Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease

Mitra Esfandiarei,1 Brikena Hoxha,1 Nicholas A Talley,1 Miranda R Anderson,2 Mustafa F Alkhouli,2 Michaela A Squire,2 Delrae M Eckman,1 Jeganathan Ramesh Babu,3 Gary D Lopaschuk,4 Tom L Broderick21Department of Biomedical Sciences, College of Graduate Studies, Midwestern University, Glendale, AZ, USA; 2Department of Physiology, Laboratory of Diabetes and Exercise Metabolism, College of Graduate Studies, Midwestern University, Glendale, AZ, USA; 3Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL, USA; 4Cardiovascular Research Centre, Mazankowski Alberta Heart Institute University of Alberta, Edmonton, AB, CanadaBackground: Studies have indicated an association between Alzheimer’s disease (AD) and increased risk of developing cardiovascular complications. Lifestyle modifiable factors, such as exercise and diet, are known to prevent cardio-cerebral disease. Recent studies demonstrate that hearts from early onset triple-transgenic AD mice exhibit pathologies, but it is not clear whether cardiovascular function is altered in this model. Methods: In this study, we measured in vivo cardiovascular function in 7-month-old male 3xTg mice and age-matched wild-type (WT) mice using high-frequency high-resolution ultrasound imaging. Results: Our findings indicated that aortic root measurements and interventricular septal dimensions were similar in 3xTg and wild-type mice. Systolic function, expressed as ejection fraction and fractional shortening, were decreased in 3xTg mice. Late (A) ventricular filling velocities, the early/atrial (E/A) ratio, and mitral valve deceleration time, all indices of diastolic function, were increased in 3xTg mice compared to WT mice. Treadmill exercise training and resveratrol supplementation in the diet for 5 months improved ejection fraction, fractional shortening, and restored diastolic deceleration times. Pulse wave velocity was ∼33% higher in 3xTg, and accompanied by a significant increase in elastin fiber fragmentation within the aortic wall, which was associated with decrease in elastin content and fiber length. Aortic wall and adventitia thickness were increased in 3xTg mice compared to the WT group. Exercise training and resveratrol supplementation, or both, improved overall aortic morphology with no change in pulse wave velocity. Conclusion: Taken together, the results indicate that the aberrations in cardiac function and aortic elastin morphology observed in the 3xTg mouse model of AD can be prevented with exercise training and treatment with resveratrol. The benefits of regular exercise training and resveratrol supplementation of heart and aortic structure in the 3xTg mouse support the value of healthy lifestyle factors on cardiovascular health.Keywords: Alzheimer’s disease, exercise, resveratrol, heart, aorta, ultrasound imaging, pulse wave velocity, aortic wall elasticity