Blood-Pool Stress MRI as a Tool for Identifying Early Biomarkers of Diabetic Heart Failure with Preserved Ejection Fraction

Microvascular dysfunction (mvD) has been implicated as the primary hallmark of several cardiac and inflammatory diseases (e.g., diabetes, heart failure), affecting millions of people worldwide. The onset and progression of microvascular disease is driven by vascular inflammation and is characterized by vascular smooth muscle cell thickening and impaired vasomodulation, resulting in reduced baseline perfusion and potentially leading to tissue damage. The ability to noninvasively assess microvascular dilation and constriction is essential to assessing intact microvascular function and dysfunction. Yet, conventional measurements based on catheterization and MRI blood oxygenation are invasive and not specific to changes in blood volume, respectively. While cardiac and skeletal muscle mvD have been predicted to be the origin of diabetic heart failure and heart failure with a preserved ejection fraction (HFpEF), current diagnostics are onlyutilized when the patient suffers from cardiac symptoms, at which point the microvascular system is already compromised. This requires a paradigm shift in diagnostics, focusing on the early detection of mvD prior to the onset of heart failure signs and symptoms. In this body of work, we propose that MRI can serve as a non-invasive imaging modality to diagnose mvD within the heart and skeletal muscle, which can offer an early diagnostic platform for diabetics who are at risk of developing HFpEF and other diabetic cardiomyopathies. By combining the use of an MRI blood-pool contrast agent, T1 – weighted imaging, and mild carbon dioxide as a vasodilator, we showcase a technology that can assess microvascular reactivity in bothcardiac and skeletal muscle. Evaluation in a non-genetically modified rat model of type II diabetesiii revealed that cardiac and skeletal muscle reactivity are compromised prior to any classical signs and symptoms of heart failure (e.g., diastolic dysfunction, hypertension, fibrosis). These findings were shortly followed by exercise intolerance and a reduction in oxygen saturation in skeletal muscle. Additionally, we show that sex-dependent differences exist from a young age and must be considered when developing diagnostic criteria for HFpEF. The studies presented in this thesis will pave the way for translating this diagnostic platform into a clinical setting, where patients suffering from type II diabetes and are prone to developing HFpEF can be diagnosed early and begin treatment, prior to exhibiting heart failure symptoms.

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