Multiple common co-morbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress and myocardial stiffening

Rationale: More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC) and diabetes mellitus (DM), although its pathophysiology remains incompletely understood. It has been proposed that the co-morbidities induce systemic inflammation, cardiac microvascular dysfunction and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and ultimately, diastolic dysfunction.

Objective: Here we tested this hypothesis in a swine model chronically exposed to three common comorbidities.

Methods and Results: - DM (induced by streptozotocin), HC (high fat diet) and HT (resulting from renal artery embolization), (DM+HC+HT) were produced in ten female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM+HC+HT group showed hyperglycemia, hypercholesterolemia, hypertriglyceridemia and hypertension, which were associated with systemic inflammation, renal dysfunction and impaired coronary small artery endothelium-dependent vasodilation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio and elevated passive cardiomyocyte stiffness, resulting in a reduced E/A ratio (measured by cardiac MRI), and increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter), while ejection fraction was maintained.

Conclusions: - The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.