Heart Failure with Preserved Ejection Fraction: Time to Revisit the Stiff Heart

Introduction

In the current era of cardiovascular disease, the diagnosis of heart failure with preserved ejection fraction (HFpEF) is a well-recognized distinct clinical entity. It has specific fundamental epidemiologic, pathophysiologic, and phenotypic differences compared with heart failure with reduced ejection fraction (HFrEF). Multiple studies have demonstrated a rising prevalence of this condition and an increasing number of HFpEF hospitalizations nationwide [1, 2]. Mortality and hospital readmission rates in HFpEF are comparable to those in HFrEF, and both conditions remain an equally unmet medical and financial need in cardiology today [2–4]. Currently there are no sex-specific implications regarding the evaluation and management of HFpEF in women compared with men. However, women with heart failure, especially elderly women, are much more likely to have the HFpEF phenotype than the HFrEF phenotype, a notable concern in light of our aging population [5]. There are a limited number of evidence-based therapies capable of reducing the morbidity and mortality associated with this condition. We therefore include this article among others in this issue of Cardiovascular Innovations and Applications focused on cardiovascular disease in women. The purpose of this article is to review the epidemiology, pathophysiology, clinical features, and current management strategies in HFpEF, especially as it pertains to women.

Epidemiology/Risk Factors

The most recently published large-scale epidemiologic data sets for HFpEF are relatively outdated [6, 7]. However, studies consistently show a steadily increasing trend in the overall prevalence of HFpEF and the number of HFpEF hospitalizations in the United States [1, 2]. Moreover, the proportion of admissions of people with HFpEF compared with HFrEF is increasing, and HFpEF is expected to become the more common phenotype of the two. Combined mortality and readmission rates at 60 and 90 days have been shown to be essentially the same for HFpEF and HFrEF, 35.3 and 36.1%, respectively [6].

There are major sex-specific differences in the prevalence and incidence of HFpEF. Studies estimate that up to twice as many women have HFpEF compared with men, a statistic that sharply contrasts with the male predominance observed in HFrEF [5, 8, 9].

The risk of HFpEF increases sharply with age. Additional risk factors such as hypertension, diabetes, obesity, COPD, and chronic renal insufficiency not only contribute to heart failure hospitalization but also increase stiffness, creating mayor impairments to myocardial relaxation and filling. HFpEF has been shown to be a disease that coexists with other comorbid conditions more frequently than HFrEF. Up to 50% of patients with HFpEF have five or more comorbid conditions. While the all-cause mortality rates for both HFpEF and HFrEF are similar, the rate of noncardiovascular death is significantly higher in HFpEF compared with HFrEF. Moreover, the greater the number of comorbidities present, the higher the mortality rate in HFpEF.

Diagnosis

Because of the nonspecific nature of the signs and symptoms of HFpEF, establishment of a true diagnosis presents many challenges. The patient history, physical examination results, serum natriuretic peptide levels, electrocardiogram, chest radiograph, transthoracic echocardiogram, and invasive hemodynamics by right-sided heart catheterization (RHC) can all provide supporting evidence for the diagnosis of HFpEF, but each has its limitations.

Current guidelines recommend that this diagnosis be considered in patients who have a clinical syndrome of heart failure (i.e., signs and symptoms of congestion and/or impaired cardiac output) with a left ventricular ejection fraction (LVEF) of greater than 50% [10]. This should be supported by abnormal brain natriuretic peptide levels and evidence of structural heart disease or abnormal diastolic function. The diagnosis of HFpEF should not be made in an asymptomatic patient regardless of abnormalities on other testing (i.e., diastolic dysfunction on transthoracic echocardiogram or elevated natriuretic peptide levels in isolation). The LVEF cutoff justifying a label of HFpEF versus HFrEF has historically been a subject of debate. In earlier proposed definitions, an LVEF greater than 40% was accepted for the diagnosis of HFpEF. However, there is now a designation known as heart failure with midrange ejection fraction, intended to classify patient with LVEF between 41 and 49% [10]. These distinctions are highly relevant as new data continue to emerge regarding the different pathophysiology of these subgroups, as well as potential differences in their response to specific therapies.

There are numerous conditions that can lead to heart failure syndromes, even in the setting of a preserved ejection fraction, and these must be excluded before a true diagnosis of HFpEF is made. These include constrictive pericarditis, infiltrative cardiomyopathies such as amyloidosis, genetic disorders of the myocardium such as hypertrophic cardiomyopathy, and any heart failure secondary to severe valvular disease. Table 1 outlines common alternative diagnoses that are clinically similar to HFpEF but that should not be included in the definition of HFpEF.

Once a clinical syndrome of heart failure is suspected and LVEF is noted to be greater than 50%, and after exclusion of the aforementioned alternative diagnoses, a diagnosis of HFpEF is supported by certain findings on a variety of additional laboratory, imaging, or invasive tests. There are multiple pitfalls in every diagnostic modality available, and these can lead to both the overdiagnosis of HFpEF when it is not truly present and the erroneous exclusion of this condition when it is in fact the correct diagnosis. The most relevant to our practice are outlined in the following sections.

Natriuretic Peptide Levels

We now know that a family of hormones called natriuretic peptides are released in response to increased atrial and ventricular myocardial stretch and wall stress that results from the elevated intracardiac pressures in heart failure patients, with the purpose of restoring sodium and fluid homeostasis [11]. The two most commonly used natriuretic peptide assays measure serum levels of B-type natriuretic peptide (BNP) and N-terminal proBNP. Both have established diagnostic and prognostic value in heart failure patients, with higher levels making the diagnosis of heart failure more likely, and in those with an existing heart failure diagnosis, higher levels suggest a worse prognosis [12]. However, there are some important distinctions in natriuretic peptide interpretation when it comes to HFpEF.

HFpEF patients have lower average natriuretic peptide levels compared with HFrEF patients, even after adjustment for other markers of congestion and disease severity [13]. There are likely several reasons for this. HFpEF patients on average have significantly smaller left ventricular dimensions and are more likely to have left ventricular hypertrophy. On the basis of Laplace’s principle, the left ventricle in HFpEF is subject to significantly lower degrees of left ventricular wall stress, one of the major triggers for natriuretic peptide release [14]. In addition, natriuretic peptides are highly metabolized in adipose tissue. As a result, obesity, which itself is a major risk factor for HFpEF, is a frequent cause of false negative natriuretic peptide results in these patients [15].

Conversely, an elevated natriuretic peptide level is nonspecific and can be seen in the absence of HFpEF. Alternative causes of elevated natriuretic peptide levels that should be ruled out before a diagnosis of HFpEF is confirmed include atrial fibrillation, chronic renal insufficiency, hypertensive urgency, pulmonary embolism, sepsis, myocardial infarction, and anemia.

Echocardiography

Transthoracic echocardiography provides an integral comprehensive assessment of cardiac structure and function that extends far beyond estimation of LVEF. Like most diagnostic tools, it can identify numerous findings that are suggestive, but not unequivocally diagnostic, of HFpEF. Left ventricular hypertrophy and left atrial enlargement are the most common structural abnormalities in HFpEF but are not always present, and image quality often limits accurate measurements [16].

Diastolic function assessment is essential but complex, and often leads to indeterminate results because of discrepancies between the different parameters that are measured. A comprehensive review of diastolic function assessment with echocardiography is beyond the scope of this article; however, current society recommendations are readily available and should be used when needed if a diagnosis of HFpEF is suspected [17].

Most indices of diastolic function use blood velocity measurements obtained with Doppler imaging to provide either quantitative or qualitative estimations of intracardiac pressures. As discussed later, many HFpEF patients have normal hemodynamics at rest and may not demonstrate the expected abnormalities needed to confirm the diagnosis, especially if they are compensated and euvolemic at the time of the examination. Parameters subject to this limitation include mitral inflow velocity patterns, E/e’ ratio for pulmonary capillary wedge pressure (PCWP) estimation, pulmonary artery pressure estimations by tricuspid and pulmonic regurgitation Doppler jets, pulmonary vein Doppler flow patterns, and inferior vena cava diameter.

Mitral annular velocity measurement by tissue Doppler imaging (TDI) is potentially exempt from this diagnostic limitation, as it is a velocity measurement of actual myocardial relaxation as opposed to blood flow. In patients with true diastolic dysfunction, mitral annular recoil from the apex to the base after systolic contraction is slow and inefficient. Therefore TDI values should be abnormally low in HFpEF regardless of loading conditions or volume status [18]. However, a wide range of normal values for TDI are reported, with additional variations defined depending on age and sex; hence no single cutoff value exists to reliably confirm or exclude diastolic dysfunction by myocardial annular velocity alone [17].

Newer echocardiographic imaging techniques, specifically myocardial strain imaging with speckle tracking software, may increase the sensitivity of echocardiography for diagnosing HFpEF. Evaluation of myocardial function with this parameter shows that longitudinal and circumferential systolic strain is significantly impaired in HFpEF patients compared with healthy controls, despite no differences in LVEF [19]. Additionally, myocardial contraction fraction, which is the ratio of left ventricular stroke volume to myocardial volume, has also been shown to be a more sensitive index of systolic function that becomes impaired in HFpEF [20, 21].

The Role of Right-Sided Heart Catheterization

From a hemodynamic standpoint, all heart failure syndromes are characterized by an abnormally reduced cardiac output, elevations in diastolic filling pressures leading to systemic and pulmonary venous congestion, or a combination of both. Invasive hemodynamic assessment by RHC remains an invaluable test in the evaluation of patients with suspected HFpEF. In patients with symptoms of heart failure and a preserved ejection fraction, an elevated PCWP and/or the presence of pulmonary venous hypertension as assessed by RHC strongly supports a diagnosis of HFpEF. Invasive RHC is the only test that can definitively distinguish pulmonary hypertension secondary to HFpEF (i.e., World Health Organization group 2 pulmonary hypertension) from other World Health Organization classifications that should not be included in the definition of HFpEF.

There is, however, a fundamental limitation to routine RHC, in that all measurements are typically obtained with the patient at rest, and ideally when the patient is clinically euvolemic. We now know that in many patients with HFpEF pulmonary artery pressure and PCWP may appear normal at rest, but increase dramatically with a moderate exercise challenge [22]. This hemodynamic response to exertion allows us to understand the profound activity intolerance that is so characteristic of this condition. Therefore in patients with suspected HFpEF who have normal findings on RHC at rest, the next diagnostic step should be exercise hemodynamics so as to maximize the sensitivity of hemodynamic testing.

Pathogenesis

The pathobiology of HFpEF is complex and incompletely understood. Initially, proposed mechanisms emphasized the concept of myocardial afterload excess secondary to arterial hypertension being the main insult by which HFpEF develops [23]. This theory was supported by the extremely high prevalence of systemic hypertension in the HFpEF population and numerous studies suggesting hypertension is a leading risk factor for HFpEF. In addition to this, pathways demonstrating the adverse myocardial dysfunction and remodeling secondary to hypertensive heart disease are well described.

There are significant sex-based differences in myocardial remodeling patterns that may explain why women are more likely to develop HFpEF. Compared with men, women exhibit a more significant degree of concentric hypertrophy in response to long-term increases in afterload, whereas men are more likely to develop eccentric hypertrophy in response to similar myocardial load alterations [24, 25]. Men also demonstrate increases in left ventricular chamber size with aging, whereas women do not [26]. The distinct left ventricular structural changes observed in women compared with men may create greater impairments in both systolic and diastolic function as well as more limitations to cardiac reserve during stress [27].

In the last 5 years a new paradigm for the development of HFpEF has been proposed, which identifies a systemic proinflammatory state created by comorbidities leading to coronary microvascular endothelial dysfunction as the underlying cause, as opposed to excessive afterload from hypertension (Figure 1) [28]. Paulus and Tschöpe [28] highlighted several compelling points supporting this pathway. They noted that large registry data show HFpEF to be more strongly associated with several comorbidities than with arterial hypertension [29]. Additionally, in HFpEF patients cardiomyocyte stiffness is not restricted to the left ventricle, but rather involves all four chambers, and in many cases is seen even in the absence of significant arterial hypertension [30].

Figure 1

Comorbidities Drive Myocardial Dysfunction and Remodeling in Heart Failure with Preserved Ejection Fraction.

Comorbidities induce a systemic proinflammatory state with elevated plasma levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), soluble ST2 (sST2), and pentraxin 3. Coronary microvascular endothelial cells reactively produce reactive oxygen species (ROS), vascular cell adhesion molecule (VCAM), and E-selectin. Production of ROS leads to formation of peroxynitrite (ONOO⁻) and reduced nitric oxide (NO) bioavailability, both of which lower soluble guanylate cyclase (sGC) activity in adjacent cardiomyocytes. Lower sGC activity decreases cyclic guanosine monophosphate (cGMP) concentration and protein kinase G (PKG) activity. Low PKG activity increases resting tension (F _passive) of cardiomyocytes because of hypophosphorylation of titin and removes the brake on prohypertrophic stimuli inducing cardiomyocyte hypertrophy. VCAM and E-selectin expression in endothelial cells favors migration into the subendothelium of monocytes. These monocytes release transforming growth factor β (TGF-β). The latter stimulates conversion of fibroblasts to myofibroblasts, which deposit collagen in the interstitial space. COPD, chronic obstructive pulmonary disease. Reprinted with permission from Paulus and Tschöpe [28].

This “multimorbidity” theory, as it has been labeled by leading authors in the field [2], fits well with what data have shown in the HFpEF population. There is an overwhelmingly high prevalence of comorbidities in HFpEF, and a consistent observation in the literature that an increasing number of comorbidities identifies the highest-risk patients [31]. However, the specific comorbidity profile for each patient differs, and while most data analyses generally adjust the data for the presence or absence of certain conditions, this is mostly done in a binary fashion to facilitate statistical analyses. Most of these comorbidities, including COPD, renal insufficiency, diabetes, and obesity, have a severity spectrum, and each of them independently correlates with long-term risk of death, and it is extremely difficult to adjust the data appropriately when statistical analyses are performed. Understanding the magnitude of this heterogeneity, we can view HFpEF as a common phenotypic end result for patients with overlapping comorbidities who are otherwise quite different from each other. From this perspective, we might understand the relative inability to identify single therapies with proven benefit when applied to the HFpEF population as a whole.

Pathophysiology

The pathophysiology of HFpEF is related to multifactorial issues [32]. During systolic contraction, left ventricular twist forces mitral annular motion toward the apex. During early diastole the untwisting process and recoil generate negative intraventricular pressure, gradient, or suction, causing rapid motion of the annulus back to the base of the heart. This aids ventricular filling by moving the annulus around the incoming column of blood.

Patients with HFpEF develop arterial stiffness, diabetes, and left ventricular hypertrophy, all of which contribute to myocardial fibrosis. Although overall ventricular function is normal, there are regional systolic issues that affect strain and relaxation. There is delayed left ventricular untwisting that leads to decreased ventricular suction, causing less recoil of the annulus. This affects early diastolic filling, requiring increased late diastolic filling from atrial contraction. With exercise, diastole shortens further, increasing end-diastolic pressure, contributing to breathlessness on exercise.

An increasing number of studies now implicate a more global degree of cardiac dysfunction in HFpEF that extends beyond sole diastolic impairments [33]. Chronotropic incompetence, impaired vasodilation, and inefficient ventriculoarterial coupling are all associated with HFpEF, each of which can contribute to the profound exertional limitations classically described by these patients [34–36].

Management

In addition to all of the diagnostic uncertainties that must be reconciled in HFpEF before an accurate diagnosis is made, the management of these patients can be equally challenging. The goals of care are fundamentally similar to those in patients with HFrEF: reduce symptoms, improve quality of life, and prevent adverse events such as death and all-cause hospitalizations.

Acute HFpEF Management

In HFpEF there are distinct derangements in cardiac pressure-volume relationships that must be understood so as to safely achieve cardiopulmonary decongestion and hemodynamic optimization. One of the central differences between HFpEF and HFrEF is the hemodynamic responses observed with vasodilator therapy. Although HFpEF patients have significantly higher arterial blood pressure compared with HFrEF patients, the pressure-volume loops in HFpEF show only a modest increase in stroke volume in response to acute vasodilation, whereas in HFrEF stroke volume response to vasodilation is much more robust [37]. It is crucial to understand this to minimize the risk of iatrogenic hypotension and kidney injury in acute HFpEF management, as the risk of postdischarge death increases when hospitalizations are complicated by these events [38].

This iatrogenic risk is also present when diuretics are used to achieve optimal volume status in hospitalized HFpEF patients. Achieving clinical euvolemia remains one of the major treatment goals and most effective ways to alleviate symptoms. However, the mechanisms of cardiopulmonary fluid overload in HFpEF are complex, and they are not merely a result of increased total blood volume. Decreased splanchnic circulation capacitance and impaired baroreceptor function both contribute to sudden mobilizations of blood volume from the splanchnic circulation into the cardiopulmonary system in HFpEF patients. This inappropriate and exaggerated volume redistribution can occur with any trigger of sympathetic activation, such as exercise or transient hypoxia. Combined with reduced cardiac chamber and pulmonary vascular compliance, this volume of blood redirected from the splanchnic vascular bed to the heart and lungs is a setup for overload and clinical decompensation [39]. While afterload reduction and diuresis are necessary in this scenario, it is important to recognize the inherent risk of overdiuresis given many HFpEF patients have only modest total body hypervolemia. Moreover, understanding the optimal rate of diuresis in these patients is equally important. Many clinicians use rising serum blood urea nitrogen and creatinine levels as the main end point for determining when patients have been diuresed to euvolemia. In HFpEF this is an oversimplified approach with many pitfalls. Various degrees of preload dependence, plasma refill rates, and degrees of renal vein congestion can all cause transient worsening in renal function in HFpEF patients, even when there is persistent congestion [40]. Given that persistent congestion on the day of discharge identifies one of the highest-risk subgroups among heart failure patients, every effort must be made to confirm that euvolemia has been truly achieved. When bedside assessment of volume status is in question, intracardiac pressure estimation by Doppler echocardiography or invasive RHC can better characterize hemodynamics and verify euvolemia.

Managing the Chronic HFpEF Patient

The wealth of data that exist demonstrating improved outcomes in HFrEF with aggressive neurohormonal blockade of the renin-angiotensin-aldosterone and sympathetic nervous systems is almost nonexistent in HFpEF. Primary outcomes in numerous clinical trials testing the efficacy of beta-blockers, ACE inhibitors, and angiotensin receptor blockers have all had negative primary end points [5, 41, 42].

There is one notable exception to the long-term trend of negative clinical trial results for pharmacotherapy in HFpEF: the TOPCAT trial [43]. This was a randomized, double-blinded multicenter trial testing the efficacy of spironolactone versus placebo in HFpEF. The significance of this trial’s findings are subject to major individual interpretation, especially with subsequent data that recently emerged regarding significant regional variability in the results of the study [44]. The original trial reported no significant differences in the primary composite end point of cardiac death, cardiac arrest, or hospitalization for heart failure. However, the secondary end point of heart failure hospitalizations was significantly less in the spironolactone arm. This established a potential role for this spironolactone in HFpEF considering that reduction in HFpEF admissions is a large unmet need in clinical practice.

The TOPCAT investigators noted, however, that for patients enrolled in Russia and Georgia, the primary outcome rates were approximately four times lower than for patients enrolled in sites in the United States, Canada, Brazil, and Argentina (the Americas). Additionally, patients enrolled in Russia and Georgia were younger, had less atrial fibrillation and diabetes, and were more often enrolled on the basis of a prior hospitalization for heart failure, as opposed to having an elevated serum natriuretic peptide level. The unusually low event rate in Russia and Georgia, coupled with subsequent data showing undetectable spironolactone metabolites in a significant portion of patients enrolled in these sites [45], has led many to question not only whether HFpEF was truly present in these patients but also whether the drug was appropriately administered. Post hoc analysis demonstrated that if trial data from the sites in Russia and Georgia sites were excluded, there was in fact a significantly lower rate of the primary outcome in the spironolactone group for patients enrolled in the Americas. The extensive data analyses from the TOPCAT trial created the basis by which current guidelines formally recommend use of spironolactone in HFpEF [46].

It is crucial to remember, however, that the risk of hyperkalemia increases with spironolactone use [47], and spironolactone should not be used if serum potassium levels are above 5 mEq/L or if creatinine levels are above 2.5 mg/dL. Moreover, serum potassium and creatinine levels should be rechecked 48 h and 1 week after initiation of spironolactone therapy to monitor the patient for these complications.

The role of combined angiotensin receptor blockade and neprilysin inhibition has not been fully explored in HFpEF. The combination of sacubitril and valsartan appears to be safe in this population, and produces greater reduction in natriuretic peptide levels than does valsartan alone [48]. The PARAGON-HF trial is ongoing and aims to prospectively determine whether this effect translates into significant reductions in adverse cardiovascular outcomes in HFpEF [49].

Invasive Hemodynamic Monitoring

A major challenge in the management of all heart failure patients, including HFpEF patients, is early detection of cardiopulmonary congestion, which is the most common cause of symptoms and hospital admissions. There are now data demonstrating that right-sided heart pressures begin to increase for up to 5 days before the onset of the congestive symptoms seen in clinical decompensation [50].This has led to the investigation of invasive hemodynamic monitoring devices that can prompt an earlier adjustment of therapy to prevent symptom worsening and hospitalizations.

The most promising data with this strategy were demonstrated in the CHAMPION trial by Abraham et al. [51]. In this trial heart failure patients, regardless of LVEF, were randomized to receive physician-guided clinic-based management alone or physician-guided clinic-based management in combination with a wireless implantable hemodynamic monitor called CardioMEMS. This is a permanent device implanted by a percutaneous approach into the main pulmonary artery that continuously monitors pulmonary artery pressure. In addition to routine clinic visits, patients in the device arm also performed periodic transmissions of the device recording, which were used to guide adjustments in their medical therapy according to prespecified algorithms. Most adjustments that occurred were changes in diuretic dosing, although vasodilator therapy was sometimes adjusted as well. The trial demonstrated that hospitalization rates were significantly reduced in the CardioMEMS group, without a significant increase in procedural complication rates. Subgroup analysis of the patients with LVEF greater than 40% (119 of 550 total patients) showed the hospitalization rate was significantly lower in the CardioMEMS-guided treatment arm [52].

The CHAMPION trial identified an opportunity to adjust therapy in HFpEF patients before the onset of clinical decompensation; however, it is important to understand the trial design if we are to extrapolate this therapy to our practice and expect similar results. The key to optimal use of hemodynamic monitoring is ensuring that the data collected can be responded to reliably and in real time. This can be accomplished only in disease management programs with sufficient infrastructure to assign a provider a dedicated role for this purpose. Without this, the window to provide timely recommendations to the patient closes, and the frequency of hospitalizations or emergency department visits will not likely change. In addition, while there was in fact no significant increase in adverse events related to the device implant itself, there is a learning curve for every invasive procedure. Complications rates are ultimately operator dependent and might still be higher than that published for the trial.

Targeting Comorbidities: The Future of HFpEF Management

As previously mentioned, the overwhelming majority of HFpEF patients have several comorbid conditions that complicate their management and constitute a major obstacle to achieving significant reductions in the rates of adverse events such as death or hospitalization. The comorbidity profile of each patient and the severity of each comorbid condition differ widely and therefore create significant heterogeneity within the HFpEF population. It is reasonable therefore to consider an individualized approach to the HFpEF patient, targeting the comorbidities that seem severest or most clinically relevant. Despite the lack of randomized multicenter trials supporting certain treatment options, there is likely still a role for symptom management and improving outcomes in HFpEF subgroups with a particularly disabling comorbidity.

There is an extensive physiologic rationale for pursuing a rhythm control strategy as opposed to rate control for atrial fibrillation in HFpEF. Tachycardia, rhythm irregularity, and the absence of atrial contraction all exacerbate the intrinsic impairment in diastolic filling and can worsen congestion and exertional limitations. Data show that right ventricular function, which itself is a powerful prognostic marker in HFpEF, is significantly better in HFpEF patients in sinus rhythm compared with those with atrial fibrillation [53, 54].

Coronary revascularization is also an option to consider if HFpEF coexists with obstructive coronary artery disease. Single-center data have shown that complete revascularization in HFpEF patients is associated with less deterioration of cardiac function, and possibly reduced mortality, than in unrevascularized or incompletely revascularized HFpEF patients. Retrospective analysis showed mortality rates with complete revascularization did not significantly differ from those in patients who had no obstructive coronary artery disease [55].

Diabetes is very common in HFpEF, and recent trials suggest that certain strategies for glycemic control, specifically with sodium/glucose cotransporter 2 (SGLT2) inhibitors, may improve heart failure outcomes in these patients [56, 57]. The two largest trials reporting reduction in heart failure events with SGLT2 inhibitors did not specify whether the patients had HFrEF or HFpEF. However, a potential benefit from these agents, specifically in HFpEF patients, is still hypothesized given the high rates of HFpEF observed in the diabetic population [58].

Obstructive sleep apnea (OSA) is very common in HFpEF, and while no randomized trial has yet demonstrated a reduction in outcomes in HFpEF with nocturnal positive pressure use, there are data suggesting the presence of OSA identifies a higher-risk HFpEF subgroup. In addition, the deleterious cardiovascular effects of untreated OSA are extensive, and very well described. Therefore we recommend screening all HFpEF patients for OSA, formal sleep studies when indicated, and if needed, referral to sleep medicine specialists for optimal treatment.

The 2017 heart failure guidelines for HFpEF focus on treatment of comorbid conditions. Treatment of hypertension, diuretics for volume overload, treatment of symptoms of coronary artery disease, and control of atrial fibrillation are emphasized. Use of aldosterone antagonists along with angiotensin receptor blockers in this patient population is associated with reduction in heart failure hospitalizations. Of note, the use of nutritional supplements and phosphodiesterase inhibitors has no benefit in HFpEF [46].

Conclusion

HFpEF is a disabling condition with rising prevalence yet incompletely understood disease mechanisms, pathophysiology, and treatment. Efforts to better characterize underlying causes and optimal management strategies are evolving rapidly, and must continue to reduce the staggering morbidity and mortality rates created by this disease. While there are a few options with evidence suggesting benefit in every patient, it seems that HFpEF is truly an entity where an individualized approach to the comorbidity profile of each patient promises the highest likelihood of treatment success.

The authors declare no conflict of interest.