Treatment of hypertension in heart failure Authors Norman M Kaplan, MD Burton D Rose, MD Section Editors George L Bakris, MD Stephen S Gottlieb, MD Deputy Editor Alice M Sheridan, MD

Last literature review version 17.1: January 2009|This topic last updated: March 5, 2007(More)

INTRODUCTIONHypertension is a risk factor for the development of heart failure (HF), both because hypertension leads to the development of left ventricular hypertrophy, and because hypertension is a risk factor for the development of coronary heart disease. The relative risk of HF among patients with hypertension, compared to that of the general population, was estimated to be 1.4 in an analysis from the First National Health and Nutrition Examination Survey [1] . (See "Epidemiology and causes of heart failure").

In addition, patients with HF of other causes may present with hypertension. In contrast to the pattern seen in the general population, in which prognosis is poorer for hypertensive than for normotensive individuals, higher blood pressure prior to treatment is a predictor of better survival in patients with HF [2-4] . It is likely that this correlation is a consequence of the fact that more severe cardiac dysfunction causes a decline in systemic blood pressure, making low blood pressure a marker for more advanced HF [4] . This observation makes it difficult to study the benefits of antihypertensive therapy in this population.

Despite this difficulty, it is well established that several classes of drugs, including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta blockers, and aldosterone antagonists, prolong survival in patients with HF, independent of their hemodynamic effects. In addition, hypertension imposes an increased hemodynamic load on the failing ventricle in patients with established HF. Small changes in afterload in HF can produce large changes in stroke volume (show figure 1). (See "Pathophysiology of heart failure: Left ventricular pressure-volume relationships").

As a result, a mechanistic argument exists for the treatment of hypertension or even "normal" blood pressure in HF to lower systemic vascular resistance. (See "Goal blood pressure" below).

Treatment of hypertension in patients with heart failure (HF) must take into account the type of heart failure that is present: systolic dysfunction, in which impaired cardiac contractility is the primary abnormality; or diastolic dysfunction, in which there is a limitation to diastolic filling and therefore in forward output due to increased ventricular stiffness [5,6] . Hypertension and ischemic heart disease are the major causes of diastolic dysfunction [6] . (See "Treatment and prognosis of diastolic heart failure").

The distinction between these two, not mutually exclusive, types of heart failure can be made by measurement of the left ventricular ejection fraction (LVEF). The LVEF is normal or increased with pure diastolic dysfunction, since contractility is not impaired. Establishing the type of HF that is present is important because it determines which antihypertensive agents should be used.

SYSTOLIC DYSFUNCTIONThe goals of antihypertensive therapy in the setting of systolic dysfunction are to reduce both preload (to diminish congestive symptoms) and afterload (to improve cardiac contractility). As a result, the preferred antihypertensive agents are diuretics, including spironolactone, ACE inhibitors and beta blockers, all of which improve survival. (See "Overview of the therapy of heart failure due to systolic dysfunction").

ACE inhibitorsACE inhibitors are one of the primary therapies for HF. When given to patients with mild to advanced HF (many of whom are not hypertensive), they increase cardiac output, diminish congestive symptoms (mostly via venodilation), reduce the rate of progressive cardiac dysfunction, and decrease cardiovascular mortality at one to four years (show figure 2) [7,8] . An ACE inhibitor is more effective in diminishing mortality than the vasodilator combination of hydralazine and isosorbide dinitrate (show figure 3) [8] .

ACE inhibitors are also beneficial in patients with asymptomatic left ventricular dysfunction. In this setting, treated patients have better preservation of cardiac function, as manifested by less ventricular dilatation and a lower incidence of progression to overt heart failure; late mortality may also be reduced (show figure 4) [9,10] . (See "Evaluation and management of asymptomatic left ventricular systolic dysfunction").

ACE inhibitors have an additional advantage in hypertensive patients with left ventricular hypertrophy, promoting more regression of left ventricular hypertrophy than beta blockers [11] . (See "Clinical implications and treatment of left ventricular hypertrophy in hypertension").

The greater benefit associated with ACE inhibitors in maintaining cardiac performance may be related to inhibition of the local cardiac renin-angiotensin system, thereby diminishing the deleterious effects of angiotensin II on myocardial function and ventricular remodeling [12] . (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action").

Despite these beneficial cardiovascular effects, ACE inhibitors generally do not improve the glomerular filtration rate in HF. To the contrary, there is a rise (usually modest) in the plasma creatinine concentration in approximately 30 percent of cases [13] . This complication is most likely to occur in patients in whom maintenance of the glomerular filtration rate is dependent upon angiotensin II, such as those on high-dose diuretic therapy. These patients are also at greater risk of first-dose hypotension. (See "Renal effects of ACE inhibitors in heart failure").

RaceAlthough black patients have a lesser antihypertensive response than whites to ACE inhibitors [14] . the bulk of evidence supports similar cardiovascular protection in patients with HF [14,15] . As a result, it is generally recommended that blacks be treated the same as whites. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on Influence of race).

DosingBeginning ACE inhibitor therapy with low doses (eg, 2.5 mg of enalapril twice daily or 6.25 mg of captopril three times daily) will reduce the likelihood of hypotension and azotemia. If initial therapy is tolerated, the dose is then gradually increased until side effects occur or maintenance doses are reached (eg, 10 mg twice daily of enalapril, 50 mg three times daily of captopril, 35 mg per day of lisinopril, or 5 mg twice daily of quinapril).

These relatively high doses are recommended because they were used in the successful trials [16] ; it remains uncertain if lower doses provide the same degree of cardiac protection. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use").

Concurrent therapy with nonsteroidal antiinflammatory drugs (including 325 of aspirin per day) can reduce the hemodynamic improvement associated with ACE inhibitors in advanced heart failure [17] . The vasoconstriction induced by angiotensin II in HF is partially ameliorated by the release of vasodilator prostaglandins; blocking this response may minimize the degree to which the vascular resistance falls after the administration of an ACE inhibitor. (See "NSAIDs: Cardiovascular effects", section on Heart failure).

Angiotensin II receptor blockersAngiotensin II receptor blocking drugs (ARBs) for the treatment of HF appear to be as effective as, or possibly slightly less effective than, ACE inhibitors when compared directly. Among patients with HF, they are most often used in patients who are intolerant of ACE inhibitors or, in preference to an ACE inhibitor in patients who are already taking an ARB for some other reason. A less certain is the use of an ARB in addition to an ACE inhibitor. However, this issue is of limited importance to the treatment of hypertension because most such patients have normal or low blood pressures (eg, mean 125/75 mmHg in CHARM-Added) [18] . (See "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use").

Beta blockersCertain beta blockers, particularly carvedilol, metoprolol, and bisoprolol, have been shown to improve overall and event-free survival in patients with mild to advanced HF (show figure 5A-5B) [19-21] . The improvement in survival appears to be additive to that induced by ACE inhibitors (show figure 6). Beta blocker therapy should be considered, independent of hypertension, in patients with New York Heart Association class II, III, or IV HF (show table 1) who have been stabilized on an ACE inhibitor, digoxin, and diuretics. (See "Use of beta blockers in heart failure due to systolic dysfunction"). Beta blockers can also provide anginal relief in patients with ischemic heart disease and rate control in patients with atrial fibrillation.

DosingBefore initiating therapy, the patient should be informed that beta blockers may lead to an increase in symptoms for four to ten weeks before any improvement is noted [22] . Guidelines for the safe initiation of therapy have been published [23] . Therapy must be begun in very low doses and the dose doubled at weekly intervals until the target dose is reached or symptoms become limiting. Initial and target doses are: for carvedilol, 3.125 mg BID and 25 to 50 mg BID (the higher dose being used in subjects over 85 kg); for metoprolol, 6.25 mg BID and 50 to 75 mg BID, and for extended-release metoprolol, 12.5 or 25 mg daily and titrated up to 200 mg/day; and for bisoprolol, 1.25 mg once daily and 5 to 10 mg once daily.

Dose increases are generally made at two week intervals. Even lower starting doses should be given to patients with recent decompensation of a systolic pressure below 85 mmHg. Every effort should be made to achieve the target dose since the improvement appears to be dose-dependent.

The patient should weigh himself or herself daily and call the physician if there has been a 1 to 1.5 kg weight gain. Weight gain alone may be treated with diuretics, but resistant edema or more severe decompensation may require the cessation (possibly transient) of the beta blocker.

Loop diureticsDiuretic therapy for signs of fluid overload (pulmonary and/or peripheral edema) is usually initiated with a loop diuretic (eg, furosemide). The fall in intracardiac filling pressure that results from diuretic-induced fluid removal with diuretics will tend to lower the cardiac output and blood pressure. The fall in output is usually well tolerated; however, an otherwise unexplained rise in BUN should be viewed as a sign of a potentially important reduction in tissue perfusion. (See "Use of diuretics in heart failure").

Aldosterone antagonistsIn addition to fluid removal with loop diuretics, a second component of diuretic therapy is the administration of an aldosterone antagonist (spironolactone or eplerenone at a dose of 25 to 50 mg/day). These agents improve survival in patients with advanced HF (show figure 7) [24] or in patients with a recent myocardial infarction and left ventricular dysfunction [25] . They may also prevent excess arrhythmic mortality in patients with mild to moderate HF [26] . There is evidence for at least two mechanisms of benefit: an elevation in the serum potassium concentration; and prevention of the toxic effect of hyperaldosteronism on the heart. (See "Use of diuretics in heart failure").

In comparison, a non-potassium-sparing diuretic alone (usually a loop diuretic) may be associated with an increased risk of arrhythmia death (relative risk 1.33 compared to no diuretic therapy in a review from the SOLVD trial [26] ). However, the data supporting this observation may be confounded by the fact that the need for loop diuretics may be correlated with more severe HF and increased mortality risk.

Other antihypertensive drugsOther antihypertensive drugs have been evaluated in the treatment of HF: The combination of hydralazine and isosorbide dinitrate prolongs survival [27] and was found to be particularly effective in blacks with HF who were already being treated with standard therapies [28] . However, it requires multiple daily doses and may produce more side effects and is less effective than an ACE inhibitor (show figure 3) [8] . Some initial studies suggested a possible deleterious effect of calcium channel blockers in patients with HF, while later trials with amlodipine and felodipine showed no mortality benefit (show figure 8) [29,30] . Thus, there is no direct role for these drugs in the management of HF. However, amlodipine and felodipine appear to be safe and well tolerated and can be used for the treatment of hypertension. (See "Calcium channel blockers in heart failure due to systolic dysfunction"). Centrally acting sympathetic blockers (such as clonidine) have been reported, in limited trials, to improve HF [31] . They are not, however, commonly used for treating hypertension in this disorder.

DIASTOLIC DYSFUNCTIONThe optimal therapy of diastolic dysfunction is uncertain. Beta blockers, ARBs, and verapamil may be beneficial in this setting: Beta blockers have a variety of beneficial effects in patients with diastolic dysfunction, including slowing of the heart rate (which allows more complete left atrial emptying, particularly during exercise), a reduction in myocardial oxygen demand, and, by lowering the blood pressure, regression of left ventricular hypertrophy [6] . Angiotensin II receptor blockers (ARBs) may also be beneficial in patients with diastolic dysfunction [32,33] . The best outcomes data come from the CHARM-Preserved trial, in which candesartan therapy was associated with a trend toward reduced cardiovascular death or hospitalization for HF [32] . Verapamil also may be useful in the treatment of pure diastolic dysfunction. This agent may improve the compliance properties of the left ventricle [5,6] . However, it is difficult to distinguish this effect from benefits related to slowing of the heart rate, both at rest and during exercise, and to a reduction in or prevention of ischemic episodes.

The role of ACE inhibitors is less clear in patients with diastolic dysfunction. The reduction in afterload can induce hypotension in some cases; however, these drugs can also lead to symptomatic improvement and a reduction in left ventricular mass [34] . An additional potential benefit is that reducing local angiotensin II production may diminish myocardial stiffness [5,6] .

Diuretics or venodilators such as nitrates and dihydropyridine calcium channel blockers should be used with caution in diastolic dysfunction. The patient who has left ventricular diastolic dysfunction with a small, stiff left ventricular chamber is particularly susceptible to excessive preload reduction, which can lead sequentially to underfilling of the left ventricle, a fall in cardiac output, and hypotension. In patients with severe LVH due to hypertension or a hypertrophic cardiomyopathy, excessive preload reduction can also create a subaortic outflow obstruction.

Regression of LVHLeft ventricular hypertrophy (LVH) is frequently present in patients with diastolic dysfunction. Regression of LVH is an important therapeutic goal, since diastolic function may be improved [35] . A meta-analysis published in 2003 attempted to evaluate the relative efficacy of different antihypertensive drugs for their ability to reverse LVH in patients with hypertension [11] . Eighty trials that included 146 and 17 active treatment and placebo arms, respectively, were evaluated. After statistical adjustments for length of therapy and degree of blood pressure lowering, the relative reductions in left ventricular mass index were (show figure 9): Angiotensin II receptor blockers (ARBs) - 13 percent Calcium channel blockers - 11 percent ACE inhibitors - 10 percent Diuretics - 8 percent Beta blockers - 6 percent

ARBs, calcium channel blockers, and ACE inhibitors produced significantly more regression than beta blockers. The clinical significance of this difference is uncertain since there is as yet no evidence that more rapid regression of LVH is associated with improved long-term clinical outcomes. (See "Clinical implications and treatment of left ventricular hypertrophy in hypertension").

RECOMMENDATIONSWhile no studies have specifically demonstrated improved outcomes with antihypertensive therapy in patients with HF, treatment is supported by the mechanistic rationale that reducing hemodynamic load is beneficial in this setting. Based upon guidelines published by the ACC/AHA in 2005, treatment of hypertension in high-risk patients and those with asymptomatic and symptomatic left ventricular dysfunction is a class I indication (show table 2A-2D) [36] .

Choice of therapyAs noted above, most patients with systolic HF are treated with ACE inhibitors or ARBs, beta blockers, and, in selected patients, an aldosterone antagonist. These agents have favorable effects on survival in HF that are independent of their effects on blood pressure. Thus, even if no blood pressure response is seen when these agents are used in a patient with HF, they should not be discontinued, but should be supplemented. As described above, appropriate agents may include amlodipine, felodipine, isosorbide dinitrate and/or hydralazine.

Goal blood pressureThe optimal target blood pressure for patients with HF has not been defined. For patients with HF due to systolic dysfunction, many experts consider the goal of therapy to be the lowest blood pressure that is not associated with symptoms of hypotension or evidence of hypoperfusion (eg, worsening prerenal azotemia). In some patients with severe HF, this may be a blood pressure as low as 90 mmHg systolic, but in patients with hypertension and HF, such a low goal is not typically achievable.

Some guidance is available in data from clinical trials in HF: In the EPHESUS trial of eplerenone versus placebo, in which most patients were treated with a beta blocker and either an ACE inhibitor or an ARB, those also treated with eplerenone had a mean blood pressure of 124/75 mmHg [25] . In the CHARM-Added trial of candesartan versus placebo, in which most patients were treated with a beta blocker and an ACE inhibitor but not an aldosterone antagonist, those also treated with candesartan had a mean blood pressure below 125/75 mmHg [18] .

In patients with HF due to diastolic dysfunction, blood pressure reduction is further complicated by the risk of excessive preload or afterload reduction in a patient with a small, stiff ventricle and a relatively invariant left ventricular ejection volume, resulting in a fall in cardiac output. In this setting the achievable blood pressure varies widely from patient to patient. As with HF due to systolic dysfunction, many experts consider the goal of therapy to be the lowest blood pressure that is not associated with symptoms of hypotension or evidence of hypoperfusion (eg, worsening prerenal azotemia).

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Overview of the therapy of heart failure due to systolic dysfunction Author Wilson S Colucci, MD Section Editor Stephen S Gottlieb, MD Deputy Editor Susan B Yeon, MD, JD, FACC

Last literature review version 17.1: January 2009|This topic last updated: February 1, 2009(More)

INTRODUCTIONHeart failure (HF) is a common clinical syndrome representing the end-stage of a number of different cardiac diseases. It can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. There are two mechanisms by which reduced cardiac output and HF occur: systolic dysfunction and diastolic dysfunction.

An overview of the management of HF due to systolic dysfunction will be presented here [1-3] . Optimal therapy of HF due to diastolic dysfunction is discussed separately. (See "Treatment and prognosis of diastolic heart failure").

Chronic versus acute decompensated HFThe following discussion will emphasize the therapeutic approach to the patient with chronic HF. The management of acute decompensated HF requiring hospitalization is presented separately. Such patients typically present with dyspnea and often have rales with or without peripheral edema [4] . (See "Treatment of acute decompensated heart failure").

Major society guidelinesSeveral major societies have published extensive guidelines for the treatment of HF [1,3,5,6] . These include the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines [1] , the 2006 Canadian Cardiovascular Society consensus conference [5] , and the 2006 Heart Failure Society of America guidelines [6] , and the 2008 European Society of Cardiology (ESC) guidelines [3] .

With few exceptions, these societies make similar recommendations regarding the treatment of HF due to systolic dysfunction [7] . Our approach is in broad agreement with these guidelines.

GENERAL PRINCIPLESThe management of HF begins with an accurate assessment of the etiology and severity of the disease. (See "Clinical manifestations and evaluation of the patient with suspected heart failure").

This is followed by a therapeutic regimen aimed at the following factors: Correction of systemic factors (eg, thyroid dysfunction, infection, uncontrolled diabetes) (show table 1). Lifestyle modification (eg, high salt intake, alcohol cessation, medication compliance). Review of drugs that may contribute to HF (eg, nonsteroidal antiinflammatory drugs, antiarrhythmic drugs, calcium channel blockers, thiazolidinediones). Treatment of the cause of the heart disease. Pharmacologic therapy directed at relieving symptoms, slowing the progression of the HF, and improving patient survival. Specialized management for HF that is refractory to maximal oral pharmacologic therapy.

The goals of therapy are clinical improvement followed by stabilization and ultimately a reduction in morbidity and mortality. The 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines made recommendations regarding serial assessment of patients with HF (show table 2) [1] .

TREATMENT OF THE UNDERLYING CARDIAC DISEASEUnderlying conditions that predispose to the development or exacerbation of HF should be identified and treated (show table 3). (See "Epidemiology and causes of heart failure", section on Predisposing conditions for HF, and see "Causes of dilated cardiomyopathy").

HypertensionHypertension is the primary cause of HF many patients. In addition, hypertension imposes an increased hemodynamic load on the failing ventricle in patients with established HF. The goals of therapy are to reduce both preload (to diminish congestive symptoms) and afterload (to improve cardiac function).

Drug therapyAngiotensin converting enzyme (ACE) inhibitors, beta blockers, and angiotensin II receptor blockers (ARBs) are the preferred antihypertensive agents because, as will be described below, they improve survival in patients with HF. Beta blockers can also provide anginal relief in patients with ischemic heart disease and rate control in those with atrial fibrillation. Beta blocker therapy should always be initiated at very low doses to minimize the risk of cardiac decompensation. (See "Initiation of therapy" below).

For patients who are still hypertensive after initiation of ACE inhibitors, beta blockers, and/or ARBs, or who cannot tolerate these drugs, appropriate agents include loop diuretics, nitrates, hydralazine, and some calcium channel blockers (eg, amlodipine and felodipine) [8] . (See "Treatment of hypertension in heart failure").

Renovascular diseaseAnother consideration in patients with HF and hypertension is renovascular disease, particularly in those with HF due to ischemic heart disease. Additional testing for renovascular disease is indicated only in patients in whom the history is suggestive (including severe or refractory hypertension, a sudden rise in blood pressure over a previously stable value, or repeated episodes of flash pulmonary edema) and in whom a corrective procedure will be performed if renovascular disease is detected. (See "Who should be screened for renovascular or secondary hypertension?").

Ischemic heart diseaseCoronary atherosclerosis is the most common cause of cardiomyopathy in the United States, comprising 50 to 75 percent of patients with HF. In addition, coronary disease may be present in patients with HF of other causes, and may sometimes be overlooked as a contributing factor [9] .

Patients with ischemic heart disease may have HF from one or both of two mechanisms: a prior myocardial infarction (MI) followed by left ventricular dysfunction and remodeling; or hibernating myocardium due to chronic but potentially reversible ischemic dysfunction [10,11] . A separate issue is that patients with idiopathic dilated cardiomyopathy, who had a normal coronary arteriogram at diagnosis, may over time develop significant coronary atherosclerosis [12] .

All patients with documented ischemic heart disease should be treated medically for relief of angina and with risk factor reduction, such as rigorous control of serum lipids. (See "Overview of the management of stable angina pectoris" and see "Secondary prevention of cardiovascular disease: Risk factor reduction").

Myocardial revascularization with angioplasty or bypass surgery may improve symptom status, exercise capacity, and prognosis in selected patients with dysfunctional yet viable (hibernating or stunned) myocardium [11] . (See "Evaluation of hibernating myocardium"). Revascularization should also be considered in patients with a history of repeated episodes of acute left ventricular dysfunction and flash pulmonary edema. (See "Pathophysiology and evaluation of acute decompensated heart failure").

Valvular diseaseValvular heart disease is the primary cause of HF in perhaps 10 to 12 percent of patients [2] In addition, valvular dysfunction is a secondary or superimposed phenomenon in many cases of HF. As an example, some degree of mitral and tricuspid regurgitation is almost always present in patients with severe dilated cardiomyopathy, regardless of etiology [13] . (See "Functional mitral regurgitation").

Valvular disease imposes a hemodynamic load on the ventricles, leading to further impairment in cardiac function, regardless of whether the valvular disease is primary or secondary. Surgical correction of valvular disease, such as aortic or mitral stenosis or regurgitation or tricuspid regurgitation, can lead to improvement in cardiac function and resolution of symptoms. (See appropriate topics for the indications for surgery with various valvular lesions).

Other factorsThere are a variety of other potentially reversible conditions that can impair left ventricular function and cause, or worsen, HF. These include alcohol abuse, cocaine abuse, obstructive sleep apnea, nutritional deficiencies, myocarditis, hemochromatosis, sarcoidosis, thyroid disease, and rheumatologic disorders such as systemic lupus erythematosus. The evaluation to detect these conditions should include a careful history, including a history of systemic or other noncardiac disease, and, in some cases, consideration of endomyocardial biopsy. (See "Causes of dilated cardiomyopathy" and see "Clinical manifestations and evaluation of the patient with suspected heart failure" and see "Endomyocardial biopsy").

PHARMACOLOGIC THERAPY OF HFThe goals of pharmacologic therapy are to improve symptoms, slow or reverse deterioration in myocardial function, and reduce mortality. Additional pharmacologic therapy is directed at the prevention of arrhythmias and embolic events and the treatment of anemia and other possible exacerbating factors (show table 1). The treatment of HF in pregnancy involves specific concern about the effects of medications on the fetus and the mother, and therefore is discussed separately. (See "Management of heart failure in pregnancy").

A number of drugs are commonly used in HF for symptom relief and improvement in outcome (show table 4) [1,3] : Improvement in symptoms can be achieved by digoxin, diuretics, beta blockers, ACE inhibitors, and ARBs. Prolongation of patient survival has been documented with ACE inhibitors, beta blockers, ARBs, hydralazine/nitrates, and, in selected patients, spironolactone and eplerenone.

A review of data from the PROVED and RADIANCE trials supported the use of combination therapy with an ACE inhibitor, digoxin, and diuretics for initial management [14] . Subsequent studies showed that beta blockers, ARBs, and spironolactone provide further benefit, depending upon New York Heart Association (NYHA) class (show table 5).

We recommend the following approach to the long-term management of patients with HF. This approach is generally in agreement with the 2005 ACC/AHA task force guidelines for the treatment of HF (show table 4) [1] . The data supporting these summary recommendations are discussed in detail in the appropriate topic reviews.

Order of therapyWe recommend the following sequence of drugs in the typical patient, with allowance for variations depending upon clinical response: Loop diuretics are introduced first for fluid control in patients in overt HF. The goal is relief of signs or symptoms of volume overload, such as dyspnea and peripheral edema. ACE inhibitors, or if not tolerated, angiotensin II receptor blockers (ARBs) are typically initiated during or after the optimization of diuretic therapy. These drugs are usually started at low doses and then titrated to goals based upon trial data. (See "ACE inhibitors" belowSee "ACE inhibitors" below). Beta blockers are initiated after the patient is stable on ACE inhibitors, again beginning at low doses with titration to trial goals as tolerated. (See "Beta blockers" belowSee "Beta blockers" below). Digoxin is initiated in patients who continue to have symptoms of HF despite the above regimen and, in patients with atrial fibrillation, digoxin may be used for rate control. (See "Digoxin" below). An ARB, aldosterone antagonist, or, particularly in black patients, the combination of hydralazine and a nitrate may be added in patients who are persistently symptomatic despite the above regimen. (See "Angiotensin II receptor blockers" below and see "Aldosterone antagonists" below and see "Hydralazine plus nitrates" below).

ACE inhibitors or beta blockers firstThe administration of ACE inhibitors before beta blockers is largely based upon clinical trials with ACE inhibitors being performed before trials of beta blockers. Subsequent randomized trials (eg, CIBIS III) suggest that the outcomes may be similar if beta blockers are given first [15-17] .

The approach we recommend is based upon the differences in time to benefit and the importance of attaining target dose between these two drug classes: ACE inhibitors provide rapid hemodynamic benefit and will not exacerbate heart failure in the short run [1] . (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on Effect of dose). The hemodynamic benefits of beta blockers are delayed (and there may be a transient worsening in cardiac function when therapy is initiated), but the long-term improvements in LVEF and survival are dose-dependent in patients who can tolerate the target dose (show figure 1) [18] . However, patients who cannot tolerate the target dose may derive similar benefit as those who can, if they attain the same degree of beta blockade, as assessed from the reduction in heart rate [19] . These observations suggest that some patients have higher sensitivity to beta blockers.

Given these considerations, we start with a low dose of an ACE inhibitor (eg, lisinopril 5 mg/day), increase to a moderate dose (eg, lisinopril 15 to 20 mg/day) at one to two week intervals, and then begin a beta blocker, gradually increasing toward the target dose or, if this cannot be achieved, the highest tolerated dose. When the beta blocker titration is completed, the ACE inhibitor titration is completed. In patients with low risk of adverse response to ACE inhibitors (good blood pressure, no hyponatremia, hyperkalemia or risk of intravascular depletion), higher doses of the ACE inhibitor can be started and the titration can be quicker.

Complications that develop during dose titration should be treated. For example, increasing the diuretic dose for fluid overload [1] . Hypotension rarely limits metoprolol titration, but may occur with carvedilol due to its additional vasodilator activity. If hypotension limits carvedilol titration, one should consider a change to metoprolol.

Since many patients with HF have low blood pressures, we generally alter the regimen only for symptoms or signs of underperfusion. A cardiologist should be consulted in patients who have difficulty attaining target doses.

ACE inhibitorsACE inhibitors improve survival in patients with all severities of myocardial disease, ranging from asymptomatic left ventricular dysfunction [20] to moderate or severe HF (show figure 2A-2C) [21-24] . However, there is some concern about their effectiveness in blacks (show figure 3) [25-27] . (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use" and see "Influence of race" below).

All patients with asymptomatic or symptomatic left ventricular dysfunction should be started on an ACE inhibitor. Beginning therapy with low doses (eg, 2.5 mg of enalapril twice daily, 6.25 mg of captopril three times daily, or 5 mg of lisinopril once daily) will reduce the likelihood of hypotension and azotemia [28] . If initial therapy is tolerated, the dose is then gradually increased at one to two week intervals to, if tolerated, a target dose of 20 mg twice daily of enalapril, 50 mg three times daily of captopril, or up to 40 mg/day of lisinopril or quinapril. Blood should be obtained in all patients one to two weeks after starting or changing a dose and periodically thereafter to assess the plasma potassium concentration and renal function.

These relatively high doses are recommended because they were used in the successful trials [1] . Although there is uncertainty if these doses are much more beneficial than lower doses, maximum dose therapy, if tolerated, is still recommended [1,29,30] . If the target doses cannot be administered or are poorly tolerated, lower doses should be used with the expectation that there are likely to be only small differences in efficacy between low and high doses [1,29] . (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on Effect of dose).

Impact of aspirinSome evidence suggests that aspirin inhibits the acute hemodynamic effects of ACE inhibitors. However, most of the evidence does not support an inhibitory effect of aspirin on the long-term outcome benefits of ACE inhibitors in HF. In patients with known coronary artery disease, ASA should still be used. However, there is no evidence for using aspirin in patients without coronary artery disease. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on Use with aspirin).

Angiotensin II receptor blockersARBs for the treatment of HF appear to be as or possibly slightly less effective than ACE inhibitors when compared directly [31,32] . The CHARM-Alternative trial demonstrated benefit from candesartan in patients with class II or III HF who could not tolerate ACE inhibitors, primarily because of cough [33] .

The 2005 ACC/AHA task force recommended an ARB in patients who cannot tolerate ACE inhibitors for this use and a class IIa recommendation for the use of an ARB as an alternative to ACE inhibitors, particularly in patients already taking an ARB for another indication (show table 4) [1] . ARBs are more expensive than ACE inhibitors. (See "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use").

A separate issue, the value of adding an ARB to appropriate doses of an ACE inhibitor, was confirmed in the CHARM-Added trial [34] . The benefit of combination therapy was also seen in a variety of subgroups including patients also treated with a beta blocker. This is an important observation since adding an ARB to an ACE inhibitor in patients treated with a beta blocker appeared to be associated with increased mortality in a post hoc subgroup analysis from the Val-HeFT trial (show figure 4) [35] .

We regard the CHARM-Added data as more definitive for several reasons: The benefits of ARBs in CHARM-Added were seen in the primary end point analysis, rather than in a post hoc analysis as in the Val-HeFT The duration of follow-up was longer in CHARM-Added (41 months versus 2 years) A greater proportion of patients in CHARM-Added were treated with a beta blocker

In addition, significant benefit was also seen in the subset of 529 patients who met the United States Food and Drug Administration (FDA) criteria for being on maximum doses of an ACE inhibitor at baseline, suggesting that similar effects could not have been achieved by increasing the dose of the ACE inhibitor [36] .

The 2005 ACC/AHA guidelines concluded that the weight of evidence was less well established (class IIb) (show table 4) and the 2005 European Society of Cardiology guidelines concluded that the weight of evidence was in favor of efficacy (class IIa) for the addition of an ARB in persistently symptomatic patients with a reduced LVEF who are already being treated with conventional therapy [1,3] .

We suggest the addition of an ARB, if tolerated, to HF therapy in patients who are still symptomatic on ACE inhibitors and beta blockers or are hypertensive. In patients with renal dysfunction or hyperkalemia, the addition of an ARB must be done with caution.

However, based upon the VALIANT trial, which found no increase in efficacy with the combination of valsartan and an ACE inhibitor, with or without a beta blocker in patients with HF who had had an acute MI within the preceding 10 days [37] , an ARB should not be added to an ACE inhibitor in the immediate post-MI setting. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials").

Beta blockersAt least certain beta blockers, particularly carvedilol, metoprolol, and bisoprolol, improve overall and event-free survival in patients with New York Heart Association (NYHA) class II to III HF (show table 5) [38-40] and probably in class IV HF [41,42] . Beta blockers with intrinsic sympathomimetic activity (such as pindolol and acebutolol) should be avoided [38] . (See "Use of beta blockers in heart failure due to systolic dysfunction").

The beta blocker trials in HF were carried out in patients receiving therapy with an ACE inhibitor; thus, the improvement in survival is additive to that induced by ACE inhibitors (show figure 5) [43,44] .

The magnitude of benefit was illustrated in a meta-analysis that included 22 trials involving more than 10,000 patients [38] . Compared to placebo, beta blockers significantly reduced mortality at one year (odds ratio 0.65) and two years (odds ratio 0.72). During the first year, it was estimated that beta blocker therapy saved 3.8 lives per 100 patients treated and was associated with four fewer hospitalizations per 100 patients treated.

Carvedilol, metoprolol, or bisoprolol is recommended for all patients with symptomatic HF, unless contraindicated (show table 4) [1] .

The controlled trials, which evaluated the role of beta blockers in HF, excluded patients with relative contraindications to beta blocker therapy. Relative contraindications in patients with HF include: Heart rate 0.24 sec Second- or third-degree atrioventricular block Severe chronic obstructive pulmonary disease History of asthma

Less information is available in patients with class IV HF. However, the COPERNICUS trial and subset analyses from MERIT-HF and CIBIS II showed an equivalent survival benefit in patients with stable class IV as in those with class II and III. Based upon the results from COPERNICUS, the FDA has approved the use of carvedilol in patients with severe heart failure. (See "Use of beta blockers in heart failure due to systolic dysfunction").

Choice of agentThe different beta blockers have distinct pharmacologic properties; metoprolol has a high degree of specificity for the beta-1 adrenergic receptor, while carvedilol blocks beta-1, beta-2, and alpha-1 adrenergic receptors. Whether the broader adrenergic blocking effects of carvedilol confer an additional advantage over beta-1 selective agents is unknown [45] .

The survival effects of carvedilol and metoprolol tartrate were directly compared in the COMET trial, which suggested that carvedilol is more effective than metoprolol in reducing mortality [46] . However, there were important concerns with the design of this study that limit its clinical application, including the degree of beta blockade achieved in the two arms of the trial and the preparation of metoprolol used (the short-acting rather than extended-release form). (See "Use of beta blockers in heart failure due to systolic dysfunction", section on Comparison of beta blockers).

Patients with low blood pressure may tolerate metoprolol better than carvedilol. Conversely, those with high blood pressure may have a greater lowering of blood pressure with carvedilol. In MERIT-HF, metoprolol resulted in a higher blood pressure than placebo, presumably because of improved cardiac function.

Initiation of therapyBecause of the need for careful attention to initial dosing and the risk of transient worsening of symptoms, it is recommended that beta blocker therapy be initiated under the consultative guidance of an experienced HF center. Among inpatients, initiation of therapy prior to hospital discharge improves beta blocker use without an increase in side effects or drug discontinuation [47] . Prior to initiation of therapy, the patient should have no or minimal evidence of fluid retention and should not have required recent intravenous inotropic therapy.

The patient should be informed that beta blockers may lead to an increase in symptoms for 4 to 10 weeks before any improvement is noted. Therapy should be begun at very low doses and the dose doubled every two weeks until the target dose is reached or symptoms become limiting [48] . Initial and target doses are: For carvedilol, 3.125 mg BID initially and 25 to 50 mg BID ultimately (the higher dose being used in subjects over 85 kg) For extended-release metoprolol, 12.5mg daily in patients with NYHA class III or IV or 25 mg daily in patients with NYHA II, and ultimately 200 mg/day. If patients receive short acting metoprolol for cost reasons, dosing is not well established, but we recommend 6.25 mg BID initially and 50 to 100 mg BID ultimately. For bisoprolol, 1.25 mg once daily initially and 5 to 10 mg once daily ultimately.

Even lower starting doses should be given to patients with recent decompensation or a systolic pressure below 85 mmHg.

Every effort should be made to achieve the target dose since the improvement appears to be dose-dependent. The proportion of patients who reach the target dose is higher in clinical trials than in the general population in which the patients are older and have more comorbid disease. However, although not optimal, even low doses appear to be of benefit and should be used when higher doses are not tolerated [19] .

What may be most important is the degree of beta blockade [19] . In comparison, aiming for a particular resting heart rate or a particular reduction in heart rate is not of proven value [49] .

The patient should weigh himself or herself daily and call the physician if there has been a 1 to 1.5 kg weight gain. Weight gain alone may be treated with diuretics, but resistant edema or more severe decompensation may require dose reduction or cessation (possibly transient) of the beta blocker. (See "Use of beta blockers in heart failure due to systolic dysfunction").

Although data about the duration of beta blocker therapy in HF are lacking, it has been suggested that patients who are doing well should not have the beta blocker withdrawn, since clinical deterioration and sudden death or death from progressive HF has been observed.

Hydralazine plus nitratesThe combination of hydralazine (started at 25 mg three times daily and titrated upward to 100 mg three times daily) and isosorbide dinitrate (40 mg three or four times daily) or mononitrate (40 to 120 mg/day) produces modest benefit in patients with HF compared to placebo [50] and is less effective than ACE inhibitors (show figure 6) [21] .

Compliance with this regimen has generally been poor because of the large number of tablets required and the greater incidence of adverse reactions. However, in the V-HeFT trials, blacks had a lesser benefit from ACE inhibition than whites, while the benefit of the hydralazine-nitrate combination was more pronounced [51] .

Blacks, and perhaps other patients, may benefit from the addition of hydralazine and nitrates to standard HF therapy. This was demonstrated in the African-American Heart Failure (A-HeFT) Trial [52,53] . In this trial, 1050 patients with NYHA class III to IV HF who identified themselves as black (of African descent) were randomly assigned to receive either placebo or a fixed-dose combination of isosorbide dinitrate (20 to 40 mg orally three times daily) plus hydralazine (37.5 to 75 mg orally three times daily). All patients were receiving other HF therapy, including ACE inhibitors in 70 percent, ARBs in 17 percent, beta blockers in 74 percent, and spironolactone in 39 percent.

The trial was terminated early because of a significantly lower mortality rate in the nitrate plus hydralazine arm (6.2 versus 10.2 percent with placebo at a mean of 10 months) (show figure 7). Active therapy was also associated with a significantly lower rate of first hospitalizations for HF and a significantly greater improvement in quality of life.

At six months, the blood pressure had fallen by a mean of 1.9/2.4 mmHg in the nitrate plus hydralazine arm compared to a small increase of 1.2/0.8 mmHg, raising the possibility that at least some of the benefit may have been due to blood pressure reduction. The following observations support a specific benefit from drug therapy: In a retrospective subgroup analysis from A-HeFT, isosorbide plus hydralazine did not lower blood pressure in patients whose baseline systolic blood pressure was below the mean (126 mmHg) [54] . However, these patients received the same relative risk reduction as patients with higher baseline blood pressure, whose blood pressure was reduced with isosorbide and hydralazine. In different trials of patients with HF, prazosin and amlodipine lowered blood pressure compared to placebo but did not improve outcomes [8,50] .

It is uncertain whether the benefit of nitrates plus hydralazine would be similar in patients who do not identify themselves as black. This combination of agents was more effective in blacks than in whites in the V-HeFT trials [51] . Reasons for a difference in benefit could include genetic differences in drug effects [55] and differences in the cause of HF (the primary cause was hypertension in 39 percent of patients in A-HeFT, compared to 7 percent of patients in the CHARM-Added and CHARM-Alternative trials) [33,34,52] .

Based upon the results of the A-HeFT trial, it is reasonable to add hydralazine plus a nitrate, if tolerated, to patients who remain symptomatic on standard therapy for HF that includes an ACE inhibitor, a beta blocker, and possibly an aldosterone antagonist, particularly in patients who identify themselves as black.

It is not clear whether hydralazine plus a nitrate would be beneficial in patients treated with both an ACE inhibitor and an ARB. Also unanswered are the roles of hydralazine plus a nitrate in black patients with NYHA class II HF or in whites or members of other ethnic populations.

While the A-HeFT trial studied a proprietary fixed-dose combination of isosorbide dinitrate plus hydralazine, it is likely that the same benefit can be achieved using separate or generic formulations of these drugs.

The 2005 ACC/AHA guidelines did not target recommendations according to race and suggested that hydralazine and a nitrate might be added in patients with persistent HF symptoms on an ACE inhibitor and beta-blocker (class IIa), or those who cannot tolerate an ACE inhibitor or ARB (class IIb) (show table 4) [1] .

The 2006 HFSA guidelines also recommend consideration of hydralzine and a nitrate in patients intolerant of ACE inhibitors or ARBs. The combination of hydralazine and isosorbide dinitrate is recommended as part of standard therapy in addition to beta-blockers and ACE inhibitors for African-American patients with LV systolic dysfunction with NYHA class III or IV HF as well as those with NYHA II HF (evidence for the later being weaker). In addition, the combination of hydralazine and isosorbide dinitrate may be considered in non-African-American patients with LV systolic dysfunction who remain symptomatic despite optimized standard therapy.

Influence of genderMeta-analyses have defined the role of ACE inhibitors and beta blockers in women with HF. A meta-analysis of ACE inhibitor trials suggested that the benefit from these drugs may not apply to women [56] . Among trials of ACE inhibitor therapy in symptomatic HF, the relative mortality risk with an ACE inhibitor was significantly reduced in men at 0.80 (95% CI 0.68-0.93) but showed only a trend toward significance in women at 0.90 (95 0.78-1.05). Until more definitive data are provided, ACE inhibitors should continue to be used in women with HF.

In contrast, women appear to benefit from beta blockers to the same degree as men [56,57] . A pooled analysis from MERIT-HF, COPERNICUS, CIBIS II, and the United States Carvedilol Heart Failure trials found that the mortality benefit from beta blocker therapy was the same in men and women (relative risk 0.66 and 0.63, respectively) [56] .

Influence of raceRace may affect the response to ACE inhibitors, hydralazine plus isosorbide dinitrate, and beta blockers in patients with HF.

ACE inhibitorsThe V-HeFT trial and a matched cohort study from the SOLVD trial suggested that there were important differences between blacks and whites in the response to ACE inhibitors [25,26,51] . Two major findings were noted: Blacks had higher rates of both progressive HF and overall mortality. In the SOLVD analysis, the respective values were 13 versus 8 per 100 patient-years in whites for hospitalization for HF and 12 versus 10 per 100 patient-years for overall mortality [25] . Blacks had a lesser response than whites to ACE inhibition with enalapril despite receiving similar doses. In the SOLVD matched cohort study, enalapril therapy in whites was associated with a significant 44 percent reduction in hospitalization for HF compared to placebo; in contrast there was no significant reduction among blacks (show figure 3) [25] .

The apparent lack of response in blacks has some biologic plausibility since similar findings have been noted in patients with hypertension. Blacks respond less well to ACE inhibitors than to most other antihypertensive drugs (show figure 8) [58] . In the matched cohort study from SOLVD, there were significant reductions in systolic and diastolic pressure with enalapril in whites (5/3.6) but not blacks [25] . (See "Treatment of hypertension in blacks"). In addition to genetic disparities, environmental differences (such as diet) could contribute to the varying response.

In contrast to these findings, another analysis of the SOLVD trials using mortality as the end point found that the relative risk (RR) of death was reduced to the same degree in both blacks and whites (RR for blacks 0.89, 95% CI 0.74-1.06; RR for whites 0.89, 95% CI 0.82-0.97) [56] . The risk reduction was significant in whites but not blacks, an observation that is likely to be explained by the smaller number of blacks in the trials (800 versus 5718). Thus, ACE inhibitors should continue to be used in black patients with HF.

Beta blockersThere are conflicting data on the efficacy of beta blockers in black patients. In the carvedilol trials, the benefit of beta blockade was of similar magnitude in blacks and nonblack patients [59] . In comparison, it appeared that blacks derived no benefit with bucindolol in the BEST trial [60] .

A meta-analysis of beta blocker trials in HF confirmed this distinction, finding different results depending upon whether or not the BEST data were included [56] . In the COPERNICUS, MERIT-HF, and United States Carvedilol Heart Failure trials, the reduction in all-cause mortality with beta blockers was the same for blacks and whites (relative risk 0.67 and 0.63 respectively). With inclusion of the data from BEST, the benefit of beta blockers remained significant for whites but was no longer significant in blacks (relative risk 0.69 and 0.97, respectively).

These observations demonstrate that bucindolol, a beta blocker with partial beta agonist activity [61] , is not effective in reducing mortality in blacks. The reasons for this difference are not clear, but (as speculated by the authors of BEST) may include race-specific differences in the beta adrenergic pathway [60] .

Hydralazine with nitratesIn the V-HeFT trials, blacks had a lesser benefit from ACE inhibition than whites, while the benefit of the hydralazine-nitrate combination was more pronounced [51] . This observation led to the design of the A-HeFT trial (African-American Heart Failure Trial), in which black patients with class III to IV HF on standard heart failure therapy (including an ACE inhibitor if tolerated) were randomly assigned to a fixed combination of hydralazine and isosorbide dinitrate or placebo. (See "Hydralazine plus nitrates" above).

Influence of diabetesDiabetic patients with HF are treated in the same fashion as nondiabetics. Data supporting this approach are available for both beta blockers and ACE inhibitors. (See "Heart failure in diabetes mellitus", section on Drug therapy).

The thiazolidinediones and metformin, which are often used in type 2 diabetics, are relatively contraindicated in patients with HF. (See "Drugs that should be avoided or used with caution" below).

DigoxinDigoxin is given to patients with HF and systolic dysfunction to control symptoms (such as fatigue, dyspnea, and exercise intolerance) and, in patients with atrial fibrillation, to control the ventricular rate. As demonstrated in the DIG trial, digoxin therapy was associated with a significant reduction in hospitalization for HF but no benefit in terms of overall mortality [62] .

However, subsequent subgroup analyses suggest that digoxin may have an effect on survival that varies with the serum digoxin concentration (SDC). Compared to placebo, survival was significantly improved when the SDC was between 0.5 and 0.8 ng/mL in men and significantly worsened when the SDC was 1.2 ng/mL (show figure 9) [63] . A similar relationship was seen in women with a nonsignificant trend toward improved survival when the SDC was between 0.5 and 0.9 ng/mL and significantly worse survival when the SDC was 1.2 ng/mL [64] . (See "Use of digoxin in heart failure due to systolic dysfunction", section on Optimal digoxin level).

The use of digoxin for the treatment of symptoms in patients with left ventricular dysfunction was given a class I recommendation by an ACC/AHA task force (show table 4) [1] . We recommend starting digoxin in patients with left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] 40 percent were randomly assigned to either candesartan (mean dose at six months 25 mg) or placebo [41] . The mean LVEF was 54 percent. Additional medications included ACE inhibitor in 19 percent, beta blocker in 56 percent, and calcium channel blocker in 31 percent.

At a median follow-up of 37 months, there was a small and almost significant difference in incidence of the primary end point of cardiovascular death or hospitalization for HF (22 versus 24 percent; adjusted hazard ratio 0.86; 95% CI 0.74-1.00) that was entirely due to a significant reduction in hospitalization for HF with candesartan (16 versus 18 percent). The overall rate of discontinuation of therapy was similar in the two groups (22 versus 18 percent). However, significantly more patients discontinued candesartan because of renal dysfunction, hyperkalemia, or hypotension. In the I-PRESERVE trial, 4128 patients with symptomatic HF (nearly all NYHA class II or III) and an LVEF 45 percent were randomly assigned to either daily irbesartan 300 mg or placebo [42] . The mean LVEF was 59 percent. Additional medications included ACE inhibitor in 26 percent, beta blocker in 59 percent, and calcium channel blocker in 40 percent.

At a mean follow-up of 49.5 months, there was no significant difference in the primary end point of death from any cause or hospitalization for a cardiovascular cause. There were also no significant differences in secondary outcomes which included death from HF or hospitalization for heart failure, death from any cause, hospitalization for a cardiovascular cause, and quality of life.

Aldosterone antagonistsAldosterone contributes to cardiac hypertrophy and fibrosis [43,44] . These processes may be preventable or even reversible by aldosterone blockade [45-47] .

The possible benefit of aldosterone antagonism in diastolic HF was suggested in a study of 30 medically treated patients with exertional dyspnea, an LVEF >50 percent, and diastolic dysfunction who were randomly assigned to either spironolactone 25 mg/day or placebo [48] . At six months, spironolactone therapy was associated with significant improvement in myocardial function by echocardiographic indices, including strain rate, peak systolic strain, and cyclic variation of integrated backscatter.

A large NIH sponsored study, TOPCAT, is evaluating the hypothesis that spironolactone is beneficial in patients with a normal ejection fraction and heart failure.

StatinsIntensive lipid lowering with statin therapy is recommended for the secondary prevention of cardiovascular disease, independent of the presence of diastolic dysfunction. (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease" and see "Treatment of lipid disorders in secondary prevention").

Initial observational data suggest that statins might be of benefit in patients with diastolic HF. This potential effect was illustrated in a report of 137 consecutive patients with HF and an LVEF 50 percent who did not have known coronary heart disease, significant valvular disease, or end-stage renal disease; one-half were treated with a statin at the discretion of the physician [49] . The patients treated with a statin had a higher baseline LDL-cholesterol concentration than those not treated but the posttherapy values were similar in the two groups. At a mean follow-up of 21 months, statin therapy was associated with a significant reduction in mortality after adjustment for differences in baseline variables (adjusted relative risk 0.20, 95% CI 0.06-0.62). In contrast to this apparent benefit from statin therapy, treatment with ACE inhibitors, ARBs, beta blockers, and calcium channel blockers had no impact on survival.

Randomized trials are required to confirm these observations. The possible mechanisms of benefit, other than treatment of coronary disease that may have been unrecognized, are not known. Statins have a variety of lipid-independent effects that could contribute to improved outcomes. (See "Mechanisms of benefit of lipid lowering drugs in patients with coronary heart disease").

Statin therapy in patients with systolic HF is discussed separately. (See "Overview of the therapy of heart failure due to systolic dysfunction", section on Statins).

Exercise conditioningDuring exercise in healthy individuals, diastolic function is enhanced so that left ventricular input remains precisely matched to LV output, despite the shortened duration of diastole resulting from the associated tachycardia. This is achieved in the normal LV by a rapid and marked decrease in intraventricular pressure during early diastole, thereby creating a greater LV "suction" effect, which enhances the transmitral pressure gradient without increasing left atrial pressure and compromising pulmonary function. This mechanism is lost in patients with diastolic dysfunction; as a result, dyspnea with exertion is often their most common complaint. (See "Pathophysiology of diastolic heart failure", section on Left ventricular diastolic function during exercise).

Long-term exercise training produces physiologic cardiac hypertrophy with enhanced diastolic function. Experimental studies suggest that exercise conditioning has the potential to reverse the diastolic dysfunction of pathologic LVH or aging [50-53] . It is not known if exercise training is beneficial in patients with diastolic HF. However, some observations support such a benefit. In one report comparing 20 distance runners with 20 sedentary individuals matched for age and systolic and diastolic blood pressure, the exercise group had less of the left ventricular diastolic dysfunction associated with "normal" aging [54] .

Any exercise training program for the potential treatment of diastolic HF should be based upon dynamic isotonic exercise, not static exercise, since the latter causes changes in cardiac geometry similar to those of hypertensive LVH [55] . (See "Components of cardiac rehabilitation and exercise prescription").

PROGNOSISThe prognosis in patients with diastolic HF differs from patients with asymptomatic diastolic dysfunction.

Symptomatic diastolic HFThe prognosis of patients with symptomatic diastolic HF is less well defined than in those with systolic HF. Data from the Framingham Heart Study, the V-HeFT trials, and several other observational series revealed varying results [7,9,56-61] . In addition, the data are not clear on whether the long-term prognosis differs between diastolic and systolic HF [62] .

In reports from the community-based Framingham Heart study and the larger Cardiovascular Health Study, prognosis was significantly better in patients with diastolic dysfunction [56,58] . In the latter study of 269 patients at least 65 years of age who had HF, the mortality rates were 87 versus 154 deaths per 1000 person-years with normal and impaired systolic function, respectively (adjusted hazard ratio 1.48 and 1.88 compared to persons with no HF and normal left ventricular systolic function) [58] .

In contrast, another community-based study from Olmsted County, Minnesota found that, after adjustment for risk factors, five-year survival was not significantly different in patients with diastolic versus systolic HF (adjusted relative risk 0.80, p = 0.37) [7] .

Among patients hospitalized for HF, the mortality rates are higher but the data are again conflicting as to whether or not the prognosis is different in diastolic and systolic HF: Among 6076 patients discharged from a Mayo Clinic Hospitals in Olmsted County, Minnesota with a diagnosis of decompensated HF over a 15 year period (1987-2001), 53 percent had a reduced LVEF and 47 percent had a preserved LVEF [9] . One-year mortality was relatively high in both groups, but slightly lower in patients with a preserved LVEF (29 versus 32 percent in patients with reduced LVEF, adjusted hazard ratio 0.96, 95% CI 0.92-1.00). Survival improved over time for those with reduced left ventricular ejection fraction (LVEF) but not for those with preserved LVEF. In a prospective evaluation of 413 patients hospitalized for HF, the relative risk for six month mortality was lower for diastolic versus systolic HF dysfunction (13 versus 21 percent, adjusted hazard ratio 0.51) [60] . In a cohort of 2802 patients discharged from 103 hospitals in Ontario with a diagnosis of decompensated HF, one-year mortality was 22 percent in patients with a preserved LVEF versus 26 percent in patients with a reduced LVEF [61] . This difference was not statistically significant.

Independent predictors of mortality in patients with diastolic heart failure in different studies include older age, male gender, NYHA class, lower LVEF, the extent of coronary artery disease, peripheral arterial disease, diabetes, impaired renal function, the degree of diastolic dysfunction as assessed by Doppler echocardiography, and increased red cell distribution width [63-68] .

Asymptomatic diastolic dysfunctionThree studies have assessed the impact of asymptomatic diastolic dysfunction on prognosis: In the Mayo Clinic cross-sectional community survey of 2042 adults 45 years of age, 21 percent had mild diastolic dysfunction, 7 percent had moderate diastolic dysfunction, and 1 percent had severe diastolic dysfunction [4] . At a median follow-up of 3.5 years, 48 subjects died. After controlling for age, sex, and the presence of systolic dysfunction, all-cause mortality was increased in patients with mild diastolic dysfunction (95 percent of whom were asymptomatic; hazard ratio 8.3) and in those with moderate to severe diastolic dysfunction (90 percent of whom were asymptomatic; hazard ratio 10.2). In another report, 3008 American Indians, 45 to 74 years of age, underwent Doppler echocardiography to determine the E/A ratio, and were followed for three years [69] . The 16 percent of patients with an E/A ratio 1.5 (restrictive pattern due to reduced compliance) (show figure 2) had a significantly higher all-cause mortality (12 and 13 versus 6 percent for normal E/A ratio) and cardiac mortality (4.5 and 6.5 versus 1.6 percent). After adjustment for covariates, an E/A ratio >1.5, but not an E/A ratio