Disentangling the Impact of Adiposity From Insulin Resistance in Heart Failure With Preserved Ejection Fraction

Obesity, insulin resistance(IR) and diabetes are common in heart failure with preserved ejection fraction(HFpEF), and associated with worsening HF. The extent to which this is principally caused by excess adiposity or diabetes is unknown. To determine the contribution of diabetes versus obesity to left heart abnormalities in HFpEF Indices of adiposity(body mass index [BMI], bioimpedance fat mass, waist circumference) and IR(HOMA-IR) were measured among PVDOMICS participants with HFpEF. Rest and exercise pulmonary capillary wedge pressure(PCWP) responses were compared stratified by obesity(BMI≥30 kg/m 2 ), IR status(HOMA IR≥2.6) and diabetes diagnosis. Interaction between diabetes and obesity with exercise PCWP were also tested in an independent HFpEF cohort. Of 276 patients with HFpEF, 246(89%) had increased waist-height ratio, and 166(60%) had BMI≥30kg/m 2 , with 114(69%) of these patients having IR and 75(45%) having diabetes. Of 110(40%) with HFpEF and BMI<30 kg/m 2 , 44(40%) had IR, and 27(25%) had diabetes (both p<.0001 vs obesity phenotype). The presence of IR was not associated with worse left heart remodeling or PCWP. In contrast, obesity (regardless of IR status) was associated with greater biventricular enlargement, worse exercise performance, poorer quality of life and higher rest and exercise PCWP (p<0.01 for all). Obesity was associated with higher rest and dynamic PCWP responses(+4.4 mmHg[95% CI +2.5 to +6.4],p<0.0001), even after adjustment for HOMA-IR(+4.7 mmHg [95% CI +2.7 to +6.7],p<0.0001). Greater fat mass, BMI, and waist circumference were associated with higher PCWP at rest and exercise(p<0.0009 for all), but HOMA-IR was not(+0.01 mmHg [95% CI −0.13 to +0.16], p=0.84). Findings were similar evaluating diabetes in place of IR, and were replicated in the independent HFpEF cohort (n=254) where BMI remained independently associated with higher rest/exercise PCWP (+0.19 mmHg[95% CI +0.11 to +0.27]per kg/m 2 ,p<0.0001), but diabetes was not. Excess adiposity is present in most patients with HFpEF, even among those not considered obese by BMI. While excess body fat is associated with IR and diabetes; cardiac remodeling, hemodynamics and functional impairment are independently correlated with body fat, but not insulin resistance. These findings suggest that diabetes is primarily a marker of greater adiposity in HFpEF, with less direct impact on HF severity.