Heart Failure

Epidemiology
Heart failure, defined as an impairment that prevents the heart from adequately perfusing body tissues to meet metabolic demands, is a major health problem that affects between 2 and 3 million Americans. With 400,000 new cases of HF diagnosed annually, the cost to the U.S. health care system is considerable, since HF is the primary reason for an estimated 1 million hospitalizations per year. In 1990, HF was responsible for approximately $10 billion in direct (e.g., hospitalization) and indirect (e.g., prolonged nursing home stays) costs.

HF has a poor prognosis. After the onset of symptoms, the five-year mortality rate in patients with HF-based on data from the Framingham Heart Study-is 62 percent in men and 42 percent in women, with 200,000 deaths attributable to HF each year in the United States alone.

Pathophysiology
Traditionally, HF has been thought to be a result of an impairment of systolic (inotropic) function, which is a reflection of decreased contractility of myocardial cells, most common in the left ventricle. More recently, impaired left ventricular (LV) filling, or diastolic dysfunction, has also been recognized as a significant contributor to the development of HF and is a reflection of reduced ventricular compliance related to scar tissue, ischemia, or hypertrophy of normal myocardial cells. Many cases of HF have components of both systolic and diastolic dysfunction.

 

Figure 1 Schematic illustration of selected types of hypertrophic responses. In A, the left ventricular dimensions are normal. With end-stage systolic dysfunction (B), cardiac chamber wall thickness remains the same or decreases in association with generalized dilatation of several cardiac chambers. Contractile activity is globally reduced. In lesser degrees of  systolic dysfunction, contractility is reduced, but cardiac chambers do not necessarily demonstrate marked dilatation. In pure diastolic dysfunction (C), symmetric thickening of the IVS and LVFW occurs at the expense of left ventricular  cavitary volume. Cardiac contractility is typically preserved, if not increased, resulting in corresponding preservation (or increase) in ejection fraction. However, overall cardiac output is reduced because the ventricle never completely  fills.

IVS = interventricular septum;
LA = left atrium; LV = left ventricle;
LVFW = left ventricular free wall;
RA = right atrium; RV = right ventricle.

In HF due to systolic dysfunction, the left ventricle is enlarged and overstretched (i.e., thinned) (Figure 1B; Figure 1A corresponds to a normal heart). Systolic dysfunction is the result of decreased cardiac contractility, which causes low cardiac output. Common causes of systolic dysfunction include scarring due to mycardial infarction and viral cardiomyopathy. The heart in end-stage HF due to systolic dysfunction is easily recognized on echocardiography as a Òbig, baggy heart.

In HF due to diastolic dysfunction, cardiac contractility is preserved or even increased (Figure 1C). The thickened and stiffened ventricle limits the amount of blood that can enter the heart, resulting in decreased ventricular filling during diastole. Ventricular dysfunction is often mixed, however, and has elements of both systolic and diastolic dysfunction.

Unfortunately, the physical examination will usually not allow the physician to reliably distinguish between systolic and diastolic dysfunction. Sometimes, a laterally displaced, dilated point of maximum impulse (PMI) may suggest that HF has a component of systolic dysfunction. On the other hand, in pure diastolic dysfunction, the PMI is not typically displaced or dilated, albeit the impulse may be abnormally sustained in duration.

It is important to recognize that diastolic and systolic dysfunction often overlap and may occur in the same patient. As an example, hypertensive patients commonly develop concentric hypertrophy with diastolic dysfunction as a result of the increase in afterload associated with persistent hypertension. If the hypertension is not controlled, LV function eventually deteriorates, and systolic dysfunction becomes superimposed on the initially hypertrophied left ventricle. Eventually, the left ventricle dilates and the diastolic dysfunction present in the early HF of hypertension evolves to dilated cardiomyopathy, so that the component of diastolic dysfunction may no longer be recognized.

Myocardial function is controlled by preload, afterload, ventricular contractility, heart rate, and heart rhythm. In HF, impaired heart function results in hemodynamic stress in the form of falling cardiac output. This stress unleashes a series of interdependent acute and chronic compensatory events, all of which are intended to maintain perfusion to vital organs.

Myocardial cell hypertrophy and increased LV wall thickness resulting from HF are accompanied by decreased ventricular compliance (increased ventricular stiffness), and, in the elderly, increased vascular resistance. The ensuing structural deterioration transforms the left ventricle from its normal elliptical shape to a rounded shape-a process known as remodeling. The rounded, or globoid, heart of late-stage HF may be accompanied by functional mitral regurgitation, ventricular dilatation, and thinning of the ventricular wall.

Neurohormonal Activation
The functional decrease in cardiac output and atrial hypertension results in arterial hypovolemia that characterizes HF. HF activates the adrenergic (sympathetic) nervous system and the renin-angiotensin-aldosterone (RAA) system, increases release of atrial natriuretic peptide (ANP), may increase the secretion of antidiuretic hormone (ADH) and renal
prostaglandins, and has long-term pathologic consequences.

Early in the course of HF, neurohormonal responses to hypovolemia lead to plasma expansion and selective vasoconstriction. The cardiovascular system compensates for the functional decrease in circulatory volume by shunting blood away from nonvital organ systems (e.g., kidneys, gastrointestinal tract), and by increasing cardiac contractility. Long-term neurohormonal adaptation to decreased perfusion results in desensitization of the heart to sympathetic stimulation, increased impedence to LV outflow, dysfunctional vascular endothelium, impaired glycolysis in fasttwitch muscles, physical deconditioning, and muscle deterioration.

In HF, norepinephrine is chronically elevated due to an increase in release and spillover from the adrenal gland, decreased plasma clearance, and decreased neuronal and non-neuronal reuptake. Norepinephrine increases afterload, causes cardiac arrhythmias, and has a direct toxic effect on the myocardium. There is a direct correlation between norepinephrine levels and both the hemodynamic severity and the poor prognosis of HF.

Decreased cardiac output, characteristic of HF, results in constriction of the kidney's efferent arterioles, which maintain the glomerular filtration rate (GFR). As HF progresses, a point is reached at which further constriction is impossible, and the GFR becomes flowdependent and decreases in tandem with additional decreases in cardiac output.

When the GFR falls, sodium is reabsorbed by the renal tubules, which activates the RAA system. The RAA system plays a key role in regulating blood pressure and vascular tone, and maintaining salt and water homeostasis. Renin, a proteolytic enzyme stored in the juxtaglomerular complex, cleaves angiotensinogen (a glycoprotein formed in the liver) to form angiotensin I. Angiotensin I is split by angiotensin-converting enzyme into angiotensin II, a potent vasoconstrictor that also stimulates the synthesis and secretion of aldosterone, which leads to sodium retention. Activation of the RAA system in HF is thought to occur in steps, as it normalizes in early-stage, compensated HF. As HF worsens, the RAA system is reactivated, and is a major contributor to the relatively intense edema and vasoconstriction typical of decompensated HF.

ADH is produced in the posterior pituitary and promotes renal tubular reabsorption of water by the kidneys in response to decreased plasma volume, as occurs in HF. Although ADH is often increased in HF, its contribution to the vascular dynamics of HF is unclear.

ANP is produced in atrial tissue of the heart in response to atrial stretch from increased blood volume. This causes natriuresis and vasodilation, and counteracts the waterretaining effect of the adrenergic and RAA systems. In early-stage HF, the vasodilatory response of peripheral arteries to ANP is preserved, but it becomes blunted as the HF enters a decompensation phase, an effect attributed to the down-regulation of ANP receptors.

One of the compensatory responses to the chronic overstimulation of the sympathetic nervous system (SNS) and the RAA system is an increased release of prostaglandins, resulting in peripheral vasodilation.

Clinical Findings
It is essential to keep in mind that mild HF is not necessarily the same as early-stage HF. Mild HF suggests that the patient's ability to function is only "mildly" affected. Earlystage HF, on the other hand, refers to the duration of pathogenic events that occur in the compensated phase of HF.

It is also important to emphasize that LV dysfunction does not always progress in a predictable fashion, nor is the degree of LV dysfunction necessarily paralleled by the clinical severity of symptoms. Some patients may present with significant symptoms of HF, yet only have minimal alteration of LV function. Other patients with only mild symptoms may come to medical attention in later stages of HF, which reflects the efficacy of the body's compensatory mechanisms.

For practical purposes, HF may be divided into high-output failure, which is usually secondary to other, noncardiac conditions, and low-output failure, which is primarily due to cardiac pump failure. High-output HF is very unusual in clinical practice and may be due to a marked hyperdynamic circulation with minimal functional myocardial abnormalities, in which the demand outstrips the capacity, resulting in a hyperkinetic state.

In low-output HF, the cardiac output falls below the tissue requirements for oxygen. It is associated with increased vascular resistance and oxygen consumption, decreased cardiac index and oxygen saturation, and lactic acidosis. Low-output HF may be "forward,"  in which oxygenated blood does not reach peripheral tissues, or "backward," in which blood backs up in the lungs.

The symptoms of low-output forward HF include weakness, fatigue, lethargy, lightheadedness, and confusion. In decompensated HF, cardiac cachexia, which is characterized by generalized exhaustion and loss of lean muscle mass, ensues. The symptoms of lowoutput backward, or congestive, HF reflect pulmonary edema, in which fluids accumulate in the lungs and result in dyspnea, initially only on exertion. Decompensated low-output backward failure is characterized by orthopnea and paroxysmal nocturnal dyspnea.

The clinical findings in HF include peripheral edema, rales, S3 gallop, sinus tachycardia, hypotension, increased jugular venous pressure, and hepatojugular reflux. Despite the presence of one or more of these signs, HF may be misdiagnosed in up to 40 percent of patients. The severity of HF can also be evaluated with chest radiography. Chest films may demonstrate cardiac enlargement, interstitial and alveolar edema, and pulmonary vascular redistribution in HF. However, HF may also be misdiagnosed using x-ray studies. Therefore, all patients suspected of having HF should be evaluated by two-dimensional echocardiography and Doppler studies to determine LV contractility, ventricular compliance, hypertrophy, and the presence or absence of other underlying conditions, such as valve pathology.

Management Strategies
HF is a syndrome that consists of a constellation of symptoms evoked by a wide range of conditions and precipitating factors (Table 1). Its management hinges on correction (when possible) of precipitating factors, treatment of acute symptoms, and compliance with long-term strategies that are intended to prolong survival.

Management of Acute Precipitating Factors
HF may be caused by noncardiac factors, including alcohol and drug abuse, excess fluid or sodium intake, fever, hyperthyroidism, hypothyroidism, anemia, hypoxia, infection, renal insufficiency, and hypertension. Control of these factors may attenuate or even eliminate the signs and symptoms of HF. Indeed, if these precipitating factors are not diagnosed and eliminated or treated, the patient could receive unnecessary or inappropriate treatment.

Management of Acute Symptoms
Acute HF with pulmonary edema is a medical emergency that requires immediate reduction of intravascular volume and myocardial oxygen demand. Such patients should be placed in an upright position and given supplemental oxygen. Some patients may require mechanical ventilation to optimize oxygenation and gas exchange. An intravenous (IV) diuretic should be administered to reduce preload, relieve pulmonary congestion, and improve oxygenation. Furosemide (Lasix) is usually given in doses of 20 to 40 mg IV, with the dose doubled, as needed, every 30 minutes until a maximum of 160 mg is reached. The initial dose depends on the severity of pulmonary congestion, duration of HF symptoms (time to allow compensatory fluid retention), renal dysfunction, and known responsiveness to furosemide.

Morphine sulfate remains an extremely effective treatment for pulmonary edema and administration should be titrated in small aliquots (2 to 5 mg IV) to reduce preload and improve cardiac performance by reducing afterload. Morphine also alleviates the sensation of air hunger, thereby indirectly reducing the level of circulating catecholamines released due to anxiety. Overadministration of morphine is unusual in patients with pulmonary edema; if respiratory depression does occur, it can be easily reversed with IV naloxone hydrochloride (Narcan).

Nitroglycerin acts by reducing both preload and afterload, thereby improving cardiac performance. Sublingual (0.4 mg), cutaneous, or IV nitroglycerin may be used, depending on the patient's clinical condition. IV nitroglycerin has a greater effect on afterload, whereas the sublingual and cutaneous forms reduce preload to a greater extent. Nitroglycerin is also indicated if angina accompanies HF.

Inotropic therapy with digoxin is generally not indicated in the treatment of acute pulmonary edema. Digoxin may be useful, however, as an antiarrhythmic agent to slow rapid atrial fibrillation or atrial flutter if these conditions accompany the HF. Central monitoring with a balloon flotation catheter occasionally may be needed if questions remain regarding hemodynamics or additional data are required to follow the patient's response to therapy.

Long-term Management
Once HF develops, unless a correctable cause is noted, continuous therapy is required to minimize morbidity and reduce mortality. It is imperative that the precipitating factors be eliminated or treated and the underlying causes of the patient's heart failure be identified and treated as completely as possible.

Thus, in addition to treatment of underlying hypertension, arrhythmias, ischemia, or valvular disease, long-term therapy for HF should be initiated, including both nonpharmacologic supportive measures and pharmacologic therapy. Nonpharmacologic measures include salt restriction (aiming for less than 2 g sodium per day), smoking cessation, elimination of alcohol intake, aerobic exercise as tolerated, and fluid restriction in patients with impaired renal function, refractory HF, or psychogenic polydipsia. Patients who are prone to developing congestive symptoms should monitor their weight daily and report any rapid weight gain in excess of 3 to 5 lb.

The pharmacologic management of HF may require the use of multiple agents, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, digoxin, nitrates, calciumchannel blockers (CCBs), and beta-adrenergic blockers. Treatment should be tailored to the underlying systolic or diastolic dysfunction.

Diuretics
Diuretics are a mainstay in the acute management of HF, and are usually the first drugs administered to the patient with congestive symptoms. They reduce the preload (venous return volume and ventricular filling pressure) and, by decreasing the effective circulating volume, relieve the symptoms of pulmonary congestion and peripheral edema. Although highly effective in the management of acute congestion, diuretics do not prevent disease progression and their long-term effect on mortality is unknown. Moreover, the use of diuretics may be associated with adverse effects on hemodynamics, renal function, and serum electrolytes. For example, they may result in reflex tachycardia, activation of the SNS and RAA system, increased blood urea nitrogen (BUN) and creatinine levels (from volume depletion), and decreased potassium and magnesium levels. Once the patient is stabilized (euvolemic), diuretics take on a lesser role in the management of HF, and are used in combination with other agents, particularly with ACE inhibitors.

The selection of a diuretic is based on the severity of the HF and whether the HF is related to systolic or diastolic dysfunction. Mild HF often responds to thiazides, such as hydrochlorothiazide (Esidrix, HydroDIURIL, Oretic, etc.), which require adequate renal function (creatinine clearance ≥ 30 mL per minute). Peripheral edema in mild HF also responds to the nonthiazide diuretic indapamide (Lozol), which has fewer adverse electrolyte and metabolic effects than hydrochlorothiazide and can be used in patients with moderate renal failure (creatinine clearance ≥ 20 mL per minute). These diuretics are ineffective with more severe degrees of renal impairment.

In moderate to severe HF, low doses of loop diuretics, such as furosemide, may be effective. Other loop diuretics include bumetanide (Bumex), which has a more rapid onset but a shorter duration of action; ethacrynic acid (Edecrin), the most ototoxic of the loop diuretics; and torsemide (Demadex), the newest of these agents, which is as effective as furosemide but has a longer duration of action, allowing for less frequent dosing. In patients with HF that is refractory to attempts at diuresis with moderate to high doses of a loop diuretic, the addition of 2.5 to 5.0 mg of metolazone (Mykrox, Zaroxolyn) 30 to 60 minutes before giving the loop diuretic may restore an effective diuretic response.

Potassium-sparing diuretics effect mild diuresis but have the advantage of conserving both potassium and magnesium, which may be more effective in maintaining electrolyte balance than cation supplementation. Potassium-sparing diuretics include amiloride (Midamor), triamterene (Dyrenium), a combination of hydrochlorothiazide and triamterene
(Dyazide, Maxzide), and spironolactone (Aldactone). Careful monitoring of potassium is required when these agents are added to a regimen that contains either ACE inhibitors or angiotensin II receptor antagonists (ARAs) due to an increased risk for hyperkalemia. Because of their weak diuretic action, potassium- sparing diuretics are mainly used as adjuncts to other, more potent diuretics.

Diuretics must be used carefully in patients with diastolic dysfunction, because they are highly volume-dependent. Excessive volume depletion could exacerbate the problem with ventricular filling.

Diuretic therapy requires careful monitoring with long-term use, since these drugs may cause hypokalemia and activate the RAA system. Diuretic-induced activation of the RAA system explains why diuretics should generally not be used on a long-term basis unless ACE inhibitors or ARAs, which block RAA activation, are added to the therapeutic regimen.

ACE Inhibitors
ACE inhibitors block circulating and tissue RAA systems by inhibiting the production of angiotensin II. These agents are both cardioprotective and vasculoprotective (Table 2). The cardioprotective effects include improved hemodynamics and electrical stability, as well as reduced SNS activity and reduced LV mass. The vasculoprotective benefits include improved endothelial function, vascular compliance and tone, as well as direct antiproliferative and antiplatelet effects. ACE inhibitors also stimulate prostaglandin synthesis, reduce the size of myocardial infarcts, reduce reperfusion injury and complex ventricular arrhythmias, and have antiatherogenic activity in cholesterol-, mechanical- and immune-mediated experimental models of atherosclerosis.

ACE inhibitors have emerged as the treatment of choice in HF with systolic dysfunction because of their neurohormonal effects and their ability to reduce both preload and afterload. The ACE inhibitor-induced reduction of angiotensin II results in reduced release of aldosterone, which in turn reduces sodium and water retention, and, by extension, decreases preload. ACE inhibitors improve the hemodynamics of HF by reducing right atrial pressure, pulmonary capillary wedge pressure, arterial blood pressure, and pulmonary and systemic vascular resistance. These agents also increase both the cardiac and stroke indices and reduce the right ventricular end-diastolic volume, thereby resulting in increased cardiac output, reduced cardiac load, and decreased myocardial oxygen consumption. They also down-regulate the SNS, which, as discussed earlier, is intimately linked to the pathogenesis of HF.

The net effects of the reversal of the pathophysiologic cascade of HF by ACE inhibitors include improvement in symptoms, functional status, exercise tolerance, and quality of life plus prolonged survival.

After initial patient stabilization, ACE inhibitor therapy may be started with a shortacting agent (e.g, captopril [Capoten]) before switching to a long-acting drug (Table 3). Initial use of short-acting ACE inhibitors minimizes the frequency and duration of ACE inhibitor-related hypotensive episodes, as it permits more rapid withdrawal of therapy. Such treatment is often not needed in more stable patients. Although there are differences among the ACE inhibitors in pharmacokinetics
and other properties, these differences are of relatively little clinical significance. Longacting ACE inhibitors are generally preferred for long-term therapy because of their decreased frequency of administration, which translates into improved patient compliance.

ACE inhibitors are indicated for use in virtually all patients with HF due to systolic dysfunction, unless there are specific contraindications to their use, such as hyperkalemia, pregnancy, clinically significant renal insufficiency, symptomatic hypotension, or a history of adverse reactions or intolerance. Potential adverse effects of ACE inhibitors include hypotension, renal impairment, hyperkalemia, cough, and angioneurotic edema. In addition, idiopathic adverse effects, such as skin eruptions, disturbances in taste, and bone marrow suppression, have been noted.

In patients who cannot tolerate ACE inhibitors because of cough or angioedema, two alternative therapeutic regimens can be used: either combination therapy with hydralazine (Apresoline) and a nitrate, or treatment with an ARA, such as losartan (Cozaar), valsartan (Diovan) or irbesartan (Avapro). Despite the ability of hydralazine and isosorbide dinitrate (Isordil, Sorbitrate) to effectively reduce preload and afterload, this combination should be considered a secondline therapy for a number of reasons. The combination is associated with a high incidence of adverse reactions, such as headache, heart palpitations, and nasal congestion. It is also likely to cause reflex tachycardia, which increases oxygen consumption. Hydralazine is often associated with tachyphylaxis. It should be kept in mind that these agents are not approved by the U.S. Food and Drug Administration as therapy for HF.

ARAs act by a somewhat different mechanism than do ACE inhibitors. Initial data suggest that they may be at least as effective as and better tolerated than ACE inhibitors. Although both ACE inhibitors and ARAs act on the RAA system, angiotensin II is also formed by enzymes other than angiotensinconverting enzymes. Thus, since ARAs bind at a site more distal to angiotensin II receptors, they more completely antagonize angiotensin II effects, including vasoconstriction, SNS activation, and aldosterone release. Unlike ACE inhibitors, ARAs do not interfere with bradykinin and prostaglandin metabolism, which has been suggested to be responsible for the cough and angioedema of ACE inhibitors.

In the ELITE study, patients with New York Heart Association (NYHA) class II-IV heart failure were randomized to receive either captopril or losartan. Preliminary data from that study suggest that survival in patients receiving losartan may be comparable to that in patients receiving captopril, although further study is warranted before general recommendations can be made. In general, side effects from ARA drugs are minimal.

Digoxin
The first effective treatment for heart failure was foxglove (Digitalis purpurea), the leaves of which were popular for the treatment of various heart conditions by English folk herbalists. Digitalis, which is obtained directly from foxglove leaves, has been abandoned in favor of digoxin, which has more consistent pharmacokinetics. Predictable pharmacokinetics are of particular importance, given digitalis’ narrow therapeutic index. Although digoxin suffered a transient waning in popularity, it appears to have regained its therapeutic currency in the treatment of HF. Digoxin reduces the rate of HF hospitalizations, improves functional class, exercise capacity, and left ventricular ejection fraction (LVEF). However, digoxin has not been shown to improve survival in patients receiving diuretics and ACE inhibitors.

Digoxin’s efficacy in treating HF hinges on its positive inotropic effects, which include increases in the force and velocity of myocardial contraction, ejection fraction, and exercise tolerance. In addition to improving the heart’s mechanical functions, digoxin slows cardiac conduction and affects neurohormonal activity.

Digoxin prolongs the refractory period of the atrioventricular (AV) node, resulting in a slowed ventricular response to supraventricular tachyarrhythmias, especially atrial fibrillation, for which digoxin remains an agent of choice, especially when the fibrillation accompanies acute myocardial infarction or LV failure. Digoxin also ameliorates the autonomic dysfunction typical of HF by attenuating SNS activity.

Digoxin is of limited use in the treatment of the patient with acute HF who is in normal sinus rhythm. However, it is an agent of choice for the long-term management of HF due to systolic dysfunction. Digoxin’s half-life ranges from 36 hours in young healthy adults to five days in elderly patients with renal failure. Digoxin’s pharmacokinetics are linear. As a result, a doubling of the daily dose results in an approximately twofold increase in serum levels. As with most drugs, digoxin requires three to five half-lives either to reach a steady state or to be eliminated from the system once a steady state has been reached. Given the length of digoxin’s half-life, achieving a steady state with therapeutic levels requires two to four weeks if no loading dose is given. Results of the PROVED and RADIANCE trials indicate that in a significant percentage of patients with HF due to systolic dysfunction, their condition worsened when digoxin was discontinued. Therefore, maintaining such patients indefinitely on digoxin, provided they have no adverse reactions, seems warranted. That said, the more recently completed Digoxin Trial failed to show reduced mortality with long-term use of this drug.

Because of digoxin's narrow therapeutic index, dosing must be titrated carefully. Conditions contributing to digoxin toxicity include renal insufficiency (with concomitant diuretic), ACE inhibitor use, and concomitant administration of potassium-depleting corticosteroids and diuretics. Symptoms of digoxin toxicity include loss of appetite, nausea and vomiting; defects in color vision, in particular for reds and greens, or seeing halos around light bulbs; symptoms that suggest psychosis; weakness, fatigue, or dizziness; cardiac arrhythmias, including frequent or multiform premature ventricular contractions (PVCs), ventricular tachycardia, atrial tachycardia with block, accelerated junctional rhythms,
rhythms with Wenckebach conduction, and atrial fibrillation with slowed or regular ventricular responses; and hyperkalemia.

Digoxin toxicity is managed by discontinuing the drug; monitoring arrhythmias; correcting acid-base, electrolyte, and volume abnormalities; and treating hypoxia, ischemia, and arrhythmias. Arrhythmias are a common manifestation of digoxin toxicity and often respond to lidocaine (Xylocaine) or phenytoin (Dilantin), or both. In extreme emergencies, digoxin antibody fragments, which bind the active portion of the digoxin molecule, may be needed to reduce the effects of digitalis toxicity.

Management of HF Caused by Systolic vs. Diastolic Dysfunction
HF caused by systolic dysfunction usually responds predictably to diuretics, ACE inhibitors, ARAs, and digoxin. In patients with diastolic dysfunction, however, higherthan- normal ventricular filling pressures are needed to generate even low-normal cardiac output. Although diuretics and nitrates may be used to relieve congestion and volume overload in HF caused by diastolic dysfunction, they must be used with caution, since overly aggressive therapy may further impair ventricular filling. Similarly, ACE inhibitors may be used in diastolic dysfunction. However, because these agents produce vasodilation, they must be used with caution so as not to excessively reduce blood pressure and exacerbate the problem with filling.

Positive inotropic agents, such as digoxin, are contraindicated in pure diastolic dysfunction because they further increase cardiac contractility. However, negative inotropic agents (lusotropic agents), such as beta-blockers or the CCBs diltiazem (Cardizem) and verapamil (Calan, Isoptin), are treatments of choice in pure diastolic dysfunction, because they allow ventricular relaxation and improve filling.

Beta-blockers
As indicated above, beta-blockers are a therapy of choice in patients with diastolic dysfunction in which contractility is preserved. These agents reduce the heart rate and contractility, resulting in increased diastolic filling and cardiac output. Recent data suggest that long-term therapy with beta-blockers may also be useful in systolic dysfunction. In patients with severe HF from end-stage congestive cardiomyopathy, beta-blockers were shown to significantly improve LV function and increase survival.

The mechanisms by which beta-blockers act to improve contractility in patients with systolic dysfunction are not completely clear, although it is thought that the effects are multifactorial and primarily the result of opposition to oversecretion of catecholamines. Chronic SNS overstimulation is one of the principal pathogenic mechanisms of HF. Effects are both structural (e.g., myocardial fibrosis and myocyte hypertrophy) and functional (e.g., tachycardia, constriction of coronary arteries, reduced ventricular filling time during diastole, impaired contractility, and arrhythmogenesis). Given the variety of effects evoked by SNS overstimulation, it might be anticipated that its down-regulation would benefit patients with HF.

Despite the recent recognition that betablockers may be of benefit in patients with HF from systolic dysfunction, these drugs should only be used with great care after standard treatment (ACE inhibitors, digoxin, and nitrates) has been maximized. Moreover, only carvedilol (Coreg), an alpha- and beta-blocker with antioxidant effects, has received FDA approval for use in this indication. If the decision is made to try beta-blocker therapy, a very low dose must be used and titrated upward on the RAA system, angiotensin II is also formed by enzymes other than angiotensinconverting enzymes. Thus, since ARAs bind at a site more distal to angiotensin II receptors, they more completely antagonize angiotensin II effects, including vasoconstriction, SNS activation, and aldosterone release. Unlike ACE inhibitors, ARAs do not interfere with bradykinin and prostaglandin metabolism, which has been suggested to be responsible for the cough and angioedema of ACE inhibitors.

In the ELITE study, patients with New York Heart Association (NYHA) class II-IV heart failure were randomized to receive either captopril or losartan. Preliminary data from that study suggest that survival in patients receiving losartan may be comparable to that in patients receiving captopril, although further study is warranted before general recommendations can be made. In general, side effects from ARA drugs are minimal.

Digoxin
The first effective treatment for heart failure was foxglove (Digitalis purpurea), the leaves of which were popular for the treatment of various heart conditions by English folk herbalists. Digitalis, which is obtained directly from foxglove leaves, has been abandoned in favor of digoxin, which has more consistent pharmacokinetics. Predictable pharmacokinetics are of particular importance, given digitalis' narrow therapeutic index. Although digoxin suffered a transient waning in popularity, it appears to have regained its therapeutic currency in the treatment of HF. Digoxin reduces the rate of HF hospitalizations, improves functional class, exercise capacity, and left ventricular ejection fraction (LVEF). However, digoxin has not been shown to improve survival in patients receiving diuretics and ACE inhibitors.

Digoxin's efficacy in treating HF hinges on its positive inotropic effects, which include increases in the force and velocity of myocardial contraction, ejection fraction, and exercise tolerance. In addition to improving the heart's mechanical functions, digoxin slows cardiac conduction and affects neurohormonal activity.

Digoxin prolongs the refractory period of the atrioventricular (AV) node, resulting in a slowed ventricular response to supraventricular tachyarrhythmias, especially atrial fibrillation, for which digoxin remains an agent of choice, especially when the fibrillation accompanies acute myocardial infarction or LV failure. Digoxin also ameliorates the autonomic dysfunction typical of HF by attenuating SNS activity.

Digoxin is of limited use in the treatment of the patient with acute HF who is in normal sinus rhythm. However, it is an agent of choice for the long-term management of HF due to systolic dysfunction. Digoxin's half-life ranges from 36 hours in young healthy adults to five days in elderly patients with renal failure. Digoxin's pharmacokinetics are linear. As a result, a doubling of the daily dose results in an approximately twofold increase in serum levels. As with most drugs, digoxin requires three to five half-lives either to reach a steady state or to be eliminated from the system once a steady state has been reached. Given the length of digoxin's half-life, achieving a steady state with therapeutic levels requires two to four ever so slowly over a period of months. Some patients may develop worsening congestion that may need to be treated with increased dosages of diuretics. With time and careful upward titration of beta-blocker doses, LV function ultimately improves in most patients.

Calcium Channel Blockers
The role of CCBs in the treatment of patients with heart failure from systolic dysfunction remains unclear. As discussed previously, negatively inotropic CCBs (i.e., verapamil and diltiazem) are drugs of choice for the treatment of HF with diastolic dysfunction. They should not be used in HF with systolic dysfunction. Dihydropyridine CCBs tend not to be negatively inotropic in vivo. However, because of the potent vasodilation they produce, they are prone to evoke neurohumoral responses in the form of SNS stimulation and reflex tachycardia, both of which are deleterious in patients with HF.

The recently completed Prospective Randomized Amlodipine Survival Evaluation (PRAISE) I Trial suggested that the dihydropyridine agent amlodipine (Norvasc) may have a different clinical effect than other dihydropyridines, and survival was increased in patients treated with this drug who had nonischemic cardiomyopathy. Survival was not increased, however, in patients so treated who had ischemic cardiomyopathy, suggesting that the true effect of amlodipine in patients with HF from systolic dysfunction may not yet be known. Results from the PRAISE II Trial that is currently in progress will hopefully help answer this question.

A recently approved CCB, mibefradil (Posicor), warrants specific comment. Unlike all other CCBs, which block the L- and T-type (long-acting) calcium channels found on the surface of many cells in the body, mibefradil selectively blocks the T-type (transient) calcium channels, which are highly specific. As a result, catecholamine production is not increased, as occurs with dihydropyridine CCBs. Because it lacks negative inotropism, has optimal vasodilatory properties, reduces blood pressure, and reverses left ventricular hypertrophy, mibefradil may become an agent of choice when a CCB is desired for treatment of HF due to systolic dysfunction.

Other HF Therapies
Management of HF also includes the use of medication, interventional cardiology, or surgery to address functional defects such as arrhythmias and ischemia. Ventricular arrhythmias are often present in patients with HF. Despite their ubiquity, treatment should be limited to potassium and magnesium supplementation for asymptomatic premature ventricular contractions (PVCs), even if frequent, or for short periods of nonsustained ventricular tachycardia. In those patients who become symptomatic due to sustained ventricular tachycardia, medical therapy with agents such as amiodarone (Cordarone) may be indicated, or, in the more refractory cases, consideration may be given to implantation of a cardioverter-defibrillator. Among other ancillary therapies for managing HF are nitrates or anticoagulants. Both are discussed at greater length under management of acute myocardial infarction (MI).

Practically speaking, the best chance for long-term survival in the patient with HF from systolic dysfunction lies with identifying a potentially reversible underlying or precipitating cause of the heart failure and then attempting to correct it. Potential surgical interventions include valve repair or replacement; coronary revascularization (bypass surgery, angioplasty, or stenting); or heart transplantation.

Finally, for the patient with end-stage HF who is otherwise healthy and not elderly, the possibility of heart transplantation should be kept in mind. For suitable candidates, long-term (five-year) survival following heart transplantation is now up to 70 percent in many centers-compared with almost certain death in those not so treated. Unfortunately, the current donor supply (about 2,000 hearts yearly in the United States) is not nearly enough for the much larger number of patients with end-stage HF who are potentially good candidates.

Other surgical procedures, such as the Batista operation, in which a portion of the poorly contractile left ventricle is excised, should be considered as purely experimental and cannot be recommended at this time.

Posted in: Heart Failure