Treatment of HFpEF: An unresolved enigma

• Published in: Vascular pharmacology 2018-04, Vol.103-105, p.68-68
• Main Authors: Urbanek, K., Cappetta, D., Coppini, R., Ciuffreda, L.P., Esposito, G., Rossi, F., Berrino, L., De Angelis, A.
• Format: Article
• Language: English
• Subjects: Blood glucose; Blood pressure; Calcium; Calcium ions; Cardiomyocytes; Cardiovascular system; Chronic obstructive pulmonary disease; Comorbidity; Diabetes mellitus; Dipeptidyl-peptidase IV; Dyslipidemia; Endothelial cells; Extrusion; Fibrosis; Heart; Heart diseases; Heart failure; Hypertension; Immune system; Infiltration; Inflammation; Inhibition; Inhibitor drugs; Insulin; Lung diseases; Macrophages; Microvasculature; Morbidity; Myocardium; Myocytes; Obstructive lung disease; Patients; Peptidase; Proteins; Renal failure; Risk analysis; Risk factors
• ISSN: 1537-1891; 1879-3649
• DOI: 10.1016/j.vph.2017.12.057

Objective: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for 50% of HF cases. While the majority of HFpEF patients do not have a recognized primary cardiac pathology, they are of advanced age, more often female and have high prevalence of non-cardiac comorbidities, such as hypertension, obesity, diabetes. chronic obstructive pulmonary disease and chronic kidney disease. In a recently proposed paradigm, HFpEF is regarded as a systemic syndrome mediated in large part by risk factors and co-morbidities, resulting in a systemic multi-organ proinflammatory state which affects the heart, leading to myocardial remodelling and dysfunction through a signalling cascade, which begins with coronary microvascular endothelial dysfunction. It subsequently involves myocardial infiltration by activated macrophages, which induce reactive interstitial fibrosis and altered communication between endothelial cells and surrounding cardiomyocytes. Current guidelines confirm that no treatment has been shown to reduce morbidity and mortality. Our recent studies aimed to determine whether the chronic administration of sitagliptin (SITA) or ranolazine (RAN) affects the course of LV dysfunction in a Dahl salt-sensitive (Dahl/SS) rat model of HFpEF. When fed high-salt diets, Dahl/SS rats develop hypertension, renal failure, insulin resistance and dyslipidemia. The development of HF by 19 weeks is not associated with a decrease in LV systolic function or an increase in LV end-diastolic diameter, which mimics the characteristics of clinically observed HFpEF. The widespread expression of dipeptidyl peptidase 4 (DPP4) in vasculature, myocardium and immune cells raises the possibility that this protein plays a role in cardiovascular function. In particular, the finding that DPP4 activity is often associated with inflammation and cardiac remodelling points to an involvement of DPP4 in the pathophysiology of HF. Additionally, one of the potential mechanisms involved in HFpEF pathophysiology is an increase late Na+ current (INa) in cardiac myocytes. RAN by selectively inhibiting late INa can decrease Na+-dependent calcium accumulation and is expected to promote Ca2 + extrusion through the Na-t-/Ca2+ exchanger improving myocyte relaxation and diastolic tension, as shown in several preclinical and clinical settings. S1TA positively modulated active relaxation and passive diastolic compliance interfering with inflammatory-related endothelial dysfunction and fibrosis associa