Abstract
Aim: To perform a deep cardiac phenotyping of type II diabetes in a rat model, with the goal of gaining new insight into the temporality of microvascular dysfunction, cardiac dysfunction, and exercise intolerance at different stages of diabetes.Methods and Results: Diabetes was reproduced using a non-obese, diet-based, low-dose streptozotocin model in male rats (29 diabetic, 11 control). Time-course monitoring over 10 months was performed using echocardiography, treadmill exercise, photoacoustic perfusion imaging in myocardial and leg skeletal muscle, flow-mediated dilation, blood panel, and histology. Diabetic rats maintained a normal weight throughout. At early times (4 months), a non-significant reduction (30%) emerged in skeletal muscle perfusion and in exercise tolerance. At the same time, diabetic rats had a normal, slightly lower ejection fraction (63 vs. 71% control, p < 0.01), grade 1 diastolic dysfunction (E/A = 1.1 vs. 1.5, isovolumetric relaxation time = 34 vs. 27 ms; p < 0.01), mild systolic dysfunction (ejection time = 69 vs. 57 ms, isovolumetric contraction time = 21 vs. 17 ms; p < 0.01), and slightly enlarged left ventricle (8.3 vs. 7.6 mm diastole; p < 0.01). Diastolic dysfunction entered grade 3 at Month 8 (E/A = 1.7 vs. 1.3, p < 0.05). Exercise tolerance remained low in diabetic rats, with running distance declining by 60%; in contrast, control rats ran 60% farther by Month 5 (p < 0.05) and always remained above baseline. Leg muscle perfusion remained low in diabetic rats, becoming significantly lower than control by Month 10 (33% SO2 vs. 57% SO2, p < 0.01). Myocardial perfusion remained normal throughout. Femoral arterial reactivity was normal, but baseline velocity was 25% lower than control (p < 0.05). High blood pressure appeared late in diabetes (8 months). Histology confirmed absence of interstitial fibrosis, cardiomyocyte hypertrophy, or microvascular rarefaction in the diabetic heart. Rarefaction was also absent in leg skeletal muscle.Conclusion: Reduced skeletal muscle perfusion from microvascular dysfunction emerged early in diabetic rats, but myocardial perfusion remained normal throughout the study. At the same time, diabetic rats exhibited exercise intolerance and early cardiac dysfunction, in which changes related to heart failure with preserved ejection fraction (HFpEF) were seen. Importantly, skeletal muscle microvascular constrictionadvanced significantly before the late appearance of hypertension. HFpEF phenotypes such as cardiac hypertrophy, fibrosis, and rarefaction, which are typically associated with hypertension, were absent over the 10 month time-course of diabetes-related heart failure.
Highlights
Type II diabetes accounts for 90% of adult diabetes cases and is an increasingly prevalent condition worldwide, affecting 1 in 11 people [1]
To ensure diabetes was maintained throughout the entire study, non-fasting blood glucose measurements from a tail vein prick were collected on a weekly basis
Our diabetes model did not induce obesity and led to the onset of hyperglycemia at Week 5, which remained significant beyond Month 9 post-diabetes (Figures 2A,B)
Summary
Type II diabetes accounts for 90% of adult diabetes cases and is an increasingly prevalent condition worldwide, affecting 1 in 11 people [1]. Many patients are undiagnosed as the condition progresses silently and slowly, and diagnosis occurs mostly late after heart damage has become irreversible, at which time few treatments remain as standard heart failure drugs fail. We adopt a well-established rat model of type II diabetes to study the temporality of abnormal developments in cardiac function, microvascular function, and exercise capacity. We lose the opportunity to discriminate the natural progression of a slowly developing disease and identify when along this timeline different structural and functional abnormalities first appear. We remedy this shortcoming by undertaking a time-resolved, longitudinal investigation of diabetic cardiomyopathy in rats, starting from 2 months old and continuing into mid-adulthood. Our goal is to attain deep cardiac and microvascular phenotyping at different stages of diabetic cardiomyopathy
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