- Heart failure (HF) is the inability of the heart to maintain an output adequate to meet the metabolic demands of the body. It is an increasingly common condition that affects approximately 5 million Americans and is associated with extremely high morbidity and mortality. It is a syndrome and not a disease.
- About 5 million cases of heart failure are prevalent in the United States.
- Incidence is estimated at 550,000 cases per year.
- The 5-year mortality rate following diagnosis with heart failure is approximately 50%.
- HF may be secondary to abnormalities in myocardial contraction (systolic dysfunction), ventricular relaxation and filling (diastolic dysfunction), or both.
- Severity can be classified according to New York Heart Association (NYHA) status, ACC/AHA stage or metabolic capacity.
- HF is manifested as organ hypoperfusion and inadequate tissue oxygen delivery due to a low cardiac output and decreased cardiac reserve, as well as pulmonary and systemic venous congestion.
- A variety of -compensatory adaptations- occur, including (a) increased left ventricular (LV) volume (dilation) and mass (hypertrophy), (b) increased systemic vascular resistance (SVR) secondary to enhanced activity of the sympathetic nervous system and elevated levels of circulating catecholamines, and (c) activation of the renin-angiotensin-aldosterone and vasopressin (antidiuretic hormone) systems. These secondary mechanisms, in conjunction with pump failure, play an important role in the pathophysiology of HF.
- Hypertension (HTN) and coronary artery disease are the most frequent causes of HF in the United States.
- Other causes include valvular heart disease, toxic or metabolic disease, infiltrative disease, infections, and drugs.
- Precipitants of HF include myocardial ischemia, HTN, arrhythmias, infection, thyroid disease, volume overload, alcohol/toxins, drugs (nonsteroidal anti-inflammatory drugs [NSAIDs], calcium channel antagonists, doxorubicin), pulmonary embolism, and dietary or medical noncompliance.
- Clinical manifestations of HF vary depending on the rapidity of cardiac decompensation, underlying etiology, age, and comorbidities of the patient.
- Extreme deterioration in cardiac output and elevated SVR result in hypoperfusion of vital organs such as the kidney (decreased urine output) and brain (confusion and lethargy) and, ultimately, cardiogenic shock.
- Exercise intolerance
- Dyspnea with exertion
- Orthopnea, paroxysmal nocturnal dyspnea
- Presyncope, palpitations, and angina may be present in varying circumstances.
- Chronic pulmonary and systemic venous congestion results in pulmonary crackles, peripheral edema, elevated jugular venous pressure, pleural and pericardial effusions, hepatic congestion, and ascites.
- Third or fourth heart sounds may be present.
- B-type natriuretic peptide (BNP) is synthesized by right and left ventricular myocytes and released in response to stretch, volume overload, and elevated filling pressures. Serum levels of BNP are elevated in patients with asymptomatic LV dysfunction as well as symptomatic HF.
- A serum BNP of <100 pg/mL has a good negative predictive value and typically excludes HF as primary diagnosis in dyspneic patients.
- BNP levels correlate with the severity of HF and predict survival.
- Associated laboratory abnormalities include elevated levels of blood urea nitrogen (BUN) and creatinine, hyponatremia, anemia, and elevated serum levels of hepatic enzymes.
- Abnormalities in the electrocardiogram (ECG) are common and include supraventricular and ventricular arrhythmias, conduction delays, and nonspecific ST-T changes.
- Radiographic evidence of cardiomegaly and pulmonary vascular redistribution is common.
- Depressed ventricular function should be confirmed by echocardiography, radionuclide ventriculography, or cardiac catheterization with left ventriculography.
- Exercise training is recommended in stable HF patients. Ideally, it should be started slowly in a monitored outpatient setting and reach a target of 20-45 minutes a day for 3-5 days a week for a total of -12 weeks. Short-term effects of exercise training in chronic stable HF patients are additive to pharmacologic treatment and are associated with a decrease in neurohormonal activation.
- Patients enrolled in exercise training programs notice increased exercise capacity, decreased symptoms, increased quality of life, and decreased hospitalization rate.
- The effects of long-term exercise training on survival are not defined.
- Restriction of physical activity may be required in acute HF exacerbations to reduce myocardial workload and oxygen consumption.
- Weight loss and fluid restriction should be instituted when appropriate.
- Patients should be counseled about smoking cessation.
- The general principle of pharmacologic therapy involves the antagonism of neurohormones that are increased in patients with HF and have deleterious effects on the myocardium and the peripheral vasculature. Vasodilator therapy and Î²-adrenergic blockade are the cornerstone of therapy for patients with HF.
- Diuretics are reserved for relieving volume overload. Most patients require a multidrug regimen to control symptoms and prolong survival.
- Î²-Adrenergic receptor antagonists are critical components of HF pharmacotherapy that block the cardiac effects of chronic adrenergic stimulation, including myocyte toxicity.
- Large randomized trials have documented the beneficial effects of Î²-adrenergic antagonists on functional status and survival in patients with NYHA class II-IV symptoms.
- Improvement in ejection fraction (EF), exercise tolerance, and functional class are common after the institution of a Î²-adrenergic antagonist.
- Typically, 2-3 months of therapy is required to observe significant effects on LV function, but reduction of cardiac arrhythmia and incidence of sudden cardiac death may occur much earlier.
- Î²-Adrenergic antagonists should be instituted at a low dose and titrated with careful attention to blood pressure (BP) and heart rate. Some patients experience volume
- retention and worsening HF symptoms that typically respond to transient increases in diuretic therapy. Individual Î²-adrenergic antagonists have unique properties, and the beneficial effect of Î²-adrenergic antagonists in HF may not be a class effect.
- Therefore, Î²-adrenergic antagonists with proven effects on patient survival in large clinical trials (bisoprolol, metoprolol succinate, and carvedilol) should be used.
- Carvedilol is the best studied Î²-adrenergic antagonist in heart failure. It has been shown to be superior to metoprolol tartrate for chronic treatment.
- Bisoprolol Metoprolol succinate
- Vasodilator therapy is another mainstay of treatment in patients with HF.
- Arterial vasoconstriction (afterload) and venous vasoconstriction (preload) occur in patients with HF as a result of activation of the renin-angiotensin-aldosterone system and adrenergic nervous system, as well as increased secretion of arginine vasopressin. Agents with predominantly venodilatory properties decrease preload and ventricular filling pressures. In the absence of LV outflow tract obstruction, arterial vasodilators reduce afterload by decreasing SVR, resulting in increased cardiac output, decreased ventricular filling pressure, and decreased myocardial wall stress. The efficacy and toxicity of vasodilator therapy depend on intravascular volume status and preload. Vasodilators should be used with caution in patients with a fixed cardiac output [e.g., aortic stenosis (AS) or hypertrophic cardiomyopathy (HCM)] or with predominantly diastolic dysfunction.
- Oral vasodilators should be the initial therapy in patients with symptomatic chronic HF and in patients in whom parenteral vasodilators are being discontinued. When treatment with oral vasodilators is being initiated in hypotensive patients, it is prudent to use agents with a short half-life.
- ACE inhibitors attenuate vasoconstriction, vital organ hypoperfusion, hyponatremia, hypokalemia, and fluid retention attributable to compensatory activation of the renin-angiotensin system.
- Treatment with ACE inhibitors decreases afterload while increasing cardiac output.
- Large clinical trials have clearly demonstrated that ACE inhibitors improve symptoms and survival in patients with LV systolic dysfunction.
- ACE inhibitors may also prevent the development of HF in patients with asymptomatic LV dysfunction and in those at high risk of developing structural heart disease or HF symptoms (coronary artery disease, diabetes mellitus, HTN). Currently, no consensus has been reached regarding the optimal dosing of ACE inhibitors in HF, although one study
- suggested that higher doses decrease morbidity without improving overall survival.
- Absence of an initial beneficial response to treatment with an ACE inhibitor does not preclude long-term benefit.
- Most ACE inhibitors are excreted by the kidneys, necessitating careful dose titration in patients with renal insufficiency. Acute renal insufficiency may occur in patients with bilateral renal artery stenosis. Additional adverse effects include rash, angioedema, dysgeusia, increases in serum creatinine, proteinuria, hyperkalemia, leukopenia, and cough.
- ACE inhibitors are contraindicated in pregnancy.
- Oral potassium supplements, potassium salt substitutes, and potassium-sparing diuretics should be used with caution during treatment with an ACE inhibitor.
- Agranulocytosis and angioedema are more common with captopril than with other ACE inhibitors, particularly in patients with associated collagen vascular disease or serum creatinine >1.5 mg/dL.
- Angiotensin II receptor blockers (ARBs) inhibit the renin-angiotensin system via specific blockade of the angiotensin II receptor.
- In contrast to ACE inhibitors, they do not increase bradykinin levels, which may be responsible for adverse effects such as cough. ARBs reduce mortality and morbidity associated with HF in patients who are not receiving an ACE inhibitor.
- ARBs should be considered in patients who are intolerant to ACE inhibitors due to cough or angioedema.
- Caution should be exercised when ARBs are used in patients with renal insufficiency and bilateral renal artery stenosis because hyperkalemia and acute renal failure can develop.
- Renal function and potassium levels should be periodically monitored.
- ARBs are contraindicated in pregnancy.
- Hydralazine acts directly on arterial smooth muscle to produce vasodilation and to reduce afterload. In combination with nitrates, hydralazine improves survival in patients with HF. A combination of hydralazine and isosorbide dinitrate (starting dose: 37.5/20 mg three times daily) when added to standard therapy with beta-blockers and ACE inhibitors has been shown to reduce mortality in black patients.
- Reflex tachycardia and increased myocardial oxygen consumption may occur, requiring cautious use in patients with ischemic heart disease.
- Nitrates are predominantly venodilators and help relieve symptoms of venous and pulmonary congestion. They reduce myocardial ischemia by decreasing ventricular filling pressures and by directly dilating coronary arteries.
- Nitrate therapy may precipitate hypotension in patients with reduced preload.
- Parenteral vasodilators should be reserved for patients with severe HF or those who are unable to take oral medications. IV vasodilator therapy may be guided by central hemodynamic monitoring (pulmonary artery atheterization) to assess efficacy and avoid hemodynamic instability. Parenteral agents should be
- started at low doses, titrated to the desired hemodynamic effect, and discontinued slowly to avoid rebound vasoconstriction.
- Nitroglycerin is a potent vasodilator, with effects on venous and, to a lesser extent, arterial vascular beds. It relieves pulmonary and systemic venous congestion and is an effective coronary vasodilator.
- Nitroglycerin is the preferred vasodilator for treatment of HF in the setting of acute myocardial infarction (MI) or unstable angina .
- Sodium nitroprusside is a direct arterial vasodilator with less potent venodilatory properties. Its predominant effect is to reduce afterload, and it is particularly effective in patients with HF who are hypertensive or who have severe aortic or mitral valvular regurgitation.
- Nitroprusside should be used cautiously in patients with myocardial ischemia because of a potential reduction in regional myocardial blood flow (coronary steal ).
- The initial dose of 0.25 mcg/kg/min can be titrated (maximum dose of 10 mcg/kg/min) to the desired hemodynamic effect or until hypotension develops. The half-life of nitroprusside is 1-3 minutes, and its metabolism results in the release of cyanide, which is metabolized hepatically to thiocyanate and then is excreted renally.
- Toxic levels of thiocyanate (>10 mg/dL) may develop in patients with renal insufficiency. Thiocyanate toxicity is manifested as nausea, paresthesias, mental status changes, abdominal pain, and seizures.
- Methemoglobinemia is a rare complication of treatment with nitroprusside.
- Recombinant BNP (nesiritide) is an arterial and venous vasodilator.
- Intravenous infusion of nesiritide reduces right atrial and left ventricular end-diastolic pressures (LVEDP) and SVR and results in an increase in cardiac output.
- It is administered as a 2-mcg/kg IV bolus followed by a continuous IV infusion starting of 0.01 mcg/kg/min. Nesiritide is approved for use in acute HF exacerbations and relieves HF symptoms early after its administration.14 It should not be used to improve renal function or to enhance diuresis. Nesiritide is not recommended for intermittent outpatient use.
- Hypotension is the most common side effect of nesiritide, and its use should be avoided in patients with systemic hypotension (systolic BP <90 mm Hg) or evidence of cardiogenic shock. Episodes of hypotension should be managed with discontinuation of nesiritide and cautious volume expansion or pressor support if necessary.
- Enalaprilat is an active metabolite of the ACE inhibitor enalapril that is available for IV administration.
- Its onset of action is more rapid and its pharmacologic half-life shorter than that of enalapril. The initial dosage is 1.25 mg IV q6h, which can be titrated to a maximum dosage of 5 mg IV q6h. Patients who take diuretics or those with impaired renal function (serum creatinine >3 mg/dL, creatinine clearance <30 mL/min) initially should receive 0.625 mg IV q6h. When dosing is being converted from IV to PO administration, enalaprilat, 0.625 mg IV q6h, is approximately equivalent to enalapril, 2.5 mg PO daily.
- Î±-Adrenergic receptor antagonists These agents have not been shown to improve survival in HF, and hypertensive patients treated with doxazosin as first-line therapy had an increased risk of developing HF.
- Digitalis glycosides increase myocardial contractility and may attenuate the neurohormonal activation associated with HF.
- Digoxin decreases the number of HF hospitalizations without altering overall mortality.
- Discontinuation of digoxin in patients who are stable on a regimen of digoxin, diuretics, and an ACE inhibitor may result in clinical deterioration.
- The toxic-therapeutic ratio is narrow , and serum levels should be followed closely, particularly in patients with unstable renal function.
- The usual daily dose is 0.125-0.25 mg and should be decreased in patients with renal insufficiency. Clinical benefits may not be related to the serum levels, and, although serum digoxin levels of 0.8-2.0 ng/mL are considered -therapeutic,- toxicity can occur in this range.
- Observations suggest that women and patients with higher serum digoxin levels (1.2-2.0 ng/mL) have an increased mortality risk.
- Drug interactions with digoxin are common. Oral antibiotics such as erythromycin and tetracycline may increase digoxin levels by 10%-40%.
- Quinidine, verapamil, flecainide, and amiodarone also increase digoxin levels significantly.
- Digoxin toxicity may be caused or exacerbated by drug interactions, electrolyte abnormalities (particularly hypokalemia), hypoxemia, hypothyroidism, renal insufficiency, and volume depletion.
- Diuretic therapy, in conjunction with restriction of dietary sodium and fluids, often leads to clinical improvement in patients with symptomatic HF.
- Frequent assessment of the patient's weight along with careful observation of fluid intake and output is essential during initiation and maintenance of therapy.
- Frequent complications of therapy include hypokalemia, hyponatremia, hypomagnesemia, volume contraction alkalosis, intravascular volume depletion, and hypotension. Serum electrolytes, BUN, and creatinine levels should be followed after institution of diuretic therapy. Hypokalemia may be life threatening in patients who are receiving digoxin or in those who have severe LV dysfunction that predisposes them to ventricular arrhythmias. Potassium supplementation or a potassium-sparing diuretic should be considered in addition to careful monitoring of serum potassium levels.
- Thiazide diuretics (hydrochlorothiazide, chlorthalidone) can be used as initial agents in patients with normal renal function in whom only a mild diuresis is desired. Metolazone, unlike other thiazides, exerts its action at the proximal as well as the distal tubule and may be useful in combination with a loop diuretic in patients with a low glomerular filtration rate.
- Loop diuretics (furosemide, ethacrynic acid, bumetanide) should be used in patients who require significant diuresis and in those with markedly decreased renal function. Furosemide reduces preload acutely by causing direct venodilation when administered IV, making it useful for managing severe HF or acute pulmonary edema. Use of loop diuretics may be complicated by hyperuricemia, hypocalcemia, ototoxicity, rash, and vasculitis.
- Furosemide and bumetanide are sulfa derivatives and may cause drug reactions in sulfa-sensitive patients. Ethacrynic acid can generally be used safely in such patients.
- Potassium-sparing diuretics do not exert a potent diuretic effect when used alone.
- Spironolactone (25 mg daily) is an aldosterone receptor antagonist that has been shown to improve survival and decrease hospitalizations in NYHA class III-IV patients.20 The potential for development of life-threatening hyperkalemia exists with the use of these agents. Gynecomastia may develop in 10%-20% of men treated with spironolactone. Serum potassium must be monitored closely after initiation; concomitant use of ACE inhibitors and NSAIDs and the presence of renal insufficiency (creatinine >2.5 mg/dL) increase the risk of hyperkalemia.
- Eplerenone, a selective aldosterone receptor antagonist without the hormonal side effects of spironolactone, is Food and Drug Administration (FDA) approved for treatment of HTN and HF and reduces mortality in patients with HF associated with acute MI.
- Inotropic agents Sympathomimetic agents are potent drugs that are primarily used to treat severe HF. Beneficial and adverse effects are mediated by stimulation of myocardial Î²-adrenergic receptors. The most important adverse effects are related to the arrhythmogenic nature of these agents and the potential for exacerbation of myocardial ischemia. Treatment should be guided by careful hemodynamic and ECG monitoring. Patients with refractory chronic HF may benefit symptomatically from continuous ambulatory administration of IV inotropes as palliative therapy or as a bridge to mechanical ventricular support or cardiac transplantation.2 However, this strategy may increase the risk of life-threatening arrhythmias or indwelling catheter-related infections.
- Dopamine should be used primarily for stabilization of the hypotensive patient.
- Dobutamine is a synthetic analog of dopamine.
- Dobutamine tolerance has been described, and several studies have demonstrated increased mortality in patients treated with continuous dobutamine. Dobutamine has no significant role in the treatment of HF resulting from diastolic dysfunction or a high-output state.
- Phosphodiesterase inhibitors increase myocardial contractility and produce vasodilation by increasing intracellular cyclic adenosine monophosphate. Milrinone is currently available for clinical use and is indicated for treatment of refractory HF. Hypotension may develop in patients who receive vasodilator therapy or have intravascular volume contraction, or both. Milrinone may improve hemodynamics in patients who are treated concurrently with dobutamine or dopamine. Data suggest that in-hospital short-term milrinone administration in addition to standard medical therapy does not reduce the length of hospitalization or the 60-day death or rehospitalization rate when compared with placebo.
- Minimization of medications with deleterious effects in HF should be attempted.
- Negative inotropes (e.g., verapamil, diltiazem) should be avoided in patients with impaired ventricular contractility, as should over-the-counter Î² stimulants [e.g., compounds containing ephedra, pseudoephedrine hydrochloride (Sudafed)].
- NSAIDs, which antagonize the effect of ACE inhibitors and diuretic therapy, should be avoided if possible.
- Coronary revascularization reduces ischemia and may improve systolic function in some patients with coronary artery disease.
- Cardiac resynchronization therapy or biventricular pacing appears to be beneficial in patients with an ejection fraction of 35% or less, NYHA class III-IV HF, and conduction abnormalities (left bundle branch block and atrioventricular delay). It has been demonstrated to improve quality of life and reduce the risk of death in carefully selected patients.
- An intra-aortic balloon pump (IABP) can be considered for patients in whom other therapies have failed, have transient myocardial dysfunction, or are awaiting a definitive procedure such as transplantation.
- The IABP is positioned in the aorta with its tip distal to the left subclavian artery.
- Balloon inflation is synchronous with the cardiac cycle and results in significant preload and afterload reduction, with decreased myocardial oxygen demand and improved coronary blood flow, resulting in improved cardiac output.
- Severe aortoiliac atherosclerosis and aortic valve insufficiency are contraindications to IABP placement.
- Ventricular assist devices require surgical implantation and are indicated for patients with severe HF after cardiac surgery, for individuals with intractable cardiogenic shock after acute MI, and for patients whose conditions deteriorate while they await cardiac transplantation.
- Currently available devices vary with regard to degree of mechanical hemolysis, intensity of anticoagulation required, and difficulty of implantation.
- The decision to institute ventricular assist device circulatory support must be made in consultation with a cardiac surgeon who has experience with this procedure.
- Ventricular assist devices improve survival in patients with refractory HF who are not candidates for cardiac transplantation.
- Cardiac transplantation is an option for selected patients with severe end-stage HF that has become refractory to aggressive medical therapy and for whom no other conventional treatment options are available.
- Candidates considered for transplantation should be younger than 65 years (although selected older patients may also benefit), have advanced HF (NYHA class IIIâ??IV), have a strong psychological support system, have exhausted all other therapeutic options, and be free of irreversible extracardiac organ dysfunction that would limit functional recovery or predispose them to posttransplantation complications.
- Survival rates of 90% at 1 year and 70% at 5 years have been reported since the introduction of cyclosporine-based immunosuppression.
- In general, functional capacity and quality of life improve significantly after transplantation.
- Posttransplant complications include acute and chronic rejection, typical and atypical infections, and adverse effects of immunosuppressive agents.
- Cardiac allograft vasculopathy (coronary artery disease/chronic rejection) and malignancy are the leading causes of death after the first posttransplant year.
- Fluid and free water restriction (<1.5 L/d) is especially important in the setting of hyponatremia (serum sodium <130 mEq/L) and volume overload.
- Administration of oxygen may relieve dyspnea, improve oxygen delivery, reduce the work of breathing, and limit pulmonary vasoconstriction in patients with hypoxemia. Sleep apnea has prevalence as high as 37% in the HF population. Treatment with nocturnal positive airway pressure improves symptoms and LV EF.
- Dialysis or ultrafiltration may be necessary in patients with severe HF and renal dysfunction who cannot respond adequately to fluid and sodium restriction and diuretics. Other mechanical methods of fluid removal such as therapeutic thoracentesis and paracentesis may provide temporary symptomatic relief of dyspnea. Care must be taken to avoid rapid fluid removal and hypotension.
- End-of-life considerations may be necessary in the patient with advanced HF that is refractory to therapy. Discussions regarding the disease course, treatment options, survival, functional status, and advance directives should be addressed
- early in the treatment of the patient with HF. For those with end-stage disease (stage D, NYHA class IV) with multiple hospitalizations and severe decline in their functional status and quality of life, hospice and palliative care should be considered.