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Background Heterogeneity in the underlying processes that contribute to heart failure with preserved ejection fraction ( HF p EF ) is increasingly recognized. Diabetes mellitus is a frequent comorbidity in HF p EF , but its impact on left ventricular and arterial structure and function in HF p EF is unknown. Methods and Results We assessed the impact of diabetes mellitus on left ventricular cellular and interstitial hypertrophy (assessed with cardiac magnetic resonance imaging, including T1 mapping pregadolinium and postgadolinium administration), arterial stiffness (assessed with arterial tonometry), and pulsatile arterial hemodynamics (assessed with in‐office pressure‐flow analyses and 24‐hour ambulatory monitoring) among 53 subjects with HF p EF (32 diabetic and 21 nondiabetic subjects). Despite few differences in clinical characteristics, diabetic subjects with HFpEF exhibited a markedly greater left ventricular mass index (78.1 [95% CI , 70.4–85.9] g versus 63.6 [95% CI , 55.8–71.3] g; P =0.0093) and indexed extracellular volume (23.6 [95% CI , 21.2–26.1] mL/m 2 versus 16.2 [95% CI , 13.1–19.4] mL/m 2 ; P =0.0008). Pronounced aortic stiffening was also observed in the diabetic group (carotid‐femoral pulse wave velocity, 11.86 [95% CI , 10.4–13.1] m/s versus 8.8 [95% CI , 7.5–10.1] m/s; P =0.0027), with an adverse pulsatile hemodynamic profile characterized by increased oscillatory power (315 [95% CI , 258–373] mW versus 190 [95% CI , 144–236] mW; P =0.0007), aortic characteristic impedance (0.154 [95% CI , 0.124–0.183] mm Hg/mL per second versus 0.096 [95% CI , 0.072–0.121] mm Hg/mL per second; P =0.0024), and forward (59.5 [95% CI , 52.8–66.1] mm Hg versus 40.1 [95% CI , 31.6–48.6] mm Hg; P =0.0010) and backward (19.6 [95% CI , 16.2–22.9] mm Hg versus 14.1 [95% CI , 10.9–17.3] mm Hg; P =0.0169) wave amplitude. Abnormal pulsatile hemodynamics were also evident in 24‐hour ambulatory monitoring, despite the absence of significant differences in 24‐hour systolic blood pressure between the groups. Conclusions Diabetes mellitus is a key determinant of left ventricular remodeling, arterial stiffness, adverse pulsatile...

Aims Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants. Methods and results Fifty-nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO 2, peak ), ventilatory threshold (VT), and VO 2 efficiency (ratio of total work performed to O 2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t 1/2, Cr ) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO 2,peak , VT, and VO 2 efficiency than either control group (all P < 0.05). The t 1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF. Conclusions Heart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.