Key “phenotypes” of HFpEFFlora Sam, MD, FACC, FAHA, FHFSAProfessor of MedicineWhitaker Cardiovascular InstituteBoston University School of MedicineChief Scientific Officer (CSO) of ImbriaPharmaceuticals Boston, MA CHFS April 18th, 2020

Key “phenotypes” of HFpEFFlora Sam, MD, FACC, FAHA, FHFSAProfessor of MedicineWhitaker Cardiovascular InstituteBoston University School of MedicineChief Scientific Officer (CSO) of ImbriaPharmaceuticals Boston, MA CHFS April 18th, 2020 Conflict of Interest Disclosures•Grants/research support: NIH/ NHLBI•Consulting fees: •NGM Bio•Acorda•Imbria••Speaker fees: N/A•Other: CSO Imbria•I willnotdiscussoff-label uses Polling QuestionAccording to evidence-based guidelines, which of the following is recommended therapy for HFpEF?A) sacubitril/valsartanB) SGTL2 inhibitorC) exercise training & caloric restrictionD) mineralocorticoid therapyE) exercise trainingF) sildenafil Shah SJ et al. Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap. Circulation.2016 Jul 5;134(1):73-90. HFpEF: “no evidence-based therapies” Clinical characteristics and risk factors from larger HFpEF trials Andersen et al, CurrCardiolRep (2014) 16:501 Phenotype heat map (phenomap) of HFpEF Shah S J et al. Circulation. 2015;131:269-279 Survival from cardiovascular hospitalization or death stratified by phenogroup Shah S J et al. Circulation. 2015;131:269-279 HFpEF Lee et al., Circulation. Relation of Disease Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction, Volume: 119, Issue: 24, Pages: 3070-3077 Hypertension and HFpEF •Symptomatic control•Long-standing hypertension is a predisposing factor for HFpEF,àexcellent blood pressure control is needed in these patients to achieve a blood pressure ≤130/80 mm Hg,•Some observational analyses have cautioned against excessively lowering the systolic blood pressure to levels <120 mm Hg•β-blockers studies in HFpEF patients have been less encouraging. In a patient-level meta-analysis of 11 randomized trials with 14 262 patients with HF in sinus rhythm, β-blocker reduced the risk of all-cause and cardiovascular mortality over a median 1.3-year follow-up in those with mid-range EF (ie, 40%–49%), but not in those with EF ≥50%•β-blockers, ACE inhibitors, ARBs, and ARNIs is limited, and have no role in HFpEF without an alternative indication (e.g., hypertension, chronic kidney disease, etc). Hypertension and HFpEF Obesity and HFpEF SavjiN et al. The Association ofObesityand Cardiometabolic Traits With IncidentHFpEFand HFrEF. JACC Heart Fail.2018 Aug;6(8):701-709. Diabetes and HFpEF Meagher P et al. Heart Failure With Preserved Ejection Fraction inDiabetes: Mechanisms and Management. Can J Cardiol.2018 May;34(5):632-643. Chronic kidney disease and HFpEF Frvande WouwJ et al. ChronicKidneyDisease as a Risk Factor for HeartFailureWith Preserved Ejection Fraction: A Focus on Microcirculatory Factors and Therapeutic Targets. Front Physiol.2019 Sep 4;10:1108. Atrial fibrillation and HFpEF Kotecha D et al, Heart Failure With Preserved EjectionFraction andAtrial Fibrillation: Vicious Twins. J Am Coll Cardiol.2016 Nov 15;68(20):2217-2228. Other phenotypes:•IHD / CAD associated HFpEF•Pulmonary HTN HFpEF Physical Activity to Prevent and Treat HF •Increasedcardiorespiratory fitnessis strongly associated with decreased incident HF and has benefit in bothHFrEF and HFpEF. •Exercise training has functional benefits in HFpEF and HFrEF but only survival benefits in HFrEF•In HFrEF, the HF-ACTION (Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure) trial was a prospective RCT of ET in 2,231 HFrEF patients with NYHA functional class II to IV symptoms. Patients were randomized to usual care plus aerobic ET, consisting of 36 supervised sessions followed by home-based training, or usual care alone. Exercise did not significantly affectall-cause mortalityor all-cause hospitalization; however, there was a reduction in mortality seen after adjustment for covariates. Men and women undergoing ET had equal improvement of peak VO2at 3months. Exercise and HFpEF•In HFpEF,ET has been proven to be efficacious for improving peak VO2. •Centers for Medicare & Medicaid Services coverage for cardiac rehabilitation in HFpEF has been limited.•Recently, a small study suggested that HFpEF patients had greater peak VO2improvement in response to 16-week supervised moderate-intensityendurance trainingcompared with those with HFrEF. JAMA. 2016;315(1):36-46. doi:10.1001/jama.2015.17346 Therapy for HFpEF in 2020 (regardless of phenotype)•HFpEF is a multifactorial condition with coronary microvascular dysfunction secondary to systemic inflammation, obesity, inactivity, and plasma volume expansion.•Similar to HFrEF management, comorbidities and risk factors such as blood pressure and weight control are keyInterventionTrial NameClinical TrialRegistrationNumberPrimary Outcome Primary OutcomeOPTIMIZE-HFPEFNCT02425371Clinical score statusEmpagliflozin(SLGT-2inhibitor)EMPEROR-PreservedNCT03057951Composite of cardiac mortality or HF hospitalizationsDapagliflozin(SLGT-2inhibitor)PRESERVED-HFNCT03030235Natriuretic peptide levels SpironolactoneSPIRRITNCT02901184All-cause mortalityNeprilysininhibitorsPARALLAXNCT03066804Quality of life Thank you for your attention