David A. Kass

BackgroundHypertension (HTN) has long been a significant modifiable risk factor for heart failure with preserved ejection fraction (HFpEF). Contemporary HFpEF cohorts have predominantly metabolic comorbidities (obesity and diabetes), suggesting a shift in HFpEF phenotype. We hypothesized that HTN is both less prevalent and less severe in contemporary HFpEF.MethodsWe conducted a systematic review and analysis of 17 HFpEF clinical trials from 2003 and 2022 for enrollment systolic blood pressure (SBP), diastolic blood pressure (DBP), comorbidities, and anti-hypertensive use. Searches were identified using PubMed Central. Trends in blood pressure over time were assessed by averaging enrollment blood pressures in one-year increments and calculating univariate linear regression and Pearson R correlation coefficient. We subsequently assessed enrollment SBP and DBP in HFpEF patients (EF ≥ 50 …

Direct sarcomere activating drugs (myotropes) have emerged as one alternative to inotropes in heart failure. The only myotropes that have been evaluated clinically involve myosin modulation, which does not increase maximum calcium activated tension (T max), observed in heart failure with reduced (HFrEF) and obese preserved (HFpEF) ejection fraction. Here, we tested if troponin modulation with the sarcomere activator CK-136 (1 uM) can augment T max. We isolated permeabilized myocytes from HFrEF (n= 5), HFpEF (n= 9, 5 w/severe obesity and reduced T max and 4 w/o), and non-failing human (n= 6) and porcine controls and obtained tension-Ca relationships with CK-136. Consistent with its calcium sensitizing effect, CK-136 reduced Ca for 50% T max (EC 50) by 25% in non-failing controls, 19% in HFrEF (p= 0.01), 16% in HFpEF w/o severe obesity (p= 0.05), and 18% in HFpEF w/severe obesity (p= 0.01 …

* Corresponding author. Tel:+ 1 410 955 7153; fax:+ 1 410 367 2225, E-mail: dkass@ jhmi. edu

Heart failure with preserved ejection fraction (HFpEF) is a complex, multiorgan syndrome. Cardiac man ifestations include diastolic stiffening and impaired relaxation, normal resting systolic function but de pressed systolic reserve, and modest hypertrophy. 1 Although diastolic dysfunction remains a benchmark of HFpEF, the extent to which myofibrils, the contrac tile organelles of myocytes, contribute to this behavior remains unknown. HFpEF animal models historically emphasized hypertension and ventricular hypertrophy to achieve diastolic dysfunction, and recently have in corporated obesity and diabetes as they are increas ingly prevalent. Popular rodent models include Zucker obese/spontaneously hypertensive rats 2 and mice given a high fat diet (HFD) and the constitutive NO synthase inhibitor, Nω nitro l arginine methyl ester (ʟ NAME)(HFD+ ʟ NAME). 3 However, neither model de veloped diastolic disease …

BackgroundHeart failure with preserved ejection fraction (HFpEF) encompasses >50% of all HF and is a heterogeneous syndrome with few proven treatments. Phenomapping is a machine-learning based technique for sub-group identification which we sought to perform in an obese HFpEF cohort, a predominant form of HFpEF in which phenomapping to date is limited.MethodsWe prospectively studied 378 patients with HFpEF and performed detailed clinical, laboratory, echocardiographic, and hemodynamic phenotyping. A total of 207/378 (55%) and 104/378 (28%) underwent right heart catheterization and pulmonary function testing, respectively. We then assembled 104 clinical, laboratory, echocardiographic, and hemodynamic features for phenomapping using machine learning cluster analysis. Variables were compared between group clusters using a Kruskal Wallis test.ResultsCluster analysis (Figure 1A …

Diastolic dysfunction is a hallmark of heart failure with preserved ejection fraction (HFpEF) and its subphenotypes, including one that is observed comorbidly with obesity/diabetes (Ob/Dm) and the “classic” phenotype defined by hypertension/hypertrophy (Ht/Hp). Previous experiments revealed reduced maximal contractile force (Fmax) in human Ob/Dm cardiomyocytes compared to controls. While Fmax was not reduced in Ht/Hp cardiomyocytes, excessive tension under diastolic calcium was observed, suggesting unique subcellular mechanisms that elevate diastolic and preserve systolic force, and potentially impede relaxation in Ht/Hp samples. To investigate these mechanisms, we assessed force production and activation/relaxation kinetics in myofibrils from Ht/Hp-HFpEF patient biopsies. Ht/Hp myofibrils showed a prolonged linear relaxation phase, indicating excessive actomyosin interactions following calcium …

BackgroundHeart failure with preserved ejection fraction (HFpEF) was once predominantly a disease of older patients with hypertension and left ventricular hypertrophy. However, the prevalent phenotype has markedly changed to one of obesity and metabolic syndrome. Scoring algorithms derived from prior common HFpEF phenotypes, including the H2FPEF and HFA-PEFF scores, have yet to be evaluated in a predominantly obese HFpEF cohort.HypothesisWe sought to determine the performance of HFpEF diagnostic tools in the Johns Hopkins University (JHU) HFpEF cohort, a predominantly obese, urban HFpEF cohort.MethodsWe identified 160 HFpEF individuals from June 2013 to November 2022 from the JHU HFpEF registry. HFpEF was defined as signs and symptoms of clinical heart failure, left ventricular (LV) ejection fraction ≥ 50% by echo, and at least two of the following: 1) structural heart disease …

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