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HFpEF, a Disease of the Vasculature: A Closer Look at the Other Half

      Abstract

      Patients with heart failure are commonly divided into those with reduced ejection fraction (EF<40%) and those with preserved ejection fraction (HFpEF; EF>50%). For heart failure with reduced EF, a number of therapies have been found to improve patient morbidity and mortality, and treatment is guideline based. However for patients with HFpEF, no treatment has been found to have clinical benefit. To objectively assess treatments for HFpEF, a comprehensive PubMed literature search was performed using the terms HFpEF, heart failure, smooth muscle, myosin, myosin phosphatase, and PKG (up to December 31, 2017), with an unbiased focus on pathophysiology, cell signaling, and therapy. This review provides evidence that could explain the lack of clinical benefit in treating patients with HFpEF with sildenafil and long-acting nitrates. Furthermore, the review highlights the vascular abnormalities present in patients with HFpEF, and these abnormalities of the vasculature could potentially contribute to the pathophysiology of HFpEF. Thus, focusing on HFpEF as a vascular disease could result in the development of novel and effective treatment paradigms.

      Abbreviations and Acronyms:

      cAMP (cyclic adenosine 3′,5′-monophosphate), cGMP (cyclic guanosine monophosphate), EF (ejection fraction), HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction), KO (knockout), LV (left ventricular), LZ (leucine zipper), MLCK (myosin light chain kinase), MLCP (myosin light chain phosphatase), MYPT1 (myosin-targeting subunit of myosin light chain phosphatase), NM (nonmuscle), NO (nitric oxide), PDE (phosphodiesterase), PKA (protein kinase A), PKG (protein kinase G), RLC (regulatory light chain), SM (smooth muscle)
      Article Highlights
      • No therapy has been found to have clinical benefit in patients with heart failure with preserved ejection fraction (HFpEF).
      • The lack of benefit of stimulation of the nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling pathway in treating patients with HFpEF is easily rationalized and could have been predicted.
      • Heart failure with preserved ejection fraction is associated with both resting vasoconstriction and a decrease in sensitivity to nitric oxide–mediated vasodilatation, which can be explained by changes in the expression of vascular smooth muscle contractile proteins.
      • Targeting the vascular abnormalities associated with HFpEF could result in the development of novel and effective treatments of this disease.
      Heart failure, which affects approximately 5 million Americans, is classified by either a reduced ejection fraction (HFrEF) or a preserved ejection fraction (HFpEF). Heart failure with reduced ejection fraction is defined as an ejection fraction (EF) of less than 40%, and the American College of Cardiology/American Heart Association recommends guideline-directed medical therapy with a therapeutic regimen of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker or angiotensin receptor-neprilysin inhibitor along with a β-blocker and an aldosterone antagonist for patients with chronic symptomatic HFrEF. A preserved EF is currently defined as an EF of greater than 50% with normal left ventricular (LV) size (LV end-diastolic volume index <97 mL/m2) and evidence of reduced diastolic LV function.
      • McMurray J.J.
      • Adamopoulos S.
      • Anker S.D.
      • et al.
      ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC [published correction appears in Eur Heart J. 2013;34(2):158].
      Patients with an EF between 40% and 50% can be characterized as either HFrEF or HFpEF, although there is evidence for more accurate classification as HFrEF.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      Heart failure with preserved ejection fraction is often associated with other comorbidities including hypertension, corrected valvular disorders, atrial fibrillation, diabetes mellitus, obesity, sleep disordered breathing, lung disease, and renal disease.
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      The proportion of patients with HFpEF is estimated to be 50%,
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      and the prevalence of HFpEF is increasing; that is, 38% and 54% of all documented heart failure cases in Olmsted County, Minnesota, were classified as HFpEF in 1987 and 2001, respectively.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Owan T.E.
      • Hodge D.O.
      • Herges R.M.
      • Jacobsen S.J.
      • Roger V.L.
      • Redfield M.M.
      Trends in prevalence and outcome of heart failure with preserved ejection fraction.
      It is postulated that the rapid rise of HFpEF, in addition to increased awareness, is due to the surge in obesity, metabolic syndrome, and hypertension in the general population.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      Mortality rates and hospitalization rates are similar among patients with HFrEF and those with HFpEF.
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      However, patients with HFpEF have been found to have higher mortality from noncardiac causes.
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      • Chan M.M.
      • Lam C.S.
      How do patients with heart failure with preserved ejection fraction die?.
      Immense strides have been made in the treatment of HFrEF with improvement in mortality rates due to advanced therapies,
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      but currently there are no available therapies found to improve outcomes in patients with HFpEF.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      To understand the dichotomy between HFpEF and HFrEF, it is important to reflect on similarities as well as differences. Clinical differences suggest older median age, female sex, and a higher frequency of comorbidities to be present in patients with HFpEF, as mentioned above.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      The initial presentation of patients with HFpEF and those with HFrEF is often similar, given the nonspecific symptoms of heart failure. Fatigue, dyspnea on exertion, lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea are all symptoms described by patients presenting with heart failure. A detailed history and physical examination can provide further insight into the etiology of heart failure. It is important to note that in between heart failure exacerbations, patients with HFpEF can be relatively asymptomatic.
      Transthoracic echocardiography is the next step in differentiating HFpEF from HFrEF. As mentioned, the accepted definition of HFpEF is currently an EF greater than 50% in the presence of clinical symptoms of heart failure.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines
      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.
      • Borlaug B.A.
      • Paulus W.J.
      Heart failure with preserved ejection fraction: Pathophysiology, diagnosis, and treatment.
      Left ventricular size is evaluated by echocardiography, and a normal LV size is seen commonly in HFpEF rather than ventricular dilatation in HFrEF.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • van Heerebeek L.
      • Borbély A.
      • Niessen H.W.
      • et al.
      Myocardial structure and function differ in systolic and diastolic heart failure.
      With the lack of ventricular dilatation, there is less wall stress associated with HFpEF, which underscores the rationale of why brain natriuretic peptide levels are either lower or even normal in patients with HFpEF, except during episodes of an acute heart failure exacerbation.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Iwanaga Y.
      • Nishi I.
      • Furuichi S.
      • et al.
      B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure.
      Heart failure with preserved ejection fraction is also often associated with elevated pulmonary artery systolic pressures (>35 mm Hg), right ventricular systolic dysfunction, and functional regurgitation of the tricuspid and mitral valves.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      Echocardiography often reveals markers of cardiac remodeling (LV mass >95 g/m2 in women or >115 g/m2 in men; left atrial volume >34 mL/m2), elevated left atrial pressure, E/A ratio (the ratio of peak velocity flow in early diastole [the E wave] to peak velocity flow in late diastole caused by atrial contraction [the A wave]) >2.0, E/e' ratio (the ratio of mitral peak velocity of early filling [E] to early diastolic mitral annular velocity [e']) > 1.5, and abnormal relaxation (e' measured at the septal wall of mitral annulus, septal e' <8). Exercise stress testing can be used to provide information on functional limitations, presence of chronotropic incompetence, and presence of hemodynamically significant coronary artery disease, whereas cardiopulmonary testing can clarify any concomitant pulmonary diagnosis or the presence of deconditioning. Right heart catheterization illustrates the degree of pulmonary hypertension associated with heart failure, and cardiac magnetic resonance imaging may be needed if there is concern for infiltrative or inflammatory cardiomyopathy.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      Hypertrophic cardiomyopathy, infiltrative cardiac disease, primary valvular disorders, and pericardial disease should be ruled out because they require specific therapy.
      Although HFpEF and HFrEF can and often will have the same clinical presentation, these are 2 separate entities
      • Borlaug B.A.
      • Paulus W.J.
      Heart failure with preserved ejection fraction: Pathophysiology, diagnosis, and treatment.
      • Borlaug B.A.
      • Redfield M.M.
      Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum.
      • Paulus W.J.
      • Tschöpe C.
      • Sanderson J.E.
      • et al.
      How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.
      and therapies that improve outcomes in HFrEF have no benefit on outcomes in HFpEF.
      • Borlaug B.A.
      • Redfield M.M.
      Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum.
      The treatment of HFpEF is currently focused on expert consensus
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      and largely concentrated on controlling volume overload and treating comorbidities.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      However, the lack of evidence-based treatment guidelines for HFpEF gives an incredible opportunity for further studies, investigations, and advancements in a disease that affects half the population with heart failure.

      Rationale for the Review and Methods

      There have been significant advances in the treatment of HFrEF. Although not due to the lack of attempts, no study has reported an improvement in morbidity and/or mortality in patients with HFpEF. There is extensive literature on cardiac and vascular signaling, which is altered in HFpEF. Thus, we performed a comprehensive PubMed literature search with an unbiased focus on cardiac and vascular smooth muscle (SM) pathophysiology and cell signaling as well as therapy for HFpEF. Our intent is to provide clinicians with the evidence required to ascertain why the clinical trials in HFpEF have failed to report benefit as well as provide evidence for a novel hypothesis—vascular abnormalities play an important role in the development of this disease.
      For this study, a PubMed literature search was performed using the terms HFpEF, heart failure, smooth muscle, myosin, myosin phosphatase, and PKG (up to December 31, 2017). We reviewed all clinical trials for HFpEF, and then reviewed the literature supporting the hypothesis on which the clinical trials were based. Finally, we examined the literature describing the cell signaling pathways regulating contractility and hypertrophy in cardiac myocytes as well as contractility in vascular SM.

      Pathophysiology/Cardiac Abnormalities

      Cardiac Etiologies—Diastolic Dysfunction

      As mentioned, diastolic dysfunction remains the focus of the pathophysiology of HFpEF, and the components of diastolic dysfunction include left LV hypertrophy, impaired relaxation, and LV stiffening. Hypertension results in pressure overload, eventually leading to LV hypertrophy and diastolic dysfunction, which results in left atrial hypertension, pulmonary venous hypertension, and right-sided remodeling and dysfunction.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      Diastolic dysfunction is commonly seen in the elderly population,
      • Redfield M.M.
      • Jacobsen S.J.
      • Burnett Jr., J.C.
      • Mahoney D.W.
      • Bailey K.R.
      • Rodeheffer R.J.
      Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
      and it has been estimated that 70% of patients older than 75 years have some degree of diastolic dysfunction when evaluated by noninvasive imaging, but do not have signs and symptoms consistent with heart failure.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      • Redfield M.M.
      • Jacobsen S.J.
      • Burnett Jr., J.C.
      • Mahoney D.W.
      • Bailey K.R.
      • Rodeheffer R.J.
      Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
      Delayed active relaxation and myocardial stiffness are the components of diastolic dysfunction.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      Passive LV stiffness is thought to be responsible for the elevated LV filling pressures.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • Gladden J.D.
      • Linke W.A.
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      This myocardial stiffness is thought to be secondary to extracellular matrix abnormalities and changes in the cardiomyocyte itself, such as increased cardiomyocyte diameter, higher myofibrillar density, and increased cardiomyocyte stiffness and fibrosis.
      • Reddy Y.N.
      • Borlaug B.A.
      Heart failure with preserved ejection fraction.
      • van Heerebeek L.
      • Borbély A.
      • Niessen H.W.
      • et al.
      Myocardial structure and function differ in systolic and diastolic heart failure.
      Left ventricular hypertrophy, delayed active relaxation, and passive LV stiffness are the characteristics of diastolic dysfunction that have been reproduced in canine models. Specifically, HFpEF has been modeled in elderly dogs (aged 8-13 years) by bilateral renal wrapping to induce hypertension and administration of an aldosterone agonist to increase cardiac remodeling and effects of long-standing hypertension. Old hypertensive dogs had evidence of concentric LV hypertrophy, delayed active relaxation, and passive LV chamber stiffness.
      • Degen C.V.
      • Bishu K.
      • Zakeri R.
      • Ogut O.
      • Redfield M.M.
      • Brozovich F.V.
      The emperor's new clothes: PDE5 and the heart.
      • Shapiro B.P.
      • Lam C.S.
      • Patel J.B.
      • et al.
      Acute and chronic ventricular-arterial coupling in systole and diastole: insights from an elderly hypertensive model.
      • Zakeri R.
      • Levine J.A.
      • Koepp G.A.
      • et al.
      Nitrate's effect on activity tolerance in heart failure with preserved ejection fraction trial: rationale and design.
      In models of diastolic heart failure, elderly dogs illustrate LV systolic and arterial stiffness. This will eventually result in increased afterload and impairment of LV relaxation, which translates into increased filling pressures.
      • Munagala V.K.
      • Hart C.Y.
      • Burnett Jr., J.C.
      • Meyer D.M.
      • Redfield M.M.
      Ventricular structure and function in aged dogs with renal hypertension: a model of experimental diastolic heart failure.

      Cardiac Etiologies—Cardiac Hypertrophy and Protein Kinase G Signaling

      G protein–coupled receptors provide the foundation of cardiac molecular signaling, particularly related to β-adrenergic stimulation (Figure 1).
      • MacLeod K.T.
      Recent advances in understanding cardiac contractility in health and disease.
      β-Adrenergic agonists bind to β receptors (β1 receptors), a G protein–coupled receptor, which in turn activates adenylate cyclase and results in the production of cyclic adenosine 3′,5′-monophosphate (cAMP), which will then activate protein kinase A (PKA). Protein kinase A phosphorylates and activates the L-type Ca2+ channel, which results in increased Ca2+ influx and enhanced contractility. Ca2+ binds to troponin C, which causes a shift in the position of the troponin-tropomyosin complex that allows myosin cross-bridges to interact with actin and force production. Protein kinase A also increases the rate of relaxation. The PKA phosphorylation of phospholamban releases its inhibitory effect on sarcoplasmic reticulum calcium ATPase (SERCA), and this increases the rate of Ca2+ uptake by the sarcoplasmic reticulum; higher Ca2+ load in the sarcoplasmic reticulum will enhance Ca2+ release. Protein kinase A also phosphorylates ryanodine receptors, increasing calcium leakage. Thus, it is postulated that an important mechanism of heart failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cAMP.
      • Han Y.S.
      • Arroyo J.
      • Ogut O.
      Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state.
      In mice, overexpression of β1 receptors results in cardiac hypertrophy and fibrosis and overexpression of PKA produces cardiomyocyte hypertrophy and fibrosis; thus, the role of PKA in mediating both physiological and pathological cardiac hypertrophy is well accepted.
      • Frey N.
      • Olson E.N.
      Cardiac hypertrophy: the good, the bad, and the ugly.
      Figure thumbnail gr1
      Figure 1Protein kinase A signaling in cardiac muscle. Activation of the β1-adrenergic receptor activates adenylate cyclase via G protein–coupled receptors and results in an increase in cAMP, which activates PKA. The PKA-mediated phosphorylation (P) of PLB and TN increases lusitropy, whereas the phosphorylation of the L-type Ca2+ channel increases intracelluar Ca2+, which binds to TN to activate the thin filament to increase cardiac contractility (refer to text and reference 18 for details). In addition, PKA signaling mediates cardiac hypertrophy by increasing transcription as well as by increasing Ca2+ and subsequently activating calcineurin (refer to text and reference 19 for details). Both natriuretic peptides and NO activate guanylate cyclase, which results in an increase in cGMP and the activation of PKG. Protein kinase G has been suggested to counteract PKA-mediated cardiac hypertrophy (refer to text and references 20 and 21 for details). ATP = adenosine triphosphate; cAMP = cyclic adenosine 3′,5′-monophosphate; cGMP = cyclic guanosine monophosphate; GMP = guanosine monophosphate; Gs = alpha subunit of G protein; GTP = guanosine 5′-triphosphate; NO = nitric oxide; P = phosphorylation of protein; PDE = phosphodiesterase; PKA = protein kinase A; PKG = protein kinase G; PLB = phospholamban; RyR = ryanodine receptor; SERCA = sarcoplasmic reticulum calcium ATPase; SR = sarcoplasmic reticulum; Tm = tropomyosin; TN = troponin.
      Although the role of cAMP-PKA signaling in the regulation of both cardiac contractility and hypertrophic signaling is well accepted (Figure 1), recently, cyclic guanosine monophosphate (cGMP) and its target kinase protein kinase G (PKG) have been proposed to counteract PKA-mediated cardiac hypertrophic signaling.
      • Zhang M.
      • Kass D.A.
      Phosphodiesterases and cardiac cGMP: evolving roles and controversies.
      Nitric oxide (NO) and natriuretic peptides both stimulate soluble guanylyl cyclase, increasing cGMP and resulting in the activation of PKG. However, it is well recognized that cGMP is increased in states of chronic stress, so why is this not protective against hypertrophy? The initial hypothesis was that during chronic stress, cGMP catabolism is also increased.
      • Takimoto E.
      • Champion H.C.
      • Li M.
      • et al.
      Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.
      Phosphodiesterases (PDEs) hydrolyze cGMP, and 7 isoforms are thought to be expressed in the heart.
      • Kim G.E.
      • Kass D.A.
      Cardiac phosphodiesterases and their modulation for treating heart disease.
      Three PDEs (PDE5, PDE6, and PDE9) are specific for cGMP; PDE6 is involved in photoreceptor signaling
      • Wensel T.G.
      Signal transducing membrane complexes of photoreceptor outer segments.
      and not expressed in cardiomyocytes.
      • Azevedo M.F.
      • Faucz F.R.
      • Bimpaki E.
      • et al.
      Clinical and molecular genetics of the phosphodiesterases (PDEs).
      The expression of PDE5 has been proposed to increase in heart failure and is thought to be associated with increased remodeling.
      • Kim G.E.
      • Kass D.A.
      Cardiac phosphodiesterases and their modulation for treating heart disease.
      Several studies
      • Takimoto E.
      • Champion H.C.
      • Li M.
      • et al.
      Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.
      • Takimoto E.
      • Champion H.C.
      • Li M.
      • et al.
      Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load.
      • Takimoto E.
      • Belardi D.
      • Tocchetti C.G.
      • et al.
      Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5 [published correction appears in Circulation. 2007;115(20):e536].
      used PDE overexpression and knockdown mouse lines to exhibit that PDE5A inhibition suppressed cellular and molecular remodeling while improving cardiac function in states of chronic pressure overload. The inhibition of PDE5A was also noted to reverse preexisting hypertrophy while improving function. This study identified that increased PDE5A expression reversed hypertrophy and improved EF in states of chronic loading stress and pressure overload.
      • Takimoto E.
      • Champion H.C.
      • Li M.
      • et al.
      Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.
      On the basis of these results, PDE5 inhibition was targeted as a potential treatment for HFpEF. However, the RELAX trial,
      • Redfield M.M.
      • Chen H.H.
      • Borlaug B.A.
      • et al.
      RELAX Trial
      Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
      which specifically investigated the effect of PDE5 inhibition on exercise capacity in patients with HFpEF, failed to report any benefit.
      It was initially unclear why there was little benefit of PDE5 inhibition in patients with HFpEF, but the expression of PDE5 in the myocardial tissue is not universally accepted. Degen et al
      • Degen C.V.
      • Bishu K.
      • Zakeri R.
      • Ogut O.
      • Redfield M.M.
      • Brozovich F.V.
      The emperor's new clothes: PDE5 and the heart.
      did not detect PDE5 in tissue homogenates from the left ventricles of mice, canines (normal controls and those with HFpEF), and human heart with or without heart failure, but PDE5 was detected in both the murine and bovine lung samples, used as positive controls. Overall, this study indicated that if PDE5 is expressed in human cardiac tissue, it is below the level required for detection with immunoblotting, which could explain the lack of clinical benefit of PDE5 inhibition in treating cardiac hypertrophy. Similarly, a number of other groups were unable to detect the expression of PDE5 expression in cardiomyocytes,
      • Corbin J.D.
      • Beasley A.
      • Blount M.A.
      • Francis S.H.
      High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors.
      • Lukowski R.
      • Rybalkin S.D.
      • Loga F.
      • Leiss V.
      • Beavo J.A.
      • Hofmann F.
      Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes.
      • Patrucco E.
      • Domes K.
      • Sbroggió M.
      • et al.
      Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis.
      and furthermore, others did not detect PDE5 in either canine
      • Corbin J.D.
      • Beasley A.
      • Blount M.A.
      • Francis S.H.
      High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors.
      or human
      • Corbin J.D.
      • Beasley A.
      • Blount M.A.
      • Francis S.H.
      High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors.
      • Wallis R.M.
      • Corbin J.D.
      • Francis S.H.
      • Ellis P.
      Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.
      cardiac tissue. Also of note, Vandeput et al
      • Vandeput F.
      • Krall J.
      • Ockaili R.
      • et al.
      cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium.
      reported that there was no PDE5 activity in the normal and failing human LV myocardium. It is speculated that the limitation of PDE5A as therapy for heart failure is based on not only the lack of significant expression in the human heart
      • Degen C.V.
      • Bishu K.
      • Zakeri R.
      • Ogut O.
      • Redfield M.M.
      • Brozovich F.V.
      The emperor's new clothes: PDE5 and the heart.
      but also the fact that it specifically targets nitric oxide synthase (NOS)-dependent cGMP.
      • Kim G.E.
      • Kass D.A.
      Cardiac phosphodiesterases and their modulation for treating heart disease.
      • Lee D.I.
      • Zhu G.
      • Sasaki T.
      • et al.
      Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease.
      Oxidative stress can result in an uncoupling and attenuation of the soluble guanylyl cyclase-NO pathway, resulting in oxygen radicals instead of NO. Of note, PDE9A is a cGMP-selective PDE, specifically targeting natriuretic peptide–induced cGMP; PDE9A was originally reported to be primarily expressed in the brain, gut, and kidneys; however, Lee et al
      • Lee D.I.
      • Zhu G.
      • Sasaki T.
      • et al.
      Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease.
      reported that PDE9A expression was elevated in human heart failure, particularly HFpEF. Therefore, it has been proposed that PDE9A inhibition is an attractive alternative for the treatment of HFpEF. However, unless a repeat of the RELAX trial
      • Redfield M.M.
      • Chen H.H.
      • Borlaug B.A.
      • et al.
      RELAX Trial
      Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
      is desired, we would suggest that rigorous studies exhibiting PDE9A expression in cardiac tissue should be performed before planning future clinical trials.
      Moving away from the focus on PDE inhibition, cGMP-PKG signaling remains the focus of therapy for heart failure. If PKG is the primary downstream target of cGMP, should we focus more on PKG modulation to counteract abnormal remodeling? It has been postulated that increasing PKG activity in heart failure would improve remodeling and prevent further hypertrophy (Figure 1). However, recent studies question the importance of PKG signaling in modulating cardiac hypertrophy. Lukowski et al
      • Lukowski R.
      • Rybalkin S.D.
      • Loga F.
      • Leiss V.
      • Beavo J.A.
      • Hofmann F.
      Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes.
      exposed mice with global PKG knockout (KO) to both hormonal (isoproterenol infusion) and mechanical (transaortic constriction) stress, and the KO mice developed similar levels of ventricular hypertrophy as did wild-type controls. These data raise the question of the overall role and importance of PKG in the decreasing PKA-mediated cardiac hypertrophy. Also, Patrucco et al
      • Patrucco E.
      • Domes K.
      • Sbroggió M.
      • et al.
      Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis.
      found that angiotensin II (AngII) infusion did not result in an increase in cardiac hypertrophy in cardiac-specific PKG KO mice compared with wild-type controls. If PKG enhancement does not significantly improve hypertrophy and remodeling, then one could reasonably conclude that any therapy aimed at increasing the cGMP-PKG signaling, that is, NO, PDE inhibitors, guanylate cyclase activators or natriuretic peptides, would not be beneficial, which is consistent with the results of the trial of long-acting nitrate therapy in HFpEF.
      • Redfield M.M.
      • Anstrom K.J.
      • Levine J.A.
      • et al.
      NHLBI Heart Failure Clinical Research Network
      Isosorbide mononitrate in heart failure with preserved ejection fraction.
      Another proposed mechanism of HFpEF is the modulation of PKA and PKG phosphorylation sites on cardiac titin. Hamdani et al
      • Hamdani N.
      • Bishu K.G.
      • von Frieling-Salewsky M.
      • Redfield M.M.
      • Linke W.A.
      Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction.
      illustrated that obesity, diabetes, and hypertension resulted in passive myocardial stiffness and reduced phosphorylation of titin's PKA/PKG sites, which therefore contributed to the development of HFpEF. However, further studies are required to confirm a role of modulating titin compliance as a therapy for HFpEF.

      Vascular Etiologies—Arterial Stiffness

      As further information is gathered about the pathophysiology of HFpEF, it is important to consider the vascular abnormalities associated with both HFrEF and HFpEF. These abnormalities include resting vasoconstriction, a decreased sensitivity to NO, and vasculature changes associated with aging. There is an important relationship between the heart and the circulatory system, and this interaction is often underplayed when discussing heart failure. Aortic stiffness, associated with increased pulse wave velocity, has been observed as an independent risk factor for cardiovascular disease. Arterial stiffness is associated with increases in systolic blood pressure, mean arterial blood pressure, and pulse pressure.
      • Coutinho T.
      • Bailey K.R.
      • Turner S.T.
      • Kullo I.J.
      Arterial stiffness is associated with increase in blood pressure over time in treated hypertensives.
      This association between arterial stiffness and long-standing hypertension underscores the interplay of hypertension and HFpEF. Also, isolated systolic hypertension is noted in patients, particularly female patients with HFpEF, which indicates reduced arterial compliance or increased peripheral resistance.
      Aortic wall thickness was originally attributed to the extracellular matrix,
      • Berry C.L.
      • Greenwald S.E.
      • Rivett J.F.
      Static mechanical properties of the developing and mature rat aorta.
      but there is new evidence to suggest that vascular SM activation produces increases in stiffness.
      • Gao Y.Z.
      • Saphirstein R.J.
      • Yamin R.
      • Suki B.
      • Morgan K.G.
      Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?.
      Gao et al
      • Gao Y.Z.
      • Saphirstein R.J.
      • Yamin R.
      • Suki B.
      • Morgan K.G.
      Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?.
      determined that increased passive aortic stiffness occurs beyond physiological strain levels and vascular SM contractility accounts for close to half of aortic stiffness. The underlying mechanism of increased aortic stiffness secondary to vascular SM contractile activation is thought to be secondary to focal adhesions.
      • Saphirstein R.J.
      • Gao Y.Z.
      • Jensen M.H.
      • et al.
      The focal adhesion: a regulated component of aortic stiffness.
      The Src kinase inhibitor PP2 typically suppresses focal adhesions, and the tyrosine phosphorylation of focal adhesion proteins is impaired with age because of decreased Src expression.
      • Gao Y.Z.
      • Saphirstein R.J.
      • Yamin R.
      • Suki B.
      • Morgan K.G.
      Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?.
      Animal models confirm that older mice lose the response to inhibition of Src on stress and stiffness.
      • Gao Y.Z.
      • Saphirstein R.J.
      • Yamin R.
      • Suki B.
      • Morgan K.G.
      Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?.
      In addition to changes in focal adhesions, there is thought to be a second more active component leading to increased arterial stiffness (Figure 2). Smooth muscle contains both nonmuscle (NM) and SM myosin, and both assemble in filaments and are regulated by phosphorylation.
      • Brozovich F.V.
      • Nicholson C.J.
      • Degen C.V.
      • Gao Y.Z.
      • Aggarwal M.
      • Morgan K.G.
      Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders.
      In all muscles, the number of myosin heads (cross-bridges) attached to act in determines force. In cardiac, skeletal muscle, and SM myosin, adenosine diphosphate release from actomyosin is fast. However, the kinetics of both adenosine triphosphatase and adenosine diphosphate release for NM myosin are slower.
      • Kovács M.
      • Wang F.
      • Hu A.
      • Zhang Y.
      • Sellers J.R.
      Functional divergence of human cytoplasmic myosin II: kinetic characterization of the non-muscle IIA isoform.
      • Wang F.
      • Kovács M.
      • Hu A.
      • Limouze J.
      • Harvey E.V.
      • Sellers J.R.
      Kinetic mechanism of non-muscle myosin IIB: functional adaptations for tension generation and maintenance.
      Therefore, NM myosin spends a higher percentage of its overall duty cycle attached to actin.
      • Zhang W.
      • Gunst S.J.
      Non-muscle (NM) myosin heavy chain phosphorylation regulates the formation of NM myosin filaments, adhesome assembly and smooth muscle contraction.
      Therefore, an increase in NM myosin expression would increase the number of attached cross-bridges per unit time, which would result in an increase in SM tone and/or vascular resistance. Furthermore, NM myosin is increased in systemic hypertension.
      • Contard F.
      • Sabri A.
      • Glukhova M.
      • et al.
      Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.
      Thus, in patients with HFpEF, NM myosin expression could potentially increase in the vasculature. An increase in NM myosin expression would lead to increased contractility and force, resulting in an increase in arterial stiffness, which will ultimately produce cardiac hypertrophy and remodeling.
      Figure thumbnail gr2
      Figure 2Regulation of vascular tone. In vascular smooth muscle, activation of G protein–coupled receptors and Gq/11 will lead to an increase in IP3 and DAG. Inositol trisphosphate binds to the IP3 receptor and results in Ca2+ release from the SR, which binds to calmodulin. The Ca2+-calmodulin complex activates MLCK to produce vasoconstriction. Diacylglycerol activates CPI-17, which inhibits MLCP to increase vascular tone. G protein signaling via the activation of G12/13 increases RhoA, which activates Rho kinase. Rho kinase phosphorylates (P) MYPT1 to inhibit MLCP activity to increase vascular tone. In contrast, ACh activates muscarinic receptors on endothelial cells, which results in an activation of NO synthase to produce NO, which in turn activates guanylate synthase and results in an increase in cGMP. Similarly, natriuretic peptides bind to their receptor, which activates guanylate cyclase. The increase in cGMP activates PKG, which decreases intracellular Ca2+ by phosphorylating the K+ channel, Ca2+ channel, and IP3 receptor. Protein kinase G also phosphorylates the LZ+ MYPT1 subunit of MLCP, which activates MLCP, which in turn produces a Ca2+-independent vasodilatation (refer to text and reference 41). ACh = acetylcholine; CPI-17 = protein phosphatase 1 regulatory subunit 14A; cGMP = cyclic guanosine monophosphate; DAG = diacylglycerol; GMP = guanosine monophosphate; GPCR = G protein coupled receptor; GTP = guanosine 5′-triphosphate; Gq/11 = alpha 11 subunit of G protein; G12/13 = alpha 12/13 subunit of G protein; IP3 = inositol trisphosphate; IP3R = inositol trisphosphate receptor; LZ+/LZ− MYPT1 = leucine zipper positive/leucine zipper negative isoform of the myosin-targeting subunit of myosin light chain phosphatase; MLCK = myosin light chain kinase; MLCP = myosin light chain phosphatase; MYPT1 = myosin-targeting subunit of myosin light chain phosphatase; NM = nonmuscle; NO = nitric oxide; P = phosphorylation of protein; PDE = phosphodiesterase; PKC = protein kinase C; PKG = protein kinase G; SM = smooth muscle; SR = sarcoplasmic reticulum.

      Vascular Etiologies—PKG Signaling

      Protein kinase G also plays a role in the regulation of vascular tone in normal physiology and pathophysiology, including in patients with HFpEF (Figure 2). Nitric oxide diffuses into SM cells and stimulates soluble guanylate cyclase, which results in conversion of guanosine 5′-triphosphate to cGMP, which then activates PKG. In SMs, PKG phosphorylates a number of targets including K+ channel, L-type Ca2+ channel, and sarcoplasmic reticulum, all of which decrease intracellular Ca2+.
      • Brozovich F.V.
      • Nicholson C.J.
      • Degen C.V.
      • Gao Y.Z.
      • Aggarwal M.
      • Morgan K.G.
      Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders.
      In addition, PKG phosphorylates the myosin-targeting subunit (MYPT1) of myosin light chain phosphatase (MLCP), which dephosphorylates the regulatory light chain (RLC) of SM myosin. The phosphorylation of the RLC activates the SM myosin adenosine triphosphatase,
      • Sellers J.R.
      • Adelstein R.S.
      The mechanism of regulation of smooth muscle myosin by phosphorylation.
      and the increase in the interaction of myosin with actin (regulated by RLC phosphorylation) increases force and/or vascular tone. Therefore, the dephosphorylation of the RLC by MLCP produces vasorelaxation. Myosin light chain kinase (MLCK) phosphorylates the RLC, and therefore, both total RLC phosphorylation and vascular tone are regulated by the balance between the activities of MLCK and MLCP. Myosin light chain phosphatase is a trimeric enzyme consisting of a catalytic subunit, a 20-kDa subunit, and MYPT1. The myosin-targeting subunit of MLCP is phosphorylated by Rho kinase (Thr696
      • Kitazawa T.
      • Gaylinn B.D.
      • Denney G.H.
      • Somlyo A.P.
      G-protein-mediated Ca2+ sensitization of smooth muscle contraction through myosin light chain phosphorylation.
      and/or Thr853
      • Velasco G.
      • Armstrong C.
      • Morrice N.
      • Frame S.
      • Cohen P.
      Phosphorylation of the regulatory subunit of smooth muscle protein phosphatase 1M at Thr850 induces its dissociation from myosin.
      ), which inhibits MLCP activity. In addition, alternative messenger RNA splicing produces 2 MYPT1 isoforms, differing by the presence or absence of a COOH-terminal leucine zipper (LZ) domain.
      • Brozovich F.V.
      • Nicholson C.J.
      • Degen C.V.
      • Gao Y.Z.
      • Aggarwal M.
      • Morgan K.G.
      Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders.
      • Khatri J.J.
      • Joyce K.M.
      • Brozovich F.V.
      • Fisher S.A.
      Role of myosin phosphatase isoforms in cGMP-mediated smooth muscle relaxation.
      Protein kinase G activates MLCP by phosphorylating LZ+ MYPT1 isoforms at Ser667, which results in a Ca2+-independent increase in MLCP activity
      • Yuen S.L.
      • Ogut O.
      • Brozovich F.V.
      Differential phosphorylation of LZ+/LZ− MYPT1 isoforms regulates MLC phosphatase activity.
      and subsequent vasorelaxation.
      • Yuen S.L.
      • Ogut O.
      • Brozovich F.V.
      Differential phosphorylation of LZ+/LZ− MYPT1 isoforms regulates MLC phosphatase activity.
      • Huang Q.Q.
      • Fisher S.A.
      • Brozovich F.V.
      Unzipping the role of myosin light chain phosphatase in smooth muscle cell relaxation.
      However, PKG-mediated MYPT1 phosphorylation has been found to be dependent on MYPT1 isoform expression; LZ+ MYPT1 isoforms, but not LZ− MYPT1 isoforms, are phosphorylated and subsequently activated by PKG.
      • Yuen S.L.
      • Ogut O.
      • Brozovich F.V.
      Differential phosphorylation of LZ+/LZ− MYPT1 isoforms regulates MLC phosphatase activity.
      • Yuen S.
      • Ogut O.
      • Brozovich F.V.
      MYPT1 protein isoforms are differentially phosphorylated by protein kinase G.
      The LZ MYPT1 domain is therefore important for the regulation of MLCP activity and thus vascular tone. The expression of LZ+/LZ− MYPT1 decreases in heart failure
      • Karim S.M.
      • Rhee A.Y.
      • Given A.M.
      • Faulx M.D.
      • Hoit B.D.
      • Brozovich F.V.
      Vascular reactivity in heart failure: role of myosin light chain phosphatase.
      • Chen F.C.
      • Ogut O.
      • Rhee A.Y.
      • Hoit B.D.
      • Brozovich F.V.
      Captopril prevents myosin light chain phosphatase isoform switching to preserve normal cGMP-mediated vasodilatation.
      • Chen F.C.
      • Brozovich F.V.
      Gene expression profiles of vascular smooth muscle show differential expression of mitogen-activated protein kinase pathways during captopril therapy of heart failure.
      and pulmonary arterial hypertension.
      • Konik E.A.
      • Han Y.S.
      • Brozovich F.V.
      The role of pulmonary vascular contractile protein expression in pulmonary arterial hypertension.
      Because a decrease in the expression of LZ+/LZ− MYPT1 is associated with animal models of HFrEF, it is possible that there is also a decrease in LZ+/LZ− expression in patients with HFpEF. Thus in HFpEF, a decrease in LZ+ MYPT1 expression would contribute to the decrease in sensitivity to NO-mediated vasodilation and also increase vascular tone.

      Predictions/Trials

      As discussed above, the dogma is that patients with HFpEF display reduced levels of PKG activity and lower cGMP levels, which results in cardiac hypertrophy,
      • Kim G.E.
      • Kass D.A.
      Cardiac phosphodiesterases and their modulation for treating heart disease.
      although recent studies do call this into question. Furthermore, PDE inhibitors are incredibly specific, which makes PDEs an ideal therapeutic target. Therefore, the NO-cGMP-PKG signaling network has been suggested to be an important target of therapy for HFpEF. As previously noted, the RELAX trial
      • Redfield M.M.
      • Chen H.H.
      • Borlaug B.A.
      • et al.
      RELAX Trial
      Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
      hypothesized that PDE5 inhibition with sildenafil would have beneficial effects on patients with HFpEF. However, the RELAX trial results
      • Redfield M.M.
      • Chen H.H.
      • Borlaug B.A.
      • et al.
      RELAX Trial
      Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
      indicated that sildenafil did not increase plasma cGMP activity, and furthermore, sildenafil did not increase exercise capacity or improve clinical status. The reason for the lack of improvement in symptoms can be linked to the aforementioned lack of PDE5 expression in cardiac muscle.
      • Degen C.V.
      • Bishu K.
      • Zakeri R.
      • Ogut O.
      • Redfield M.M.
      • Brozovich F.V.
      The emperor's new clothes: PDE5 and the heart.
      • Lukowski R.
      • Rybalkin S.D.
      • Loga F.
      • Leiss V.
      • Beavo J.A.
      • Hofmann F.
      Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes.
      • Patrucco E.
      • Domes K.
      • Sbroggió M.
      • et al.
      Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis.
      Because of the results of the RELAX trial, attention has now turned to increasing NO availability via the addition of nitrates to increase PKG activity. However, treatment with isosorbide mononitrate did not have clinical benefit.
      • Redfield M.M.
      • Anstrom K.J.
      • Levine J.A.
      • et al.
      NHLBI Heart Failure Clinical Research Network
      Isosorbide mononitrate in heart failure with preserved ejection fraction.
      The Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction trial
      • Reddy Y.N.
      • Lewis G.D.
      • Shah S.J.
      • et al.
      INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): rationale and design.
      focuses on impaired NO-cGMP signaling as a central pathway leading to HFpEF, with an alternative approach to restore NO-cGMP signaling via the addition of an inorganic nitrite. However, if cardiac hypertrophy and function are not different in response to isoproterenol or pressure overload in PKG KO mice compared with wild-type controls,
      • Lukowski R.
      • Rybalkin S.D.
      • Loga F.
      • Leiss V.
      • Beavo J.A.
      • Hofmann F.
      Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes.
      it is unlikely that targeting the cGMP-PKG pathway by administering soluble guanylate cyclase activators, natriuretic peptides, nitrates, and/or nitrite will either improve cardiac hypertrophy or have clinical benefit. This hypothesis and these data are consistent with the results of the Nitrate's Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial
      • Redfield M.M.
      • Anstrom K.J.
      • Levine J.A.
      • et al.
      NHLBI Heart Failure Clinical Research Network
      Isosorbide mononitrate in heart failure with preserved ejection fraction.
      and would predict that the Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction trial
      • Reddy Y.N.
      • Lewis G.D.
      • Shah S.J.
      • et al.
      INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): rationale and design.
      would also not have a significant clinical benefit.

      Future Studies/Novel Approaches to Treatment

      Future studies are needed to develop treatments to improve symptoms and survival in patients with HFpEF. There are 2 components of HFpEF: cardiac muscle hypertrophy/diastolic dysfunction and vascular dysfunction, that is, an increased vascular tone and a decrease in the sensitivity of the vasculature to NO. To date, no therapy aimed at cardiac muscle has proven beneficial, but there is still the other half of the disease to focus on—the vasculature. One could suggest that HFpEF is primarily a disease of vasculature, which then results in diastolic dysfunction. Arterial stiffness is known to be directly associated with longitudinal increases in blood pressure in hypertensive patients,
      • Coutinho T.
      • Bailey K.R.
      • Turner S.T.
      • Kullo I.J.
      Arterial stiffness is associated with increase in blood pressure over time in treated hypertensives.
      with hypertension being one of the most common associations of HFpEF. If arterial stiffness and resistance to NO are altered, can we improve the pathophysiology of HFpEF?
      We suggest that future studies should focus on the regulation of vascular tone and the acquisition of substantial preclinical data before the design of a clinical trial. During hypertension,
      • Contard F.
      • Sabri A.
      • Glukhova M.
      • et al.
      Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.
      an increase in NM myosin expression would result in increased arterial stiffness. Furthermore, if there is a concomitant decrease in LZ+/LZ− MYPT1 expression, this would produce a decrease in sensitivity to NO as well as an increase in systemic vascular resistance. Therefore, we would suggest that future studies should focus on investigating the expression of NM myosin and LZ+/LZ− MYPT1 in HFpEF and possibly targeting the expression and/or activation of these proteins. As the push continues to elucidate an effective therapy for HFpEF, we encourage a shift of focus from diastology to the regulation of vascular function.

      Conclusion

      For patients with HFpEF, no therapy has been found to have clinical benefit. However, vascular abnormalities including resting vasoconstriction (arterial stiffness) and a decrease in sensitivity to NO-mediated vasodilatation are an important part of this clinical syndrome. Thus, both studying patients at earlier time points in the disease process and mechanistic studies that focus on HFpEF as a vascular disease may reveal novel targets and treatment paradigms that would improve morbidity and mortality in patients with this disease.

      Supplemental Online Material

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