Insulin resistance with associated hyperinsulinemia as a risk factor for the development and worsening of HFpEF

The prevalence of insulin resistance (IR) with associated hyperinsulinemia (HI) is increasing worldwide, as is the prevalence of heart failure with preserved left ventricular ejection fraction (HFpEF). This narrative review aims to explore the epidemiological and pathophysiological relationship between IR/HI and HFpEF, the possible mechanisms by which IR/HI could underlie HFpEF development and worsening, and the actual and future therapeutic implications of this interplay. The prevalence of IR in patients with HF is not negligible, and we will go through the existing literature highlighting this epidemiological association and the longitudinal data supporting a causative link. We will give a brief overview of molecular and physiological mechanisms connecting IR and HFpEF, such as the alteration of vascular homeostasis resulting in endothelial dysfunction and arterial hypertension, myocardial and vascular wall cell growth resulting in microvascular and macrovascular alterations of coronary circulation, and concentric remodeling of the left ventricle resulting in increased stiffness and diastolic dysfunction. We will review the concept of "diabetic cardiomyopathy" as a study model of these correlations. Finally, we will go through existing antidiabetic drugs with a current or potential future role in the treatment of HFpEF and summarize evidence on lifestyle and rehabilitative interventions in the field. Many of the cardiovascular abnormalities caused by IR/HI may be a contributing factor to the development and worsening of HFpEF. Further research is warranted to explore whether early diagnosis and specific treatment of IR/HI in at-risk populations may prevent HFpEF or delay its progression.