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Approximately half of people with heart failure have HFpEF. The prevalence of HFpEF relative to HFrEF is growing by 10% per decade,127 and the hospitalizations caused by HFpEF continue to increase at a high rate.128 The increasing HFpEF epidemic is related to increasing rates of common comorbidities that are believed to drive the pathophysiology, including obesity, hypertension, and metabolic syndrome, along with aging of the population.127,128,129,130,131,132,133 In striking contrast to HFrEF where numerous drugs and devices improve outcomes, there is no proven effective treatment that prolongs life in HFpEF.134 The lack of efficacy of these therapies underscores the fundamental differences between these two phenotypically distinct forms of heart failure,135,136 as well as our incomplete understanding of the pathophysiology.137
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Similarities and Differences Between Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction
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The traditional cutoff for defining HFpEF has been an ejection fraction of > 50% in the presence of clinical heart failure.130 Patients with heart failure and an ejection fraction < 40% are defined as having HFrEF.134 Patients with an ejection fraction from 40% to 50% have a borderline decrease in ejection fraction, which has been variably classified as either HFpEF or HFrEF in clinical trials, although emerging evidence supports the idea that this group is more accurately classified as HFrEF.138,139,140,141 Although it should be obvious that the dichotomization of heart failure patients according to ejection fraction alone is arbitrary and flawed,142,143 this method is unlikely to be replaced given the widespread use of echocardiography and the well-characterized risk factor profile, pathophysiology, and outcomes in the two heart failure phenotypes as defined according to this nosology.130,137,141
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There are a number of key differences between HFpEF and HFrEF (Table 70–11), the most obvious of which is ventricular dilatation in HFrEF.144 Eccentric LV remodeling in HFrEF increases wall stress, resulting in greater natriuretic peptide release.145 As such, BNP or NT-proBNP levels are typically much lower in people with HFpEF, and among stable outpatients, they are often normal.146,147 There are also important microscopic differences, including increased cardiomyocyte diameter, higher myofibrillar density, and increased cardiomyocyte stiffness in HFpEF as compared to HFrEF.144 Patients with HFrEF have depressed contractility. Patients with HFpEF have stiffer ventricles and vasculature, which leads to much greater blood pressure lability with changes in loading associated with dietary indiscretion or physical exercise (Fig. 70–10).135,148,149 Whereas vasodilator therapies are pushed aggressively in HFrEF despite low arterial pressure, it is unclear whether this practice is beneficial or even could be harmful in HFpEF.135
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Despite the many differences in ventricular structure and function in HFpEF and HFrEF, there are many similarities. Hemodynamic derangements including elevation in filling pressures, pulmonary hypertension, and impaired cardiac output reserve are common to both, as are symptoms of severe exercise intolerance resulting in reduced aerobic capacity and poor quality of life.135,150,151
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The relative prevalence of HFpEF increased from 38% to 54% of all heart failure cases in Olmsted County, Minnesota, between 1987 and 2001.127 This increase is likely related in part to increased recognition of the syndrome, but it also coincides with rising rates of comorbidities that are associated with the pathogenesis, including hypertension, obesity, atrial fibrillation, and diabetes.133,152 A recent analysis of US data showed that among incident heart failure cases between 2005 and 2008, 52% of patients had HFpEF, 33% had HFrEF, and 16% had borderline systolic dysfunction (ejection fraction of 40%-50%).131
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Comorbidities are common to both HFpEF and HFrEF, but patients with HFpEF are generally older, more hypertensive, obese, diabetic, and more likely to display atrial fibrillation.137,153,154,155,156 Although comorbidities influence ventricular-vascular structure and function in HFpEF, fundamental disease-specific changes drive the disorder, indicating that HFpEF is not merely an amalgamation of comorbidities.157 Furthermore, morbidity and mortality in patients with HFpEF greatly exceed what is observed in patients with the same comorbid conditions, but who do not manifest heart failure.158
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Risk factors for HFpEF are well established and include hypertension, older age, diastolic dysfunction, kidney disease, anemia, and diabetes.159,160,161 LV diastolic compliance deteriorates as part of normal aging,162,163 even in community-dwelling volunteers free of cardiovascular disease.164 Age-related effects appear to accelerate in the presence of obesity.164,165,166 Sedentary lifestyle is an independent risk factor for HFpEF, and increasing leisure time activity reduces that risk in a dose-dependent fashion.167,168 Poor fitness is also associated with concentric ventricular remodeling and diastolic dysfunction,169 which are common precursors of HFpEF. Prior myocardial infarction is more common in HFrEF than HFpEF,170 but recent data have shown that coronary artery disease is common in HFpEF and associated with adverse outcome, independent of other predictors (Fig. 70–11).171 Decreases in myocardial microvascular density are also present in HFpEF and may contribute to ischemia.172
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Hospitalization and rehospitalization risk is similar in HFpEF and HFrEF.153,154 Although some community-based studies have reported similar mortality in HFpEF and HFrEF,127,173 others have reported better outcomes in HFpEF.174 While mode of death is largely cardiovascular in HFpEF patients enrolled in trials,175 noncardiovascular causes of death are common in HFpEF patients seen in the community.176,177
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Diastolic dysfunction was formerly considered to be the sole pathophysiologic driver in HFpEF, but recent studies have shown far more complex abnormalities in LV systolic function, right heart function, the vasculature, endothelium, and periphery (including skeletal muscle) in HFpEF (Fig. 70–12).178
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Left Ventricular Dysfunction
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Elevated diastolic filling pressures at rest or with exercise are uniformly present in HFpEF (Fig. 70–13).146,179 It is important not to equate diastolic dysfunction with HFpEF, as the former is quite prevalent in the general population and is essentially part of normal aging.164,180 While echocardiographic indices have been established to estimate filling pressures as well as intrinsic chamber stiffness and compliance of the ventricle, these measures have greater variability than invasive assessments.181,182,183 Indeed, echocardiography does not reveal substantial diastolic dysfunction at rest in up to a third of HFpEF patients.184,185,186 On the other hand, invasive studies have generally shown diastolic abnormalities to be universal in patients with HFpEF, although in patients with earlier stages of disease, provocative maneuvers such as exercise or saline loading are required to elicit the pathologic changes.146,179,187,188,189,190,191,192,193
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The normal enhancement of LV relaxation with increasing heart rates is lost in HFpEF, and this along with abnormalities in chamber compliance may lead to exercise-induced pulmonary venous hypertension and exercise intolerance.179,194,195 Patients with progressively greater elevation in filling pressures have more advanced HFpEF as evidenced by greater multisystem reserve limitation and increased risk of death.196,197
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Although the ejection fraction is normal or near-normal in HFpEF, LV systolic function is impaired, as shown using tissue Doppler imaging,198,199 myocardial strain imaging,200,201 and load-independent indices of chamber and myocardial contractility.149 Patients with more profound impairments in systolic function and deformation display increased risk of death.149,201 This may be related to abnormalities in calcium handling,202 β-adrenergic signaling,203,204 myocardial energetics,205,206 or tissue perfusion reserve.171,172
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While systolic function at rest is only modestly impaired, a number of studies have also identified dramatic limitations in systolic reserve with stress that importantly contribute to decline in peak cardiac output and exercise intolerance in HFpEF (Fig. 70–12).188,189,196,199,205,207,208,209 Systolic reserve limitations beget diastolic limitations, because inability to contract to a smaller LV end-systolic volume in HFpEF limits the amount of elastic recoil favoring diastolic suction of blood from left atrium to ventricle during the following diastole.189,204,207,209
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Pulmonary Hypertension and Right Ventricular Dysfunction
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Pulmonary hypertension (PH) has been reported to be present in over three-fourths of patients with HFpEF in some studies, initially developing as a form of “passive” PH related to elevated pulmonary capillary wedge pressure (PCWP).150,210 Chronic elevations in PCWP induce pulmonary arteriolar and venous remodeling, resulting in increased pulmonary vascular resistance.150,211 The presence and severity of PH in HFpEF are independently associated with increased mortality and represent a potential target for treatment.210,212
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Depending on how it is defined, right ventricular dysfunction is present in roughly one-third of patients with HFpEF.213,214 Patients with right ventricular dysfunction typically display more advanced heart failure, renal dysfunction, atrial fibrillation, tricuspid regurgitation, and LV dysfunction. The presence of right ventricular dilatation and dysfunction in HFpEF predicts increased risk of death, independent of the severity of PH and other covariates.213,214,215
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Chronotropic Incompetence
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Heart rate is the major determinant of cardiac output augmentation with exercise as opposed to stroke volume, with an increase of 200% to 400% at peak exercise.216,217 Most studies in HFpEF have demonstrated chronotropic incompetence in the majority of studied patients.188,189,207,208,218,219,220 This appears to be mediated more by reduced adrenergic sensitivity than decreased sympathetic outflow, since catecholamine levels increase similarly in patients with HFpEF and controls despite marked differences in chronotropic reserve.208 There is additional evidence for autonomic dysregulation in HFpEF. Three studies have shown that the normal decrease in heart rate following exercise is blunted, and one study has observed that arterial baroreflex sensitivity is depressed in HFpEF.207,208,220 Reduction in heart rate was recently shown to decrease exercise capacity in patients with HFpEF in a small trial.221
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Peripheral Abnormalities
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According to the Fick principle, decreased peak oxygen (O2) consumption (VO2) can be related to limitations in cardiac output reserve, limitations in arterial-venous O2 content difference, or both.178 The latter is related to how effectively O2 is distributed, extracted, and used in the skeletal muscles during exercise.222 Abnormalities in cardiac output reserve are clearly present in HFpEF.188,189,191,207,208,223,224 Recent research has also identified abnormalities in peripheral O2 extraction and utilization in a significant subset of patients with HFpEF.192,225,226 The mechanism of inadequate peripheral utilization of O2 may be related to impaired muscle O2 extraction, impaired autonomic regulation of blood flow, or problems with macro- or microvascular perfusion to the muscular bed. Recent studies examining histopathologic changes in both skeletal and cardiac muscle have revealed that vascular rarefaction may be present in HFpEF patients, potentially contributing to impaired nutritive blood flow in the heart and periphery.172,227,228,229 Exercise training, which improves aerobic capacity and quality of life in HFpEF,230,231 appears to work mainly through beneficial effects in the periphery in people with HFpEF,232 although one study did observe evidence of direct cardiac effects.233
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Endothelial Dysfunction
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Impaired flow-mediated vasodilation, a marker of abnormal endothelial function, has been observed in HFpEF, and the degree of dysfunction has been correlated with severity of symptoms, exercise impairment, pulmonary vascular disease, and risk of heart failure hospitalization.207,234,235,236 However, not all studies in HFpEF have observed abnormal endothelial function, at least when examined in larger conduit vessels.237,238,239 Nonetheless, there is substantial evidence that endothelial dysfunction plays a central role in the pathophysiology in a number of patients,240 and numerous clinical trials have been or are being performed targeting this pathway, as discussed later.223,241,242,243,244,245,246
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A patient with a low ejection fraction who is short of breath can be confidently diagnosed with an echocardiogram. In contrast, patients with a normal ejection fraction who are short of breath may have HFpEF, a non-HFpEF cardiac cause of symptoms (eg, valvular heart disease), or a noncardiac etiology. These patients often require a much more thoughtful evaluation to demonstrate objective evidence of elevated filling pressures and/or inadequate cardiac output. This is further complicated by the presence of early HFpEF where there may not be clinically detectable signs of congestion at rest, but there is marked elevation of filling pressures with exercise.146
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The clinical diagnosis of HFpEF can be confidently performed at the bedside purely by physical examination and history, provided that the patient has demonstrable evidence of elevated filling pressures at rest and is in decompensated heart failure. Once a clinical diagnosis of heart failure is made in a patient with normal ejection fraction (≥ 50%), it is important to exclude alternative etiologies, such as pericardial or valvular disease, that would be treated differently.247
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Elevated natriuretic peptide levels are strongly supportive of the diagnosis of HFpEF with a normal ejection fraction and have prognostic value.134 However, it is important to remember that BNP levels are lower in obesity and that elevated BNP levels can occur with atrial fibrillation (even in the absence of heart failure), renal failure, or right ventricular strain from primary pulmonary arterial hypertension or pulmonary emboli. Importantly, a normal BNP (or NT-proBNP) level does not exclude the diagnosis of HFpEF.146,147
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Echocardiography is essential in the evaluation of patients suspected of having HFpEF. Beyond measurement of ejection fraction, echocardiography provides assessment of LV diastolic function,215,248 LV filling pressures (high E/e′ ratio),249 systolic function and LV strain,200,201 left atrial remodeling,250,251 structural remodeling such as concentric LV hypertrophy, inferior vena caval dilatation (an assessment of right atrial pressure),251,252 elevation in right ventricular systolic pressures (to estimate pulmonary artery pressure), and qualitative or quantitative impairments in right ventricular function.210,213,214 In the proper clinical setting, identification of one or more of these echocardiographic abnormalities is highly supportive of the diagnosis of HFpEF (Table 70–12).
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The gold standard diagnostic test remains direct measurement of intracardiac pressures by right and left heart catheterization.253,254 Determination of filling pressures at rest may be inadequate if patients are euvolemic or if symptoms occur only with exercise.146,188 In these situations, right heart catheterization with exercise stress should be considered. The presence of an elevated mean PCWP (≥ 15 mm Hg at rest or ≥ 25 mm Hg with exercise) is diagnostic of HFpEF.130,146,188,191,192
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There is no proven effective treatment that improves mortality in HFpEF (Fig. 70–14). Current practice guidelines recommend control of volume overload with diuretics and management of comorbidities.134 Although treatment of arterial hypertension clearly reduces the risk of incident HF,255,256 prior trials testing antihypertensive agents in HFpEF have not been associated with improved outcomes,257,258,259 and at this point, there is no clear answer as to which agents to use to treat hypertension or how aggressively to treat blood pressure in HFpEF. Recent studies have emphasized the importance of lifestyle interventions such as exercise and weight loss, which improve exercise capacity and quality of life.231,260,261
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Diuretics decrease filling pressures to effectively treat acute decompensated heart failure, regardless of etiology, and are recommended to control fluid overload.6,134 The CHAMPION trial has provided strong evidence supporting the treatment of elevated filling pressures in order to prevent fluid accumulation and decompensation of heart failure, including HFpEF.262,263 In this trial, patients with recent heart failure hospitalization and NYHA class III symptoms underwent implantation of a pulmonary artery pressure monitor and were randomized to care based on investigator knowledge of invasive pressures versus standard care. The trial showed a significant reduction in heart failure hospitalizations overall and in ancillary analysis restricted to patients with HFpEF. The number needed to treat to prevent one HFpEF hospitalization over 18 months was 2. Although this was not a trial of diuretics per se, the vast majority of medication changes based on invasive pressure data were changes in diuretic dosing, and these data certainly reinforce the importance of control of congestion with diuretics in people with HFpEF. These data also reveal a new role for implantable hemodynamic monitors to help manage patients with advanced (NYHA class III) HFpEF with recent heart failure hospitalization.262,263
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Renin-Angiotensin-Aldosterone System Inhibition
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Three large, placebo-controlled, randomized trials testing ACE inhibitors and ARBs in HFpEF have been conducted to date.257,258,259 There was a nonsignificant reduction in the composite outcome of cardiovascular death or heart failure hospitalizations with candesartan in the CHARM-Preserved study.257 This trial defined HFpEF using an ejection fraction partition value of 40% and included more men and patients with coronary disease than are generally seen in HFpEF, suggesting that many of the participants had a phenotype resembling HFrEF. The larger Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial comparing irbesartan to placebo in a more typical HFpEF patient population was unequivocally neutral, overall and across all of the prespecified secondary analyses presented.259 The Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) trial randomized older patients (age ≥ 70 years) to perindopril or placebo and found that perindopril was associated with a trend toward decreased all-cause mortality and hospitalization for heart failure at 1 year, but over the entire 3-year study period, there was no reduction in the primary end point.258 Thus, the available data do not support the use of ACE inhibitors/ARBs as a disease-modifying therapy in HFpEF, although they are clearly safe and still may be effective as antihypertensives in this population.
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The mineralocorticoid receptor antagonist spironolactone was recently tested in a randomized controlled trial in HFpEF (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]), and there was no significant reduction in the composite primary end point of cardiovascular death, heart failure hospitalization, or aborted cardiac death as compared to placebo.264 There was signal of benefit in higher risk populations, including patients enrolled on the basis of elevated natriuretic peptide levels. A post hoc subgroup analysis identified heterogeneity in response comparing subjects enrolled in the Americas as opposed to Russia and the Republic of Georgia, wherein spironolactone improved the composite end point of the trial in subjects enrolled in the Americas but not in Eastern Europe.265 Notably, the event rate in the latter group was much lower as compared to participants in the Americas, raising concern over whether all of these patients truly had heart failure. In another ancillary study from TOPCAT, it was found that ejection fraction modified the treatment response to spironolactone.140 Patients with lower ejection fraction (but still meeting the entry criteria) were observed to benefit from spironolactone as compared to placebo, whereas patients with higher ejection fraction (especially > 55%) did not.
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A smaller trial observed that spironolactone improved estimated LV filling pressures (E/e′ ratio) in people with early-stage HFpEF, but the co-primary end point of exercise capacity and secondary end points including quality of life were not improved.266 Given the signal of benefit in TOPCAT and the fact that filling pressures may improve, mineralocorticoid antagonists are reasonable choices in patients with HFpEF where azotemia and hyperkalemia are not problematic, particularly if there is additional role for more diuresis.
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β-Blockers are commonly prescribed for patients with diastolic dysfunction based on the notion that slowing the sinus rate will prolong diastole and promote ventricular filling.267 Despite this theoretical benefit, there is little to no evidence that β-blockers improve exercise capacity or clinical outcomes, although data are quite limited in this regard.268,269,270,271,272 A recent meta-analysis suggested a possible decrease in all-cause mortality associated with β-blockade in HFpEF,273 and analysis of data from the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial showed no interaction between ejection fraction and the benefits of the β-blocker nebivolol, although the number of patients with “true HFpEF” (ie, ejection fraction ≥ 50%) in this trial was great.269 One concern with β-blockers is the common presence of chronotropic incompetence in people with HFpEF, which will predictably worsen with initiation of a β-blocker.208,268 A large multicenter trial testing β-blockers in HFpEF is urgently needed to better inform treatment decisions.
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The DIG trial included a cohort of 988 patients with heart failure and relatively preserved ejection fraction (> 45%) in sinus rhythm.274 There was a trend to decreased heart failure hospitalizations, but this was negated by an increased number of admissions for unstable angina. There was no effect on mortality. Digoxin is often used for rate control in atrial fibrillation when low blood pressure limits rate-controlling medication, given its minimal hypotensive effects. Retrospective data suggest an increased mortality with digoxin use for atrial fibrillation in heart failure, but prospective trials are lacking.275,276
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Direct nitric oxide (NO) donors such as the organic nitrates increase cellular levels of cyclic guanosine monophosphate (cGMP), a key second messenger that activates kinases that may improve diastolic relaxation and compliance. Nitrates also decrease preload, allowing the ventricle to function at lower volumes, where operating stiffness may be lower as a result of the curvilinear end-diastolic pressure–volume relationship in HFpEF.130 However, patients with HFpEF may display excessive reduction in blood pressure and stroke volume with nitrates.135
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In a placebo-controlled crossover trial, isosorbide mononitrate was recently tested in 110 subjects with HFpEF.245 The primary end point of the trial was chronic activity levels, assessed using hip-worn accelerometry devices, and key secondary end points included exercise capacity (6-minute walk distance), natriuretic peptide levels, and quality of life scores. Compared to placebo, isosorbide mononitrate tended to reduce activity levels, an effect that became more dramatic at higher doses. There was no improvement in exercise capacity and a numerical trend to worsening quality of life and natriuretic peptide levels.245 These data do not support the use of organic nitrates for HFpEF, but they should not be interpreted to indicate that other NO-enhancing therapies will not be effective. Isosorbide mononitrate has been shown to worsen endothelial function in humans,277 which is known to be problematic in HFpEF.207 In addition, the exaggerated blood pressure–lowering effects might have contributed to decreased activity levels.135 More targeted interventions that deliver NO at the time of greatest need, such as inorganic nitrite, might be more effective and are being evaluated in this population.223
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Phosphodiesterase-5 Inhibitors
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An alternative method to restore NO signaling is to decrease the degradation of its downstream second messenger (cGMP) using phosphodiesterase-5 inhibitors. In animal models of pressure-overload hypertrophy, sildenafil improves ventricular structure and function dramatically,278 and a small pilot trial reported improvements in PH and right heart function with sildenafil.279 However, in the Phosphdiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial, sildenafil did not improve exercise capacity, neurohormones, ventricular function, or quality of life.242 There may also be untoward effects of sildenafil on ventricular contractility that offset any potential benefits on endothelial and vascular function.280 A more recent trial testing sildenafil in patients with HFpEF and invasively proven PH again showed no improvement in hemodynamics or clinical parameters.281
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In a prospective observational study of HFpEF, statin therapy was associated with significantly lower mortality (relative risk of death 0.20) over a median follow-up of 12 months, whereas ACE inhibitor, ARB, β-blocker, and calcium channel blocker therapy had no association with survival.282 However, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Heart Failure [GISSI-HF] trial, which tested the effects of rosuvastatin on death and death or cardiovascular hospitalization in patients with chronic heart failure, found no benefit in the subgroup of patients included with relatively preserved ejection fraction (> 40%).283 More recent data from a Swedish registry and meta-analysis of prior trials have suggested that statins may be beneficial in HFpEF.284,285 As with β-blockers, a large-scale, multicenter, placebo-controlled trial is urgently needed to clarify the role of statins in patients with HFpEF.
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Nonpharmacologic Interventions
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Relatively small-sized trials have consistently shown that exercise training in HFpEF improves exercise capacity as well as quality of life.230,231,232,233,237,260,261 It appears that these benefits are mediated by the periphery and are largely independent of the heart,232 although one study did observe improvements in diastolic function.233 Further study is needed to clarify the best modes and duration of training as well as better methods to optimize adherence and chronically sustain increases in activity levels.261
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Dietary interventions may also prove effective. In a small, single-center trial, 3 weeks of treatment with a salt-restricted Dietary Approaches to Stop Hypertension (DASH) diet improved diastolic function, arterial stiffness, and ventricular arterial coupling in 13 subjects with HFpEF.286 Kitzman et al231 performed a randomized trial comparing exercise training, caloric restriction, or both to attention control. Both exercise training and caloric restriction improved exercise capacity, and the combination of both interventions was additive, supporting the concept that increases in activity levels and diet may be effective to at least improve morbidity in HFpEF.
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Management of Comorbidities
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Coronary artery disease is common in patients with HFpEF, seen in roughly 50% to 67% of patients defined angiographically or anatomically from postmortem exams.171,172 Hwang et al171 have recently shown that the presence of coronary disease is independently associated with increased mortality in HFpEF. Patients undergoing complete revascularization had better maintenance of ventricular function over time and improved survival as compared to patients not receiving complete revascularization (Fig. 70–15).171 Intriguingly, stress testing identified the presence or absence of coronary disease poorly, with very high rates of false-positive and false-negative tests. At present, there are no prospective trial data to guide decisions regarding revascularization for patients with coronary disease and HFpEF, although consensus guidelines recommend revascularization if symptoms of heart failure are deemed to be related to coronary ischemia.134
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Atrial fibrillation is common in HFpEF, seen in two-thirds of patients at some point during their lifespan.287 Patients with HFpEF and atrial fibrillation are more likely to display right heart dilatation and dysfunction, tricuspid regurgitation, and exercise limitation, and they have a higher risk of death in long-term follow-up, independent of other confounders.213,214,250,287,288 There is no clear-cut advantage for rhythm control as opposed to rate control in HFrEF,289 but this has never been tested in patients with HFpEF. Recent studies have shown that aggressive efforts to restore and maintain sinus rhythm in patients with HFpEF and atrial fibrillation can be successful and may be associated with improvements in ventricular function if sinus rhythm can be maintained.290 Further study is required to understand the management of atrial fibrillation in patients with HFpEF.
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Given the high prevalence of obesity in HFpEF, diabetes, metabolic syndrome, and sleep apnea are also commonly observed in patients. There are no data evaluating the effects of treating these comorbidities in this population, and treatment is recommended according to their respective guidelines.
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Numerous promising therapies are currently being studied in clinical trials for HFpEF. Sacubitril (a combined valsartan/neprilysin inhibitor) showed convincing superiority compared to enalapril in HFrEF,291 and in the phase II Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) trial, this treatment showed greater improvements in NT-proBNP as compared to ARB alone.241 A larger pivotal trial (PARAGON [Efficacy and Safety of LCZ696 Compared with Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction]) is currently under way (NCT01920711) with intended enrollment of 4300 patients with an ejection fraction > 45%.
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A recent double-blind, randomized trial demonstrated that acute administration of inorganic sodium nitrite markedly improved hemodynamic abnormalities developing during exercise, with substantial reduction in exercise LV filling pressures and improved cardiac output reserve.223 Another acute crossover study testing inorganic nitrate (precursor to nitrite) delivered as beetroot juice also observed improvements in peak exercise capacity.246 Larger scale studies testing this novel therapy are currently under way. The If current blocker ivabradine, which slows the heart rate in patients in sinus rhythm, has variably been shown to improve or worsen exercise capacity in patients with HFpEF.221,292 A larger scale clinical trial is currently under way to help inform understanding regarding this novel approach. As described earlier, phase III studies testing β-blockers and statins remain a critical unmet need in our understanding regarding the treatment of HFpEF.