Heart Failure With a Normal Left Ventricular Ejection Fraction: Epidemiology Pathophysiology, Diagnosis and Management

REVIEW ARTICLE

Heart Failure With a Normal Left Ventricular Ejection Fraction: Epidemiology, Pathophysiology, Diagnosis and Management Nadish Garg, MD, Annamalai Senthilkumar, MD, Maen B. Nusair, MD, Neha Goyal, MD, Rajeev K. Garg, MD and Martin A. Alpert, MD

Abstract: Heart failure (HF) with a normal left ventricular (LV) ejection fraction (HFNEF) occurs in 40-71% of patients with HF and carries a prognosis similar to that of HF with a reduced LV ejection fraction (LVEF). The pathophysiology of HFNEF is distinct from that of HF with a reduced LVEF and is characterized by impaired relaxation of myocardium, LV stiffness and, in many cases, increased arterial stiffness. Systemic hypertension accounts for most cases of HFNEF in the United States. Those with HFNEF tend to be older and obese. Diabetes mellitus and atrial fibrillation occur with disproportionately high frequency in HFNEF. The diagnosis of HFNEF requires the presence of symptoms or signs of HF, a normal or near-normal LVEF and evidence of LV diastolic dysfunction based on cardiac catheterization or Doppler echocardiographic techniques and/or elevation of plasma natriuretic peptide levels. Current guidelines for management of HFNEF include control of systolic and diastolic hypertension, control of the ventricular rate in patients with atrial fibrillation and judicious use of diuretics. In selected cases, coronary revascularization or restoration of sinus rhythm in those with atrial fibrillation may be indicated. To date, no drug or drug group has consistently improved survival in HFNEF. For this reason and because of the poor long-term prognosis, preventative measures and effective treatment of underlying causes and precipitating factors are particularly important in avoiding HF exacerbations in patients with HFNEF. Key Indexing Terms: Heart failure; Normal left ventricular ejection fraction; Pathophysiology; Diagnosis; Management. [Am J Med Sci 2013;346(2):129–136.]

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here are an estimated 5.8 million persons with heart failure (HF) in the United States and 23 million people with this condition worldwide.1,2 Reportedly, 40% to 71% of those with HF in the United States have a normal or near-normal left ventricular (LV) ejection fraction (LVEF). HF with a normal LVEF (HFNEF) is a growing health problem that is underrecognized and undertreated in clinical practice.1–17 The early symptoms of HFNEF may be nonspecific, resulting in delays in diagnosis and treatment.18–24 The causes and pathophysiology of HFNEF are distinct from those of HF with a reduced LVEF (HFREF).1–24 This review discusses the epidemiology, etiology, pathophysiology, clinical manifestations, diagnosis, management and prognosis of HFNEF.

DEFINITION OF HEART FAILURE Heart failure has been defined as a complex clinical syndrome that can result from any structural or functional From the Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, Missouri. Submitted June 19, 2012; accepted in revised form September 13, 2012. The authors have no financial or other conflicts of interest to disclose. Correspondence: Martin A. Alpert, MD, Room CE-338, University of Missouri Health Sciences Center, Five Hospital Drive, Columbia, MO 65212 (E-mail: [email protected]).

The American Journal of the Medical Sciences



cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.1,2 The term HFNEF refers to patients with HF whose LVEF is normal or near normal.1,2 The term “HF with a preserved LVEF” is preferred by some because of variability in the definition of normal LVEF among studies assessing this syndrome. Both terms are synonymous and have replaced the designation “diastolic heart failure.”

EPIDEMIOLOGY Data from population-based epidemiological studies indicate that the incidence of HFNEF in the United States approaches and perhaps exceeds that of HFREF.3–18 In a study of 6076 patients hospitalized with HF in Olmstead County, Minnesota,4–6,10,11 the prevalence of HFNEF averaged 43% and increased from 38% to 54% of all HF patients during a 15-year follow-up period.4–6,10,11 From an epidemiological point of view, HFNEF is highly prevalent in older and obese persons and in females.1–18 It is associated with a high incidence of systemic hypertension (70%–88%), diabetes mellitus (17%–46%), atrial fibrillation (30%–37%), coronary artery disease (37%–42%) and pulmonary hypertension (83%).3,5,10–13,18–22 In the Olmstead County study, the proportion of patients with systemic hypertension increased from 48% to 63% during the 15-year follow-up period. Similar trends were noted for diabetes mellitus (from 32% to 36%) and atrial fibrillation (from 29% to 41%).4–6,10,11 Overall, the reported prevalence of HFNEF among those with HF ranges from 40% to 71% (mean, 56%).3–17 The reported prevalence of HFNEF in African Americans with HF is variable.326,8217 In hospitalized patients with HF, the prevalence of HFNEF ranges from 29% to 55% (mean, 41%).13,20–24 Studies assessing the prevalence of HFNEF are hampered by variable definitions of normal LVEF.1–25 In most recent studies, a cut point of 50% has been used to differentiate normal from reduced LVEF.

ETIOLOGY The major underlying causes of heart failure with HFNEF are shown in Table 1.1,2,8,13,19 The complete list of causes of HFNEF is both lengthy and diverse. However, systemic hypertension accounts for most cases of HFNEF in the United States.13224 The remainder of this review will focus on causes of HFNEF that produce alterations in LV diastolic function.

PATHOPHYSIOLOGY The pathophysiology of HFNEF is distinct from that of HFREF and is characterized by impaired relaxation of myocardium (diastolic dysfunction), LV stiffness and arterial stiffness.25–33 Patients with HFNEF often have concentric LV hypertrophy (a form of LV hypertrophy characterized by relative wall thickness or mass to volume ratio .0.45) or concentric LV remodeling. In most of these patients, LV diastolic chamber size is normal.26,34 Stroke volume is typically increased.18 LV end-diastolic stiffness is increased, which

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TABLE 1. Major underlying causes of heart failure with a normal left ventricular ejection fraction Hypertensive heart disease Coronary artery disease Cardiomyopathies: hypertrophic, restrictive/infiltrative Pericardial disorders: constrictive pericarditis, pericardial effusion Valvular heart disease (stenosis, regurgitation) Endocardial disorders Various forms of congenital heart disease High cardiac output states Pulmonary heart disease Miscellaneous: diabetes mellitus, chronic kidney disease

contributes to increased LV diastolic end-diastolic pressure, smaller filling volumes and impaired diastolic filling (based on transmitral Doppler flow indices and abnormal tissue Doppler mitral annular inflow velocities).34 Left atrial enlargement and dysfunction are commonly present.24,35 Pressure-volume loops in HFNEF are characterized by increased LV end-diastolic pressure and normal LV end-diastolic volume.26,34 In contrast, pressure-volume loops in HFREF are typically characterized by both increased LV end-diastolic pressure and increased LV end-diastolic volume.26 The mechanism of LV diastolic dysfunction in HFNEF is not clearly understood but is thought to be related to abnormalities intrinsic and extrinsic to the myocardium.25–37 Intrinsic (myocardial) abnormalities have been attributed to an increased cytosolic diastolic calcium concentration and a delayed decline in cytosolic calcium concentration during diastole.28,30,31,33 The giant protein titin is thought to play a role in the development of LV diastolic dysfunction.36 Collagen, a major extracellular protein, undergoes significant architectural alterations in conditions that predispose to LV diastolic dysfunction.37 In addition to LV diastolic dysfunction, HFNEF is characterized by increased LV and arterial stiffness.32 This causes the LV to become increasingly sensitive to alterations in volume, both at rest and during exercise.38,39 LV stiffness and diastolic dysfunction worsen during hand-grip exercise.26 Thus, patients with HFNEF develop exercise intolerance and blood pressure lability with relatively modest increases in LV volume.33,34 This is particularly common in the elderly. The pathophysiology of HFNEF in the elderly is even more complex because of comorbidities that may affect LV volume, such as anemia and renal dysfunction. Patients with HFNEF have an altered physiological response to exercise compared with normal individuals.38 Compared with healthy controls, patients with HFNEF have lower exercise capacity, increased peak oxygen consumption, a higher heart rate response during exercise and less vasodilation.38 They develop a marked increase in LV end-diastolic pressure with small increments in LV end-diastolic volume.39 In one study, increasing the heart rate to 120 beats per minute by right ventricular pacing, in patients with HFNEF, lowered cardiac output and stroke volume and increased LV end-diastolic pressure, suggesting the presence of increased LV stiffness.26 In contrast to hypertensive LV hypertrophy without HF, patients with HFNEF had a substantial rise in LV end-diastolic pressure during hand-grip exercise.26

CLINICAL PRESENTATION Many of the clinical manifestations of chronic HFNEF are similar to those of chronic HFREF.19,38,40 Early symptoms

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include lassitude, fatigue, exercise intolerance and nocturia. Dypnea on exertion, orthopnea and paroxysmal nocturnal dyspnea and a nonproductive nocturnal cough may occur during the early to intermediate stages. Progression to dypnea at rest and edema are late stage symptoms. Because of poor LV compliance HFNEF often presents as acute pulmonary edema. Gallop rhythm (usually a fourth heart sound), jugular venous distension, hepatojugular reflux, pulmonary crackles and lower extremity edema commonly occur. Hepatomegaly and ascites occur commonly with some causes of HFNEF. As noted previously, patients with HFNEF tend to be older, are often obese (86%) and have high prevalence of diabetes mellitus (17%– 46%), coronary artery disease (37%–42%), systemic hypertension (70%–88%), atrial fibrillation (30%–37%) and pulmonary hypertension (83%).3,5,10–13,18–22 Due to poor LV compliance in most cases, an abrupt increase in blood pressure or new onset atrial fibrillation may precipitate acute pulmonary edema.38,39,41 As previously noted, systemic hypertension is the most common underlying cause of HFNEF and shares several pathological and demographic characteristics with hypertensive LV hypertrophy without HF.3217,42 Both may produce concentric LV hypertrophy and left atrial remodeling. Both have similar age, gender and ethnicity distribution. However, in contrast to those with hypertensive LV hypertrophy, patients with HFNEF have more severe LV hypertrophy, larger left atrial volume, more severely impaired tissue Doppler indices of LV diastolic dysfunction and greater elevation of pulmonary artery systolic pressure.24,42 The product of LV mass index and left atrial volume seems to be the best discriminator between the 2 entities with sensitivity and specificity values for HFNEF of 83.8% and 82.5%, respectively.24 Atrial fibrillation occurs commonly in patients with HFNEF function and is associated with more severe LV diastolic dysfunction than in patients with HFNEF in sinus rhythm.41 Patients with HFNEF and atrial fibrillation have higher hospital readmission rates, lower 6-minute walk distances, lower quality of life, lower functional capacity and a worse prognosis than those in sinus rhythm.41 Left atrial enlargement and delayed left atrial emptying are thought to be important mechanisms for development of atrial fibrillation in patients with HFNEF.41 Poor ventricular rate control may contribute to pulmonary edema in such patients.41 Coronary artery disease is a common underlying cause of both HFREF and HFNEF.1–17,43,44 Acute episodes of myocardial ischemia contribute to LV diastolic dysfunction in both types of patients and may precipitate acute pulmonary edema.13,21,23,43,44 Myocardial revascularization may prevent such episodes and reduce the frequency of episodes of pulmonary edema in patients with HFNEF associated with coronary artery disease.43 HFNEF is associated with a high prevalence of pulmonary hypertension. In one community-based study, the prevalence of pulmonary hypertension among patients with HFNEF was 83%.22 Pulmonary hypertension was a strong predictor of adverse outcomes independent of age.22 Pulmonary hypertension in such patients involves both precapillary and postcapillary components, as is suggested by persistent elevation of pulmonary artery systolic pressure despite reduction of elevated pulmonary capillary wedge pressure.22 Pulmonary hypertension in patients with HFNEF is often severe.22 Although diabetes mellitus is commonly present in patients with HFNEF, the reasons for this association are uncertain.45,46 Diabetic cardiomyopathy, if it exists, seems to be characterized primarily by LV diastolic dysfunction. Indeed, impairment of LV diastolic dysfunction has been described early in diabetes mellitus in the absence of LV systolic Volume 346, Number 2, August 2013

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dysfunction. In the Candesartan Heart Failure Assessment of Mortality and Morbidity (CHARM) study, the prevalence of diabetes mellitus was 28% in those with an LVEF .40% and was associated with significantly higher mortality and rehospitalization rates compared to patients with a lower LVEF.46 Obstructive sleep apnea has been postulated to be a risk factor for HF.47,48 In a study of 27 patients with newly diagnosed obstructive sleep apnea, the prevalence of LV diastolic dysfunction diagnosed using Doppler echocardiographic flow indices was significantly greater than in controls without obstructive sleep apnea. Treatment with nocturnal continuous positive airway pressure reversed these alterations.48

DIAGNOSIS All of the proposed criteria for diagnosis of HFNEF require the presence of symptoms or signs of HF.49–53 However, symptoms or signs, while necessary, are not sufficient to diagnosis HFNEF. Additional information aimed at excluding patients with moderate to severe LV systolic dysfunction and confirming the presence of LV diastolic dysfunction are required to diagnose HFNEF.49–53 Diagnostic techniques include cardiac catheterization, 2-dimensional and Doppler echocardiography, tissue Doppler imaging and measurement of plasma natriuretic peptide levels.53–60 Cardiac catheterization has long been the diagnostic standard for LV diastolic dysfunction in patients with HFNEF. The most commonly used criteria are elevation of LV enddiastolic pressure (.16 mm Hg) or pulmonary capillary wedge pressure (.12 mm Hg).49–53 A variety of noninvasive techniques have been used to assess LV diastolic function in patients with HFNEF.26,49–56 Two-dimensional echocardiography and cardiac Doppler echocardiography have been used most commonly for this purpose.26,54–56 The presence of increased LV mass serves as a substrate for LV diastolic dysfunction. Left atrial enlargement, at times severe, is commonly encountered in patients with HFNEF and is an important predictor of mortality in such patients.56 Transmitral Doppler flow indices such as a ratio of early to late inflow velocities (E/A) ,1 or prolongation of the E wave deceleration time suggest impaired LV diastolic filling as does pseudonormalization (reversal of the E/A ratio with Valsalva’s maneuver) and a restrictive pattern (transmitral E wave velocity . twice transmitral A wave velocity). Abnormal pulmonary vein Doppler flow has also been used to diagnose LV diastolic function. Both transmitral and pulmonary vein indices of diastolic function are load dependent. Tissue Doppler imaging, which is capable of assessing myocardial velocity by imaging the mitral annulus and is thought to be load independent, has been used to assess LV diastolic function in patients with HFNEF. The ratio of the peak transmitral Doppler flow velocity in early diastole (E) to peak early diastolic mitral annular velocity on tissue Doppler imaging (E9) correlates well with LV filling pressure and seems to be a more sensitive indicator of diastolic function than transmitral Doppler flow indices alone. Plasma levels of natriuretic peptides including B-type natriuretic peptide (BNP) and N-terminal proBNP (NTproBNP) are elevated in patients with HFNEF but to a lesser extent than in patients with HFREF.57–60 Natriuretic peptide levels tend to be higher in patients with HFNEF who present with acute pulmonary edema or advanced HF than in those with mild to moderate chronic HF. Elevation of a plasma NTproBNP level in patients with HFNEF is a strong predictor of morbidity at 1 year.59 Conversely, plasma natriuretic peptide levels may be relatively low during the early stages of HFNEF Ó 2013 Lippincott Williams & Wilkins

and may be indistinguishable from those of healthy individuals.57–60 Negative predictive values for HF are 96% for BNP values ,100 pg/mL and 93% for NT-pro-BNP levels ,120 pg/ mL, underscoring the usefulness of these peptides in differentiating noncardiac dyspnea from HFNEF.60 It is important to remember that plasma natriuretic peptide levels may be elevated in patients with atrial fibrillation and in patients with renal dysfunction in the absence of clinical HF and that plasma natriuretic levels tend to be lower in obese than in lean individuals with HF of similar severity. Four sets of guidelines for diagnosis of HFNEF have been published since 1998.34,49–52 All of these sets of guidelines have required the presence of symptoms or signs of HF and a normal or near normal LVEF and LV end-diastolic volume.49–52 Earlier guidelines required a variety of noninvasive indices of diastolic dysfunction or either an LV end-diastolic pressure .16 mm Hg or a pulmonary capillary wedge pressure .12 mm Hg for diagnosis.30–52 We recommend using the most recent set of guidelines for diagnosis of HFNEF, which was published in 2007 by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.49 These guidelines are as follows: (1) the presence of symptoms or signs of HF, (2) LVEF .50% and LV end-diastolic volume ,97 mL/m2 and (3) evidence of LV diastolic dysfunction on tissue Doppler imaging (E/E9 .15 or E/E9 or 8–15 plus a plasma NT-proBNP level .220 pg/mL).49

MANAGEMENT Management of HFNEF begins with risk factor modification. Control of systemic hypertension, optimization of intravascular volume and heart rate control in patients with atrial fibrillation are examples of such modifications.1,2,61,62 Given the high prevalence of systemic hypertension, aggressive control of blood pressure is particularly important in preventing HF in such patients by preventing remodeling (LV hypertrophy) and subsequent diastolic dysfunction. Optimization of volume status may help to prevent the congestive features of HFNEF. Both may be difficult to achieve in patients with anemia, chronic kidney disease, obesity and in the elderly. Rate control in atrial fibrillation prolongs the diastolic filling period, providing more time for left atrial emptying, thereby, lowering left atrial pressure. Treatment of myocardial ischemia and control of diabetes mellitus may also prevent LV remodeling that predisposes to diastolic dysfunction and increased ventricular stiffness. Once HFNEF becomes clinically manifest, it is essential to identify underlying causes and precipitating factors, some of which overlap with the preventive measures discussed previously.1,2,61,62 Although the distribution of underlying heart disease in patients with HFNEF differs from that of HFREF, they are etiologically similar: Table 1 lists major underlying causes of HFNEF. The most common precipitating factors of HFNEF are physical activity, noncompliance with dietary salt restriction or medications, acute myocardial infarction or ischemia, abrupt and severe worsening of hypertension, tachyarrhythmias and bradyarrhythmias, selected drugs and toxins, infective endocarditis, other infections (particularly, pulmonary infections), pericardial effusion, pulmonary embolism and high cardiac output states (eg, anemia, hyperthyroidism, obesity and pregnancy). Identification and modification of these underlying causes and precipitating factors may help to prevent exacerbations of HFNEF. Nonpharmacological measures in all patients include restriction of dietary sodium (usually #2 g/d). Appropriate restriction of physical activity, which is then liberalized

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as HF improves, is also warranted. In certain circumstances, selected nonpharmacological measures may address specific causes of HFNEF (eg, valve replacement/repair, permanent pacemaker implantation and ablation therapy for selected tachyarrhythmias). However, most patients with HFNEF will require pharmacotherapy to improve symptoms. Although the effects of pharmacotherapy on neurohormonal activation, hemodynamics, LV remodeling, clinical manifestations, functional capacity, quality of life and survival have been studied extensively in patients with HFREF, such is not the case in patients with HFNEF. Pharmacological therapies that have been studied in patients with HFNEF include diuretics, non-dihydropyridine calcium channel blockers, beta-blockers, blockers of the reninangiotensin-aldosterone system, digitalis, phosphodiesterase inhibitors and HMG-CoA reductase inhibitors (statins).63–94 Diuretics are used commonly in the treatment of HFNEF; however, objective evidence of their efficacy and their effect on prognosis is limited. In the Hong Kong Diastolic Heart Failure Study, the use of diuretics alone or in combination with either ramipril or irbesartan was evaluated in patients with an LVEF .45%.63 Diuretic use alone was associated with improvement in quality of life, 2-dimensional Doppler echocardiographic signs of LV diastolic dysfunction, tissue Doppler indices of LV diastolic function and plasma NT-proBNP levels after 1 year of follow-up. In a study of patients with acute decompensated heart failure, intravenous diuretics and ultrafiltration produced similar significant improvements in dyspnea score.64 Approximately, 25% of patients in this study had HFNEF. Diuretic therapy seems to be particularly useful in patients with acute pulmonary edema and preserved LV systolic function. Because many patients with HFNEF have increased LV stiffness and poor LV compliance, they are extremely sensitive to changes in intravascular and intracardiac volume. Thus, diuretic therapy in patients with HFNEF requires close monitoring to avoid hemodynamic compromise and impairment of renal perfusion and function. Non-dihydropyridine calcium channel blockers (verapamil and diltiazem) would seem to be particularly well suited for treatment of HFNEF.65–67 Apart from their antihypertensive and antiischemic effects, they possess negative chronotropic and direct lusitropic properties.65 Setaro et al66 reported improvement in exercise capacity and peak LV filling rate after five weeks of treatment with verapamil in patients with HF, an LVEF.45% and echocardiographic evidence of LV diastolic dysfunction. Bonow et al67 reported an increase in LV peak filling rate in 78% and an improvement in symptoms during graded exercise in 63% of 55 patients with hypertrophic cardiomyopathy treated with verapmil for 4 weeks. These benefits peristed for 2 years and abated after withdrawal of verapmil therapy. Additional studies involving larger numbers of patients with HFNEF are required to clarify the role of calcium channel blockers in this population. Beta-blockers, like non-dihydropyridine calcium channel blockers have a negative chronotropic effect. They reduce myocardial ischemia and blood pressure. Beta-blockers have been shown to improve LV diastolic filling and reduce LV enddiastolic pressure in patients with hypertrophic cardiomyopathy.68,69 Studies assessing mortality in patients with a normal or near-normal LVEF have produced conflicting results.70–77 One study reported a 43% relative risk reduction is mortality at 25 months with beta-blocker therapy.70 In another study, nebivolol significantly reduced mortality in elderly patients whose LVEF was .35%.73,74 Other studies have reported decreases in mortality of 6% (carvedilol) and 30% (propranolol).75,76 In contrast, the Organized Program to Initiate Life-Saving Treatment in

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Hospitalized Patients with Heart Failure trial showed no survival benefit with beta-blocking use in patients with HFNEF.77 Studies assessing noninvasive indices of diastolic filling have also produced conflicting results in patients with normal or near-normal LVEF.71,78 One study demonstrated greater reduction in pulmonary capillary wedge pressure, LV mass and greater improvement in myocardial oxygen consumption and transmitral E/A ratio with nebivolol compared with atenolol.72 The results of these studies do not demonstrate a consistent survival benefit associated with the use of beta-blocker or alpha/beta-blockers in patients with HFNEF. The variability in outcomes may reflect differences in comorbidities among studies that might be influenced positively by beta-adrenergic blockade. In patients with HFREF, activation of the renin-angiotensinaldosterone system contributes to clinical manifestations by sodium and water retention and remodeling that in turn predisposes to progressive worsening of LV systolic function, worsening HF and eventually death. The role of the renin-angiotensin-aldosterone system in HFNEF is less well understood. Multiple studies have assessed the effects of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on mortality in patients with normal or near-normal LVEF.79–86 Retrospective analysis of the second Vasodilator Heart Failure trial showed a decrease in mortality of 40% with enalapril compared with isosorbide dinitrate/ hydralazine in patients with LVEF .35%.80 Two smaller studies also reported survival benefits in such patients using a variety of angiotensin converting enzyme inhibitors.81,82 In contrast, a study of elderly patients with HF and an LVEF .40% treated with perindopril showed no survival benefit at 1 year but did demonstrate reduction of HF hospitalization and improved HF symptoms in those treated with this drug.79 Two large studies assessing the effect of angiotensin receptor blockade on mortality failed to show survival benefit.83–85 The CHARMPreserved trial showed no reduction in mortality at 3 years with candesartan compared with placebo but did report a reduction in hospitalization in those receiving candesartan.83,84 The Irbesartan in Heart Failure with Preserved Systolic Function (I-PERSERVE) trial showed no benefit of irbesartan over placebo on either mortality or HF hospitalization rate in patients with an LVEF followed for more than 4 years.85,86 The Hong Kong Diastolic Heart Failure trial showed an improvement in tissue Doppler indices of diastolic function and lower plasma natriuretic peptide levels with the use of ramapril or irbesartan in patients with HFNEF but no survival benefit or reduction in HF hospitalization rates with the addition of thse drugs.63 In a study of 30 patients with HFNEF (LVEF.50%) and evidence of LV diastolic dysfunction, spironolactone therapy was associated with improvement in exertional dypnea and echocardiographic indices of LV diastolic function compared with placebo after 6 months of therapy.87 A prospective double-blind randomized placebo-controlled trial entitled Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist is underway to assess the effect spironolactone on cardiovascular death, cardiac arrest and hospitalization for HF in patients with HF and an LVEF.45%.88 Similarly, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial, which assesses the role of spironolactone in older patients with HFNEF is also currently in progress.89 To date, however, there is little evidence that blockade of the renin-angiotensin-aldosterone system improves survival in patients with HFNEF. In the Digoxin Investigators Group trial, digoxin failed to improve mortality compared with placebo both in patients with reduced and in those with normal or near-normal LV systolic function and HF.90,91 Volume 346, Number 2, August 2013

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Guazzi et al92 studied 44 patients with HF, an LVEF .50% and pulmonary hypertension (pulmonary artery systolic pressure .40 mm Hg). The phosphodiesterase inhibitor sildenafil, but not placebo, significantly reduced mean pulmonary artery pressure improved right ventricular function, decreased right atrial pressure and reduced breathlessness and fatigue. Fukuta et al93 reported a significant relative risk reduction in mortality of 0.20 in patients with HF, an LVEF .50% treated with statins and followed for 21 months. Whether the mortality improvement was specifically related to HF is uncertain.93,94 There are multiple limitations in the aforementioned studies that may have contributed to the wide disparity in outcomes. These include variability in the definition of HFNEF, variability in the incidence of coronary artery disease/myocardial infarction among studies, variability in LV geometry, lack of assessment of LV diastolic function in some studies and small patient populations in many of the studies.

PROGNOSIS Prognosis of patients with HFNEF has been assessed in 3 ways: (1) in community-based population studies without reference to specific therapies, (2) in hospitalized patients without reference to specific therapies and (3) in studies assessing the effects of specific pharmacological therapies. In the community-based Framingham Heart Study, the prognosis was significantly better in patients with HFNEF than in patients with HFREF.12 Similar results were noted in the Cardiovascular Health Study, which assessed mortality rates in 269 patients older than 65 years with HF. In those with HFNEF, the mortality rate was 87 deaths per 1000 personyears, whereas in patients with HFREF, the mortality rate was 154 deaths per 1000 person-years.95 Adjusted hazard ratios were 1.48 and 1.88, respectively, for HFNEF and HFREF when compared with persons with no HF and a normal LVEF.95 Other community population-based studies have reported similar short-term (30–90 days) and long-term (1–5 year) mortality rate in patients with HFNEF and those with HFREF.3–6,10,11,96–99 In the Mayo Clinic study of 6076 hospitalized patients, followed from 1987 to 2001, 1-year mortality was 29% in those with HFNEF and 32% in patients with HFREF (hazard ratio: 0.96, CI: 0.92–1.00).3–6,10,11 At 5 years, the cumulative mortality rates were 65% for patients with HFNEF and 68% in patients with HFREF.3–6,10,11 Smith et al96 studied 413 hospitalized patients with HF and reported 6-month mortality rates of 13% for those with HFNEF versus 21% for patients with HFREF (hazard ratio:

0.51). Bhatia et al3 reported outcomes of 2502 patients discharged from 103 Canadian hospitals with a diagnosis of decompensated heart failure. At 1 year, there was no significant difference in mortality rates between those with HFNEF (22%) and patients with HFREF (26%).3 Independent predictors of mortality in studies of patients with HFNEF include older age, male gender, NYHA functional class, lower LVEF, extent of coronary artery disease, peripheral arterial disease, diabetes mellitus, impaired renal function, severity of diastolic dysfunction assessed noninvasively and increased red cell distribution width.91,96–101 Causes of death in patients with HFNEF were evaluated in the I-PRESERVE study, which showed no benefit of irbesartan on mortality in patients with HFNEF.98 Sixty percent died of cardiovascular causes (sudden death in 26%, progressive HF in 14%, myocardial infarction in 5% and stroke in 10%).98 Thirty percent died of noncardiovascular causes.98 In 10% of patients with HFNEF, the cause of death was unknown.98 The annual mortality rate in the I-PRESERVE study was 5% per year for patients with HFNEF.98 Although some variation exists, nearly all studies comparing HFNEF with HFREF have failed to consistently demonstrate significant differences in morbidity variables such as heart failure hospitalization rates, quality of life indicators, myocardial oxygen consumption and 6-minute walk distances. It is apparent from the preceding discussion of pharmacotherapy of HFNEF that no 1 drug or drug group has consistently produced improvement in mortality relative to placebo. Among those studied, beta-blockers and alpha/beta blockers seem to be the most promising drug therapies. However, in studies assessing the effects of beta-blockers and alpha/beta blockers on mortality in HFNEF that have shown a survival benefit, it is not clear whether this benefit resulted from treatment of HF or from the anti-ischemic, antiarrhythmic and antihypertensive effects of these drugs.

SUMMARY AND RECOMMENDATIONS HFNEF is a common clinical syndrome that is characterized by symptoms and signs of HF, a normal or near-normal LVEF and evidence of diastolic LV dysfunction based on cardiac catheterization or noninvasive cardiac assessment. Systemic hypertension and coronary artery disease account for most cases of HFNEF in the United States. As with HFREF, the first step in management consists of preventative measures and treatment of underlying causes and precipitating factors known to produce HF exacerbations. Studies assessing pharmacotherapy of HFNEF have failed to identify a specific drug or group of drugs that has consistently improved morbidity and reduced mortality. However, many of

TABLE 2. Recommendations for treatment of patients with heart failure and normal left ventricular ejection fraction1,2 Level Recommendation Class evidence Physicians should control systolic and diastolic hypertension in accordance with published guidelines Physicians should control ventricular rate in patients with atrial fibrillation. Physicians should use diuretics to control pulmonary congestion and peripheral edema. Coronary revascularization is reasonable in patients with coronary artery disease in whom symptomatic or demonstrable myocardial ischemia is judged to be having an adverse effect on cardiac function. Restoration and maintenance of sinus rhythm in patients with atrial fibrillation might be useful to improve symptoms. The use of beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers or calcium antagonists in patients with controlled hypertension might be effective to minimize symptoms of heart failure. The use of digitalis to minimize symptoms of heart failure is not well established.

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I I I IIa

A C C C

IIb IIb

C C

IIb

C

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these pharmacological therapies may be useful in reducing symptoms of HFNEF (eg, diuretics) or in the management of comorbidities, such as systemic hypertension, coronary artery disease and atrial fibrillation. The long-term prognosis of HFNEF remains poor and is similar to that of HFREF in most studies. The American College of Cardiology/American Heart Association guidelines for treatment of HFNEF reflect these observations and are heavily reliant on expert opinion. These guidelines are shown in Table 2. At the present time, there is insufficient evidence to recommend pharmacotherapy as a means of improving survival of patients with HFNEF. REFERENCES 1. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guidelines update for the diagnosis and management of chronic heart failure. Circulation 2005;112:e154–235. 2. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:e391. 3. Bhatia RS, Tu JV, Lee DS. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355: 260–9. 4. Redfield MM, Jacobsen SJ, Burnett JC, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003;289:194–202. 5. Senni M, Redfield MM. Heart failure with preserved systolic function. A different natural history? J Am Coll Cardiol 2001;38:1277–82. 6. Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282. 7. Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure: mechanisms and management. Ann Intern Med 1992;117:502–10. 8. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol 2004;43:317–27. 9. Aurigemma GP. Diastolic heart failure—a common and lethal condition by any name. N Engl J Med 2006;355:308–10.

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