Abstract
BackgroundPatients with coexistent chronic heart failure (CHF) and diabetes mellitus (DM) demonstrate greater exercise limitation and worse prognosis compared with CHF patients without DM, even when corrected for cardiac dysfunction. Understanding the origins of symptoms in this subgroup may facilitate development of targeted treatments. We therefore characterized the skeletal muscle phenotype and its relationship to exercise limitation in patients with diabetic heart failure (D‐HF).MethodsIn one of the largest muscle sampling studies in a CHF population, pectoralis major biopsies were taken from age‐matched controls (n = 25), DM (n = 10), CHF (n = 52), and D‐HF (n = 28) patients. In situ mitochondrial function and reactive oxygen species, fibre morphology, capillarity, and gene expression analyses were performed and correlated to whole‐body exercise capacity.ResultsMitochondrial respiration, content, coupling efficiency, and intrinsic function were lower in D‐HF patients compared with other groups (P < 0.05). A unique mitochondrial complex I dysfunction was present in D‐HF patients only (P < 0.05), which strongly correlated to exercise capacity (R 2 = 0.64; P < 0.001). Mitochondrial impairments in D‐HF corresponded to higher levels of mitochondrial reactive oxygen species (P < 0.05) and lower gene expression of anti‐oxidative enzyme superoxide dismutase 2 (P < 0.05) and complex I subunit NDUFS1 (P < 0.05). D‐HF was also associated with severe fibre atrophy (P < 0.05) and reduced local fibre capillarity (P < 0.05).ConclusionsPatients with D‐HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D‐HF.
Highlights
Chronic heart failure (CHF) and type 2 diabetes mellitus (DM) remain two primary causes of mortality and morbidity.[1]
Patients in the chronic heart failure (CHF) and diabetic heart failure (D-HF) groups had no differences in terms of cardiac function, disease severity (i.e. NYHA), VO2peak, or aetiology, drug/device therapies
Differences were detected between groups for each respiratory state, with complex I oxidative phosphorylation (OXPHOS) in D-HF 43% (P = 0.008; Figure 1A) and 49% (P < 0.0001; Figure 1A) lower than DM and CHF, respectively
Summary
Chronic heart failure (CHF) and type 2 diabetes mellitus (DM) remain two primary causes of mortality and morbidity.[1] Approximately 25% of CHF patients have coexistent DM [i.e. diabetic heart failure (D-HF)], which is currently increasing in prevalence.[2] Patients with D-HF have worse symptoms, exercise limitation, and mortality compared with either CHF or DM.[3,4] the mechanisms underlying the pathophysiological phenotype of D-HF patients, and potential for targeted interventions, remain poorly established. Conclusions Patients with D-HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D-HF
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