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<p>Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and is highly prevalent among individuals with diabetes. Although diabetes is traditionally regarded as a comorbidity, accumulating clinical and experimental evidence suggests that it may contribute importantly to HFpEF pathophysiology. Classical diabetic complications are fundamentally microvascular in nature, characterized by endothelial dysfunction, capillary rarefaction, impaired nitric oxide signaling, and barrier disruption. Similar abnormalities are increasingly recognized in HFpEF, in which coronary microvascular dysfunction is highly prevalent and independently associated with adverse outcomes. Epidemiological studies demonstrate that both type 1 and type 2 diabetes confer substantial risk for preclinical diastolic dysfunction and overt HFpEF, with concomitant renal involvement further amplifying risk within the cardiovascular-kidney-metabolic continuum. Mechanistically, cardiometabolic stress promotes systemic endothelial activation, inflammatory amplification, metabolic inflexibility, and structural microvascular remodeling extending beyond the myocardium to skeletal muscle and kidney. Experimental studies indicate that endothelial-specific molecular perturbations can induce or ameliorate HFpEF phenotypes in diabetic settings, implicating cytoskeletal regulation, metabolic substrate transport, ubiquitin signaling, and mitochondrial dynamics. Emerging multi-omic and spatial transcriptomic analyses further reveal structured microvascular and metabolic reprogramming within the diabetic myocardium. Collectively, these findings support the concept that cardiometabolic HFpEF may represent a cardiac manifestation of diabetic microvascular disease and highlight upstream endothelial dysfunction as a potential therapeutic target in cardiometabolic HFpEF.</p>

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HFpEF as a diabetic complication: the central role of microvascular dysfunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Yosuke Nagai,
  • Keiichiro Matoba,
  • Rimei Nishimura

摘要

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and is highly prevalent among individuals with diabetes. Although diabetes is traditionally regarded as a comorbidity, accumulating clinical and experimental evidence suggests that it may contribute importantly to HFpEF pathophysiology. Classical diabetic complications are fundamentally microvascular in nature, characterized by endothelial dysfunction, capillary rarefaction, impaired nitric oxide signaling, and barrier disruption. Similar abnormalities are increasingly recognized in HFpEF, in which coronary microvascular dysfunction is highly prevalent and independently associated with adverse outcomes. Epidemiological studies demonstrate that both type 1 and type 2 diabetes confer substantial risk for preclinical diastolic dysfunction and overt HFpEF, with concomitant renal involvement further amplifying risk within the cardiovascular-kidney-metabolic continuum. Mechanistically, cardiometabolic stress promotes systemic endothelial activation, inflammatory amplification, metabolic inflexibility, and structural microvascular remodeling extending beyond the myocardium to skeletal muscle and kidney. Experimental studies indicate that endothelial-specific molecular perturbations can induce or ameliorate HFpEF phenotypes in diabetic settings, implicating cytoskeletal regulation, metabolic substrate transport, ubiquitin signaling, and mitochondrial dynamics. Emerging multi-omic and spatial transcriptomic analyses further reveal structured microvascular and metabolic reprogramming within the diabetic myocardium. Collectively, these findings support the concept that cardiometabolic HFpEF may represent a cardiac manifestation of diabetic microvascular disease and highlight upstream endothelial dysfunction as a potential therapeutic target in cardiometabolic HFpEF.