# Phenotype-specific models, mechanisms, and treatment of HFpEF

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $599,342

## Abstract

Project summary
Heart failure (HF) with preserved ejection fraction (HFpEF) is a major public health burden currently affecting
more than three million Americans and leading to significant morbidity and mortality. HFpEF prevalence is
expected to further increase with the aging population and the concomitant diffusion of recognized risk factors
such as obesity, diabetes mellitus, and hypertension. HFpEF is a complex multi-organ, systemic syndrome that
drastically reduces patients’ quality of life. Importantly, patients’ survival rate after first hospitalization is very
limited, as effective treatment options for HFpEF are currently inadequate. Notably, almost all therapies
developed for the better characterized HF with reduced ejection fraction (HFrEF) have been shown to be
ineffective in HFpEF, implying the existence of different underlying mechanisms of disease yet to be identified.
The lack of effective treatment options for HFpEF is now one of the major unmet needs in the medical field and
may be due also to the large phenotypic heterogeneity observed in patients. In fact, HFpEF phenotypic diversity
represents an obstacle for timely diagnosis of HFpEF and is not entirely captured by most preclinical animal
models and clinical trials. Sex differences are thought to contribute to this phenotypic variability. Indeed, HFpEF
is more common in women, who experience worse symptoms but have lower risk of mortality than men. Overall,
HFpEF phenotypic heterogeneity hampers our understanding of the mechanisms underlying altered excitation-
contraction coupling (ECC) and increased propensity for ventricular arrhythmias (i.e., one of the leading causes
of death among HFpEF patients). Our overarching hypothesis is that, because of the presence of different HFpEF
subphenotypes, an effective therapy may benefit from a subgroup-targeted approach. We have previously
demonstrated the power of mechanistic modeling and data-driven precision medicine techniques to classify and
discriminate cardiac phenotypes. In this Project, we propose a novel integrative computational/experimental
approach aimed at i) identifying the key molecular and cellular functional changes in HFpEF in a preclinical
animal model, and ii) concomitantly investigating the impact of HFpEF heterogeneity in disease mechanisms
and therapy. Informed by novel functional and transcriptomic data, we will develop a refined modeling platform
that allows for new quantitative predictions amenable to experimental testing, as well as translation of
experimental findings across species. In synergy with the NHLBI initiatives HeartShare and Accelerating
Medicines Partnership, completion of the studies proposed in this Project will provide new mechanistic insights
into HFpEF phenotypic diversity in contractile dysfunction and arrhythmogenesis and help targeting new
therapeutic strategies to different subpopulations of HFpEF patients.

## Key facts

- **NIH application ID:** 10979765
- **Project number:** 1R01HL171057-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Stefano Morotti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $599,342
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979765

## Citation

> US National Institutes of Health, RePORTER application 10979765, Phenotype-specific models, mechanisms, and treatment of HFpEF (1R01HL171057-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979765. Licensed CC0.

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