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Congestive heart failure (CHF) is a major medical problem that is steadily increasing with the rising age of the general population and overall reduction in cardiovascular mortality. In the United States, incidence is 400,000 patients per year, with a prevalence of 5 million Americans. CHF now comprises the most common hospital discharge diagnosis for those over age 65, and is believed to account for 1.5 percent of total health care spending. Other estimates suggest that 2 percent of western adult populations are affected by heart failure.^,

The prognosis after diagnosis is guarded and worsens with the extent of myocardial dysfunction. In the Framingham study, the five year mortality following initial diagnosis was approximately 60 percent for men and 45 percent for women in the era prior to ACE inhibitors. More recent studies show a six year mortality of 80 percent in men and 65 percent in women. In patients with functional class IV heart failure, the one year mortality is approximately 60 percent. This decreases to 25 to 30 percent for class III and 10 to 15 percent for class II CHF.

Chronic heart failure consists of two components; myocardial failure and congestive failure. Myocardial failure is the initial insult and may result from chronic pressure overload as in hypertension, diffuse cell loss as in cardiomyopathy, or segmental cell loss as in ischemic heart disease. The result is a reduction in cardiac output and a decrease in left ventricular ejection fraction. Despite the biochemical and mechanical changes resulting from myocardial failure, experimental studies show that residual myocardial reserve exists that can be activated if the heart is appropriately stimulated. Myocardial failure is best quantified by decrease in left ventricular (LV) ejection fraction. Congestive heart failure reflects the neurohormonal and peripheral adaptive response to reduced cardiac output. Sympathetic and renin-angiotensin activation result in heightened peripheral vascular resistance and salt and water retention leading to congestion and edema. These peripheral changes correlate well with symptoms; congestive heart failure is best quantified by exercise performance.

The neurohormonal changes observed in heart failure include increased plasma catecholamines, antidiuretic hormone (ADH), atrial natiuretic factor (ANF) and activation of the renin-angiotensin-aldosterone system. Increased sympathetic nervous activity in heart failure produces an increase in heart rate and contractility. The increased sympathetic response helps to maintain the circulation early in the disease. With time, however, it may become exaggerated and contribute to the progression of the disease in what is frequently termed the vicious cycle of heart failure. Chronic impairment of left ventricular function results in a decrease in cardiac output. A reflex increase in systemic vascular resistance occurs, mediated by sympathetic activation and angiotensin II, further increasing afterload and decreasing cardiac output. Decreased renal perfusion activates the renin angiotensin system, thereby increasing preload by increasing salt and water retention. Sustained increase in catecholamines may produce cardiac necrosis and arrhythmias as well as decreased myocardial responsiveness by promoting down-regulation of the beta adrenergic pathway in the failing human heart - primarily due to reduced beta-1 density with beta-2 receptor density minimally affected.

The most common causes of left ventricular systolic dysfunction in the United States are coronary artery disease (CAD), hypertension and idiopathic dilated cardiomyopathy. Once the syndrome of CHF has been diagnosed and the degree of left ventricular systolic dysfunction quantified, the evaluation focuses on the underlying disease and determining whether it is reversible. The diagnostic evaluation required when a patient presents with chronic heart failure includes studies necessary to:

• Determine the type and degree of cardiac dysfunction
• Establish if there are any correctable etiologic factors
• Determine prognosis
• Guide treatment

For example, patients with valvular disease may benefit from appropriate valve replacement or repair and patients with CAD may require risk factor reduction, anti-ischemic therapy or revascularization. A transthoracic 2-D echocardiogram is particularly valuable to assess LV mass, size, function and to identify potential etiologies (i.e. valvular lesions or segmental wall motion abnormalities suggestive of CAD). CAD must be excluded as a potential contributing factor and patients with angina should undergo cardiac catheterization if they are candidates for interventional procedures or surgery. In patients with known CAD but no angina, noninvasive testing with thallium (with exercise and reinjection) may demonstrate ischemic or viable tissue. In patients with CHF and multiple CAD risk factors, a similar approach should be taken - i.e. noninvasive testing to exclude reversibly ischemic tissue.

Non-pharmacologic therapy is aimed primarily at the reduction of sodium intake. Patients should be told not to add salt at the table or while cooking, and taught how to read the salt content on prepared food labels. As a rule, prepared foods and fast foods have high salt content, as do some over-the-counter medications. Smoking cessation should be strongly recommended (see chapter 3), alcohol intake limited and moderate exercise suggested. Pharmacologic therapy includes treatment with vasodilators, diuretics, positive inotropes and beta blockade. The sequence in which these agents should be added continues to evolve. Vasodilators are now first-line therapy for heart failure, followed by treatment with diuretics and digoxin. The role of beta blockade in this population is gaining increasing acceptance, and there are provocative data on therapy with spironolactone. The latter remain investigational approaches. For appropriate patients with refractory heart failure, cardiac transplantation is a last option.

When formulating pharmacologic therapeutic strategies for the failing myocardium, one may draw an analogy to a wagon drawn by an old and tired horse. The driver could whip the horse, but this may exhaust the horse’s energy reserve and hasten its demise (inotropes). Slowing the horse’s pace conserves its energy stores so it arrives at its destination in better shape (ß-blockers). Alternatively, the driver could lighten the load by removing a portion of the cargo, reducing energy expenditure and prolonging the horse’s life (vasodilators). Purchasing a new horse would be analogous to heart transplant. At the present time we have no therapy that can clearly reverse heart failure.

Frequently, our approach to treatment is dictated by the point at which it is being implemented. In the early stages of heart failure, the aim of therapy should be myocardial preservation rather than stimulation. Therefore angiotensin-converting enzyme (ACE) inhibition and perhaps beta blockade may be the most appropriate agents to delay the onset of congestive failure and prolong survival. With advanced heart failure, symptomatic relief and prolongation of survival are the major goals.

Studies such as SOLVD indicate that vasodilators are beneficial early in heart failure. In class I patients, reduction in afterload and decreased myocardial tension by lowered intraventricular pressure and dimension may decrease the amount and progression of reactive hypertrophy. Thus, therapy with vasodilators is thought to delay the overall deterioration of cardiac function. Animal studies by Pfeffer et al. support this concept. While patients with class I CHF are asymptomatic, they frequently receive no drug therapy. However, treatment with ACE inhibitors may prevent the development of congestive symptoms (as well as reducing mortality after acute myocardial infarction). In the SOLVD prevention trial, treatment with enalapril decreased the incidence of clinical CHF and reduced the rate of hospital admissions when compared to placebo. In the SAVE trial, patients with acute MI and EF less than 40 percent treated within two weeks with captopril derived a 19 percent reduction in the risk of death compared to those treated with placebo. Only vasodilators have been demonstrated to prolong survival in placebo-controlled trials of patients with heart failure. The question of whether we should screen with echocardiography for asymptomatic left ventricular dysfunction remains a contentious one; we do not currently recommend this strategy.

The CONSENSUS, SOLVD, and VHEFT-II trials all support the use of ACE inhibition in patients with class II to IV heart failure unless the agents are contraindicated due to shock, angioneurotic edema or significant hyperkalemia. Low doses are initially used (captopril 6.25 mg tid, enalapril 2.5 mg bid, lisinopril 5 mg qd) and slowly titrated up over weeks to targeted doses (captopril 50 mg tid, enalapril 20 mg bid, lisinopril 40 mg qd). The ATLAS trial demonstrated that intermediate and high doses of ACE inhibitors are more effective than very low doses.^, Recent trials demonstrate efficacy and safety of ACE inhibition in very old patients with heart failure (those 85 and older). Although the data to support the use of ACE inhibition in heart failure are very strong, these drugs are underused and underdosed in clinical practice.^,

Data from both VHEFT-I and VHEFT-II support the role of isordil and hydralazine for patients with class II to IV CHF, particularly when the patients are ACE intolerant. In VHEFT-I, combined therapy with hydralazine plus isosorbide dinitrate produced a modest increase in survival as compared to placebo or prazosin in patients with moderate heart failure receiving optimal doses of digoxin and diuretics. This survival was identical to the subsequent hydralazine-isordil limb of VHEFT-II. Some studies have suggested benefits from combined ACE-hydralazine-isordil therapy. The combination of ACE-inhibition and angiotensin II receptor blockade has also been investigated and preliminary trials suggest that angiotensin II type 1 receptor blockers (ARBs) provide additional benefit in patients with severe heart failure.^, The CHARM trial, currently underway, is studying the benefit of ARB therapy in patients with mild heart failure.

Patients with heart failure develop sodium retention and generally require therapy with diuretics. In patients with mild heart failure, thiazide diuretics are used first. When the heart failure becomes more severe and renal perfusion declines, loop diuretics become more effective. When diuretic drug resistance develops, then combinations of diuretic drugs that act on different segments of the nephron are often beneficial (e.g. a thiazide and a loop diuretic, or amiloride and hydrochlorothiazide). Hypokalemia and contraction alkalosis are frequent side effects of vigorous diuretic therapy. Acetazolamide may help to promote bicarbonate excretion in this situation, and potassium supplementation is frequently required.

A single daily dose of diuretic at each patient’s renal threshold is generally more effective than several smaller doses of diuretics. Patients should be instructed to follow a 2 gm sodium diet, restrict fluid intake to 1,500 to 2,000 cc per day and weigh themselves daily. While being actively diuresed, patients should lose approximately 0.5 kg a day. When they achieve euvolemic status ("dry weight"), diuretic therapy may need to be titrated down and adjusted according to weight fluctuations. The Agency for Health Care Policy and Research and the American College of Cardiology have published guidelines for the outpatient management of heart failure, both of which stress that for stable patients, carefully following symptoms is more important than repeating noninvasive tests. Patients should be instructed to call their physician if they have an unexplained weight gain of more than five pounds and regular follow-up should be scheduled. Telemonitoring can reduce emergency department visits and hospitalization in patients with severe heart failure.

Inotropic Agents

Digoxin has been used in patients with congestive heart failure for over 200 years. The efficacy of digoxin therapy for patients in sinus rhythm remained controversial for many years, however several recent studies support the effectiveness of the drug in both early and advanced heart failure in all patients.^,, Digoxin remains the only effective oral inotrope currently available. Its beneficial effect may result both from positive inotropy and from withdrawal of sympathetic tone.

Chronic beta blockade has been demonstrated to alleviate symptoms, improve hemodynamics and reduce the frequency of hospitalization in studies involving selected groups of patients with dilated cardiomyopathy.^, Potential mechanisms for efficacy of chronic beta blockade include both direct myocardial effects and peripheral effects. Chronic beta blockade may afford a myocardial protective effect by blocking the direct toxic effects of catecholamines. Prolonged infusion of high dose catecholamines can produce patchy diffuse myocardial necrosis in experimental animals; beta blockade may upregulate beta receptors and thus improve hemodynamic response to catecholamine stimulation. It may restore the ability of the noradrenergic sympathetic nerves to synthesize norepinephrine. Other potential actions include anti-ischemic and anti-arrhythmic effects as well as prevention of a hypertrophic response. Beta blockade will also interrupt neurohormonal stimulation characteristic of heart failure. It will directly block sympathetically induced arterial and venous vasoconstriction and will reduce renin-angiotensin and ADH stimulation.

Carvedilol is a non-selective beta blocker and alpha blocker as well as a potent antioxidant. In four placebo-controlled double-blind studies which enrolled a total of 1094 patients, cardiovascular mortality was significantly decreased in all classes of heart failure as was the rate of hospitalization. These results may be difficult to apply in clinical practice because of pre-randomization open-label run-in periods to select patients for the studies. This promising agent is still undergoing clinical trials. Beta-blockers other than carvedilol may also have a mortality benefit in class II-III CHF, as demonstrated in the CIBIS II and MERIT-HF trials. Long-acting metoprolol, for example, has been shown to reduce the combined endpoint of total mortality and all-cause hospitalization by almost 20 percent.

Asymptomatic ventricular arrhythmias should not be treated in heart failure. Amiodarone has no adverse effect in patients with heart failure and some studies have suggested an improvement in survival in patients with dilated cardiomyopathy. Routine use of this agent for the prevention of sudden death is not recommended at this time.

Selection of cardiac transplant candidates is based on accurately assessing prognosis. Generally, candidates are patients with an expected survival of less than one year. These are patients with severe (class III to IV) CHF with ejection fractions below 20 percent and documented reduced exercise capacity with measurement of oxygen consumption. Other poor prognostic indicators include: presence of coronary artery disease, intraventricular conduction defects, hyponatremia, persistent tachycardia, chronic hypotension, elevated pulmonary capillary wedge pressure and reduced cardiac index. To qualify for transplant, these patients should not have any significant co-morbidity such as severe pulmonary disease (FEV1 < 1 liter), renal insufficiency (creatinine > 2.5), cirrhosis, diabetes with end organ damage, severe peripheral vascular disease, morbid obesity, active infection, malignancy other than skin cancer, cerebral vascular disease and so on. These patients are referred to specialized transplant teams where a thorough evaluation is performed to assess both the need for transplant and eligibility.

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