Abstract
E487K point mutation of aldehyde dehydrogenase (ALDH) 2 (ALDH2*2) in East Asians intrinsically lowers ALDH2 activity. ALDH2*2 is associated with diabetic cardiomyopathy. Diabetic patients exhibit heart failure of preserved ejection fraction (HFpEF) i.e. while the systolic heart function is preserved in them, they may exhibit diastolic dysfunction, implying a jeopardized myocardial health. Currently, it is challenging to detect cardiac functional deterioration in diabetic mice. Stress echocardiography (echo) in the clinical set-up is a procedure used to measure cardiac reserve and impaired cardiac function in coronary artery diseases. Therefore, we hypothesized that high-fat diet fed type-2 diabetic ALDH2*2 mutant mice exhibit HFpEF which can be measured by cardiac echo stress test methodology. We induced type-2 diabetes in 12-week-old male C57BL/6 and ALDH2*2 mice through a high-fat diet. At the end of 4 months of DM induction, we measured the cardiac function in diabetic and control mice of C57BL/6 and ALDH2*2 genotypes by conscious echo. Subsequently, we imposed exercise stress by allowing the mice to run on the treadmill until exhaustion. Post-stress, we measured their cardiac function again. Only after treadmill running, but not at rest, we found a significant decrease in % fractional shortening and % ejection fraction in ALDH2*2 mice with diabetes compared to C57BL/6 diabetic mice as well as non-diabetic (control) ALDH2*2 mice. The diabetic ALDH2*2 mice also exhibited poor maximal running speed and distance. Our data suggest that high-fat fed diabetic ALDH2*2 mice exhibit HFpEF and treadmill exercise stress echo test is able to determine this HFpEF in the diabetic ALDH2*2 mice.
Highlights
The prevalence of diabetes mellitus is increasing globally, in Asia which constitutes almost 60% of the global diabetic patients [1]
After 4 months, we found a significant increases in the heart rate after exercise in both C57BL/6 and ALDH2Ã2 mice free of diabetes and ALDH2Ã2 mice with 4 months of type-2 diabetes (Fig 4A and 4B)
There was no decrease in % fractional shortening (FS) and % ejection fraction (EF) in diabetic C57BL/6 and diabetic ALDH2Ã2 mice relative to control C57BL/6 and ALDH2Ã2 mice before exercise (Fig 5A, 5B and 5C)
Summary
The prevalence of diabetes mellitus is increasing globally, in Asia which constitutes almost 60% of the global diabetic patients [1]. The development of heart failure is more severe in patients with diabetes compared to non-diabetic patients[9] This is due to impediments in early diagnosis and prevention [10, 11]. Evaluating abnormalities in left ventricular function in patients with type-2 diabetes is difficult because these patients typically exhibit a normal or preserved ejection fraction, and abnormalities in diastolic function are difficult to detect using regular echocardiography. These same problems extend to animal models of type-2 diabetes mellitus (T2DM), metabolic syndrome and other cardio-metabolic syndromes [15,16,17]. In the clinical setting, self-reported heart failure-related symptoms such as dyspnea at rest or with exertion, early onset fatigue, exercise intolerance and palpitations all represent important disease defining information that cannot be self-reported or captured in mice
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