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INTRODUCTION — Diastolic heart failure (DHF) is a major cause of heart failure with preserved ejection fraction (HF-PEF) (table 1). DHF is a clinical syndrome in which patients have symptoms and signs of heart failure (HF), normal or near normal left ventricular (LV) systolic function, and evidence of diastolic dysfunction (eg, abnormal LV filling and elevated filling pressures) .
The treatment and prognosis of patients with DHF will be reviewed here. Issues related to etiology, clinical manifestations, diagnosis, and pathophysiology are discussed separately. (See "Clinical manifestations and diagnosis of diastolic heart failure" and "Pathophysiology of diastolic heart failure" and "Cellular mechanisms of diastolic dysfunction".)
IMPAIRED RESPONSE TO STRESS — Patients with diastolic heart failure have particular difficulty in tolerating certain kinds of hemodynamic stress:
Episodes of hemodynamic decompensation may result in pulmonary congestion or edema severe enough to be life-threatening. This phenomenon, called flash pulmonary edema, is discussed in detail separately. (See "Evaluation of acute decompensated heart failure".) Studies using implantable hemodynamic monitors have shown that LV diastolic pressures rise in a progressive fashion prior to apparent abrupt onset of acute heart failure [2-8]. While the development of symptoms is rapid, the increases in diastolic pressure occur gradually over a period of weeks.
TREATMENT — The treatment of diastolic heart failure (DHF) remains empiric, since trial data are limited.
General principles — Recommendations for treatment of patients with DHF were published in 2013 by the American College of Cardiology Foundation/American Heart Association in the guideline on HF [9,10]. The following two strong recommendations were included:
A clinical practice review concurred with the American College of Cardiology/American Heart Association (ACC/AHA) guidelines and provided specific examples of clinical therapies appropriate to achieving these goals (table 2) .
Pneumococcal vaccination is recommended for all patients with heart failure [11,12]. Annual influenza vaccination is now recommended for all individuals 6 months of age and older. (See "Pneumococcal vaccination in adults" and "Seasonal influenza vaccination in adults".)
Choice of medications — The choice of medications in patients with DHF is determined by two factors:
The guidelines concluded that efficacy was less well established for the administration of specific drugs, such as beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers .
An important caveat is that the patient who has LV diastolic dysfunction with a small, stiff left ventricular chamber is particularly susceptible to excessive preload reduction, which can lead sequentially to underfilling of the LV, a fall in cardiac output, and hypotension. In patients with severe left ventricular hypertrophy (LVH) due to hypertension or hypertrophic cardiomyopathy, excessive preload reduction can also create subaortic outflow obstruction.
For these reasons, the administration of diuretics or venodilators such as nitrates and dihydropyridine calcium channel blockers must be performed with caution. Careful attention is required for symptoms of ventricular underfilling such as weakness, dizziness, near syncope, and syncope.
Digoxin is generally not used in patients with DHF because systolic function is intact. The DIG ancillary trial, a parallel study to the DIG trial, evaluated the role of digoxin in patients with heart failure (HF) and a left ventricular ejection fraction (LVEF) >45 percent [14,15]. At a mean follow-up of 37 months, digoxin had no effect on all-cause or cause-specific mortality, or all-cause or cardiovascular hospitalization . (See "Use of digoxin in heart failure due to systolic dysfunction".)
Antihypertensive therapy — Lowering the systemic blood pressure was associated with reduced rate of HF in some large randomized hypertension treatment trials, particularly those including diuretic therapy [16,17]. The choice of a specific antihypertensive agent must be individualized in the presence of coexisting diseases such as diabetes mellitus or chronic obstructive pulmonary disease. (See "Choice of therapy in primary (essential) hypertension: Recommendations".)
Regression of LVH is an important therapeutic goal, since it may improve diastolic function . 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 . 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 (figure 1):
ARBs, calcium channel blockers, and ACE inhibitors produced 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 outcomes. The choice of antihypertensive therapy is usually based upon other factors. (See "Choice of therapy in primary (essential) hypertension: Recommendations".)
Chronic AF — LV filling in DHF occurs largely in late diastole and is therefore more dependent than normal hearts on atrial contraction. Tachycardia is also deleterious by shortening the time of diastole. (See "Clinical manifestations and diagnosis of diastolic heart failure", section on 'Pathophysiology'.)
For these reasons, restoration and maintenance of sinus rhythm is preferred when atrial fibrillation (AF) occurs in patients with DHF. When this cannot be achieved, rate control becomes important. Beta blockers and calcium channel blockers are the usual first-line agents, with digoxin most often being used in patients with systolic HF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy".)
A combination of these drugs may be required to achieve adequate heart rate control. It is important to measure heart rate during moderate exercise and not to base heart rate control solely on values obtained in the resting state.
An important component of the management of atrial fibrillation, regardless of whether rhythm control or rate control is chosen, is anticoagulation to prevent systemic embolization. (See "Rhythm control versus rate control in atrial fibrillation".)
Antiischemic therapy — Myocardial ischemia often precipitates and/or contributes to DHF. Ischemia can result from CHD and/or LVH with subendocardial ischemia. In such patients, beta blockers and calcium channel blockers are preferred. Nitrates are also effective but, as mentioned above, the reduction in preload can lead to hypotension in selected patients. (See "Overview of the care of patients with stable ischemic heart disease".)
Revascularization by percutaneous coronary intervention or coronary artery bypass graft surgery may be required in patients with drug-resistant ischemic DHF. (See "Medical therapy versus revascularization in the management of stable angina pectoris".)
Beta blockers — Beta blockers have a variety of potential beneficial effects in patients with DHF including slowing the heart rate (which increases the time available for both LV filling and coronary flow, particularly during exercise), reducing myocardial oxygen demand, and, by lowering the blood pressure, causing regression of LVH [20,21]. Slowing the heart rate is particularly important in the treatment of pulmonary congestion due to ischemic DHF and, as noted above, in patients in atrial fibrillation.
In the small SWEDIC trial, 113 patients with symptoms of HF, normal left ventricular ejection fraction, and abnormal diastolic function were randomly assigned to treatment with carvedilol or placebo, with echocardiographic assessment at baseline and six months . Carvedilol therapy resulted in a significant improvement in the E/A ratio, but no significant improvement in deceleration time, isovolumic relaxation time, or pulmonary vein flow velocity.
Beta blockers may also directly improve diastolic function in patients with idiopathic dilated cardiomyopathy and those with an acute myocardial infarction; both are settings in which beta blockers are recommended because they improve survival [23,24]. Slowing of the heart rate may contribute to this effect by providing more time for calcium exit from myocytes, thereby reversing the cellular calcium overload characteristic of diastolic dysfunction. (See "Cellular mechanisms of diastolic dysfunction".)
However, direct evidence of the clinical efficacy of beta blocker therapy in patients with DHF is lacking. While the SENIORS trial suggested that nebivolol (a beta blocker with vasodilating properties) may be beneficial in patients with HF and preserved systolic function, an OPTIMIZE-HF registry study found no clinical benefit of beta blocker therapy in this population.
At present, there is no good demonstration that beta blockade is beneficial in the treatment of DHF.
Calcium channel blockers — Calcium channel blockers may also be useful in the treatment of DHF. These agents have been purported to have a direct "lusitropic" (relaxation-enhancing) effect. However, it is difficult to distinguish this effect from the benefits related to slowing of the heart rate, both at rest and during exercise, and to a reduction in or prevention of ischemic episodes. (See "Calcium channel blockers in the management of stable angina pectoris".)
The following observations from small studies are consistent with the possible efficacy of verapamil:
ACE inhibitors — There is no clear evidence from randomized clinical studies that ACE inhibitor therapy directly improves overall morbidity or mortality in patients with DHF. Because patients with DHF frequently have co-morbidities such as renal insufficiency, ACE inhibitors should be used carefully to avoid the risk of renal dysfunction and hypotension. Despite these concerns, ACE inhibitors play an important role in the treatment of the disease processes that underlie the development of DHF, namely, hypertension, coronary artery disease and diabetes.
The more general efficacy of ACE inhibitors in patients with DHF was assessed in the PEP-CHF trial in which 850 patients ≥70 years of age with diastolic dysfunction: 79 percent had a history of hypertension; patients with substantial LV systolic dysfunction or valve disease were excluded . The patients were randomly assigned to an ACE inhibitor (perindopril) or placebo. At one year, treatment with perindopril was associated with an almost significant trend toward reduction in the primary end point of combined all-cause mortality and unexpected hospitalization for HF (8.0 versus 12.4 percent, HR 0.69; 95% CI 0.47-1.01); this effect was entirely due to fewer unexpected hospitalizations for HF. The patients treated with perindopril also had significant improvements in functional class and six minute walk distance.
While benefit from ACE inhibitors may be mediated by its blood pressure effects, it is also possible that there might be a reduction in myocardial angiotensin II production, which can diminish myocardial stiffness. Evidence in support of this hypothesis has been provided by a study of patients with DHF due to aortic stenosis-induced LVH . The intracoronary infusion of enalaprilat, which produced no evidence of systemic ACE inhibition but presumably impaired cardiac angiotensin II production, improved diastolic distensibility and relaxation. Similar benefits may occur in patients with ischemic heart disease  and during experimental low-flow ischemia in hypertrophied hearts with ischemic diastolic dysfunction . (See "Actions of angiotensin II on the heart" and "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action".)
Angiotensin II receptor blockers — There is no clear evidence from randomized clinical studies that ARB therapy directly improves overall morbidity or mortality in patients with DHF. There is no clear evidence of improved diastolic function with angiotensin II receptor blocker treatment as compared to other therapies in patients with asymptomatic left ventricular diastolic dysfunction or overt DHF.
Angiotensin II receptor blockers (ARBs) may be beneficial in patients with left ventricular diastolic dysfunction due to hypertension, although the data on impact compared to other agents are limited [18,19,36-39]. In various studies of hypertensive patients with LVH, ARBs caused more regression of LVH than beta blockers [19,37], a change that was associated with an improvement in LV diastolic filling . In other studies, losartan treatment improved exercise tolerance and quality of life (which were not improved by hydrochlorothiazide)  and reduced myocardial fibrosis and stiffness . (See "Clinical implications and treatment of left ventricular hypertrophy in hypertension", section on 'Effect of antihypertensive therapy'.)
However, a large randomized trial in patients with hypertension and diastolic dysfunction demonstrated that improvement in diastolic function with angiotensin II receptor blocker therapy was similar to that with other antihypertensive therapy . The trial included 382 patients who were treated with antihypertensive drugs not related to angiotensin inhibition and then randomly assigned to valsartan or placebo . There were similar improvements in the two groups in blood pressure control and diastolic function, as measured by myocardial relaxation velocity of the lateral mitral annulus (E').
Outcomes of treatment with angiotensin II receptor blockers in patients with HF and preserved left ventricular ejection fraction (LVEF) were investigated in two large trials:
The possible benefit of aldosterone antagonism in DHF 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 . 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.
Phosphodiesterase-5 inhibition — Beneficial hemodynamic response to the phosphodiesterase-5 inhibitor sildenafil (50 mg three times per day) was observed in a randomized placebo-controlled trial of 44 patients with DHF with LVEF ≥50 percent and pulmonary hypertension (pulmonary artery systolic pressure >40 mmHg) . At six months, there was no response to placebo but sildenafil led to significant improvements in mean pulmonary artery pressure (reduced by 16.7 mmHg), right ventricular function (7.9 mm increase in mean tricuspid annular systolic excursion), and mean right atrial pressure (reduced by 12.4 mm). Quality of life measures of breathlessness, fatigue, and emotional function were significantly improved with sildenafil but not placebo. Similar results were observed at 12 months. These findings require confirmation in a larger trial.
Statins — Intensive 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 cardiovascular disease" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
Initial observational data suggest that statins might be of benefit in patients with DHF. Randomized trials are required to confirm these observations. Statin therapy in patients with HF is discussed in detail separately. (See "Statin therapy in patients with heart failure".)
Exercise conditioning — During 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 'Normal response to 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].
Small randomized trials suggest that exercise training improves functional capacity in patients with heart failure with preserved left ventricular ejection fraction (HF-PEF, which is largely attributed to DHF). This evidence is discussed separately. (See "Cardiac rehabilitation in patients with heart failure", section on 'Effect on functional capacity'.)
Any exercise training program for the potential treatment of DHF should be based upon dynamic isotonic exercise, not static exercise, since the latter causes changes in cardiac geometry similar to those of hypertensive LVH . (See "Components of cardiac rehabilitation and exercise prescription".)
Implantable hemodynamic monitor — As discussed separately, a randomized trial found that use of an implantable hemodynamic monitor (IHM) decreased heart failure hospitalizations in a population of patients that included patients with DHF . (See "Possibly effective emerging therapies for heart failure", section on 'Outpatient monitoring via device'.) While such devices are not yet available for clinical use, they are currently being evaluated by the FDA. The reasons for possible efficacy are unknown, but may include more aggressive titration of medications as well as earlier recognition of problems.
Treatment differences between SHF and DHF — The results of the randomized clinical trials in patients with DHF (or HFPEF) have demonstrated that while neurohumoral antagonists such as beta blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers are effective in treatment of systolic heart failure (SHF), they do not decrease morbidity and mortality in DHF. These data suggest that there are fundamental differences in the pathophysiology underlying SHF versus DHF. In addition, these data suggest that future studies should target different and novel mechanisms in DHF. When choosing medications for hypertension, co-morbidities should be considered.
PROGNOSIS — Asymptomatic diastolic dysfunction is a predictor of future cardiovascular morbidity, but prognosis differs from that in patients with symptoms of heart failure (ie, diastolic heart failure [DHF]).
Asymptomatic diastolic dysfunction — Moderate to severe diastolic dysfunction without heart failure (HF) is a predictor of mortality as illustrated by the following studies:
Symptomatic patients (ie, DHF) — The prognosis of patients with symptomatic DHF is less well defined than in that of patients with systolic HF. Data from the Framingham Heart Study, the V-HeFT trials, and several observational series revealed varying results [58-65]. In addition, the data are not clear on whether the long-term prognosis differs between diastolic and systolic HF .
In reports from the community-based Framingham Heart study and the larger Cardiovascular Health Study, prognosis was significantly better in patients with diastolic dysfunction [60,62]. 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) .
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) .
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:
Independent predictors of mortality in patients with DHF in different studies include older age, male gender, New York Heart Association (NYHA) class, lower LVEF, the extent of coronary artery disease, peripheral artery disease, diabetes, impaired renal function, the degree of diastolic dysfunction as assessed by Doppler echocardiography, and increased red cell distribution width [67-72].
Causes of death — The mode of death was evaluated in patients with symptomatic DHF (NYHA class II to IV HF with LVEF ≥45 percent) enrolled in the I-Preserve trial . The annual mortality rate was 5 percent. Sixty percent of deaths were cardiovascular (26 percent sudden, 14 percent HF, 5 percent myocardial infarction, and 9 percent stroke), 30 percent were noncardiovascular (including cancer and infection/sepsis), and 10 percent were of unknown cause. Irbesartan treatment did not affect the mortality rate or the distribution of mode of death.
Morbidity — Nearly every study that has compared morbidity outcomes in systolic heart failure (SHF) and DHF have found equivalent rates [65,74-78]. These include the rate and frequency of hospitalization for heart failure, symptomatic status as measured by abnormalities in myocardial oxygen consumption, six-minute walk distance, Minnesota Living with Heart Failure questionnaire (MLHFQ) scores, and other quality of life indicators. Therefore, patients with DHF have a morbidity burden equivalent to that in patients with SHF.
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