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Heart failure with preserved ejection fraction: an update on pathophysiology, diagnosis, treatment, and prognosis

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients have symptoms and signs of HF with normal or near-normal left ventricular ejection fraction (LVEF ≥50%). Roughly half of all patients with HF worldwide have an LVEF ≥50% and nearly half have an LVEF <50%. Thanks to the increased scientific attention about the condition and improved characterization and diagnostic tools, the incidence of HF with reduced ejection fraction (HFrEF) dropped while that of HFpEF has increased by 45%. HFpEF has no single guideline for diagnosis or treatment, the patient population is heterogeneously and inconsistently described, and longitudinal studies are lacking. To better understand and overcome the disease, in this review, we updated the latest knowledge of HFpEF pathophysiology, introduced the existing promising diagnostic methods and treatments, and summarized its prognosis by reviewing the most recent cohort studies.

Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Heart failure; HFpEF; HFrEF; Pathophysiology


Introduction

Heart failure (HF) is when the heart is unable to pump sufficient blood to maintain blood flow to meet the body's needs. HF is a common, costly, and potentially fatal condition (11. Metra M, Teerlink JR. Heart failure. Lancet 2017; 390: 1981–1995, doi: 10.1016/S0140-6736(17)31071-1.
https://doi.org/10.1016/S0140-6736(17)31...
). In 2015, it affected about 40 million people globally (11. Metra M, Teerlink JR. Heart failure. Lancet 2017; 390: 1981–1995, doi: 10.1016/S0140-6736(17)31071-1.
https://doi.org/10.1016/S0140-6736(17)31...
). Overall, around 2% of adults have HF, and in those over the age of 65, this increases to 6–10% (11. Metra M, Teerlink JR. Heart failure. Lancet 2017; 390: 1981–1995, doi: 10.1016/S0140-6736(17)31071-1.
https://doi.org/10.1016/S0140-6736(17)31...
).

In the past, heart failure with reduced left ventricular ejection fraction (HFrEF) was the most commonly diagnosed clinical entity in HF patients. However, with the improvement of diagnostic tools, especially with the introduction of new echocardiography modalities, HF has recently been classified into three subtypes, namely HFrEF, heart failure with preserved ejection fraction (HFpEF), and HF mid-range ejection fraction (HFmrEF), according to the ejection fraction, natriuretic peptide levels, and the presence of structural heart disease and diastolic dysfunction (22. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200, doi: 10.1093/eurheartj/ehw128.
https://doi.org/10.1093/eurheartj/ehw128...
).

HFpEF is a vital component of HF. Patients with HFpEF have significant morbidity and mortality but, unlike HFrEF,there are currently no effective validated therapies. In addition, HFpEF is poorly investigated (33. Amgalan D, Kitsis RN. A mouse model for the most common form of heart failure. Nature 2019; 568: 324–325, doi: 10.1038/d41586-019-00983-4.
https://doi.org/10.1038/d41586-019-00983...
). To better understand the mechanisms underlying this disease and help scientists to explore future therapies, we updated here the latest knowledge of the pathophysiology, diagnosis, treatment, and prognosis of HFpEF (33. Amgalan D, Kitsis RN. A mouse model for the most common form of heart failure. Nature 2019; 568: 324–325, doi: 10.1038/d41586-019-00983-4.
https://doi.org/10.1038/d41586-019-00983...
).

Pathophysiology

LV structure and remodeling

The structural remodeling that often occurs in HFpEF differs dramatically from that in HFrEF. Early descriptive studies in HFpEF suggested that concentric left ventricular (LV) hypertrophy with normal chamber size was typical (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). However, several patients with hemodynamic evidence of HF do not have structural remodeling of the heart but have normal LV geometry (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). Thus, the absence of structural heart disease does not exclude the diagnosis of HFpEF. Many, but not all, patients with HFpEF exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by the following features (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
): 1) normal or near-normal end-diastolic volume; 2) increased wall thickness and/or LV mass; 3) increased ratio of myocardial mass to cavity volume; and 4) increased relative wall thickness (RWT). The RWT is defined as either 2 X (posterior wall thickness) / (LV diastolic diameter) or as (septal wall thickness + posterior wall thickness) / (LV diastolic diameter). At the structural level, cardiomyocytes in HFpEF are thicker and less elongated than in HFrEF, and collagen content is increased compared with control populations (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). By comparison, patients with HFrEF typically exhibit a pattern of eccentric remodeling with an increase in end-diastolic volume, an increase in LV mass but little increase in wall thickness, and a substantial decrease in the ratios of mass to volume and thickness to radius (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
).

LV diastolic limitations

Diastolic dysfunction is defined as the inability to fill the ventricle to an adequate preload volume (end-diastolic volume; EDV) at acceptably low pressures (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Diastolic function is often conceptualized as the totality of an active process of pressure decay (relaxation) during early diastole related to myofilament dissociation and calcium reuptake, and ‘passive’ stiffness associated with the viscoelastic properties that are governed by mechanical changes from the sarcomere to extracellular matrix, chamber, and pericardium (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Diastolic dysfunction and HFpEF are not synonymous terms (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the LV, regardless of whether the LVEF is normal or abnormal and whether the patient is symptomatic or not (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Thus, diastolic dysfunction refers to unusual mechanical properties of the ventricle (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). HFpEF denotes the signs and symptoms of clinical HF in a patient with a normal LVEF and LV diastolic dysfunction (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Diastolic dysfunction alone is essentially part of normal human aging and is seen in many people that do not or never will have HFpEF. However, the presence of diastolic dysfunction is a risk factor for developing HFpEF (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

Most, although not all, studies have demonstrated that the rate of LV pressure decay during isovolumic relaxation (time constant τ) is prolonged in HFpEF (66. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura RA. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011; 97: 964–969, doi: 10.1136/hrt.2010.212787.
https://doi.org/10.1136/hrt.2010.212787...
). The minimal LV diastolic pressure or completion of relaxation normally occurs by 3.5 times the value of τ (normal τ <45 ms) after the mitral opening (66. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura RA. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011; 97: 964–969, doi: 10.1136/hrt.2010.212787.
https://doi.org/10.1136/hrt.2010.212787...
). However, when the heart rate increases, the left ventricle must enhance relaxation to allow for faster pressure decay. In HFpEF, this enhancement is lost, contributing to LV and left atrial (LA) pressure elevation (66. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura RA. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011; 97: 964–969, doi: 10.1136/hrt.2010.212787.
https://doi.org/10.1136/hrt.2010.212787...
).

Delayed relaxation is, however, only part of the problem in early diastole in HFpEF. The healthy left ventricle functions as a ‘vacuum cleaner’ that prevents LA hypertension by enhancing suction in response to increases in venous return (77. Ohara T, Niebel CL, Stewart KC, Charonko JJ, Pu M, Vlachos PP, et al. Loss of adrenergic augmentation of diastolic intra-LV pressure difference in patients with diastolic dysfunction: evaluation by color M-mode echocardiography. JACC Cardiovasc Imaging 2012; 5: 861–870, doi: 10.1016/j.jcmg.2012.05.013.
https://doi.org/10.1016/j.jcmg.2012.05.0...
). Studies have shown that the ‘vacuum cleaner’ function of the LV in patients with HFpEF is lost, especially when the heart rate is elevated. The filling of the LV can only rely on the high pressure of the LA (77. Ohara T, Niebel CL, Stewart KC, Charonko JJ, Pu M, Vlachos PP, et al. Loss of adrenergic augmentation of diastolic intra-LV pressure difference in patients with diastolic dysfunction: evaluation by color M-mode echocardiography. JACC Cardiovasc Imaging 2012; 5: 861–870, doi: 10.1016/j.jcmg.2012.05.013.
https://doi.org/10.1016/j.jcmg.2012.05.0...
).

Ventricular passive diastolic stiffness is also an essential determinant of the increase in LV filling pressures in HFpEF (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Most, but not all, studies have shown that, on average, LV end-diastolic stiffness is increased in patients with HFpEF (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). In the absence of endocardial or pericardial disease, diastolic LV dysfunction results from increased myocardial stiffness. Two compartments within the myocardium regulate its diastolic stiffness: the extracellular matrix and the cardiomyocytes. A stiffness change within one compartment is also transmitted to the other compartment via matricellular proteins (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Previous studies in the last 15 years have pointed to the importance of determinants within the cardiac myocytes, particularly the sarcomeric macromolecule titin in diastolic ventricular passive stiffness (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). The (giant) elastic sarcomeric protein titin is the dominant regulator of myocardial passive tension, and thus of the cardiomyocyte-derived stiffness (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Up to 80% of left ventricular passive stiffness may be explained by titin, especially when sarcomere lengths are still within physiological boundaries, while in over-stretched sarcomeres the contribution of the extracellular matrix becomes more dominant (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Titin regulates cardiomyocyte stiffness at the transcriptional and post-translational levels. At the transcriptional level, titin shifts from its compliant isoform N2BA toward its stiff isoform N2B have been postulated to contribute to diastolic dysfunction in HFpEF (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Post-translational modification of the titin N2B segment by protein kinase A (PKA)- and G (PKG)-mediated phosphorylation has been shown to change cardiomyocyte passive tension (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Diastolic intracellular calcium handling is a major determinant of LV relaxation. Dephosphorylated phospholamban (PLN) is an inhibitor of sarcoplasmic/endoplasmic reticulum Ca(2+)ATPase 2a (SERCA2a), but PKA-catalyzed (or CaMKII) phosphorylation of PLN results in the dissociation of PLN from SERCA2a, thus activating this Ca2+ pump and augmenting SERCA2a activity (99. Tanaka K, Wilson RM, Essick EE, Duffen JL, Scherer PE, Ouchi N, et al. Effects of adiponectin on calcium-handling proteins in heart failure with preserved ejection fraction. Circ Heart Fail 2014; 7: 976–985, doi: 10.1161/CIRCHEARTFAILURE.114.001279.
https://doi.org/10.1161/CIRCHEARTFAILURE...
,1010. Lyle MA, Brozovich FV. HFpEF, a disease of the vasculature: a closer look at the other half. Mayo Clin Proc 2018; 93: 1305–1314, doi: 10.1016/j.mayocp.2018.05.001.
https://doi.org/10.1016/j.mayocp.2018.05...
). Cardiomyocyte Ca2+ accumulation in the absence of concomitant enhancement of SERCA activity leads to elevated diastolic Ca2+, Ca2+ transients with preserved or enhanced amplitude, and slower Ca2+ reuptake kinetics with impaired relaxation. The inability of SERCA to expeditiously resequester Ca2+ becomes particularly evident at elevated stimulation frequencies, which may in part explain the chronotropic intolerance of the myocardium and reduced exercise capacity of HFpEF patients (1111. Peana D, Domeier TL. Cardiomyocyte Ca(2+) homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction. Curr Opin Pharmacol 2017; 33: 17–26, doi: 10.1016/j.coph.2017.03.005.
https://doi.org/10.1016/j.coph.2017.03.0...
). Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na+/K+‐ATPase (NKA) inhibition may increase contractility and facilitate active relaxation, improving systolic as well as diastolic heart function, both of which would be beneficial effects in the treatment of chronic HF (1212. Wallner M, Khafaga M, Kolesnik E, Vafiadis A, Schwantzer G, Eaton DM, et al. Istaroxime, a potential anticancer drug in prostate cancer, exerts beneficial functional effects in healthy and diseased human myocardium. Oncotarget 2017; 8: 49264–49274, doi: 10.18632/oncotarget.17540.
https://doi.org/10.18632/oncotarget.1754...
). Researchers have proposed that the diverse comorbidities of HFpEF contribute to a systemic inflammatory state, which induces microvascular endothelial inflammation resulting in endothelial dysfunction, reactive oxygen species production, and reduced nitric oxide (NO) bioavailability (1313. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62: 263–271, doi: 10.1016/j.jacc.2013.02.092.
https://doi.org/10.1016/j.jacc.2013.02.0...
). This finding provides a novel therapeutic target to improve diastolic stiffness and it is speculated to mechanistically tie together the loss of NO bioavailability in HFpEF with conventional risk factors including obesity, aging, and metabolic syndrome (1313. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62: 263–271, doi: 10.1016/j.jacc.2013.02.092.
https://doi.org/10.1016/j.jacc.2013.02.0...
).

Diastolic dysfunction is not common in HFpEF. Diastolic dysfunction cannot be observed by echocardiography at rest in one-third of patients with HFpEF (1414. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 588–595, doi: 10.1161/CIRCHEARTFAILURE.109.930701.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Many patients with HFpEF in the early stages did not present an increase in LV filling pressure at rest (1414. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 588–595, doi: 10.1161/CIRCHEARTFAILURE.109.930701.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). These patients usually have normal plasma levels of type B natriuretic peptide (BNP), which leads clinicians to make a false diagnosis of no HF (1414. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 588–595, doi: 10.1161/CIRCHEARTFAILURE.109.930701.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). This can be explained since natriuretic peptides are released and produced in response to increased myocardial wall tension. HFpEF is characterized by hypertrophic hearts with a small LV cavity, and this structural abnormality in itself does not elevate end-diastolic wall stress much, as can be perfectly concluded from Laplace's law (1515. Meijers WC, van der Velde AR, de Boer RA. Biomarkers in heart failure with preserved ejection fraction. Neth Heart J 2016; 24: 252–258, doi: 10.1007/s12471-016-0817-7.
https://doi.org/10.1007/s12471-016-0817-...
). In addition, obesity is associated with lower than normal BNP levels, and these findings may explain the reduction in BNP levels observed in patients with HFpEF (1414. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 588–595, doi: 10.1161/CIRCHEARTFAILURE.109.930701.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

Studies have shown that diastolic dysfunction in HFpEF does not appear to impair net LV filling, but this level of filling is at the expense of abnormal pressure elevation (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). In a prospective trial, aggressive treatment to reduce LV filling pressure in HFpEF was associated with a reduction in HF hospitalization (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
,1616. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011; 377: 658–666, doi: 10.1016/S0140-6736(11)60101-3.
https://doi.org/10.1016/S0140-6736(11)60...
). This further demonstrates that the importance of diastolic dysfunction in HFpEF should not be underestimated. Increased LA pressure can lead to dyspnea, secondary pulmonary hypertension, and atrial remodeling, which may make patients prone to right ventricular (RV) dysfunction and atrial fibrillation (1414. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 588–595, doi: 10.1161/CIRCHEARTFAILURE.109.930701.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

The most conspicuous and commonly present abnormalities in patients with HFpEF are related to diastolic dysfunction. This may present with impairments in relaxation, increases in chamber stiffness, or both. These abnormalities lead to an increase in LV filling pressures at rest or during exercise that causes dyspnea.

LV systolic limitations

Although ejection fraction is the measure that is used most often clinically to assess systolic function, it is more appropriately viewed as a reflection of ventricular-arterial coupling (1717. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Cardiol Clin 2011; 29: 269–280, doi: 10.1016/j.ccl.2011.03.003.
https://doi.org/10.1016/j.ccl.2011.03.00...
). By definition, the LV ejection fraction (EF) and most indices of contractile function are normal or nearly normal in patients with HFpEF. However, EF is a poor and nonspecific index of contractile function. EF can be low owing to very high afterload despite normal contractility, or it can be normal even when contractile function is impaired when afterload is low. Multiple studies have shown that, despite relative preservation in LV EF, patients with HFpEF display subtle abnormalities in systolic function. Studies evaluating load-independent measures of chamber and myocardial contractile function have shown that there are decreases in systolic function in patients with HFpEF compared with age-matched healthy controls as well as asymptomatic hypertensives (1717. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Cardiol Clin 2011; 29: 269–280, doi: 10.1016/j.ccl.2011.03.003.
https://doi.org/10.1016/j.ccl.2011.03.00...
). This finding of impaired systolic function has been confirmed in numerous studies utilizing tissue Doppler and strain imaging techniques (1717. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Cardiol Clin 2011; 29: 269–280, doi: 10.1016/j.ccl.2011.03.003.
https://doi.org/10.1016/j.ccl.2011.03.00...
). These abnormalities are most conspicuously noted in longitudinal contraction and motion of the basal LV in the region of the mitral annulus (1717. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Cardiol Clin 2011; 29: 269–280, doi: 10.1016/j.ccl.2011.03.003.
https://doi.org/10.1016/j.ccl.2011.03.00...
).

Abnormalities in LV systolic properties are strongly associated with adverse outcomes in patients with HFpEF (1818. Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 2016; 37: 3293–3302.). Inability to augment systolic function also causes and worsens diastolic reserve in HFpEF (1818. Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 2016; 37: 3293–3302.). These relatively mild abnormalities in systolic function at rest become much more significant limitations during exercise, which further burden an already impaired heart. Prior studies have shown that the inability to augment cardiac output during exercise is related mainly to poor systolic reserve, where a contractile function cannot be supplemented during stress in a usual fashion. This limits the ability to augment forward stroke volume and reduces cardiac output and end-organ perfusion (1818. Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 2016; 37: 3293–3302.).

Ventricular dyssynchrony

Ventricular dyssynchrony is a difference in the timing, or lack of synchrony, of contractions in different ventricles in the heart. Large differences in timing of contractions can reduce cardiac efficiency and is correlated with HF (1919. Liu S, Guan Z, Jin X, Meng P, Wang Y, Zheng X, et al. Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex. Int J Med Sci 2018; 15: 108–114, doi: 10.7150/ijms.21956.
https://doi.org/10.7150/ijms.21956...
). Mechanical dyssynchrony is a term used to describe systolic and diastolic mechanical variability. A previous study has suggested that approximately 30% of patients with a narrow QRS have mechanical dyssynchrony. HFrEF patients exhibited increased systolic dyssynchrony compared to HFpEF patients despite a narrow QRS complex in addition to the more reduced diastolic and systolic function (1919. Liu S, Guan Z, Jin X, Meng P, Wang Y, Zheng X, et al. Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex. Int J Med Sci 2018; 15: 108–114, doi: 10.7150/ijms.21956.
https://doi.org/10.7150/ijms.21956...
). Although electrical dyssynchrony (bundle branch block) is uncommon in patients with HFpEF, studies have shown that systolic and diastolic mechanical dyssynchrony is fairly prevalent (1919. Liu S, Guan Z, Jin X, Meng P, Wang Y, Zheng X, et al. Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex. Int J Med Sci 2018; 15: 108–114, doi: 10.7150/ijms.21956.
https://doi.org/10.7150/ijms.21956...
). The magnitude of dyssynchrony is related to the extent of diastolic dysfunction and the magnitude of aerobic limitation (1919. Liu S, Guan Z, Jin X, Meng P, Wang Y, Zheng X, et al. Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex. Int J Med Sci 2018; 15: 108–114, doi: 10.7150/ijms.21956.
https://doi.org/10.7150/ijms.21956...
). While therapies for dyssynchrony, such as biventricular pacing, provide benefits to HFrEF patients, no benefit is appreciable in HFpEF patients at this time (1919. Liu S, Guan Z, Jin X, Meng P, Wang Y, Zheng X, et al. Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex. Int J Med Sci 2018; 15: 108–114, doi: 10.7150/ijms.21956.
https://doi.org/10.7150/ijms.21956...
). Evidence demonstrated that targeting the improvement of diastolic and systolic function instead of managing systolic dyssynchrony might be of great importance in the treatment of HFpEF (1919. Liu S, Guan Z, Jin X, Meng P, Wang Y, Zheng X, et al. Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex. Int J Med Sci 2018; 15: 108–114, doi: 10.7150/ijms.21956.
https://doi.org/10.7150/ijms.21956...
).

Atrial dysfunction and atrial fibrillation

The left atrium functions as an essential barrier between the LV and the pulmonary circulation, by facilitating LV filling through its conduit and booster functions and by shielding the pulmonary vasculature from full LV pressure oscillations in concert with the mitral valve apparatus (2020. Santos AB, Roca GQ, Claggett B, Sweitzer NK, Shah SJ, Anand IS, et al. Prognostic relevance of left atrial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2016; 9: e002763, doi: 10.1161/CIRCHEARTFAILURE.115.002763.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). In a healthy heart, about 80% of LV filling occurs in early diastole, and the remaining 20% depends primarily on LA contraction. Studies have shown that early-stage HFpEF patients may be more dependent on LA contraction to achieve LV filling than healthy people (2020. Santos AB, Roca GQ, Claggett B, Sweitzer NK, Shah SJ, Anand IS, et al. Prognostic relevance of left atrial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2016; 9: e002763, doi: 10.1161/CIRCHEARTFAILURE.115.002763.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). In the more advanced stages of HFpEF, progressive atrial dilatation and loss of atrial contractile reserve are more likely to occur, especially under stress (2020. Santos AB, Roca GQ, Claggett B, Sweitzer NK, Shah SJ, Anand IS, et al. Prognostic relevance of left atrial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2016; 9: e002763, doi: 10.1161/CIRCHEARTFAILURE.115.002763.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). LA dysfunction in HFpEF is associated with a higher risk of HF hospitalization independent of potential clinical confounders, but not independent of LV strain and filling pressure. Impairment in LV systolic and diastolic function largely explain the association between impaired LA function and a higher risk of HF hospitalization in HFpEF (2020. Santos AB, Roca GQ, Claggett B, Sweitzer NK, Shah SJ, Anand IS, et al. Prognostic relevance of left atrial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2016; 9: e002763, doi: 10.1161/CIRCHEARTFAILURE.115.002763.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

Atrial fibrillation is common in HFpEF, identified at some point in two-thirds of patients, and its presence is associated with decreased exercise capacity, development and worsening of RV dysfunction, and increased mortality (2121. Mohammed SF, Hussain I, AbouEzzeddine OF, Takahama H, Kwon SH, Forfia P, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014; 130: 2310–2320, doi: 10.1161/CIRCULATIONAHA.113.008461.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). The importance of LA function in HFpEF is underscored by observations that atrial fibrillation is very poorly tolerated in patients with HFpEF (2121. Mohammed SF, Hussain I, AbouEzzeddine OF, Takahama H, Kwon SH, Forfia P, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014; 130: 2310–2320, doi: 10.1161/CIRCULATIONAHA.113.008461.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Atrial dilatation precedes atrial fibrillation and is associated with chronic LV diastolic dysfunction as well as comorbidities commonly associated with HFpEF, such as obesity and disordered breathing during sleep (2121. Mohammed SF, Hussain I, AbouEzzeddine OF, Takahama H, Kwon SH, Forfia P, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014; 130: 2310–2320, doi: 10.1161/CIRCULATIONAHA.113.008461.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). At this time, prospective data comparing rate and rhythm control strategies in HFpEF are lacking. Data indicate that impairments in LA function are also associated with adverse prognosis and a more significant burden of pulmonary hypertension in patients with HFpEF, even among patients in sinus rhythm without atrial fibrillation (2121. Mohammed SF, Hussain I, AbouEzzeddine OF, Takahama H, Kwon SH, Forfia P, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014; 130: 2310–2320, doi: 10.1161/CIRCULATIONAHA.113.008461.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

RV dysfunction and pulmonary vascular disease

Roughly 70 to 80% of patients with HFpEF display pulmonary hypertension (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
). As left atrial and pulmonary venous pressures increase due to diastolic dysfunction, this increases the pulmonary artery pressure through passive back-transmission of this hydrostatic pressure. With more advanced stages of HFpEF, there may also be changes in pulmonary vascular structure and function leading to a "precapillary" component where pulmonary vascular resistance increases (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
). In patients with HFpEF, each 10-mmHg increment in pulmonary artery pressure is associated with a 28% increase in 3-year mortality (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
). The chronic obstructive pulmonary disease commonly coexists with HFpEF, can worsen pulmonary hypertension, and also makes determining whether symptoms of dyspnea are primarily related to the heart or lungs (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
). The presence of pulmonary hypertension (PH) in HFpEF is associated with adverse outcomes, including increased mortality and HF hospitalization rates (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
). Reducing pulmonary artery pressure through diuretic use (which reduces LV and LA pressures) decreases HF hospitalizations in HFpEF (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
), but other trials testing PH-specific therapies in HFpEF have failed to show a convincing benefit (2222. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016; 18: 1472–1487, doi: 10.1002/ejhf.630.
https://doi.org/10.1002/ejhf.630...
,2323. Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, et al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 2015; 36: 2565–2573, doi: 10.1093/eurheartj/ehv336.
https://doi.org/10.1093/eurheartj/ehv336...
).

Prior studies have reported that RV dysfunction is present in HFpEF based upon non-invasive measures of RV shortening or systolic velocities (2424. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J 2019; 40: 689–697, doi: 10.1093/eurheartj/ehy809.
https://doi.org/10.1093/eurheartj/ehy809...
). Studies have also demonstrated that RV dysfunction is common in HFpEF, seen in 20 to 35% of patients (2424. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J 2019; 40: 689–697, doi: 10.1093/eurheartj/ehy809.
https://doi.org/10.1093/eurheartj/ehy809...
). Similar to what is seen in the left side of the heart, there is also RV diastolic and systolic dysfunction in HFpEF, at least in the more advanced stages of the disease. RV dysfunction seems to develop more in patients with lower LVEF, with more severe PH, and in patients with atrial fibrillation. The presence of RV dysfunction is a potent marker of increased morbidity and mortality, independent of the severity of PH in HFpEF (2424. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J 2019; 40: 689–697, doi: 10.1093/eurheartj/ehy809.
https://doi.org/10.1093/eurheartj/ehy809...
). Deterioration in RV function was much greater than that seen in the LV over time. The development of RV dysfunction in HFpEF was associated with both prevalent and incident atrial fibrillation (AF), higher body weight, presence of coronary disease, higher pulmonary artery and LV filling pressures, and RV dilation. One study showed patients with HFpEF developing incident RV dilation had a nearly two-fold increased risk of death (adjusted hazard ratio 1.89, 95%CI: 1.01-3.44) (2424. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J 2019; 40: 689–697, doi: 10.1093/eurheartj/ehy809.
https://doi.org/10.1093/eurheartj/ehy809...
). Therefore, among patients with normal LVEF and significant RV dysfunction, an advanced stage of HFpEF should be suspected (2424. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J 2019; 40: 689–697, doi: 10.1093/eurheartj/ehy809.
https://doi.org/10.1093/eurheartj/ehy809...
).

Pericardial restraint

The normal pericardium restrains ventricular filling, contributing to the elevation in intracardiac pressures that develop during conditions of increased venous return such as exercise (66. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura RA. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011; 97: 964–969, doi: 10.1136/hrt.2010.212787.
https://doi.org/10.1136/hrt.2010.212787...
). Patients with HFpEF characteristically develop marked increases in filling pressures with exercise or volume loading owing to diastolic dysfunction (66. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura RA. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 2011; 97: 964–969, doi: 10.1136/hrt.2010.212787.
https://doi.org/10.1136/hrt.2010.212787...
). Further study is required to determine whether pericardial restraint or enhanced diastolic ventricular interaction contributes to the pathophysiology of HFpEF, which would then raise the question as to whether surgical approaches to remove pericardial restraint might improve symptoms related to venous congestion (2525. Borlaug BA, Carter RE, Melenovsky V, DeSimone CV, Gaba P, Killu A, et al. Percutaneous pericardial resection: a novel potential treatment for heart failure with preserved ejection fraction. Circ Heart Fail 2017; 10: e003612, doi: 10.1161/CIRCHEARTFAILURE.116.003612.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). One recent study demonstrates that pericardial resection through a minimally-invasive percutaneous approach mitigates the elevation in LV filling pressures with volume loading in both normal animals and a pig model with diastolic dysfunction (2525. Borlaug BA, Carter RE, Melenovsky V, DeSimone CV, Gaba P, Killu A, et al. Percutaneous pericardial resection: a novel potential treatment for heart failure with preserved ejection fraction. Circ Heart Fail 2017; 10: e003612, doi: 10.1161/CIRCHEARTFAILURE.116.003612.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Further study is warranted to determine whether this method is safe and produces similar acute and chronic hemodynamic benefits in people with HFpEF.

Vascular stiffening and dysfunction

In addition to impaired contractile reserve, inadequate vasodilation seems to contribute to the inability to reduce end-systolic volume and increase stroke volume in patients with HFpEF (2626. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Cardiol Clin 2011; 29: 447–459, doi: 10.1016/j.ccl.2011.06.004.
https://doi.org/10.1016/j.ccl.2011.06.00...
). Attenuated reductions in mean systemic vascular resistance and effective arterial elastance, increases in pulse wave velocity and arterial elastic moduli, and impairments in aortic distensibility with exercise, which are all associated with the severity of exercise disability, have been observed in patients with HFpEF (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
). People with HFpEF frequently display increased arterial stiffness and reduced central aortic compliance (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
). This increases the lability of blood pressure swings in HFpEF with changes in fluid volume or vasodilator medicine use (2626. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Cardiol Clin 2011; 29: 447–459, doi: 10.1016/j.ccl.2011.06.004.
https://doi.org/10.1016/j.ccl.2011.06.00...
). Patients with greater arterial stiffening display greater elevation in LV filling pressures and more depressed cardiac output reserve during exercise (2626. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Cardiol Clin 2011; 29: 447–459, doi: 10.1016/j.ccl.2011.06.004.
https://doi.org/10.1016/j.ccl.2011.06.00...
). As such, management of blood pressure can be very challenging in HFpEF, with patients oscillating between severe uncontrolled hypertension and hypotension from day to day.

Patients with HFpEF display endothelial dysfunction compared with age-matched controls. Endothelium-dependent vasodilation is impaired in HFpEF, and the presence and severity of endothelial dysfunction is associated with more severe HF symptoms, worse exercise capacity, and higher event rates (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
). Just as systolic dysfunction contributes to impairment in LV diastolic suction, cross-talk occurs between vascular stiffening and diastolic reserve. Acute increases in arterial pressure prolong relaxation, particularly in failing hearts (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
).

Chronotropic reserve and autonomic tone

Chronotropic incompetence, broadly defined as the inability of the heart to increase its rate according to increased activity or demand, is common in patients with cardiovascular disease, produces exercise intolerance, which impairs quality-of-life, and is an independent predictor of major adverse cardiovascular events and overall mortality (2828. Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation 2011; 123: 1010–1020, doi: 10.1161/CIRCULATIONAHA.110.940577.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Chronotropic incompetence is extremely common in HFpEF, with reported prevalence of 57 to 77%. The chronotropic reserve is depressed in HFpEF (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
) even compared with older, age-matched controls and independent of rate-slowing medication use. Similar to HFrEF (2828. Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation 2011; 123: 1010–1020, doi: 10.1161/CIRCULATIONAHA.110.940577.
https://doi.org/10.1161/CIRCULATIONAHA.1...
), this is likely related to downstream deficits in β-adrenergic stimulation, because the increase in plasma catecholamines with exercise is identical in HFpEF and healthy controls (2929. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 114: 2138–2147, doi: 10.1161/CIRCULATIONAHA.106.632745.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Cardiac output is equal to the product of stroke volume and heart rate, and the inability to augment heart rate with exercise, together with the known impairment in stroke volume reserve in HFpEF, significantly limits cardiac output responses to exercise in many patients (3030. Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail 2013; 15: 776–785, doi: 10.1093/eurjhf/hft026.
https://doi.org/10.1093/eurjhf/hft026...
). While chronotropic incompetence is common in HFpEF, there is no evidence at this time that rate-adaptive pacing is beneficial in patients with HFpEF (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
).

Evidence exists for abnormalities in autonomic balance in HFpEF. In an early study, cardio acceleration during the initial phase of exercise, which is driven predominantly by the withdrawal of parasympathetic tone, was blunted in patients with HFpEF (2929. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 114: 2138–2147, doi: 10.1161/CIRCULATIONAHA.106.632745.
https://doi.org/10.1161/CIRCULATIONAHA.1...
), although heart rate deficits have been reported only at peak exercise in most subsequent studies (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
). Heart rate recovery, defined as the reduction in heart rate after cessation of activity, is also frequently abnormal in patients with HFpEF (3131. Phan TT, Shivu GN, Abozguia K, Davies C, Nassimizadeh M, Jimenez D, et al. Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 29–34, doi: 10.1161/CIRCHEARTFAILURE.109.877720.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). This marker is related to autonomic tone, as patients with excessive sympathoexcitation and impaired parasympathetic tone have a slower reduction in heart rate after exercise compared with healthy controls. This abnormality in heart rate recovery is independently associated with adverse outcome.

Peripheral factors

In normal individuals, the degree to which peripheral oxygen extraction (i.e., arterio-mixed venous O2 content difference, [C(a-v)O2]) increases in response to exercise (≅2.5×) (3232. Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 2003; 126: 413–423, doi: 10.1093/brain/awg028.
https://doi.org/10.1093/brain/awg028...
) is much greater than changes in systolic volume (≅1.3×) and similar to increases in heart rate (≅2.5×) (3232. Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 2003; 126: 413–423, doi: 10.1093/brain/awg028.
https://doi.org/10.1093/brain/awg028...
). Several previous studies have found that patients with HFpEF are not able to increase heart rate and systolic volume normally during exercise (3333. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kuhl U, et al. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol 2011; 57: 977–985, doi: 10.1016/j.jacc.2010.10.024.
https://doi.org/10.1016/j.jacc.2010.10.0...
), which implies a greater reliance on the ability to increase C(a-v)O2 to augment oxygen uptake (VO2) (3232. Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 2003; 126: 413–423, doi: 10.1093/brain/awg028.
https://doi.org/10.1093/brain/awg028...
). One study demonstrates that peak C(a-v)O2 was a significant determinant of exercise capacity in HFpEF (3434. Dhakal BP, Malhotra R, Murphy RM, Pappagianopoulos PP, Baggish AL, Weiner RB, et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail 2015; 8: 286–294, doi: 10.1161/CIRCHEARTFAILURE.114.001825.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). The essential functional limitation imposed by impaired O2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function and represents a potential target for therapeutic intervention (3434. Dhakal BP, Malhotra R, Murphy RM, Pappagianopoulos PP, Baggish AL, Weiner RB, et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ Heart Fail 2015; 8: 286–294, doi: 10.1161/CIRCHEARTFAILURE.114.001825.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). How to reconcile these conflicting results is not clear at this time; however, they underscore the substantial pathophysiological heterogeneity within the spectrum of HFpEF, and point to the important need for improved methods to individualize therapies to specific phenotypes (3030. Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail 2013; 15: 776–785, doi: 10.1093/eurjhf/hft026.
https://doi.org/10.1093/eurjhf/hft026...
).

Lower extremity skeletal muscle has been found to display increased intramuscular fat content in patients with HFpEF compared with age-matched control individuals, the extent of which was inversely correlated with exercise capacity. Also, morphological and histochemical changes in skeletal muscle have also been described in HFrEF, including marked abnormalities in skeletal muscle mass, composition, capillary density, fiber type, oxidative metabolism, mitochondrial mass, and mitochondrial function (3535. Maurer MS, Teruya S, Chakraborty B, Helmke S, Mancini D. Treating anemia in older adults with heart failure with a preserved ejection fraction with epoetin alfa: single-blind randomized clinical trial of safety and efficacy. Circ Heart Fail 2013; 6: 254–263, doi: 10.1161/CIRCHEARTFAILURE.112.969717.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Some of these abnormalities in the skeletal muscle have also been observed in cardiac muscle, suggesting the presence of a systemic process (3636. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015; 131: 550–559, doi: 10.1161/CIRCULATIONAHA.114.009625.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Intriguingly, improvements in physical capacity noted with exercise training appear to be mediated not by the heart, but rather by improvement in these abnormalities that are peripheral to the heart in the muscle and vasculature. In addition, another study indicated that the proportion of lean body mass and leg mass in HFpEF was reduced compared to age-matched control individuals (3737. Haykowsky MJ, Brubaker PH, Morgan TM, Kritchevsky S, Eggebeen J, Kitzman DW. Impaired aerobic capacity and physical functional performance in older heart failure patients with preserved ejection fraction: role of lean body mass. J Gerontol A Biol Sci Med Sci 2013; 68: 968–975, doi: 10.1093/gerona/glt011.
https://doi.org/10.1093/gerona/glt011...
). Anemia is a common comorbidity in older adults with HFpEF and is associated with worse outcomes (3535. Maurer MS, Teruya S, Chakraborty B, Helmke S, Mancini D. Treating anemia in older adults with heart failure with a preserved ejection fraction with epoetin alfa: single-blind randomized clinical trial of safety and efficacy. Circ Heart Fail 2013; 6: 254–263, doi: 10.1161/CIRCHEARTFAILURE.112.969717.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Anemia impairs oxygen-carrying capacity, and the severity of anemia predicts mortality, but the role of treatment is uncertain (3535. Maurer MS, Teruya S, Chakraborty B, Helmke S, Mancini D. Treating anemia in older adults with heart failure with a preserved ejection fraction with epoetin alfa: single-blind randomized clinical trial of safety and efficacy. Circ Heart Fail 2013; 6: 254–263, doi: 10.1161/CIRCHEARTFAILURE.112.969717.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). One study demonstrated that administration of epoetin alfa to older adult patients with HFpEF compared with placebo did not change LVEDV, LV mass, nor improved submaximal exercise capacity or quality of life (3535. Maurer MS, Teruya S, Chakraborty B, Helmke S, Mancini D. Treating anemia in older adults with heart failure with a preserved ejection fraction with epoetin alfa: single-blind randomized clinical trial of safety and efficacy. Circ Heart Fail 2013; 6: 254–263, doi: 10.1161/CIRCHEARTFAILURE.112.969717.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

As described above, peripheral endothelial dysfunction has been reported in HFpEF (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
) and might impair dynamic flow-mediated dilatation responses during exercise while also impairing matching of perfusion to regional demand in skeletal muscle microcirculation (3535. Maurer MS, Teruya S, Chakraborty B, Helmke S, Mancini D. Treating anemia in older adults with heart failure with a preserved ejection fraction with epoetin alfa: single-blind randomized clinical trial of safety and efficacy. Circ Heart Fail 2013; 6: 254–263, doi: 10.1161/CIRCHEARTFAILURE.112.969717.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

Combined factors for cardiovascular reserve limitation

Obviously, HFpEF is not merely caused by one pathophysiological factor, but in fact is a complex, highly integrated, multisystem loss of cardiac and vascular reserve capacity affecting the left and right ventricles, diastolic and systolic function, atrial reserve, heart rate and rhythm, autonomic control, the vasculature and microcirculation, and the periphery (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). Patients with HFpEF typically display a conglomeration of several reserve impairments that combine to cause symptomatic HF, but the dominant contributors can differ from patient to patient (2727. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854, doi: 10.1016/j.jacc.2010.03.077.
https://doi.org/10.1016/j.jacc.2010.03.0...
). For now, it remains unclear what processes lead to the cardiac, vascular, and peripheral limitations that cause the clinical syndrome of HFpEF (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). However, it is clear from epidemiological studies that the leading risk factors for HFpEF are older age, systemic hypertension, obesity and sedentary lifestyle, and myocardial ischemia, which seem to interact with cardiovascular aging to promote the transition to symptomatic HFpEF (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). Improved understanding of how these risk factors affect the heart and vasculature might improve our understanding of combined reserve limitation in HFpEF (1313. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62: 263–271, doi: 10.1016/j.jacc.2013.02.092.
https://doi.org/10.1016/j.jacc.2013.02.0...
).

Cardiac aging

Recent studies have defined aging as an essential factor in the HFpEF epidemic (88. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670–679, doi: 10.1093/eurheartj/ehq426.
https://doi.org/10.1093/eurheartj/ehq426...
). Aging may contribute independently to deterioration of diastolic function (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). Specific alterations in structure and function in aging, such as ventricular arterial stiffening, vascular dysfunction, impaired Ca2+ regulation, decreased β-adrenergic reserve, and physical deconditioning, have been identified as critical contributing causes for HFpEF (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). As observed by Borlaug et al. (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
), LV stiffness increases with normal aging, despite excellent control of blood pressure and reductions in LV mass. Normal aging is associated with many of the same abnormalities that develop in patients with HFpEF, including diastolic dysfunction, loss of systolic and diastolic reserve, vascular stiffening, and chronotropic incompetence. The cardiac aging process might be accelerated in people with HFpEF (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
), and studies suggest that this acceleration is enhanced in women and with weight gain (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). In addition to passive chamber stiffness, diastolic relaxation also becomes compromised with aging, impairing the effects of diastolic suction (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Aging is also associated with impaired endothelium-dependent vasodilatation. In HFpEF, these combined limitations are exaggerated compared to normal aging (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
).

Physiological cardiac aging is associated with an increase in cardiac fibrosis, LV hypertrophy, valvular degeneration, and mainly diastolic dysfunction (3838. Zhang X, Azhar G, Williams ED, Rogers SC, Wei JY. MicroRNA clusters in the adult mouse heart: age-associated changes. Biomed Res Int 2015; 2015: 732397.). MicroRNAs (miRNAs) are endogenous small noncoding RNAs, 20–23 nucleotides in length, which have emerged as important post-translational regulators of numerous cardiovascular processes, from myocardial infarction to cardiac aging (3939. Dong S, Ma W, Hao B, Hu F, Yan L, Yan X, et al. microRNA-21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up-regulating Bcl-2. Int J Clin Exp Pathol 2014; 7: 565-574.). Numerous miRNAs have been described to be differently expressed and to regulate different cell types and pathways during cardiac aging (3838. Zhang X, Azhar G, Williams ED, Rogers SC, Wei JY. MicroRNA clusters in the adult mouse heart: age-associated changes. Biomed Res Int 2015; 2015: 732397.). More recently, studies have revealed that miRNA-34a has been implicated in cardiac aging and might have an important role in cardiac aging via effects on apoptosis, DNA damage, and telomere shortening (3838. Zhang X, Azhar G, Williams ED, Rogers SC, Wei JY. MicroRNA clusters in the adult mouse heart: age-associated changes. Biomed Res Int 2015; 2015: 732397.). It was demonstrated that, in HFrEF, microRNA-21 (miR-21) could inhibit the apoptosis of cardiac fibroblasts, leading to cardiac hypertrophy and myocardial fibrosis, but the role of miR-21 in HFpEF remains unknown. A recent study suggested that miR-21 promoted the development of HFpEF by up-regulating the expression of anti-apoptotic gene Bcl-2 and thereby suppressing the apoptosis of cardiac fibrosis (3939. Dong S, Ma W, Hao B, Hu F, Yan L, Yan X, et al. microRNA-21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up-regulating Bcl-2. Int J Clin Exp Pathol 2014; 7: 565-574.).

Although our understanding of these processes in the human heart is still in its infancy, cardiac aging may also involve autophagy, a process by which by-products of cell damage are cleared (3838. Zhang X, Azhar G, Williams ED, Rogers SC, Wei JY. MicroRNA clusters in the adult mouse heart: age-associated changes. Biomed Res Int 2015; 2015: 732397.). A new study shows that administration of growth/differentiation factor 11 partially reversed age-associated changes in cardiac structure and function in mice.

Obesity and related comorbidities

Aging seems to be the dominant risk factor for HFpEF. However, obesity and obesity-related comorbidities, such as metabolic syndrome, sedentary lifestyle, and hypertension, are also commonly observed and interact with aging to confer an increased risk of HFpEF (44. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2014; 11: 507–515, doi: 10.1038/nrcardio.2014.83.
https://doi.org/10.1038/nrcardio.2014.83...
). Symptoms in HFpEF patients were ascribed to comorbidities that are very frequent among HFpEF patients such as obesity, hypertension, and diabetes. Considering that obesity represents an incubator for other comorbidities (diabetes, hypertension, metabolic syndrome), it is expected that more than 80% of HFpEF patients are overweight or obese (4040. Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-output heart failure: a 15-year experience. J Am Coll Cardiol 2016; 68: 473–482, doi: 10.1016/j.jacc.2016.05.043.
https://doi.org/10.1016/j.jacc.2016.05.0...
). Earlier studies suggested that symptoms of dyspnea in obese patients were likely simply related to excess body mass, not cardiac abnormalities (4141. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017; 136: 6–19, doi: 10.1161/CIRCULATIONAHA.116.026807.
https://doi.org/10.1161/CIRCULATIONAHA.1...
), but current disease paradigms have begun to embrace the importance of obesity in the pathophysiology of HFpEF, particularly as a cause of systemic inflammation, oxidative stress, and depressed nitric oxide availability that drive cardiac and extracardiac manifestations of disease (4141. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017; 136: 6–19, doi: 10.1161/CIRCULATIONAHA.116.026807.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). The increases in blood volume and thus cardiac loading in obesity may cause structural and functional alterations that contribute to HF (4040. Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-output heart failure: a 15-year experience. J Am Coll Cardiol 2016; 68: 473–482, doi: 10.1016/j.jacc.2016.05.043.
https://doi.org/10.1016/j.jacc.2016.05.0...
).

Previous studies have reported that subjects with HFpEF may display increased LV diastolic diameter and plasma volume compared to control subjects (4141. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017; 136: 6–19, doi: 10.1161/CIRCULATIONAHA.116.026807.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). One study demonstrated that obese subjects with HFpEF had greater estimated plasma volume, LV remodeling, RV enlargement, and increased total heart volume compared to non-obese HFpEF. The LV in obese patients with HFpEF displayed dilation but also an increase in the ratio of LV mass to volume, indicating that concentric remodeling was present (4141. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017; 136: 6–19, doi: 10.1161/CIRCULATIONAHA.116.026807.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

In fact, the role of obesity in HFpEF may be of therapeutic interest (4040. Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-output heart failure: a 15-year experience. J Am Coll Cardiol 2016; 68: 473–482, doi: 10.1016/j.jacc.2016.05.043.
https://doi.org/10.1016/j.jacc.2016.05.0...
). Studies have shown that weight gain, increased obesity, and central obesity may accelerate age-related ventricular sclerosis, especially in women (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Weight loss secondary to bariatric surgery improves diastolic function (4040. Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-output heart failure: a 15-year experience. J Am Coll Cardiol 2016; 68: 473–482, doi: 10.1016/j.jacc.2016.05.043.
https://doi.org/10.1016/j.jacc.2016.05.0...
). Besides, long-term exercise-preserving athletes did not exhibit typical age-related loss of LV compliance compared to sedentary individuals, suggesting that fitness can reduce the harmful effects of obesity on the heart, although separating these two components apart is difficult (4040. Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-output heart failure: a 15-year experience. J Am Coll Cardiol 2016; 68: 473–482, doi: 10.1016/j.jacc.2016.05.043.
https://doi.org/10.1016/j.jacc.2016.05.0...
). Considering that pharmacological studies were mostly unsatisfactory in patients with HFpEF, a different approach is necessary. In the meantime, weight reduction appears as a good alternative until the medical approach provides a better outcome in this population of the patients (4040. Reddy YNV, Melenovsky V, Redfield MM, Nishimura RA, Borlaug BA. High-output heart failure: a 15-year experience. J Am Coll Cardiol 2016; 68: 473–482, doi: 10.1016/j.jacc.2016.05.043.
https://doi.org/10.1016/j.jacc.2016.05.0...
).

Diagnosis of HFpEF

HFpEF is a clinical syndrome in which patients have symptoms and signs of HF, a normal or near-normal left ventricular ejection fraction (LVEF ≥50%), and evidence of cardiac dysfunction as a cause of symptoms (e.g., abnormal left ventricular filling and elevated filling pressures) (22. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200, doi: 10.1093/eurheartj/ehw128.
https://doi.org/10.1093/eurheartj/ehw128...
). Major HF guidelines reflect reasonable consensus on minimum criteria for the diagnosis of HFpEF while acknowledging diagnostic challenges (22. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200, doi: 10.1093/eurheartj/ehw128.
https://doi.org/10.1093/eurheartj/ehw128...
).

The latest report from Reddy et al. (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
) reveals a simple and evidence-based way to diagnose HFpEF. There are three main steps in this method: 1) identification of patients with suspected HFpEF based upon clinical evaluation, including history, physical examination, and echocardiography; 2) use of the H2FPEF score to estimate the probability of presence of HFpEF versus non-cardiac causes of symptoms (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
); and 3) if H2FPEF score is intermediate (or low but the diagnosis remains uncertain), further testing (including natriuretic peptide level and/or right heart catheterization) is indicated. This approach is displayed in Figure 1.

Figure 1
Description of the H2FPEF score and point allocations for each clinical characteristic (top), with associated probability of having heart failure with preserved ejection fraction (HFpEF) based on the total score as estimated from the model (bottom).

Identification of patients with suspected HFpEF

Clinical manifestations of HFpEF are the same as those for general HF, including HFrEF. By far, dyspnea (including dyspnea on exertion, paroxysmal nocturnal dyspnea, or orthopnea) and fatigue are the most common symptoms. Physical signs of HF (such as elevated jugular venous pressure, pulmonary rales, and lower extremity edema) may or may not be present (4343. Solomon SD, Rizkala AR, Lefkowitz MP, Shi VC, Gong J, Anavekar N, et al. Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial. Circ Heart Fail 2018; 11: e004962, doi: 10.1161/CIRCHEARTFAILURE.118.004962.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

Echocardiography is a key component of the diagnosis and evaluation of patients with suspected HF. Evaluation of patients with HF includes Doppler transthoracic echocardiography to evaluate LVEF, estimate pulmonary artery systolic pressure, assess left ventricular filling pressure, and assess cause of HF (4343. Solomon SD, Rizkala AR, Lefkowitz MP, Shi VC, Gong J, Anavekar N, et al. Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial. Circ Heart Fail 2018; 11: e004962, doi: 10.1161/CIRCHEARTFAILURE.118.004962.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). However, if the LVEF cannot be adequately assessed by echocardiography, alternative methods including cardiovascular magnetic resonance, cardiac radionuclide ventriculography, and cardiac computed tomography are suggested (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

Causes of the clinical syndrome of HF with an LVEF ≥50% other than HFpEF include a cardiomyopathy (e.g., hypertrophic or restrictive cardiomyopathy), cardiac amyloidosis, significant valve disease (severe stenosis or regurgitation or at least moderate mixed stenosis and regurgitation), pericardial disease (e.g., constrictive pericarditis), and high-output HF (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Clinical evaluation including echocardiography is helpful in identifying these conditions (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

From the above, HFpEF should be suspected in individuals with all three of the following features: 1) one or more symptoms of HF such as dyspnea or fatigue; physical signs of HF may or may not be present; 2) an LVEF ≥50%; and 3) no apparent cause of HF symptoms other than HFpEF.

Estimation of HFpEF probability using the H2FPEF score

In patients with suspected HFpEF, we suggest using the H2FPEF score to estimate the probability of HFpEF versus non-cardiac causes of dyspnea. This clinically validated score is the sum of the points based on the following clinical variables (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
): 1) Heavy: body mass index >30 kg/m2 (two points); 2) Hypertensive: two or more antihypertensive medicines (one point); 3) Atrial fibrillation (AF): paroxysmal or persistent (three points); 4) Pulmonary hypertension (PH): pulmonary artery systolic pressure >35 mmHg using Doppler echocardiography (one point); 5) Elder: age >60 years (one point); 6) Filling pressure: Doppler echocardiographic E/e' >9 (one point) (Figure 2).

Figure 2
Approach to diagnosis of heart failure with preserved ejection fraction (HFpEF). LVEF: left ventricular ejection fraction; BNP: brain natriuretic peptide; NT-proBNP: N-terminal pro-brain natriuretic peptide; PCWP: pulmonary capillary wedge pressure.

The probability that HFpEF is the cause of symptoms increases with increasing total H2FPEF score (range 0 to 9). A low H2FPEF score of 0 or 1 is associated with a low (<25%) probability of HFpEF. An intermediate H2FPEF score of 2 to 5 is associated with an intermediate (40 to 80%) probability of HFpEF. A H2FPEF score of 6 or greater is associated with a greater than 90% probability of HFpEF and is thus considered diagnostic for HFpEF.

Further testing for low or intermediate H2FPEF score patients

A low score of 0 or 1 suggests that symptoms are most likely due to a non-cardiac cause, and such reasons should be investigated (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). However, if the cause of symptoms remains uncertain after evaluation for non-cardiac causes, cardiology consultation and right heart catheterization are suggested to determine if HFpEF is present (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

With an intermediate H2FPEF score of 2 to 5, we should take further steps to assess the following: 1) Is the natriuretic peptide level high (BNP >100 pg/mL or NT-proBNP >300 pg/mL)?; 2) Is there an absence of significant lung disease? If the above criteria are satisfied, then HFpEF can be diagnosed. If any of the above or both are not met, we suggest cardiology consultation and right heart catheterization (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

Right heart catheterization is not universally required for diagnosis and evaluation of HFpEF (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). However, in selected patients with intermediate H2FPEF scores (and selected patients with low H2FPEF score with undetermined causes of symptoms), cardiology consultation and right heart catheterization for assessment of cardiac filling pressures at rest and exercise is the clinical gold standard to make or exclude the diagnosis of HFpEF (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). On right heart catheterization, pulmonary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg during exercise is diagnostic for HFpEF. Pressures are measured at end-expiration. Exercise is performed during right heart catheterization with cycle ergometry (in patients with internal jugular venous access) or arm abduction with weights (in those with femoral venous access) (1414. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3: 588–595, doi: 10.1161/CIRCHEARTFAILURE.109.930701.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

Evidence and limitations of the H2FPEF score method

The H2FPEF score was derived from data of 414 patients with an LVEF ≥50% (267 with HFpEF confirmed by pulmonary capillary wedge pressure and 147 with non-cardiac dyspnea) and validated in a test cohort of 100 patients (61 with HFpEF) (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). The odds of HFpEF doubled for each 1-unit H2FPEF score increase (odds ratio 1.98; 95%CI: 1.74–2.30), with an area under the curve of 0.841. The H2FPEF score was superior to an algorithm based on expert consensus (increase in area under the curve of 0.169; 95%CI: 0.120–0.217). In the independent test cohort, the area under the curve was 0.886. We suggest the use of the H2PEF score as a general guide in patients with suspected HFpEF while recognizing the limitations of this score (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). The score has not been validated in more extensive and diverse populations. The score includes two elements from echocardiography (estimated pulmonary artery systolic pressure [PASP] and E/e' ratio), which are subject to inaccurate results with suboptimal image acquisition and interpretation (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
).

Treatment and prognosis of HfpEF

Clinical trials in HFpEF have produced neutral results to date and treatment is largely directed toward associated conditions (e.g., hypertension) and symptoms (e.g., edema). This approach is consistent with recommendations for treatment of patients with HFpEF included in the 2013 American College of Cardiology Foundation/American Heart Association (ACC/AHA) HF guidelines (4444. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147–e239, doi: 10.1016/j.jacc.2013.05.019.
https://doi.org/10.1016/j.jacc.2013.05.0...
). The following two strong recommendations were included: 1) Systolic and diastolic hypertension should be controlled in accordance with published clinical practice guidelines to prevent morbidity; 2) Diuretics should be used to relieve symptoms due to volume overload. Similar recommendations were included in the 2016 European Society of Cardiology HF guidelines (22. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200, doi: 10.1093/eurheartj/ehw128.
https://doi.org/10.1093/eurheartj/ehw128...
).

The management of HFpEF differs from the management of HFrEF (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). The results of clinical trials have demonstrated that while neurohumoral antagonists such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) as well as cardiac resynchronization are effective in HFrEF, these therapies do not decrease morbidity and mortality in HFpEF (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). These data suggest that there are fundamental differences in the pathophysiology underlying HFrEF and HFpEF. All the therapies that improve mortality in HFrEF also reverse the LV dilatation in HFrEF. Since patients with HFpEF have no or minimal LV dilatation, these agents are not as effective in HFpEF. Although asymptomatic diastolic dysfunction is a risk factor for the development of HFpEF and mortality, data are lacking on the efficacy of therapy to reduce the risk of progression to HFpEF(4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
).

Diastolic function worsens as part of aging even in individuals without other forms of cardiovascular disease (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Asymptomatic diastolic dysfunction is a predictor of future cardiovascular morbidity, but prognosis differs from that in patients with symptoms of HFpEF (55. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 2013; 6: 944–952, doi: 10.1161/CIRCHEARTFAILURE.113.000383.
https://doi.org/10.1161/CIRCHEARTFAILURE...
).

In this section, we will discuss the HFpEF treatment around the management of associated conditions and pharmacologic therapy. As for the prognosis of HFpEF, we will discuss it in detail using the latest clinical trials.

Management of associated conditions

A key component in the treatment of HFpEF patients is treating the contributing factors and the comorbidities of the disease (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
). This method plays a significant role in the clinical course of the disease (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
). One study has pointed out that the most common comorbidities include hypertension, lung disease, coronary artery disease, atrial fibrillation (AF), obesity, anemia, diabetes mellitus, kidney disease, and sleep-disordered breathing. These comorbidities have a significant implication for the clinical course, and the vast majority of subsequent hospitalizations in patients with HFpEF are not because of HF (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
).

Hypertension remains one of the major modifiable risk factors in HFpEF development and progression. Of nearly 400 cases of new HF in the Framingham study, 91% were preceded by the development of hypertension (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
). Treatment of hypertension has been shown to prevent the development of HF in several clinical trials, particularly among the elderly (4747. Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, et al. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2008; 118: 2259–2267, doi: 10.1161/CIRCULATIONAHA.107.762229.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Reduced incidence of HF in post-menopausal women has also been associated with markers of healthy lifestyles including high-quality diet, increased physical activity, maintenance of healthy body weight, and lack of tobacco use, which are similar to the non-pharmacological treatment recommendations for hypertension. The choice of a specific antihypertensive agent must be individualized in the presence of coexisting diseases such as diabetes mellitus or chronic obstructive pulmonary disease. However, there may be class-specific effects. In an ancillary analysis of data from the ALLHAT trial, chlorthalidone reduced the incidence of new-onset HFpEF compared with amlodipine, lisinopril, and doxazosin, whereas both lisinopril and chlorthalidone were effective in reducing the incidence of HFrEF (4747. Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, et al. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2008; 118: 2259–2267, doi: 10.1161/CIRCULATIONAHA.107.762229.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). Diuretics or venodilators, such as nitrates, should be used with caution. Patients with a small, stiff left ventricular chamber are particularly susceptible to excessive preload reduction, which can lead to underfilling of the left ventricle, a fall in cardiac output, and hypotension (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
). LV hypertension is frequently present in patients with diastolic dysfunction. Regression of LV hypertension is an important therapeutic goal since diastolic function may be improved. Studies utilizing a variety of agents such as beta-blockers, diuretics, and calcium channel blockers demonstrated regression of LV hypertension, though medications targeting the renin-angiotensin-aldosterone system (RAAS) led to higher rates of LV hypertension reversal. The optimal therapy of hypertension in patients with HFpEF (i.e., diastolic dysfunction) is uncertain. The management of hypertension is a cornerstone of HFpEF management, and careful matching of antihypertensive treatments to patient phenotype holds great promise for improving outcomes in patients with HFpEF (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
).

Atrial fibrillation (AF) and HF often co-exist. The presence of one increases the likelihood of the other and each can cause the other (4848. Cha YM, Redfield MM, Shen WK, Gersh BJ. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation 2004; 109: 2839–2843, doi: 10.1161/01.CIR.0000132470.78896.A8.
https://doi.org/10.1161/01.CIR.000013247...
). AF is common in HFpEF, identified at some point in two-thirds of patients, and its presence is associated with increased morbidity and mortality. AF can impair myocardial function by multiple mechanisms and HF may result or worsen. Most observational studies evaluating the impact of AF in patients with HF, and the converse, were performed many years ago (4646. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293, doi: 10.1016/j.jacc.2014.08.036.
https://doi.org/10.1016/j.jacc.2014.08.0...
). They present conflicting data as to whether AF is an independent predictor of mortality in patients with HF. As suggested in the 2013 ACC/AHA HF guidelines, AF is managed in patients with HFpEF according to published clinical practice guidelines to improve symptomatic HF (4444. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147–e239, doi: 10.1016/j.jacc.2013.05.019.
https://doi.org/10.1016/j.jacc.2013.05.0...
). For the AF treatment in HFpEF patients, rhythm control is prior to rate control. Rhythm can be controlled with antiarrhythmic drug therapy, catheter ablation, or surgical ablation, which is the preferred approach in patients with HF who are hemodynamically unstable or who are persistently symptomatic despite adequate rate control. Surgical ablation is the treatment of choice in patients with recent-onset AF in whom there is an exacerbation of HF even if rate control is achieved (4848. Cha YM, Redfield MM, Shen WK, Gersh BJ. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation 2004; 109: 2839–2843, doi: 10.1161/01.CIR.0000132470.78896.A8.
https://doi.org/10.1161/01.CIR.000013247...
). Most often, the efficacy of successful restoration and long-term maintenance of sinus rhythm is dependent in part on how long a patient has been in persistent AF, but several other predictors exist including left atrial size. Both antiarrhythmic drug therapy and catheter ablation are available to achieve this end in select patients (4848. Cha YM, Redfield MM, Shen WK, Gersh BJ. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation 2004; 109: 2839–2843, doi: 10.1161/01.CIR.0000132470.78896.A8.
https://doi.org/10.1161/01.CIR.000013247...
). Rate control to prevent rapid AF acutely and/or chronically usually leads to an improvement in symptoms in patients with HF. In addition, slowing of the ventricular rate often leads to a moderate or, in some cases, marked improvement in left ventricular function. Beta-blockers and calcium channel blockers are the usual first-line agents. For patients who cannot receive a beta-blocker due to issues such as bronchospasm, a non-dihydropyridine calcium channel blocker may be used. Digoxin should be used more cautiously (4848. Cha YM, Redfield MM, Shen WK, Gersh BJ. Atrial fibrillation and ventricular dysfunction: a vicious electromechanical cycle. Circulation 2004; 109: 2839–2843, doi: 10.1161/01.CIR.0000132470.78896.A8.
https://doi.org/10.1161/01.CIR.000013247...
). An important component of the management of AF, regardless of whether rhythm control or rate control is chosen, is anticoagulation drug use to prevent systemic embolization.

Myocardial ischemia in HFpEF can result from epicardial coronary artery disease (CAD), high wall stress, or microvascular dysfunction (3636. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015; 131: 550–559, doi: 10.1161/CIRCULATIONAHA.114.009625.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). CAD is common among patients with HFpEF. As an example, a series of patients with HFpEF reported that two-thirds of patients had anatomically significant CAD (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). The presence of CAD was an independent predictor of increased mortality, along with more considerable deterioration in LV systolic function over time. Patients with HFpEF and symptoms and signs of ischemia are treated with standard therapy. Beta-blockers are preferred for initial treatment and prevention of anginal symptoms (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). Calcium channel blockers and long-acting nitrates are alternatives if beta-blockers are contraindicated or cause side effects; they can also be added as combination therapy if monotherapy is not successful (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). Short-acting nitrates are used for immediate angina relief. Patients with coronary artery disease with drug-resistant ischemic HFpEF may require coronary revascularization by percutaneous coronary intervention or coronary artery bypass graft surgery (4444. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62: e147–e239, doi: 10.1016/j.jacc.2013.05.019.
https://doi.org/10.1016/j.jacc.2013.05.0...
). In a single-center, retrospective series, revascularization was associated with improved survival and less deterioration in EF (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). However, prospective trial data are not available regarding the effects of revascularization in HFpEF. The optimal management also requires periodic evaluation (every 6 to 12 months) of the patient's clinical status, using the history, physical examination, and on occasion, the electrocardiogram (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
).

Hyperlipidemia is the abnormally elevated levels of any or all lipids or lipoproteins in the blood. Treatment of lipid levels is recommended for the primary and secondary prevention of cardiovascular disease (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). Two large randomized trials found that statins do not have a beneficial effect in patients with HFrEF (4949. Ohte N, Little WC. Statins beneficial for heart failure with preserved ejection fraction but not heart failure with reduced ejection fraction? Circ J 2015; 79: 508–509, doi: 10.1253/circj.CJ-15-0016.
https://doi.org/10.1253/circj.CJ-15-0016...
). However, observational data suggest that statins might be of benefit in patients with HFpEF (4949. Ohte N, Little WC. Statins beneficial for heart failure with preserved ejection fraction but not heart failure with reduced ejection fraction? Circ J 2015; 79: 508–509, doi: 10.1253/circj.CJ-15-0016.
https://doi.org/10.1253/circj.CJ-15-0016...
). Randomized trials are required to confirm these observations (4545. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63: 2817–2827, doi: 10.1016/j.jacc.2014.03.034.
https://doi.org/10.1016/j.jacc.2014.03.0...
). We recommend the use of statins in patients with HFpEF who have an indication for statin therapy.

Pharmacologic therapy

Treatment of HFpEF is mostly governed by the management of associated conditions and symptoms since there is limited direct evidence to support a specific drug regimen. Based on the available evidence, we suggest treatment with a mineralocorticoid receptor antagonist in patients with HFpEF who can be appropriately monitored. Diuretics are used to treat volume overload, but as noted above, care must be taken to avoid volume depletion (5050. Adamson PB, Abraham WT, Bourge RC, Costanzo MR, Hasan A, Yadav C, et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 2014; 7: 935–944, doi: 10.1161/CIRCHEARTFAILURE.113.001229.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). Other medications such as ARBs, ACE inhibitors, calcium channel blockers, and beta-blockers are used as treatment for hypertension, but lack proven efficacy to alter clinical outcomes in HFpEF (5151. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018; 39: 26–35, doi: 10.1093/eurheartj/ehx564.
https://doi.org/10.1093/eurheartj/ehx564...
). We recommend against the use of phosphodiesterase-5-inhibitors, organic nitrates such as isosorbide, or digoxin (aside from use for ventricular rate control in atrial fibrillation) to treat HFpEF (5252. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016; 119: 880–886, doi: 10.1161/CIRCRESAHA.116.309184.
https://doi.org/10.1161/CIRCRESAHA.116.3...
).

For patients with clear evidence of HFpEF (including increased brain natriuretic peptide [BNP] or NT-proBNP) who can be carefully monitored for changes in serum potassium and renal function, we suggest treatment with a mineralocorticoid receptor antagonist. The serum potassium should be <5.0 mEq/L and estimated glomerular filtration rate should be ≥30 mL·min−1·(1.73 m2)−1. Evidence to support this approach comes from the Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist (TOPCAT) trial (5252. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016; 119: 880–886, doi: 10.1161/CIRCRESAHA.116.309184.
https://doi.org/10.1161/CIRCRESAHA.116.3...
,5353. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014; 370: 1383–1392, doi: 10.1056/NEJMoa1313731.
https://doi.org/10.1056/NEJMoa1313731...
).

Diuretics improve symptoms of HF patients and are widely used irrespective of LVEF (5252. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016; 119: 880–886, doi: 10.1161/CIRCRESAHA.116.309184.
https://doi.org/10.1161/CIRCRESAHA.116.3...
). Loop diuretics are the primary treatment for reducing congestive symptoms associated with hypervolemia. However, in HFpEF, maintaining optimal volume status is often difficult. Patients with HFpEF are highly sensitive to volume changes and generally have a narrow window between volume overload, causing congestive symptoms, and hypovolemia. Overly aggressive diuresis may result in further reductions in cardiac output, hypotension, and decreased renal function (5252. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016; 119: 880–886, doi: 10.1161/CIRCRESAHA.116.309184.
https://doi.org/10.1161/CIRCRESAHA.116.3...
). The beneficial effect of diuretics was suggested by an ancillary study from the CHAMPION trial, in which medical treatment decisions driven by the knowledge of pulmonary artery pressure data were associated with a significant reduction in hospitalizations for HF (5050. Adamson PB, Abraham WT, Bourge RC, Costanzo MR, Hasan A, Yadav C, et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 2014; 7: 935–944, doi: 10.1161/CIRCHEARTFAILURE.113.001229.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). The majority of medication changes were in diuretic usage, and mean diuretic dose increased significantly more in the pulmonary artery pressure-guided treatment group. These data provide indirect evidence supporting the efficacy of diuretics to reduce morbidity in HFpEF.

Evidence of efficacy of beta blocker therapy in patients with HFpEF is lacking. An individual patient-level meta-analysis of 11 randomized controlled trials of beta blockers in patients with HF found no evidence of benefit in the small subgroup of patients in sinus rhythm with LVEF ≥50% (5151. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018; 39: 26–35, doi: 10.1093/eurheartj/ehx564.
https://doi.org/10.1093/eurheartj/ehx564...
). There was no consistent benefit from beta blockers among patients with atrial fibrillation. The effects of beta blockers in patients in sinus rhythm varied according to baseline LVEF: for patients with baseline LVEF <40%, beta blocker therapy significantly reduced all-cause mortality; for patients with baseline LVEF of 40 to 49%, all-cause mortality was nominally but not statistically significantly lower with beta blocker therapy; for patients with baseline LVEF of ≥50%, beta blocker therapy did not reduce all-cause mortality (5151. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018; 39: 26–35, doi: 10.1093/eurheartj/ehx564.
https://doi.org/10.1093/eurheartj/ehx564...
). We suggest not using beta blockers for HFpEF in the absence of an alternative indication, such as angina.

Hypertension is one of the leading causes of HFpEF in older adults and calcium channel blockers (CCB) is one of the commonly prescribed anti-hypertensive drugs (5252. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016; 119: 880–886, doi: 10.1161/CIRCRESAHA.116.309184.
https://doi.org/10.1161/CIRCRESAHA.116.3...
). Because there is currently no evidence-based guideline recommendation for the use of CCBs in HFpEF, these drugs were likely used for the control of blood pressure and heart rate. These findings suggest that the negative inotropic and chronotropic effects of CCBs had no negative association with outcomes in HFpEF (5252. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016; 119: 880–886, doi: 10.1161/CIRCRESAHA.116.309184.
https://doi.org/10.1161/CIRCRESAHA.116.3...
). CCBs have been shown to have variable effects on cardiovascular outcomes in HF patients. One study demonstrated that, in real-world hospitalized older HFpEF patients not receiving prior CCBs, a new discharge prescription for CCBs had no associations with the primary composite endpoint of total mortality or HF hospitalization and individual endpoints of mortality or hospitalization, regardless of the class of CCBs (5454. Patel K, Fonarow GC, Ahmed M, Morgan C, Kilgore M, Love TE, et al. Calcium channel blockers and outcomes in older patients with heart failure and preserved ejection fraction. Circ Heart Fail 2014; 7: 945–952, doi: 10.1161/CIRCHEARTFAILURE.114.001301.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). CCBs may also be useful in the treatment of hypertension in patients with HFpEF, though the evidence is very limited (5555. Kitzman DW, Brubaker P, Morgan T, Haykowsky M, Hundley G, Kraus WE, et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2016; 315: 36–46, doi: 10.1001/jama.2015.17346.
https://doi.org/10.1001/jama.2015.17346...
). CCBs are generally used as a third- or fourth-line antihypertensive in HFpEF patients with severe hypertension (5454. Patel K, Fonarow GC, Ahmed M, Morgan C, Kilgore M, Love TE, et al. Calcium channel blockers and outcomes in older patients with heart failure and preserved ejection fraction. Circ Heart Fail 2014; 7: 945–952, doi: 10.1161/CIRCHEARTFAILURE.114.001301.
https://doi.org/10.1161/CIRCHEARTFAILURE...
). In addition, as discussed separately, in patients with hypertrophic cardiomyopathy, verapamil may improve symptoms and measures of LV diastolic function.

There is no evidence from randomized clinical studies that ACE inhibitor therapy directly improves overall morbidity or mortality in patients with HFpEF (5656. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27: 2338–2345, doi: 10.1093/eurheartj/ehl250.
https://doi.org/10.1093/eurheartj/ehl250...
). Because patients with HFpEF frequently have comorbidities such as renal insufficiency, ACE inhibitors should be used carefully to avoid the risk of renal dysfunction and hypotension (5656. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27: 2338–2345, doi: 10.1093/eurheartj/ehl250.
https://doi.org/10.1093/eurheartj/ehl250...
). Despite these concerns, ACE inhibitors play an important role in the treatment of the disease processes that contribute to the development of HFpEF, namely hypertension, coronary heart disease, diabetes, and chronic kidney disease (5656. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27: 2338–2345, doi: 10.1093/eurheartj/ehl250.
https://doi.org/10.1093/eurheartj/ehl250...
). ACE inhibitors are beneficial in hypertensive heart disease. The reduction in systemic pressure can theoretically lead to regression of LV hypertension and a gradual improvement in diastolic function. The clinical efficacy of an ACE inhibitor in patients with HFpEF was assessed in the PEP-CHF trial in which 850 patients ≥70 years of age had diastolic dysfunction: 79% had a history of hypertension; patients with substantial LV systolic dysfunction or valve disease were excluded. Overall, there was no impact of ACE inhibitor on the primary endpoint (5656. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27: 2338–2345, doi: 10.1093/eurheartj/ehl250.
https://doi.org/10.1093/eurheartj/ehl250...
). A post hoc analysis at one year found that treatment with perindopril was associated with an almost significant trend toward reduction in the primary endpoint of combined all-cause mortality and unexpected hospitalization for HF; this effect was entirely due to fewer unexpected hospitalizations for HF. The patients treated with perindopril also had significant improvements in functional class and six-minute walk distance (5656. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27: 2338–2345, doi: 10.1093/eurheartj/ehl250.
https://doi.org/10.1093/eurheartj/ehl250...
).

ARBs, like ACE inhibitors, help blunt the adverse cardiovascular effects of angiotensin II. However, ARBs exert their effect further downstream and block the association of angiotensin II with its receptor AT1 (5757. Kanwar M, Walter C, Clarke M, Patarroyo-Aponte M. Targeting heart failure with preserved ejection fraction: current status and future prospects. Vasc Health Risk Manag 2016; 12: 129–141, doi: 10.2147/VHRM.S83662.
https://doi.org/10.2147/VHRM.S83662...
). There is no evidence from randomized clinical studies that ARB therapy directly improves overall morbidity or mortality in patients with HFpEF. There is no evidence of improved diastolic function with ARB treatment compared with other therapies in patients with asymptomatic LV diastolic dysfunction or overt HFpEF (5757. Kanwar M, Walter C, Clarke M, Patarroyo-Aponte M. Targeting heart failure with preserved ejection fraction: current status and future prospects. Vasc Health Risk Manag 2016; 12: 129–141, doi: 10.2147/VHRM.S83662.
https://doi.org/10.2147/VHRM.S83662...
). Two large, randomized, double-blind, placebo-controlled trials have evaluated morbidity and mortality outcomes with ARB use in the HFpEF population. The first one is CHARM-Preserved trial, which demonstrated a moderate benefit for HF hospitalizations in the use of ARBs in the HFpEF population (5757. Kanwar M, Walter C, Clarke M, Patarroyo-Aponte M. Targeting heart failure with preserved ejection fraction: current status and future prospects. Vasc Health Risk Manag 2016; 12: 129–141, doi: 10.2147/VHRM.S83662.
https://doi.org/10.2147/VHRM.S83662...
,5858. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362: 777–781, doi: 10.1016/S0140-6736(03)14285-7.
https://doi.org/10.1016/S0140-6736(03)14...
). The I-PRESERVE trial, that followed the CHARM-Preserved trial, failed to support the potential improvement in clinical outcomes that CHARM-Preserved demonstrated (5959. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008; 359: 2456–2467, doi: 10.1056/NEJMoa0805450.
https://doi.org/10.1056/NEJMoa0805450...
). Besides, two other small trials have examined ARB use in patients with HFpEF. Both studies examined the effects of an ARB (losartan or valsartan) on exercise tolerance in patients with HFpEF and demonstrated conflicting results compared to placebo (6060. Parthasarathy HK, Pieske B, Weisskopf M, Andrews CD, Brunel P, Struthers AD, et al. A randomized, double-blind, placebo-controlled study to determine the effects of valsartan on exercise time in patients with symptomatic heart failure with preserved ejection fraction. Eur J Heart Fail 2009; 11: 980–989, doi: 10.1093/eurjhf/hfp120.
https://doi.org/10.1093/eurjhf/hfp120...
).

We recommend against the use of organic nitrates to treat HFpEF. Evidence of efficacy is lacking and a randomized trial found that use of isosorbide mononitrate tended to reduce activity levels in patients with HFpEF (6161. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015; 373: 2314–2324, doi: 10.1056/NEJMoa1510774.
https://doi.org/10.1056/NEJMoa1510774...
). There are many clinical trials that have proven that phosphodiesterase-5 inhibitors have no benefit for HFpEF. Based on the results of these trials, we do not use phosphodiesterase-5 inhibitors for the treatment of HFpEF (2323. Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, et al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 2015; 36: 2565–2573, doi: 10.1093/eurheartj/ehv336.
https://doi.org/10.1093/eurheartj/ehv336...
). The DIG ancillary trial, a parallel study to the DIG trial, evaluated the role of digoxin in patients with HF and an LVEF >45% (6262. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 2006; 114: 397–403, doi: 10.1161/CIRCULATIONAHA.106.628347.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). At a mean follow-up of 37 months, digoxin had no effect on all-cause or cause-specific mortality, or all-cause or cardiovascular hospitalization (6262. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 2006; 114: 397–403, doi: 10.1161/CIRCULATIONAHA.106.628347.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). We recommend against the use of digoxin to treat patients with HFpEF except for atrial fibrillation with poorly controlled ventricular rate.

Prognosis

The prognosis of patients with HFpEF is less well defined than that of patients with HFrEF. Population-based data from hospitalized patients have shown similar outcomes in patients with HFpEF and HFrEF (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
). However, a large meta-analysis, including community-based studies and trials, observed lower mortality in HFpEF compared to HFrEF, though survival was still much worse than in people without HF (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
,6464. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J 2012; 33: 1750–1757, doi: 10.1093/eurheartj/ehr254.
https://doi.org/10.1093/eurheartj/ehr254...
). Since diastolic dysfunction is common in subjects in the age group at risk for HFpEF, it is possible that HFpEF may be over-diagnosed in patients with echocardiographic evidence of diastolic dysfunction and a clinical syndrome that mimics HF (but not due to HF) such as pulmonary disease, obesity, kidney disease, or deconditioning (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
).

Among patients hospitalized for HF, the mortality rates are high but the data are again conflicting as to whether or not the prognosis is different in HFpEF and HFrEF (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
). Among 6076 patients discharged from a Mayo Clinic Hospital in Olmsted County, Minnesota with a diagnosis of decompensated HF over a 15-year period (1987 to 2001), 53% had HFrEF and 47% had HFpEF. One-year mortality was relatively high in both groups but slightly lower in patients with HFpEF (29 versus 32% in patients with HFrEF, adjusted HR 0.96, 95%CI: 0.92–1.00). Survival improved over time for those with HFrEF but not for those with HFpEF. In a prospective evaluation of 413 patients hospitalized for HF, the relative risk for six-month mortality was lower for HFpEF than for HFrEF (13 vs 21%, adjusted HR 0.51). In a cohort of 2802 patients discharged from 103 hospitals in Ontario with a diagnosis of decompensated HF, one-year mortality was 22% in patients with HFpEF vs 26% in patients with HFrEF. This difference was not statistically significant (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
).

Independent predictors of mortality in patients with HFpEF in different studies include older age, male gender, New York Heart Association (NYHA) class, lower LVEF, the extent of coronary artery disease, peripheral artery disease, diabetes, impaired renal function, the degree of diastolic dysfunction as assessed by Doppler echocardiography, elevated plasma natriuretic peptide levels, pulmonary hypertension, RV dysfunction, and increased red cell distribution width (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
).

The proportions of cardiovascular and non-cardiovascular deaths among patients with HFpEF have varied among trials and epidemiologic studies, with higher proportions of non-cardiovascular deaths in population-based studies (6565. Chan MM, Lam CS. How do patients with heart failure with preserved ejection fraction die? Eur J Heart Fail 2013; 15: 604–613, doi: 10.1093/eurjhf/hft062.
https://doi.org/10.1093/eurjhf/hft062...
). The mode of death was evaluated in patients with symptomatic HFpEF (NYHA class II to IV HF with LVEF ≥45%) enrolled in the I-Preserve trial (6666. Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB, et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial. Circulation 2010; 121: 1393–1405, doi: 10.1161/CIRCULATIONAHA.109.909614.
https://doi.org/10.1161/CIRCULATIONAHA.1...
). The annual mortality rate was 5%. Sixty percent of deaths were cardiovascular (26% sudden death, 14% HF, 5% myocardial infarction, and 9% stroke), 30% were non-cardiovascular (including cancer and infection/sepsis), and 10% were of unknown cause. Irbesartan treatment did not affect the mortality rate or the distribution of mode of death. In a community-based study that did not include trial participants, the rate of non-cardiovascular death was substantially higher, likely reflecting the greater frailty and higher comorbidity burden seen in patients in the general population compared with trial participants (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
,6767. Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective. Circ Heart Fail 2008; 1: 91–97, doi: 10.1161/CIRCHEARTFAILURE.107.743146.
https://doi.org/10.1161/CIRCHEARTFAILURE...
)

Morbidity outcomes in HFrEF and HFpEF are similar. These include the rate and frequency of hospitalization for HF, symptomatic status as measured by abnormalities in myocardial oxygen consumption, six-minute walk distance, Minnesota Living with HF Questionnaire scores, and other quality-of-life indicators. Therefore, patients with HFpEF have a morbidity burden equivalent to that of patients with HFrEF (6363. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–269, doi: 10.1056/NEJMoa051530.
https://doi.org/10.1056/NEJMoa051530...
).

Summary

In particular, we should note that HFpEF and diastolic dysfunction are not synonymous. LVEF is an essential clinical indicator. Patients with HFpEF have LVEF ≥50%, usually with standard heart size and typically exhibit concentric remodeling or hypertrophy. The most apparent and common abnormality in HFpEF patients is associated with diastolic dysfunction. Diastolic dysfunction may coexist with slack damage or increased chamber stiffness or both. These abnormalities, in turn, lead to difficult breathing. In addition to diastolic dysfunction, patients with HFpEF also exhibit limitations such as systolic dysfunction (6868. Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation 2006; 113: 296–304, doi: 10.1161/CIRCULATIONAHA.104.481465.
https://doi.org/10.1161/CIRCULATIONAHA.1...
), contractile reserve (6969. Norman HS, Oujiri J, Larue SJ, Chapman CB, Margulies KB, Sweitzer NK. Decreased cardiac functional reserve in heart failure with preserved systolic function. J Card Fail 2011; 17: 301–308, doi: 10.1016/j.cardfail.2010.11.004.
https://doi.org/10.1016/j.cardfail.2010....
), pulmonary hypertension (7070. Rosenkranz S, Kramer T, Gerhardt F, Opitz C, Olsson KM, Hoeper MM. Pulmonary hypertension in HFpEF and HFrEF: Pathophysiology, diagnosis, treatment approaches. Herz 2019; 44: 483–490, doi: 10.1007/s00059-019-4831-6.
https://doi.org/10.1007/s00059-019-4831-...
), right ventricular dysfunction (7171. Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J 2014; 35: 3452–3462, doi: 10.1093/eurheartj/ehu193.
https://doi.org/10.1093/eurheartj/ehu193...
), vascular and endothelial abnormalities (7272. Gevaert AB, Boen JRA, Segers VF, Van Craenenbroeck EM. Heart failure with preserved ejection fraction: a review of cardiac and noncardiac pathophysiology. Front Physiol 2019; 10: 638, doi: 10.3389/fphys.2019.00638.
https://doi.org/10.3389/fphys.2019.00638...
), left atrial dysfunction (2020. Santos AB, Roca GQ, Claggett B, Sweitzer NK, Shah SJ, Anand IS, et al. Prognostic relevance of left atrial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2016; 9: e002763, doi: 10.1161/CIRCHEARTFAILURE.115.002763.
https://doi.org/10.1161/CIRCHEARTFAILURE...
), and peripheral abnormalities (7373. Farris SD, Moussavi-Harami F, Stempien-Otero A. Heart failure with preserved ejection fraction and skeletal muscle physiology. Heart Fail Rev 2017; 22: 141–148, doi: 10.1007/s10741-017-9603-x.
https://doi.org/10.1007/s10741-017-9603-...
). Patients with HFpEF often have associated comorbidities such as hypertension and metabolic syndrome contributing to impaired endothelial function. This, in turn, adversely remodels aortic and downstream arterial hemodynamics, worsening the pathophysiology in HFpEF (7373. Farris SD, Moussavi-Harami F, Stempien-Otero A. Heart failure with preserved ejection fraction and skeletal muscle physiology. Heart Fail Rev 2017; 22: 141–148, doi: 10.1007/s10741-017-9603-x.
https://doi.org/10.1007/s10741-017-9603-...
). The complex interaction of all these pathophysiological mechanisms is responsible for exacerbating symptoms and worsening HFpEF results. Changes in ventricular, vascular, and peripheral structures and functions leading to HFpEF are thought to be associated with aging and co-morbidities common in HFpEF, including hypertension, obesity, insulin resistance, sedentary lifestyle, and coronary artery disease. This interaction may be mediated by low levels of inflammation and loss of availability of nitric oxide (Figure 3).

Figure 3
Mechanisms in heart failure with preserved ejection fraction (HFpEF) outlined in this review. LV: left ventricle; RV: right ventricle.

About half of all HF patients worldwide have LVEF ≥50%. The main contributors to HFpEF are systemic hypertension, aging, coronary artery disease, diabetes, metabolic syndrome, obesity, and kidney disease. Occult coronary heart disease is a common and potentially reversible cause of HFpEF. In the diagnosis of HFpEF, it is vital to exclude mimics including non-HF conditions and other causes of HF with LVEF ≥50%, such as valvular heart disease, pericardial disease, cardiomyopathy, cardiac amyloidosis, and high output HF. Regarding the diagnostic approach, we highly recommend H2FPEF score diagnostic method from Barry A Borlaug's latest study (4242. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138: 861–870, doi: 10.1161/CIRCULATIONAHA.118.034646.
https://doi.org/10.1161/CIRCULATIONAHA.1...
), which is simple, efficient, and easy to implement clinically. In his procedure, natriuretic peptide levels are helpful in the differential diagnosis of patients with a moderate probability of HFpEF.

An essential component in the treatment of HFpE is the treatment of contributing factors and comorbidities that often occur and significantly affect clinical processes. The most common include high blood pressure, lung disease, coronary artery disease, obesity, anemia, diabetes, kidney disease, and sleep-disordered breathing. The general principles for the treatment of HFpEF are to control pulmonary congestion and peripheral edema, treat systolic hypertension, prevent rapid heart rate (especially in patients with atrial fibrillation), and establish coronary revascularization in patients with coronary heart disease. Diuretics or intravenous dilators must be used with caution in patients with left ventricular diastolic dysfunction with a small, stiff left ventricle. When atrial fibrillation occurs in patients with HFpEF, restoration and maintenance of sinus rhythm is preferred, followed by rate control. We do not recommend the use of beta-blockers to treat HFpEF without alternative indications such as angina. For patients with clear HFpEF evidence (including increased BNP), we recommend monitoring changes in serum potassium and renal function and treatment with mineralocorticoid antagonists. We do not recommend the use of organic nitrates, phosphodiesterase-5 inhibitors, or digoxin (except for ventricular rate control of atrial fibrillation) for the treatment of patients with HFpEF. Exercise training is the only intervention that can continuously improve HFpEF's functional capacity and quality of life. The morbidities of HFpEF patients are almost identical to that of HFrEF patients. Mortality rates for both HFpEF and HFrEF are high; so far, published data on mortality differences are contradictory.

HFpEF is a complex disorder caused by multifactorial stresses secondary to comorbidities. The current challenge is finding new multidirectional strategies to abrogate cardiac remodeling. Exploring detail pathophysiological mechanisms, seeking easy and popular diagnostic approaches, and finding a precise treatment are the main objectives to overcome HFpEF.

Acknowledgments

This study was funded by Zhengzhou University Overseas Virtual Research Institute and China Scholarship Council (No. 201708410121).

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  • Erratum

    The Brazilian Journal of Medical and Biological Research has been informed by the authors that the second affiliation “German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany” was cited erroneously and should be withdrawn from the published article “Heart failure with preserved ejection fraction: an update on pathophysiology, diagnosis, treatment, and prognosis”.
    The correct list of authors and institutions is as follows:
    1Berlin Institute of Health Center for Regenerative Therapies & Berlin – Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany
    2Klinik für Augenheilkunde, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
    3Department of Orthopedic Surgery, Henan Provincial People's Hospital, Zhengzhou, Henan, China
    4Department of Cardiovascular Surgery, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
    Correspondence: Chengshan Gao: <chengshangao@yahoo.com>

Publication Dates

  • Publication in this collection
    05 June 2020
  • Date of issue
    2020

History

  • Received
    30 Nov 2019
  • Accepted
    7 Apr 2020
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