Impact of Comorbidities on Myocardial Remodeling and Dysfunction In Heart Failure with Preserved Ejection Fraction

Heart failure (HF) with preserved ejection (HFpEF) is widely prevalent and associated with poor outcome and incompletely understood pathophysiology.In contrast to HF with reduced EF (HFrEF), modern HF pharmacotherapy did not improve outcome in HFpEF, which emphasizes the urgent need to elucidate responsible pathogenetic mechanisms in HFpEF.Over the last decennium, myocardial structure, cardiomyocyte function and intramyocardial signaling were shown to be specifically altered in HFpEF.Myocardial remodelling and dysfunction in HFpEF comprises myocardial hypertrophy and fibrosis and increased cardiomyocyte stiffness.Increased cardiomyocyte stiffness in HFpEF importantly contributes to high left ventricular (LV) diastolic stiffness and results from specific changes in transcriptional and posttranslational modifications of the giant elastic sarcomeric protein, titin.Increased systemic vascular inflammation, endothelial dysfunction and oxidative stress resulting in reduced nitric oxide (NO) bioavailability appear importantly involved in increased diastolic LV stiffness and adverse remodelling in HFpEF.Recently, a new paradigm for HFpEF was proposed, which suggests that prevalent comorbidities, such as overweight/obesity, diabetes, hypertension, chronic pulmonary obstructive disease, anemia and chronic kidney dysfunction drive myocardial dysfunction and remodelling through coronary microvascular endothelial inflammation.Additional demographic characteristics in HFpEF are older age and female predominance, which could contribute to maladaptive cardiovascular structural and functional changes in a synergistic manner with the prevalent comorbidities.Although HFpEF is associated with more impaired cardiovascular abnormalities and worse outcome beyond the level explainable by comorbidities alone, the rationale for an important involvement of noncardiac comorbidities in myocardial dysfunction and remodeling in HFpEF seems plausible.In the following review, this rationale of an important involvement of comorbidities in HFpEF pathophysiology is further addressed in light of the proposed new HFpEF paradigm.