title: Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap.
abstract: Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.).
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.).
authors.forename: Dalane W
authors.initials: DW
authors.lastname: Kitzman
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.).
authors.forename: Barry A
authors.initials: BA
authors.lastname: Borlaug
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.).
authors.forename: Loek
authors.initials: L
authors.lastname: van Heerebeek
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.).
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (L.v.H., W.J.P.); Department of Cardiology, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands (L.v.H.); Department of Medicine, Medical University of South Carolina (MUSC) and the RHJ Department of Veterans Affairs Medical Center, Charleston (M.R.Z.); and Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (D.A.K.). wj.paulus@vumc.nl.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
mesh_terms: D003131:Combined Modality Therapy; D015897:Comorbidity; D003327:Coronary Disease / Q000150:complications; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006333:Heart Failure / Q000628:therapy*; D006801:Humans; D006973:Hypertension / Q000150:complications; D006976:Hypertension, Pulmonary / Q000150:complications; D007249:Inflammation; D007674:Kidney Diseases / Q000150:complications; D008297:Male; D018908:Muscle Weakness / Q000150:complications; D010641:Phenotype; D057285:Precision Medicine; D015398:Signal Transduction; D013318:Stroke Volume
keywords: diastole; heart failure; heart failure, diastolic; phenotype; therapeutics; ventricular function, left