Abstract Body: Heart failure with preserved ejection fraction (HFpEF) is a growing global health burden characterized by limited mechanistic understanding and a lack of effective therapies. Driven by comorbidities like aging, obesity, and hypertension, HFpEF pathophysiology is increasingly linked to coronary microvascular dysfunction, which affects 69–81% of patients and correlates with poor outcomes. However, the chronology of vascular events leading to diastolic failure remains unclear due to a lack of preclinical models that accurately recapitulate the human phenotype.

We assess the hypothesis that early microvascular impairment is a driver of HFpEF progression that precedes measurable diastolic failure. We propose that myocardial hypoxia-triggered upregulation of Angiopoietin-like 4 (ANGPTL4), a multifunctional vascular and metabolic regulator, mediates the link between early vascular remodeling and subsequent diastolic stiffening.

We established a three-hit mouse model combining aging, obesity, and hypertension (Angiotensin II) (Figure 1). We integrated a preclinical cardiac MRI pipeline with automated deep-learning analysis, arterial spin labeling for myocardial blood flow (MBF) assessment, ultrasound for mitral valve inflow measurements, and micro-CT for lung imaging to longitudinally phenotype structural and functional remodeling from baseline to two months (Figure 1). Findings were validated through histology for vessel density and fibrosis, RNA sequencing, and UK Biobank data.

Multimodal analysis revealed significant myocardial pathology appearing within 7 days of Angiotensin. Early events included significant reductions in MBF and vessel density, coinciding with increased fibrosis (Figure 2). These changes preceded hallmark HFpEF phenotypes- diastolic dysfunction-, which peaked at 14 days. Molecular profiling identified significant transcriptional upregulation of ANGPTL4 in hearts, localized within endothelial cells and myofibroblasts, suggesting a link to microvascular and fibrotic remodeling (Figure 3). The UKBB cohort confirmed that ANGPTL4 plasma levels increased with age and genome-wide association study revealed strong associations between ANGPTL4 and key HFpEF phenotypes (Figure 3).

In conclusion, our refined model demonstrates that microvascular stress is an early pathological driver of diastolic stiffening in HFpEF. The upregulation of ANGPTL4 identifies it as a potential biomarker and mechanistic link between vascular remodeling and disease progression.