Abnormal skeletal muscle and myocardial vasoreactivity manifests prior to heart failure in a diabetic cardiomyopathy rat model

Background: Microvascular dysfunction (MVD) is a recognized sign of disease in heart failure progression. Intact blood vessels exhibit abnormal vasoreactivity in early stage, subsequently deteriorating to rarefaction and reduced perfusion. In managing heart failure with preserved ejection fraction (HFpEF), earlier diagnosis is key to improving management. In this study, we applied a steady-state blood-pool magnetic resonance imaging (MRI) method to investigate if it can sensitively detect abnormal leg muscle vasoreactivity, a sign of MVD, posited to manifest before structural and functional cardiac changes emerge in a diabetes model of HFpEF.

Methods: Male and female Sprague-Dawley rats were maintained on either a high-fat, high-sugar diet or a control diet for 6 months after the induction of diabetes (n = 5 per group). Beginning at month 1 or 2 post-diabetes and every 2 months thereafter, rats underwent steady-state blood-pool MRI to assess vasoreactivity in the heart or skeletal muscle, respectively. A T1-reducing blood-pool agent was administered and the T1 relaxation time dynamically measured as animals breathed in elevated CO₂ levels to modulate vessels.

Results: In male rats, the normally unresponsive heart to 10% CO₂ revealed a pro-vasoconstriction response beginning at 5 months post-diabetes. Abnormal leg skeletal muscle vasoreactivity appeared even earlier, at 2 months: the usual vasodilatory response to 5% CO₂ was interrupted with periods of vasoconstriction in diseased rats. In female rats, differences were observed between healthy and diseased animals only in the first 2 months post-diabetes and not later. In the heart, vasodilation to 10% CO₂ seen in healthy females was abolished in diabetic females. In skeletal muscle, 5% CO₂ was suboptimal in inducing reproducible vasoreactivity, but young diabetic females responded by vasodilation only.

Conclusions: Abnormal vasoreactivity presented earlier than overt functional changes in both heart and skeletal muscle in diabetic cardiomyopathy, and steady-state blood-pool MRI offered early diagnosis of microvascular dysfunction.