MRI-based in vivo detection of coronary microvascular dysfunction before alterations in cardiac function induced by short-term high-fat diet in mice

Endothelial dysfunction is one of the hallmarks of vascular abnormalities in metabolic diseases and has been repeatedly demonstrated in coronary and peripheral circulation in mice fed high-fat diet (HFD), particularly after long-term HFD. However, the temporal relationship between development of coronary microvascular endothelial dysfunction and deterioration in diastolic and systolic cardiac function after short-term feeding with HFD has not yet been studied. This study aimed to correlate the changes in coronary microvascular endothelial function and global cardiac performance indices in vivo after short-term feeding with HFD in mice. Short-term feeding with a HFD (60% fat + 1% cholesterol) resulted in severely impaired coronary microvascular function, as evidenced by the diminished effect of nitric oxide synthase inhibition (by L-NAME) assessed using T(1) mapping via in vivo MRI. Deterioration of coronary microvascular function was detected as early as after 7 days of HFD and further declined after 8 weeks on a HFD. HFD-induced coronary microvascular dysfunction was not associated with impaired myocardial capillary density and was present before systemic insulin resistance assessed by a glucose tolerance test. Basal coronary flow and coronary reserve, as assessed using the A(2A) adenosine receptor agonist regadenoson, were also not altered in HFD-fed mice. Histological analysis did not reveal cardiomyocyte hypertrophy or fibrosis. Increased lipid accumulation in cardiomyocytes was detected as early as after 7 days of HFD and remained at a similar level at 8 weeks on a HFD. Multiparametric cardiac MRI revealed a reduction in systolic heart function, including decreased ejection rate, increased end-systolic volume and decreased myocardial strain in diastole with impaired ejection fraction, but not until 4 weeks of HFD. Short-term feeding with HFD resulted in early endothelial dysfunction in coronary microcirculation that preceded alteration in cardiac function and systemic insulin resistance.