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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.<\/jats:p>","DOI":"10.1161\/circulationaha.116.021884","type":"journal-article","created":{"date-parts":[[2016,6,29]],"date-time":"2016-06-29T19:19:21Z","timestamp":1467227961000},"page":"73-90","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":955,"title":["Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction"],"prefix":"10.1161","volume":"134","author":[{"given":"Sanjiv J.","family":"Shah","sequence":"first","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalane W.","family":"Kitzman","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry 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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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Zile","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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