Myocardial and Skeletal Muscle Microvascular Dysfunction Manifests Prior to Diabetic Cardiomyopathy: Sex-Dependent Differences
Authors: Loai Sadi , Cheng Hai-Ling 
Published: May 2024

Introduction: Microvascular dysfunction is a recognized sign of disease in heart failure progression. Blood vessels exhibit abnormal vasoreactivity in early stage, subsequently deteriorating to rarefaction and reduced perfusion. In managing heart failure patients, where diagnosis is typically possible only when the hypertrophic heart is irreversibly damaged, earlier diagnosis is key to improving management. In this study, we apply a blood-pool MRI method for assessing vasomodulation to investigate if it can sensitively detect abnormal leg muscle vasoreactivity posited to manifest before myocardial mvD. Methods: Male and female Sprague-Dawley rats were maintained on a high-fat, high-sugar diet or a control diet for 6 months after the induction of diabetes. Beginning at month 1 or 2 post-induction and every 2 months thereafter, rats underwent blood-pool MRI to assess vasoreactivity in the heart or skeletal muscle, respectively. Ablavar, a T1-reducing blood-pool contrast agent, was administered and the T1 relaxation time dynamically measured as animals breathed in mild CO2 levels to modulate vessels and elicit a vasodilatory response. CO2 levels were set at 5% for skeletal muscle and 10% for cardiac muscle, and the gas was administered for 10 minutes. At the final timepoint, invasive laser Doppler perfusion measurements in leg muscle were recorded to verify MRI results. Results/Discussion: In this study, we provide the first demonstration that both skeletal muscle and myocardial microvascular vasoreactivity is altered in a non-obese rodent model of type II diabetes, prior to the development of heart failure symptoms. In male rats, the normally unresponsive heart to 10% CO2 reveals 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 is interrupted with periods of vasoconstriction in diseased rats. In female rats, differences were observed between healthy and diseased animals only within the first two months post-diabetes and not later. In the heart, vasodilation to 10% CO2 seen in healthy animals was abolished in diabetes. In skeletal muscle, 5% CO2 was suboptimal in inducing reproducible vasoreactivity, but young diabetic females responded by vasodilation only. Conclusion: Abnormal vasoreactivity presents earlier than overt structural and functional cardiac changes in both sexes in HFpEF and can be detected using blood-pool MRI in leg skeletal muscle before the myocardium. Our non-invasive MRI technology sets the foundation for a paradigm shift in diagnosing mvD during the early stages of HFpEF, opening the door for early intervention. This work was supported by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation/Ontario Research Fund, Dean’s Spark Professorship, Medicine by Design Pivotal Experiment Fund [to H.L.M.C.]; Ted Rogers Centre for Heart Research PhD Education Fund, Scintica Instrumentation Inc [to S.L.]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.