Background Characterization of myocardial structural changes in heart failure (HF) with preserved ejection fraction (HFpEF) has been hindered by limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction and myocardial fibrosis may contribute to HFpEF pathophysiology. Methods and Results We identified HFpEF patients (n=124) and age-appropriate control patients (non-cardiac death, no HF diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. Using whole field digital microscopy and automated analysis algorithms in full thickness left ventricular (LV) sections, microvascular density (MVD), myocardial fibrosis and their relationship were quantified. Subjects with HFpEF had heavier hearts (median 538 g; 169% of age/sex/body size expected heart weight vs. 335 g; 112% in controls), more severe CAD (65% with ≥ one vessel with >50% diameter stenosis in HFpEF vs 13% in controls), more LV fibrosis (median % area fibrosis, 9.6 vs. 7.1) and lower MVD (median 961 vs. 1316 vessels per mm2) than control (p <0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r = − 0.28, p=0.004) and HFpEF (r = − 0.26, p=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis and MVD were similar in HFpEF patients with vs without CAD. Conclusions In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction and myocardial fibrosis than controls. Each of these findings may contribute to the LV diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

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Objective Determine the frequency of left ventricular (LV) amyloid in heart failure with preserved ejection fraction (HFpEF). Background LV amyloid deposition can cause diastolic dysfunction and HFpEF. Methods Autopsy LV specimens from patients with ante-mortem diagnosis of HFpEF without clinically apparent amyloid (n=109) and Control subjects (n=131) were screened with sulfated alcian blue and subsequent Congo red staining with micro-dissection for mass spectrometry-based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. Results Presence of wtTTR amyloid was associated with age at death and male sex; but the age-and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF than Control (Odds ratio 3.8, 95% confidence interval 1.5–11.3; p=0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in five (5%) patients (80% male), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%). While wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p=0.005) and lower age, sex, and body size-adjusted heart weight (p=0.04). Conclusion Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.

Background Patients with heart failure and preserved ejection fraction (HFpEF) display increased adiposity and multiple comorbidities, factors that in themselves may influence cardiovascular (CV) structure and function. This has sparked debate as to whether HFpEF represents a distinct disease or an amalgamation of comorbidities. We hypothesized that fundamental CV structural and functional alterations are characteristic of HFpEF, even after accounting for body size and comorbidities. Methods and Results Comorbidity adjusted CV structural and functional parameters scaled to independently generated and age appropriate allometric powers were compared in community-based cohorts of HFpEF patients (n=386) and age/gender-matched healthy (CON, n=193) and hypertensive (HTN, n=386) controls. Within HFpEF patients, body size and concomitant comorbidity adjusted CV structural and functional parameters and survival were compared in those with and without individual comorbidities. Among HFpEF patients, comorbidities (obesity, anemia, diabetes and renal dysfunction) were each associated with unique clinical, structural, functional and prognostic profiles. However, after accounting for age, gender, body size and comorbidities, greater concentric hypertrophy, atrial enlargement and systolic, diastolic and vascular dysfunction were consistently observed in HFpEF compared to CON and HTN. Conclusions Comorbidities influence ventricular-vascular properties and outcomes in HFpEF, yet fundamental disease-specific changes in cardiovascular structure and function underlie this disorder. These data support the search for mechanistically-targeted therapies in this disease.