Heart Failure With Preserved Ejection Fraction

Heart Failure With Preserved Ejection Fraction Yogesh N.V. Reddy, MD, and Barry A. Borlaug, MD Abstract: Heart failure (HF) is one of the largest drivers of morbidity and health care expenditure in the world and continues to increase in prevalence at an alarming rate. Most of this increasing burden is related to the rapidly expanding population of HF with preserved ejection fraction (HFpEF), largely driven by the increasing rates of obesity, hypertension, and metabolic syndrome in western countries. In the last 3 decades, there have been tremendous advances in treating patients with HF with reduced ejection fraction (HFrEF), with essentially no change in outcomes for HFpEF. The lack of efficacy for established HFrEF therapies in HFpEF underscores the fundamental differences between both these phenotypically distinct forms of HF. In this review, we will summarize the current understanding of the pathophysiology of HFpEF, discuss diagnostic and therapeutic strategies, and provide future avenues to direct clinical investigation. (Curr Probl Cardiol 2016;41:145–188.)

Introduction he estimated prevalence of heart failure (HF) is expected to increase to more than 8 million people in the United States alone by 2030, with a corresponding increase in total direct cost from $21 billion in 2012 to $53 billion.1 Half of people with HF have a preserved ejection fraction (HFpEF); the prevalence of this form of HF relative to HF with reduced ejection fraction (HFrEF) is growing by 10% per decade2 and the proportion of hospitalizations caused by HFpEF continue to increase at an alarming rate.3 This epidemic of HFpEF is believed to be related to increasing rates of common HFpEF-associated

T

Conflict of interest: The authors have nothing to disclose. Curr Probl Cardiol 2016;41:145–188. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2015.12.002

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comorbidities that are believed to drive the pathophysiology, including obesity, hypertension, and metabolic syndrome, along with the increase in average lifespan and aging of the population.1-7 In the last 3 decades, there have been tremendous advances in treating patients with HFrEF, with declining mortality related to inhibition of the renin angiotensin aldosterone system, beta blockade, device therapy, and now neprilysin inhibition.8 Unfortunately, applications of similar therapies to patients with HFpEF have been unsuccessful in altering the dismal natural history of these patients, where 5-year survival rates can be as poor as 50%.2,5,7 The lack of efficacy of these therapies underscores the fundamental differences between both these phenotypically distinct forms of HF,9,10 as well as our incomplete understanding of the pathophysiology driving outcomes.11

HFpEF vs HFrEF HF is best defined as the inability of the heart to provide organ perfusion at a rate sufficient for the metabolic demands of the body, or to do so only at the expense of elevated filling pressures.12 This diagnosis applies to both forms of HF, and indeed, signs, symptoms, functional limitation, morbidity, and mortality are quite similar in HFpEF and HFrEF.2,4,11,13-16 The echocardiogram is the initial diagnostic test performed in the evaluation of patients suspected of having HF. The traditional cut off for defining HFpEF has been an ejection fraction (EF) of 450% in the presence of clinical HF.5 Patients with HF and an EFo40% have “systolic” HF or HFrEF.8 Patients with an EF from 40%-50% have a borderline decrease in EF that has been variably classified as either HFpEF or HFrEF in clinical trials, though emerging evidence supports the idea that this group is more accurately classified as HFrEF.17-20 Although it should be obvious that the arbitrary dichotomization of patients with HF according to EF alone is flawed,21,22 this method is unlikely to be supplanted in the near future given the widespread availability of echocardiography and the wellcharacterized risk factor profiles, pathophysiology, and outcomes in both the HF phenotypes as defined according to this scheme.5,11,20 Gary S. Francis, MD: There remains some modest uncertainty regarding the definition and nomenclature of HFpEF. Various names and acronyms have been applied (J.E. Sanderson, JACC HF 2014:2:93-94), and the term “diastolic HF” is still preferred by some. However, the term HFpEF has emerged and is now widely applied. As with HFrEF, HFpEF is a syndrome with many phenotypes (S.S. Shah, et.al. Circulation 2015;181:269-279). With such a wide variation of phenotypes, it is not simple to define. Clinically, it is “heart 146

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failure” manifested by dyspnea and accompanied by numerous co-morbid conditions, as pointed out by the authors. Many patients (although not all), manifest impaired left heart filling by echocardiography and eccentric left ventricular (LV) remodeling.

The pathophysiological mechanisms underlying disease initiation and progression in HFrEF are very well-characterized, from animal models to observational human studies to clinical trials, and it is well-established that the primary drivers of disease are neurohormonal activation and eccentric cardiac remodeling.8,23 Indeed, ventricular dilation is a key factor distinguishing HFrEF and HFpEF (Fig 1).24 An important implication of this finding is that wall stress is lower in HFpEF than HFrEF.25 As diastolic wall stress is the key determinant of brain natriuretic peptide (BNP) release,25 it is not surprising that BNP levels are much lower (and often normal) in patients with HFpEF.26,27 In addition to gross pathologic HFrEF

h

r

σ≈

r*P 2h h r

HFpEF FIG 1. Heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation (increased chamber radius, r), low wall thickness (h) relative to chamber radius, and high filling pressure (P). This increases wall stress (s) that serves as the predominant stimulus for natriuretic peptide release. In contrast, patients with HF and preserved ejection fraction (HFpEF) have normal chamber size and often concentric remodeling (higher wall thickness, h), resulting in lower natriuretic peptide levels. (Color version of figure is available online.)

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differences, there are important microscopic differences, including increased cardiomyocyte diameter, higher myofibrillar density, and increased cardiomyocyte stiffness in HFpEF as compared with HFrEF.24 Key differences between HFpEF and HFrEF are summarized in Table 1. In addition to ventricular dilatation, patients with HFrEF display severely depressed contractility and shallow end systolic pressure volume relationships, whereas patients with HFpEF display steep end systolic pressure-volume relationships, despite mildly depressed chamber and myocardial contractility.9,28,29 An important implication of this fundamental difference is that patients with HFpEF display much greater hypotensive effects from vasodilation, whereas HFrEF patients enjoy greater improvement in forward flow from vasodilator therapy, with relatively little effect on arterial pressure (Fig 2). In contrast to HFrEF, HFpEF does not have a well-defined model of progression and there can be significant heterogeneity in phenotypic expression.30 The initial description of this entity was based on the occurrence of HF in concentrically hypertrophied hearts with a normal EF and small cavity size (often in the setting of hypertension).31-33 Because this disorder was believed to be primarily related to diastolic dysfunction, it was initially described as “diastolic” HF. More recent studies have made it clear that diastolic dysfunction is not universally present in people with HFpEF,34-36 and that other mechanisms play an important role in the pathophysiology,12,29,35,37-63 as shall be discussed later.

Epidemiology Multiple studies have all shown that HFpEF accounts for about half of all cases of HF, and its prevalence is growing.2,4,6,13 The relative prevalence of HFpEF increased from 38%-54% of all HF cases in Olmsted County, MN between 1987 and 2001.2 This increase coincided with rising rates of hypertension, obesity, atrial fibrillation, and diabetes, and it is expected to continue to grow with the increased longevity being achieved in the Western world.7,64 A recent analysis of the United States data showed that among incident HF cases between 2005 and 2008, 52% of patients had HFpEF, 33% had HFrEF, and 16% had borderline systolic dysfunction (EF 40%-50%).6 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 (Table 1).11,15,16,65,66 Although comorbidities influence ventricular-vascular structure and function in HFpEF, fundamental disease-specific changes drive the disorder, indicating that 148

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TABLE1. Structural and functional differences between HFpEF and HFrEF. HFpEF Structural differences Systolic function Mildly depressed systolic function with ejection fraction 450% Concentric LV remodeling Left ventricular (LV) remodeling LV dimensions LV chamber dimension remains normal with a higher LV massvolume ratio High related to comorbidities, with Prevalence of variable contribution to an Coronary artery individual patient symptoms disease (CAD) Low Prevalence of previous Myocardial infarction Prevalence of left Low with less electrical remodeling bundle branch block Functional differences Pressure volume loops show an End systolic upward or leftward shift of the LV pressureend systolic pressure volume volume relationship (end systolic relationship elastance), reflecting increased end systolic myocardial stiffness Afterload reduction leads to more Response to systolic hypotension with a smaller afterload increase in stroke volume due to an reduction increased LV end systolic elastance in HFpEF Diuresis leads to a larger than Response to expected decrease in systolic blood preload pressure due to a stiff reduction and ventriculovascular system diuresis Wall tension and Thicker walls and smaller LV cavities BNP release lead to decreased wall stress with less elevation in BNP for any given PCWP Clinical differences Age Older median age Sex More likely to be female Hypertension High prevalence of systolic hypertension Comorbidities Higher frequency and severity of comorbid conditions such as

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HFrEF Severely depressed systolic function with ejection fraction o50% Eccentric LV remodeling

LV dilation with a lower LV massvolume ratio High and represents the underlying etiology in patients with ischemic cardiomyopathy High contributing to ischemic cardiomyopathy

Much higher with clinical response to cardiac resynchronization in patients with a wide LBBB Rightward and downward shift of the LV end systolic pressure volume relationship reflecting decreased myocardial contractility

Afterload reduction leads to less of decrease in systolic blood pressure with comparatively greater improvement in stroke volume A similar decrease in preload leads to less of a decline in systolic blood pressure and stroke volume An equivalent PCWP results in more wall stress and higher BNP levels

Younger median age No female predilection Less strongly associated with hypertension Comorbidities less prevalent and not essential for disease manifestation as evidenced by the observation of

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TABLE1. Continued HFpEF

Response to therapy

HFrEF

obesity, metabolic syndrome, renal young patients with isolated dysfunction, and anemia nonischemic cardiomyopathy Respond to neurohormonal Lack of response to therapies antagonism with improvement in targeting neurohormonal blockade ventricular reverse remodeling, such as ACEi-ARBs, beta blockers exercise capacity, hospitalization and mineralocorticoid antagonists risk, and mortality

LBBB, left bundle branch block.

HFpEF is not merely an amalgamation of comorbidities.67 Furthermore, morbidity and mortality in patients with HFpEF greatly exceeds what is observed in patients with the same comorbid conditions but no frank HF.68 Risk factors for HFpEF are well established and include hypertension, older age, diastolic dysfunction, kidney disease, anemia, and diabetes.69-71 LV diastolic compliance deteriorates as part of normal aging,72,73 even in community-dwelling volunteers free of cardiovascular disease and over periods as short as 4 years.74 Deleterious age-related effects on the heart appear to be accelerated in the presence of obesity, particularly in central obesity.74-76 Sedentary lifestyle is an independent risk factor for HFpEF, and increasing leisure time activity reduces that risk in a dose-dependent

End Systolic Arterial Pressure (mmHg)

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HFpEF Ees = 3.66

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HFrEF Ees = 0.54

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50 +8 ml

+23 ml

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FIG 2. In HFrEF (red), contractility is severely depressed (low Ees) and the end systolic pressure volume relationship (solid line) is very shallow. As a result, reductions in arterial afterload (Ea) result in minor reductions in blood pressure but dramatic improvements in stroke volume. In HFpEF (black), Ees is high, and similar degrees of afterload reduction cause more prominent reductions in blood pressure. (Adapted with permission from Schwartzenberg et al.9) (Color version of figure is available online.)

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fashion.77,78 Poor fitness is also associated with concentric ventricular remodeling and diastolic dysfunction.79 For reasons that remain unclear, female sex, renal dysfunction, obesity, atrial fibrillation, and microalbuminuria appear to be stronger risk factors for HFpEF than HFrEF.65,69,80 Prior myocardial infarction is more common in HFrEF than HFpEF,80 but recent data has shown that coronary artery disease (CAD) is also very common in HFpEF and associated with adverse outcome, independent of other predictors.81 Hospitalization and rehospitalization risks are similar in HFpEF and HFrEF.15,16 Although some community-based studies have reported similar mortality in HFpEF and HFrEF,2,13 others have reported somewhat better outcomes in HFpEF.82 Although mode of death is largely cardiovascular in HFpEF patients enrolled in trials,83 noncardiovascular causes of death are very common in HFpEF patients seen in the community.84,85

Pathophysiology Diastolic dysfunction is the most prevalent and typical pathophysiologic finding in patients with HFpEF, but the disease is far more complex and abnormalities in LV systolic function, right heart function, the vasculature, endothelium, and periphery (including skeletal muscle) play important roles.58 At this time, it remains unresolved whether these multisystem impairments are caused by discrete disease processes or whether they are related to unifying, underlying causes. If the former were true, this would suggest that what is referred to as HFpEF in fact represents a large number of different diseases, and this has been proposed as a potential explanation for the failure of previous clinical trials in HFpEF. However, there are also common risk factors for HFpEF including aging, diabetes-metabolic syndrome, hypertension, and obesity that could cause several of these impairments in parallel (Fig 3). If this is true, then HFpEF is more appropriately considered as a single disease entity, and therapies targeting these underlying mechanisms will be expected to hold promise. How much each component contributes to the clinical syndrome of HF in an individual with HFpEF is likely highly variable, and there are clearly patients where 1 or 2 components predominantly drive symptoms and the clinical presentation (eg, 1 patient may have severely impaired diastolic LV compliance and chronotropic incompetence, another may have mild prolongation in relaxation but excessive pulmonary hypertension (PH) and right ventricular [RV] dysfunction). In the following sections, the different pathophysiologic contributors to HFpEF will be described individually. Curr Probl Cardiol, April 2016

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A

B

Factor X

Factor Y

Factor Z

LV Diastolic Dysfunction

LV Systolic Dysfunction

Endothelial Dysfunction

Heterogenous Pathophysiology Multiple Etiologies

Factor X

LV Diastolic Dysfunction

LV Systolic Dysfunction

Endothelial Dysfunction

Heterogenous Pathophysiology Common Etiology

FIG 3. Two conceptual pathophysiologic pathways accounting for observed phenotypic traits in HFpEF. In panel (A) different factors (eg, aging, hypertension, insulin resistance, and obesity) produce different physiologic sequelae. In panel (B), one systemic factor (eg, cardiovascular aging) causes multiple different target organ limitations. It is likely that many or most patients with HFpEF display features of each of these pathways. (Color version of figure is available online.)

Diastolic Dysfunction Regardless of the multiple pathophysiological abnormalities observed in HFpEF, the presence of elevated diastolic filling pressures at rest or with exercise is uniformly present in HFpEF.26,86 The prevalence of diastolic abnormalities by echocardiography is variable in HFpEF, due in part to the complexity involved in the assessment and the requirement to often integrate multiple echo parameters.87 Although echocardiographic indices have been established to estimate filling pressures as well as intrinsic chamber stiffness and compliance properties of the ventricle, these measures have much greater variability than direct and invasive assessments.88-90 Despite the use of uniform interpretation schemes in expert core labs, clinical trial ancillary studies have failed to identify diastolic abnormalities by echocardiography in up to one-third of patients with HFpEF.34-36 On the other hand, invasive studies have generally shown diastolic abnormalities to be universal in patients with HFpEF, though in patients with earlier stages of disease, provocative maneuvers such as exercise or saline loading are required to elicit the pathologic changes.12,26,60,86,91-95 The normal 152

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enhancement of LV relaxation with increasing heart rates is lost in HFpEF, contributing to exercise induced pulmonary venous hypertension and exercise intolerance.86,96,97 Thus overall, it appears that diastolic abnormalities either at rest or with exercise play a major role in symptomatology in HFpEF, and that rest echocardiography has suboptimal sensitivity to detect diastolic dysfunction in HFpEF. Diastolic dysfunction is highly prevalent in the general population than HFpEF and is essentially part of normal aging, but it is as a rule not severe in patients without heart failure. Gary S. Francis, MD: There has recently been a resurgence of interest in the “aging process” and its relation to HFpEF (T.A. Rando, T. Finkel, N Engl J Med 2015;369:575-576, A. Laviano, N Engl J Med 2014:573-575, F.S. Loffredo, et.al. Cell; 153:828-839). It has been suggested that Growth Differentiation Factor 11 (GDF 11) is a circulating factor that reverses age-related cardiac hypertrophy in mice. Whether one can restore function to aging tissue is open to question, and more mechanistic studies are clearly necessary.

Echocardiographic detection of diastolic dysfunction is clearly a significant risk factor for progression of asymptomatic patients to HFpEF71 and also predicts increased risk of death.99 However, diastolic dysfunction alone is insufficient to cause the clinical syndrome of HF.59 The evidence for this lies in the fact that even though diastolic dysfunction is present in more than 70% of people over the age of 75 years, the majority of these individuals do not show the clinical syndrome of HFpEF.98 Only around 1 in 4 people with moderate to severe diastolic dysfunction on echo developed incident HF during long term follow up in Olmsted County, suggesting that abnormalities developing in addition to diastolic dysfunction are critical to the manifestation of HF in the setting of a normal EF, as described in the subsequent sections.71

Physiology of Diastole and Implications in HFpEF Pathophysiologically, diastolic dysfunction is defined by varying combinations of abnormal active relaxation (an energy-requiring process) and passive stiffness related to inherent properties of the myocardium, extracellular matrix, and pericardial restraint (Fig 4).5,100,101 Diastole is an extraordinarily complex process. Active relaxation requires adenosine triphosphate to initiate dissociation and reuptake of calcium from troponin C back into the sarcoplasmic reticulum, resulting in uncoupling of actin and myosin cross-bridging and return of myofibrils to their precontractile Curr Probl Cardiol, April 2016

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FIG 4. Determinants of myocardial stiffness relate to the extracellular matrix and its components as well as factors intrinsic to the cardiac myocytes. (Adapted with permission from Borlaug and Paulus5) (Color version of figure is available online.)

length.102 Abnormalities in calcium reuptake have been demonstrated in tissue from patients with hypertensive ventricular hypertrophy.103 Diastolic function is potently influenced by loading conditions.100,104 Severe or late systolic afterload elevation (as present in patients with stiff aortas and augmentation of reflected pressure waves) induces premature onset and significant slowing of pressure fall.105,106 Such prolonged slowing can lead to incomplete relaxation and elevation in end diastolic filling pressures, and this phenomenon is exaggerated when heart rate is increased.97 The complex mechanisms for afterload sensitivity of diastolic function may relate to abnormal intracardiac calcium transients107 or altered beta-adrenergic downstream signaling.108 An increased afterload can also lead to incomplete ejection, decreased stroke volume (SV), and resultant increased end systolic volume (ESV). The lower the ESV attained during the preceding contraction, the more the LV untwists and recoils during the next filling cycle—like a compressed spring releasing its potential energy, and this serves an important teleological role to enhance diastolic suction in normal hearts.109-111 Patients with HFpEF display abnormalities 154

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LV Pressure, mmHg

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HFpEF LVEDP 32mmHg

20

Normal LVEDP 15mmHg V15=53 ml

V15=83 ml

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LV Volume, ml FIG 5. The end diastolic pressure volume relationship in patients with HFpEF (green) are shifted up and to the left compared with that of the normal compliant ventricle (blue). This is related to increases in passive chamber stiffness and accounts for higher left ventricular end diastolic pressure (LVEDP) and lower chamber volume at a common filling pressure of 15 mm Hg (V15). (Adapted with permission from Andersen and Borlaug185) (Color version of figure is available online.)

in this untwisting motion, further contributing to diastolic dysfunction.38,112 Indeed, the afterload sensitivity in HFpEF is evident by the frequent presentation of these patients with acute pulmonary edema in the setting of uncontrolled hypertension.113 Passive stiffness related to inherent properties of the myocardium also contributes to the steep end diastolic pressure volume relationship in HFpEF (Fig 5).5,24,114-117 This intrinsic myocardial stiffness is related not only to abnormalities of the interstitium and extracellular matrix, but more recently has also been linked to changes in the cardiomyocyte itself. Indeed, one-third of endomyocardial biopsies in a study of patients with HFpEF demonstrated a normal collagen volume fraction, implicating intrinsic cardiomyocyte stiffness in this disorder.118 Hypophosphorylation of the elastic protein titin contributes to this cardiomyocyte stiffness and has been linked to the decreased nitric oxide (NO) bioavailability and reduced intracellular cyclic guanosine monophosphate.114 Novel approaches to improve NO bioavailability have or are being tested in clinical trials in patients with HFpEF (discussed later). Gary S. Francis, MD: The giant myofilament titin has an I-band–spanning segment that acts as a molecular spring. It develops force when sarcomeres are stretched. Molecules that are extraordinarily long and elastic, such as titin, act as molecular bungee cords to passively resist stretch, thus maintaining Curr Probl Cardiol, April 2016

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structural integrity of the muscle. Titin may contribute to LV diastolic dysfunction in HFpEF. Modification of titin, including phosphorylation status and oxidation, may alter cardiomyocyte stiffness. Phosphorylation may allow NO to acutely lower cardiomyocyte stiffness. HFpEF is characterized by a hypo-phosphorylated titin state, perhaps due to lower NO availability and low protein kinase G activity—each leading to increased cardiomyocyte stiffness. Oxidative stress also increases the stiffness of cardiomyocytes, perhaps via oxidation of titin. So, the largest molecule in the human body, titin, may be a major determinant of cardiomyocyte stiffness in syndromes such as HFpEF.

Abnormalities in LV Systolic Function By definition, the EF is preserved in people with HFpEF, but LV contractility is not. This has been shown using load-dependent indices from tissue Doppler imaging,38,119 myocardial strain imaging,50,52 and using load-independent indices of chamber and myocardial contractility.29 Patients with more profound impairments in systolic function and deformation display increased risk of death.29,52 This may be related to abnormalities in calcium handling,120 beta-adrenergic signaling,112,121 myocardial energetics,39,122 or tissue perfusion reserve.81,123 Although systolic function at rest is only modestly impaired, a number of studies have also identified dramatic limitations in systolic reserve with stress that importantly contributing to decline in peak cardiac output and exercise intolerance in HFpEF.12,37-39,41,92,124 Systolic reserve limitations beget diastolic limitations, as inability to contract to a smaller LV ESV in HFpEF limits the amount of elastic recoil favoring diastolic suction of blood from left atrium to ventricle during the following diastole.12,41,112,124

PH and RV Dysfunction PH is present in more than 80% of patients with HFpEF, initially developing as a form of “passive” PH related to elevated pulmonary capillary wedge pressure (PCWP).40,125 Chronic elevations in PCWP induce pulmonary arteriolar and venous remodeling resulting in increased pulmonary vascular resistance.125,126 The net effect of PCWP elevation is a greater decrease pulmonary artery compliance out of proportion to increases in resistance, elevating pulsatile RV loading.127 The presence and severity of PH in HFpEF is independently associated with increased mortality and represents a potential target for treatment.40,54 Depending upon how it is defined, RV dysfunction is present in roughly one-third of patients with HFpEF.57,128 Patients with RV dysfunction typically display with more advanced HF, renal dysfunction, atrial fibrillation, tricuspid regurgitation, and LV dysfunction. The latter may 156

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contribute to RV dysfunction via the phenomenon of systolic ventricular interaction, where LV septal function importantly contributes to RV ejection.57 However, it is likely that not all RV dysfunction in HFpEF is related merely to increased left-sided filling pressures. There likely exists a subset of patients where RV systolic and diastolic abnormalities develop earlier in HFpEF.129 A recent invasive study evaluating earlier stage HFpEF patients showed significant abnormalities in RV diastolic function and systolic reserve in response to adrenergic stimulation, despite the lack of gross RV dilation.54 Intriguingly, patients with HFpEF display greater pulmonary vasodilation as compared to controls, suggesting that adrenergic agonists (possibly inhaled) might be a novel treatment for PH in HFpEF.54 Gary S. Francis, MD: It is important to remember that the right and left ventricle have different embryologic origins (S. Zaffran, et.al. Circ Res 2004;95:261268). Several genes specifically control RV formation. During gestation, the RV functions as the systemic ventricle. After birth, it faces a low impedance pulmonary circulation. The RV is exquisitely sensitive to RV afterload, much more than the LV. Even very small changes in pulmonary vascular resistance, especially if sudden, can profoundly depress RV function. In response to increased afterload, the RV reverts to a fetal gene pattern. Among many changes, there is an increase in phosphodiesterase type 5 expression. This has opened the door to considering phosphodiesterase 5 inhibitors (PDE5i) for HFpEF. However, the strategy has not been fulfilled in clinical trials, perhaps because PDE5 may not be upregulated in the syndrome of HFpEF.

Autonomic Dysregulation and Chronotropic Incompetence The normal response to exercise is to increase cardiac output through parasympathetic withdrawal and increased sympathetic outflow, increasing venous return and peripheral vasodilation with a resultant increase in SV and heart rate. Heart rate is the major determinant of cardiac output augmentation with exercise as opposed to SV, with an increase of 200%400% at peak exercise.130,131 Thus, any limitation in peak heart rate will lead to an inadequate cardiac output response with decreased exercise tolerance. Most studies have demonstrated chronotropic incompetence in the majority of studied patients with HFpEF.12,37,41,92,132-134 This appears to be mediated more by adrenergic sensitivity rather than central outflow, as catecholamine levels increase similarly in HFpEF and controls despite marked differences in chronotropic reserve.37 There is additional evidence for autonomic dysregulation in HFpEF. A total of 3 studies have shown that the normal decrease in heart rate following exercise is blunted, and 1 study has observed that arterial baroreflex sensitivity is depressed in Curr Probl Cardiol, April 2016

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HFpEF.37,41,134 The latter is interesting in light of an animal study whereby experimentally-induced baroreflex failure led to marked inability to tolerate volume loading in rats.135 Whether this phenomenon applies to humans with HFpEF remains unknown at this time.

Atrial Function Epidemiological studies have identified a high prevalence of atrial fibrillation in patients with HFpEF. Considering prior history, prevalent or future atrial fibrillation, two-third of patients with HFpEF are or will be afflicted.136 Patients with HFpEF and atrial fibrillation display more severe exercise limitation, worse RV function, and lower survival compared to patients in sinus rhythm.55,57,128,136 Under normal circumstances atrial systole contributes
20% of diastolic ventricular filling, but in patients with substantial diastolic dysfunction, this can increase dramatically to
45%, explaining how loss of atrioventricular synchrony is problematic in these people.137 The development of new atrial fibrillation is a significant risk factor for the development of incident clinical HFpEF and likely heralds the transition of asymptomatic stage B to symptomatic HF in many patients.80 Independent of atrial fibrillation, primary abnormalities in left atrial size and contractile function have been observed in HFpEF, and this likely contributes to ineffective optimization of LV preload with diastolic dysfunction, particularly with exercise.48,59,138 A recent study has shown that left atrial systolic and diastolic dysfunction in HFpEF is associated with more severe PH, right ventricular dysfunction, and increased mortality.53 Thus it appears that the left atrium plays an important role to “protect” the pulmonary vasculature and right heart from chronic elevations in left heart pressure.53

Ventricular Dyssynchrony Abnormalities in ventricular synchrony during repolarization have been observed in HFpEF. This nonuniform relaxation induces an earlier and slower rate of pressure fall in diastole,139,140 potentially contributing to some of the diastolic dysfunction associated with ischemia and intraventricular conduction delay.49 Although left bundle branch block is quite uncommon in HFpEF, systolic dyssynchrony has also been identified in HFpEF and has been associated with functional limitation.139,141 It remains unclear whether this sort of nonbundle branch block type of dyssynchrony can be effectively resynchronized by pacing, and routine use of cardiac resynchronization in patients with HFpEF plays no role during this time. 158

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Abnormal Ventricular-Vascular Coupling Patients with HFpEF demonstrate reduced arterial compliance (increased stiffness or elastance) that contributes to increased afterload and augmented pulsatile LV loading.28,142-145 This arterial stiffening, coupled with increased LV stiffness during both systole and diastole, promotes marked blood pressure lability in people with HFpEF. Review of the basic tenets of ventricular-arterial coupling is necessary to understand these principles. Effective arterial elastance (Ea) is a lumped measure of arterial afterload that accounts for both pulsatile (aortic stiffness and compliance) and steady, nonpulsatile loading (systemic vascular resistance) along with heart rate. It is measured by the negative slope through the end systolic pressure volume point and end diastolic volume (Fig 6). LV end systolic elastance (Ees) or stiffness is measured by the slope of the end systolic pressure volume relationship, and is a load-independent measure of LV contractility (Fig 6). Despite impairments in chamber and myocardial contractility in HFpEF, Ees is increased on average in this population.29 This likely reflects the same factors that cause ventricular passive stiffening.29,145 The intersection of these 2 slopes (Ea and Ees) at a given preload, determines the end systolic pressure and volume achieved. As the Ea increases, the Ees should increase to match it, enabling optimal ventricular-arterial coupling and maximizing mechanical efficiency.146 In HFpEF the absolute values of Ea and Ees are increased but the ratio remains within the normal range at rest. Thus both systolic and diastolic ventricular stiffness and vascular stiffness are increased in HFpEF.

FIG 6. Ventricular-vascular coupling in normal adults and HFpEF. (Adapted with permission from Borlaug and Kass.148) Curr Probl Cardiol, April 2016

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FIG 7. Compared with normal patients (A), patients with HFpEF (B) display greater increases in blood pressure with increases in preload (end diastolic volume, EDV) as well as afterload increase (C and D). These differences are similar to comparisons of young and old healthy volunteers, where older humans have larger increases in blood pressure with higher end diastolic volume (E and F). (Adapted with permission from Borlaug and Kass.148)

The higher values of Ea and Ees lead to much larger changes in systolic blood pressure for a given change in preload or afterload (Fig 7).147,148 This is clinically evident by the large fluctuations in systolic blood pressure with diuresis and vasodilator therapy in patients with HFpEF. With exercise, ventricular-arterial interaction in HFpEF becomes even more deranged, due to abnormal vasodilation and limitations in systolic reserve.39,41,124,143 Thus, it is likely that some subsets of patients with HFpEF develop symptoms with exercise, predominantly related to marked increase in pulsatile load from central aortic stiffness as preload and SV increase with exercise. This increase in Ea (relative to Ees) with exercise can lead to worsening diastolic function, increased myocardial oxygen demand and elevated filling pressures. The contribution of central aortic stiffness and pulsatile load may partially explain the reported female predisposition to HFpEF, as women display increased central aortic stiffness compared with men.149

Peripheral Abnormalities According to the Fick principle, decreased peak O2 consumption (VO2) can be related to limitations in cardiac output reserve, limitations in arterial-venous O2 content difference, or both.58 The latter is related to how effectively O2 is distributed, extracted, and utilized in the skeletal muscles 160

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during exercise.150 Although abnormalities in cardiac output reserve have been clearly demonstrated in HFpEF,12,37,41,56,60,91,92 recent research has also identified abnormalities in peripheral O2 extraction and utilization in a significant subset of patients with HFpEF.43,45,94 The mechanism of inadequate peripheral usage of O2 may be related to impaired muscle O2 extraction, impaired autonomic regulation of blood flow, or problems with macro- or micro-vascular 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 patients with HFpEF, potentially contributing to impaired nutritive blood flow in the heart and periphery.61,62,123,151 It may be that better phenotyping of patients according to the presence of predominant peripheral or central (cardiac) limitations may allow for better individualization of therapies in people with HFpEF.12,94 Exercise training, which improves aerobic capacity and quality of life in HFpEF,152 appears to work almost exclusively through beneficial effects in the periphery in people with HFpEF,153 though 1 study did observe evidence of direct cardiac effects.154 Impaired flow–mediated vasodilation, a marker of abnormal endothelial function, has been observed in HFpEF and the degree of dysfunction correlated with severity of symptoms, exercise impairment, pulmonary vascular disease, and risk of HF hospitalization.41,155–157 However, not all studies in HFpEF have observed abnormal endothelial function, at least when examined in larger conduit vessels.158–160 Nonetheless, there is substantial evidence that endothelial dysfunction plays a central role in the pathophysiology in a number of patients,161 and numerous clinical trials have or are being performed targeting this pathway, as discussed later.91,162–167

Diagnosis Diagnosis of HF in patients with a normal EF is considerably more challenging than patients with a low EF.5 A patient with a low EF who is short of breath can be confidently diagnosed with HF without much additional diagnostic information, as there is clear cut myocardial dysfunction. In contrast, patients with a normal EF who are short of breath may have HFpEF, a non-HFpEF cardiac cause of symptoms (eg, valvular heart disease), or a noncardiac etiology (Table 2). These patients often require a much more thoughtful evaluation to demonstrate objective evidence of elevated filling pressures or inadequate cardiac output. This is further complicated by the presence of early HFpEF where there may not Curr Probl Cardiol, April 2016

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TABLE 2. Differential diagnosis of HFpEF Cardiovascular Hypertrophic cardiomyopathy Infiltrative or restrictive cardiomyopathy Pulmonary arterial hypertension Constrictive pericarditis High-output heart failure Valvular heart disease Coronary artery disease Pulmonary embolism Right ventricular myopathies Noncardiovascular Pulmonary disease Anemia Obesity Deconditioning Renal artery stenosis Thyroid disease Neuromuscular disease

be clinically detectable signs of congestion at rest, but there is marked elevation of filling pressures with exercise leading to dyspnea.26 The European Society of Cardiology has proposed a set of expert consensus guidelines that rely on demonstration of typical HF signs and symptoms, normal left ventricular ejection fraction, normal LV chamber size, and objective evidence of diastolic dysfunction. The latter may be measured invasively or noninvasively using a combination of echocardiography and plasma natriuretic peptide level testing.168 Shortcomings of this scheme include the lack of exercise assessment26 and questions regarding the sensitivity and specificity of echo-Doppler measures of diastolic function. Indeed, a number of studies have recently questioned whether diastolic dysfunction, as assessed by echocardiography, is necessary and sufficient for the diagnosis, as it is absent in roughly onethird of patients34-36 and tissue Doppler diastolic velocities do not differ between patients with HFpEF and appropriate age-matched controls.52

Clinical Examination The clinical diagnosis of HFpEF can be confidently performed at the bedside purely by physical examination and history, if the patient has demonstrable evidence of elevated filling pressures at rest and is in decompensated HF. Demonstration of an elevated jugular venous pressure is the best predictor of elevated left-sided filling pressures even in HFpEF,169–171 162

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and in the correct clinical setting is strong evidence toward the presence of clinical congestive HF. Physical examination is inaccurate in predicting EF, and echocardiography is required to prove that HFrEF is not present and to confirm physical examination evidence of a lack of valvular heart disease. In general, most would agree that patients fulfilling the Framingham criteria for the diagnosis of HF where the EF is found to be normal (450%) can be confidently diagnosed as having HFpEF, provided that alternative etiologies such as pericardial or valvular disease are not present (Table 2).172 However, the clinical examination is insensitive compared with cardiac catheterization170 and cannot evaluate for hemodynamic abnormalities developing during physiologic stresses such as exercise or volume loading.5,26,92,173 Thus, physical examination can be an adequate “rule in” test if there is marked evidence of congestion and elevated filling pressures, but examination is not an effective “rule out” test for HFpEF. Thorough history, physical examination, and additional testing to evaluate for alternative, noncardiac causes of dyspnea including chronic pulmonary disease, morbid obesity, or excessive deconditioning is essential in the evaluation for HFpEF.174 However, it is important to remember that obesity is a very common risk factor for HFpEF; patients with prevalent HFpEF are often deconditioned and chronic obstructive pulmonary disease frequently coexists with HFpEF. This can make diagnosis very challenging and invasive evaluation is often required in these circumstances.26

Echocardiography Echocardiography is absolutely essential in the evaluation of patients suspected of having HFpEF. Beyond measurement of EF, echocardiography provides a wealth of information to evaluate for common abnormalities seen in patients with HFpEF. These abnormalities include LV diastolic dysfunction,51,175 elevations in ambient LV filling pressures (high E/e’ ratio),176 LV systolic dysfunction,50,52 enlarged left atrial volume index (a barometer of the extent and duration of elevation of left-sided filling pressures),53,59 concentric LV remodeling or hypertrophy (a barometer of chronic pressure load), inferior vena caval dilatation (an assessment of right atrial pressure)59,177 elevation in right ventricular systolic pressures, and qualitative or quantitative impairments in RV function.40,57,128 A full discussion of the complexities of echocardiographic techniques to evaluate diastolic abnormalities and increased ventricular filling pressures is beyond the scope of this review, and there are many other excellent reviews on this topic.87,178 Curr Probl Cardiol, April 2016

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These indices should be looked at probabilistically when considering the diagnosis of HFpEF: the more that are present, the higher the after test probability that the patient has HFpEF. For example, if a patient with normal EF and dyspnea has left atrial enlargement, a high E/e’ ratio, reduced global longitudinal strain, and elevated pulmonary artery systolic pressure estimates, it can be concluded with a fair degree of certainty that the patient has HFpEF. However, if none of these structure-function abnormalities are present, the diagnosis is questionable and more invasive testing is required to confirm or refute the diagnosis.

Biomarker Testing Serum measurements of BNP (NT-proBNP) are powerful adjunctive tools to the clinical assessment of patients with HFpEF that are related to outcome.179–181 On average, natriuretic peptide levels are lower in HFpEF than HFrEF, reflecting the lower wall stress associated with the thickened walls and concentric remodeling often seen in HFpEF.25–27 In a study, 29% of outpatients with HFpEF with elevated PCWP had normal BNP levels.27 However, elevated natriuretic peptide levels are strongly supportive of the diagnosis of HFpEF with a normal EF and have prognostic value. Important caveats include the much lower and often normal BNP levels seen in the morbidly obese and the elevated BNP levels that can occur with atrial fibrillation (even in the absence of HF), renal failure, or right ventricular strain from primary pulmonary arterial hypertension or pulmonary emboli. Other biomarkers are currently being evaluated as potential diagnostics for HFpEF, including markers of fibrosis, inflammation, and endothelial dysfunction.182 None have yet emerged as being incrementally informative beyond the natriuretic peptides in a convincing fashion.

Right Heart Catheterization Given that the presence of elevated filling pressures either at rest or with exercise is the sine qua non of HF, the gold standard test diagnostic test remains direct measurement of intracardiac pressures by right and left heart catheterization, as reviewed elsewhere recently.183,184 Determination of rest filling pressures may be inadequate in this setting if patients are euvolemic at the time of evaluation, or if symptoms occur only with exercise.26,92 In these situations, right heart catheterization with exercise stress should be considered. The presence of an elevated mean PCWP (Z15 mm Hg at rest or Z25 mm Hg with exercise) is diagnostic of HFpEF,5,26,60,92,94 and has been shown to identify patients at increased risk of mortality, even when resting hemodynamics are completely 164

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normal.185,186 Saline loading has also been proposed in an alternative to exercise in order to stress the system to elicit hemodynamic derangements of HFpEF.173,187 However, a recent study has shown that saline loading is less sensitive when compared to the more physiologic stress of exercise.92 Exercise may be performed in either the supine or upright positions. Owing to the effects of gravity, filling pressures are lower upright, but prior studies have shown that the change in pressures during exercise is similar with upright and supine exercise.188,189 In addition to elevation in filling pressures, patients with HFpEF frequently display impaired cardiac output reserve during exercise, where the increase in blood flow to the body relative to VO2 is depressed.12,60,91 Invasive exercise testing with simultaneous expired gas analysis allows for detection of these patients, as well as other cohorts that do not appear to be constrained by cardiac output reserve.183 In normal humans, cardiac output should increase by 6 mL/min for each 1 mL/min increase in total body oxygen consumption.12 Thus, if one measures the observed increase in VO2, the predicted change in cardiac output may be solved for. If the observed increase in cardiac output is o80% of this value, the patient is deemed to have a cardiac output limitation. Some recent studies have identified a population of patients with HFpEF in whom this cardiac output limitation is not present, particularly those in whom the reduction in exercise capacity is predominantly due to peripheral factors.43,45,94 It may be that more routine use of exercise testing (possibly with noninvasive cardiac output and expired gas analysis) will be useful in the future to better phenotype patients in order to individualize therapy.12,94

Management The lack of evidence-based therapies for HFpEF is coupled to essentially unchanged mortality for this condition over the past 3 decades. This is exemplified by a longitudinal study in Olmstead County, MN where significant improvement in survival over time was noted in patients with HFrEF, but no such trend was seen for patients with HFpEF.2 This underscores the huge unmet public health need for the development of therapies to alter the natural history of patients with this condition. Unfortunately, as described below, the history of clinical trials in HFpEF is punctuated with negative results with very few established beneficial therapies.

Diuretics Diuretics decrease filling pressures to effectively treat acute decompensated HF, regardless of etiology, and are recommended to control fluid Curr Probl Cardiol, April 2016

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overload in both the American and European guidelines.8,190 Similar to HFrEF, acutely decompensated patients with HFpEF benefit from intravenous loop diuretics to rapidly relieve symptoms, and diuretics are commonly prescribed to patients with HFpEF on an ambulatory basis. In high-risk hypertensives, chlorthalidone has been shown to decrease the incidence of newly developing HFpEF possibly by decreasing the liability for fluid retention and increased filling pressures in hypertensive patients at risk for HFpEF.191 The CHAMPION trial has provided strong evidence supporting the treatment of elevated filling pressures in order to prevent fluid accumulation and decompensation of HF, including HFpEF.192,193 In this trial, patients with recent HF hospitalization and New York Heart Association (NYHA) class III symptoms underwent implantation of a pulmonary artery pressure monitor and were randomized to care based upon investigator knowledge of invasive pressures vs standard care. The trial showed a significant reduction in HF 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, the vast majority of medication changes based upon 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 III) HFpEF patients with recent HF hospitalization.192,193

Renin Angiotensin Aldosterone System Inhibition A total of 3 large placebo-controlled randomized trials testing angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) in HFpEF have been conducted to date.194–196 There was a nonsignificant reduction in the composite outcome of cardiovascular death or HF hospitalizations with Candesartan in the CHARM-Preserved study.194 This trial defined HFpEF using an EF 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 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.195 However, in a post-hoc analysis from I-PRESERVE, patients with NT-proBNP levels below the median were observed to benefit from 166

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irbesartan, an effect that was consistently observed across the different end points.197 The authors appropriately acknowledge the limitations of this post-hoc analysis but raise the intriguing hypothesis that patients with earlier stages of HFpEF (eg, patients with lower natriuretic peptide levels) may be more responsive to therapies such as ARBs. The PEP-CHF trial randomized older (aged Z70 years) to perindopril or placebo and found that perindopril was associated with a trend toward decreased all-cause mortality and hospitalization for HF at 1 year, but over the entire 3-year study period there was no reduction in the primary end point.196 Notably, there was substantial crossover between treatment groups during the study, and event rates were lower than anticipated. There were improvements in 6-minute walk distance and NYHA class in this study, but these results must be considered as hypothesis-generating only given the overall neutral trial result.196 Thus, the available data do not support the use of ACEi/ARB as a disease modifying therapy in HFpEF, though they still may be effective as antihypertensives and for alternative indications, independent of HF, such as hypertension, diabetic nephropathy, or other comorbidities. The mineralocorticoid receptor antagonist spironolactone was recently tested in a randomized controlled trial in HFpEF (TOPCAT), and there was no significant reduction in the composite primary end point of cardiovascular death, HF hospitalization, or aborted cardiac death as compared with placebo.198 However, there was signal of benefit in higher risk populations, such as 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 with those enrolled in Russia and the Republic of Georgia.199 Notably, the event rate in the latter group was much lower as compared with participants in the Americas, raising concern over whether all of these patients truly had HF. In another ancillary study from TOPCAT, it was found that EF modified the treatment response to spironolactone.19 Patients with lower EF (but still meeting the entry criteria) were observed to benefit from spironolactone as compared to placebo, whereas patients with higher EF (especially greater than 55%) did not. A smaller trial observed that spironolactone improved estimated LV filling pressures (E/e’ ratio) in people with early stage HFpEF, but the coprimary end point of exercise capacity and secondary end points including quality of life were not improved.200 Given these data, there is some difference of opinion as to how mineralocorticoid antagonists should be used in HFpEF. Some authorities are advocating use for patients with preserved renal function, low risk for hyperkalemia, and clear cut HFpEF, Curr Probl Cardiol, April 2016

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especially with elevated natriuretic peptide levels, based upon the post-hoc ancillary analysis from TOPCAT.199

Beta Blockers Beta blockers are commonly prescribed for patients with diastolic dysfunction based upon the notion that slowing the sinus rate will prolong diastole and promote ventricular filling.201 Despite this theoretical benefit, there is little to no evidence that beta blockers improve exercise capacity or clinical outcomes, although data is quite limited in this regard.202–206 One concern with beta blockers is the common presence of chronotropic incompetence in people with HFpEF.37,202 A recent meta-analysis suggested a possible decrease in all-cause mortality associated with beta blockade in HFpEF,207 and analysis of data from the SENIORS trial showed no interaction between EF and the benefits of the beta blocker nebivolol, though the number of patients with “true HFpEF” (ie, EF Z50%) in this trial was quite low.203 A large scale randomized trial of beta blockade in patients with HFpEF patients is urgently needed to better understand the role for this class of medication in HFpEF. Gary S. Francis, MD: There is seemingly a long standing misconception about heart rate (HR) and diastolic dysfunction. Many of us were taught that short LV filling time associated with an increased heart rate, especially during exercise, must impair LV filling. Exercise tachycardia was believed to limit SV during exercise. We now understand that at high levels of exercise, nearly all of the increase in VO2 is due to increasing HR (D.W. Kitzman, Circulation 2015;132:1687-1689). SV is a relatively small contributor to peak VO2 during exercise. Therefore, it is unreasonable to think that drugs that reduce HR during exercise will actually improve exertional dyspnea. -adrenergic blockers can further directly reduce diastolic function, in addition to slowing peak exercise HR, and they are not effective as therapy for HFpEF. This is particularly important to note in HFpEF, as the dyspnea that these patients suffer is mostly exertional. Moreover, HR reduction with ivabradine does not improve symptoms in patients with HFpEF (N. Pal, N. Sivaswamy, M. Mahmod, et.al. Circulation 2015;132:1719-1725). Exercise intolerance is the primary symptom of patients with HFpEF, and drugs used to slow HR are not likely to improve symptoms and may worsen exercise tolerance.

Digoxin The Digitalis Investigators Group trial included a cohort of 988 patients with HF and relatively preserved EF (445%) in sinus rhythm.208 There was a trend to decreased HF hospitalizations but this was negated by an increased number of admissions for unstable angina. There was no effect 168

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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 suggests an increased mortality with digoxin use for atrial fibrillation in HF, but prospective trials are lacking.209,210

Organic Nitrates Direct NO donors such as the organic nitrates increase cellular levels of cyclic guanosine monophosphate, 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 owing to the curvilinear end diastolic pressure volume relationship in HFpEF.5 However, patients with HFpEF may display excessive reduction in blood pressure and SV with nitrates. Schwartzenberg et al9 showed that for the same dose of nitroprusside, patients with HFpEF displayed far greater drop in blood pressure than patients with HFrEF, an effect explained by the steeper end systolic pressure volume relationship (Fig 2). Patients with HFpEF were also much more likely to display a drop in forward SV with nitroprusside, despite very high filling pressures. This is likely related to increased diastolic LV stiffness and increased reliance on high filling pressures to distend the ventricle to an adequate preload (Fig. 5).9 In a placebo-controlled crossover trial, isosorbide mononitrate was recently tested in 110 subjects with HFpEF.166 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 with 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.166 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,211 which is known to be problematic in HFpEF.41 In addition, the exaggerated blood pressure lowering effects might have contributed to decreased activity levels.9 More targeted interventions that deliver NO at the time of greatest need, such as inorganic nitrite, might be more effective are being evaluated in this population.91 Curr Probl Cardiol, April 2016

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Phosphodiesterase 5 Inhibitors An alternative method to restore NO signaling is to decrease the degradation of its downstream second messenger (cyclic guanosine monophosphate) using phosphodiesterase 5 inhibitors (PDE5i). In animal models of pressure-overload hypertrophy, sildenafil improves ventricular structure and function dramatically.212 In a small, single-center study, 1 year of treatment with sildenafil improved hemodynamics, right heart function, and gas transfer in patients with HFpEF and severe right HF.213 However, in the larger, multicenter RELAX trial, sildenafil did not improve exercise capacity, neurohormones, ventricular function, or quality of life.163 Part of this may be related to the fact that PDE5i does not appear to be upregulated in HFpEF.114 There may also be untoward effects of sildenafil on ventricular contractility that offset any potential benefits on endothelial and vascular function.214 A more recent trial testing sildenafil in patients with HFpEF and invasively-proven PH again showed no improvement in hemodynamics or clinical parameters.215

Statins In a prospective observational study of HFpEF, statin therapy was associated with significantly lower mortality (relative risk ¼ 0.20) over a median follow up of 12 months, whereas ACEi, ARB, β-blockers, and calcium channel blocker therapy had no association with survival.216 However, the GISSI-HF Trial, which tested the effects of rosuvastatin on death and death or cardiovascular hospitalization in patients with chronic HF, found no benefit in the subgroup of patients included with relatively preserved EF (440%).217 More recent data from a Swedish registry and meta-analysis of prior trials have suggested that statins may be beneficial in HFpEF.218,219 Like beta blockers, a large scale multicenter placebocontrolled trial is urgently needed to clarify the role of statins in people with HFpEF.

Nonpharmacologic Interventions Small randomized trials have consistently shown that exercise training in HFpEF improves exercise capacity as well as quality of life.152–154,158,220 It appears that these benefits are mediated by the periphery and are largely independent of the heart,153 though a study did observe improvements in diastolic function.154 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.221 170

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Dietary interventions may also prove effective. In a small, single-center trial, 3 weeks of treatment with a salt-restricted DASH diet improved diastolic function, arterial stiffness, and ventricular-arterial coupling in 13 subjects with HFpEF.222 Larger scale multicenter studies will provide greater insight into the role of dietary intervention in HFpEF.

Management of Comorbidities CAD is very common in HFpEF, seen in roughly 50%-67% of patients defined angiographically or anatomically from post-mortem examinations.81,123 Hwang et al81 have recently shown that the presence of coronary disease is independently associated with increased mortality in HFpEF. In a retrospective, single-center study, patients undergoing complete revascularization had better maintenance of ventricular function over time and higher survival as compared with patients not receiving complete revascularization.81 Intriguingly, stress testing identified the presence or absence of coronary disease poorly, with very high rates of false positive and false negative tests. At this time, there is no prospective trial data to guide decisions regarding revascularization for patients with coronary disease and HFpEF, though consensus guidelines recommend revascularization if symptoms of HF are deemed to be related to coronary ischemia.8 Atrial fibrillation is very common in HFpEF, seen in two-third of patients at some point during their lifespan.136 Patients with HFpEF and atrial fibrillation are more likely to display right heart dilatation and dysfunction, tricuspid regurgitation, exercise limitation, and they have higher risk of death in long term follow up, independent of other confounders.53,55,57,128,136 There is no clear cut advantage for rhythm as opposed to rate control in HFrEF,223 but this has never been tested in patients with HFpEF. Recent studies have shown that aggressive efforts to restore and maintain sinus rhythm in people with HFpEF and atrial fibrillation can be successful and may be associated with improvements in ventricular function if sinus rhythm can be maintained.224 Further study is required to understand the management of atrial fibrillation in people with HFpEF.

Future Directions Numerous promising therapies are currently being studied in clinical trials for HFpEF. Sacubitril (a combined valsartan-neprilysin inhibitor) showed convincing superiority compared with enalapril HFrEF,225 and in the phase II PARAMOUNT trial, this treatment showed greater Curr Probl Cardiol, April 2016

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improvements in NT-proBNP as compared with ARB alone.162 A larger pivotal trial (PARAGON) is currently underway (NCT01920711) with intended enrollment of 4300 patients with an EF 4 45%. 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 in mm Hg and improved cardiac output reserve.91 Another acute crossover study testing inorganic nitrate (precursor to nitrite) delivered as beetroot juice also observed improvements in peak exercise capacity.167 Larger scale studies testing this novel therapy are currently underway. In a subgroup analysis of the RELAX-HF trial, seralaxin, a recombinant form of the human pregnancy hormone relaxin 2, significantly improved acute dyspnea, the acute biomarker profile and all-cause mortality at 180 days in the 26% of HFpEF patients enrolled.226 The results must be interpreted with the usual caution applied to post-hoc subgroup analyses, and larger trials evaluated this drug specifically in HFpEF are eagerly awaited. 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.227,228 A larger scale clinical trial is currently underway to help inform understandings regarding this novel approach. As described above, phase 3 studies testing beta blockers and statins remain a critical unmet need in our understanding regarding the treatment of HFpEF.

Conclusion Research in the last 10 years has significantly advanced our understanding of the pathophysiology of HFpEF. From merely being considered a disorder of diastolic dysfunction, we now understand that multiple pathophysiological abnormalities described in this article contribute to global cardiovascular reserve limitation in this disease. Not all of these abnormalities have been observed in every studied patient with HFpEF, but though there is mechanistic heterogeneity among contributors to exercise intolerance, there is also abundant evidence in support of overarching systemic processes that drive structural and functional changes that cause the disease. Diagnosis of HFpEF is challenging and requires objective documentation of hemodynamic sequelae of myocardial dysfunction, which can be obtained from history and physical examination, imaging, or in some cases, invasive testing. Future research should seek to develop well validated standard diagnostic criteria for HFpEF and standardize 172

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phenotypic categories of exercise intolerance; thereby allowing us to develop targeted treatment, and hopefully improve outcomes in specific subsets of the rapidly growing epidemic of HFpEF. There is no therapy that is proven to improve survival, but interventions such as exercise training and diuretic usage based upon invasive pressure data have shown improvements in aerobic capacity, quality of life, and reduction in HF hospitalization. Given the rapidly growing epidemic of HFpEF, new therapies and understanding of the molecular mechanisms driving this syndrome are urgently needed. Many promising therapies and strategies are currently being tested and in the near future we may finally be able to help improve the debilitating shortness of breath and activity intolerance that currently plagues our patients with HFpEF. Gary S. Francis, MD: This is an excellent, comprehensive summary of our current knowledge of HFpEF. As the authors point out, HFpEF is a growing problem and will soon or already has surpassed HFrEF as the primary form of clinical HF. Dr Borlaug and colleagues have been at the forefront of this growing clinical syndrome, have studied it extensively, and are wellpositioned to review our current understanding of HFpEF. We still do not have a specific therapy for HFpEF, but important clinical trials are underway. The experience from the Mayo Clinic group is that CAD is common in patients with HFpEF (68% by coronary angiography), may strongly influence their subsequent course, and that revascularization may improve outcomes in this group (S-J Hwang, V. Melenovsky, B. Borlaug, JACC 2014;63:2817-2827). Despite the fact that many HFpEF patients are elderly, frail, and with much comorbidity, they are often in need of rather specialized evaluation. We have a low threshold to perform a right-heart catheterization, coronary angiography if appropriate, and exercise testing. We have found that these patients are best cared for in a dedicated clinic by physicians with a high interest in their care, and where patient entry into clinical trials can be facilitated.

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