Use concurrently with nitrates to prevent coronary steal 20 mg tid 80 mg tid

Also useful for angina pectoris

Spironolactone

12.5 mg 25 mg qd qd

Eplerenone

25 mg qd 50 mg qd

Weak diuretic, risk of hyperkalemia, avoid in renal dysfunction; gynecomastia Risk of hyperkalemia, avoid in renal dysfunction; no 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

Generic Name

Class

Initial Dose (mg)

Furosemide

Loop

20

Bumetanide

Loop

0.5

Torsemide

Loop

5-10

Ethacrynic acid

Loop

50

HydrochlorothiazideThiazide12.5 Metolazone

Thiazide2.5

Special Considerations Can be given intravenously; PO equivalent twice IV dose Good oral bioavailability; can be given intravenously; oral and IV doses the same Best oral availability Only diuretic with no sulfhydryl group; used if allergic to furosemide Weak diuretic; used mainly for hypertension Give ½ hr before furosemide; only available orally; 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 Dobutamine 2-20 mcg/kg/min Milrinone

0.375-0.75 mcg/kg/min

Nitroglycerin 10-500 mcg/min Nitroprusside10-500 mcg/min

Special Considerations ß receptor agonist; proarrhythmic; heart rate; ischemia Phosphodiesterase inhibitor; vasodilator; may improve pulmonary hypertension; used for patients taking beta blockers; proarrhythmic Anti-ischemic; vasodilator; limited by vascular headache; hypotension, tolerance develops rapidly Thiocyanate accumulation in renal failure; may provoke ischemia by coronary steal; vasodilator; should be given only

in intensive care unit Nesiritide

2-mcg/kg bolus; then 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 Back to Top

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. Back to Top

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. Back to Top

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 wellbeing 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: 2004; 27-37. 36. Current status of cardiac transplantation. JAMA. 280: 1998; 1692-1698.

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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 wellbeing 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.