Effects of calorie restriction on cardioprotection and cardiovascular health

Abstract

Multiple health benefits of calorie restriction (CR) and alternate day fasting (ADF) regimens are widely recognized. Experimental data concerning the effects of calorie restriction on cardiac health are more controversial, ranging from evidence that ADF protects heart from ischemic damage but results in developing of diastolic dysfunction, to reports that CR ameliorates the age-associated diastolic dysfunction. Here we investigated the effects of chronic CR on morphology and function of the cardiovascular system of aged rats and cardioprotective effect of CR against ischemic damage in the experimental rat model of MI. Cardiovascular fitness of 24-month old Fisher 344 rats maintained through life on ad libitum (AL) or CR diets was extensively evaluated via echocardiography, dobutamine stress test, pressure-volume loop analyses, pulse wave velocity measurements, and histology. Groups of 2-month old AL and 29-month old CR rats were studied for comparison. Myocardial infarction (MI) was induced by a permanent ligation of the anterior descending coronary artery in 5-month old rats maintained for 3 months on CR or AL. MI size was evaluated histologically 24 hrs following coronary ligation. Cardiac remodeling was followed-up via echocardiography. Age-associated changes in 24-month old rats consisted of 33% increase of fibrosis in the myocardium and more than 2 fold increase of the collagen in the tunica media of the aorta. There was a significant decrease in the density and total number of cardiomyocytes, while their size was increased. These morphological changes were manifested in a decline of systolic and diastolic cardiac function, increase of left ventricular and aortic stiffness, and arterio-ventricular uncoupling. Tachycardic response to dobutamine challenge was absent in the old rats. Compared to AL rats, 24-month old CR rats had reduced levels of cardiac and aortic fibrosis, increased density of cardiomyocytes that were smaller in size, attenuated diastolic dysfunction, normal systolic function and arterio-ventricular coupling. Tachycardic response to dobutamine was also intact in CR 24-month old rats and aortic stiffness was reduced. Adjustment for body weight differences through ratiometric or allometric scaling did not affect the overall pattern of differences between AL and CR rats. Attenuation of morphological and functional age-associated changes in 24-month old CR rats either was not observed at all or was smaller in 29-month old CR rats. Size of MI induced by a permanent coronary ligation as well as post-MI cardiac remodeling and function were similar in CR and AL rats. CR does not increase tolerance of myocardium to ischemic damage, but attenuates the age-associated changes in the heart and major vessels. The attenuation of age-associated changes by CR cannot be explained by the effect of lower body weight but are attributable to more intimate cellular mechanisms of CR itself. Attenuation of age-associated changes by CR waned with advancing age, and is consistent with the idea that CR postponed senescence.

Figure 1

A - Kaplan-Meier survival curves from CR and AL rats. * - p<0.001 (Logrank comparison of the curves); B - Body weight by age groups of AL and CR rats. # p<0.05 vs 2AL; * p<0.05 vs 24AL (Bonferroni correction for multiple comparison).

Figure 2

Echo indices in different age groups of AL and CR rats. # p<0.05 vs 2AL; * p<0.05 vs 24AL (Bonferroni correction for multiple comparison).

Figure 3

Heart rate response to a dobutamine challenge in different age groups of AL and CR rats. * p<0.05 dobutamine vs control in the same group (Bonferroni correction for multiple comparison).

Figure 4

Histological assessment of the myocardium in different age group of AL and CR rats. A – Representative H&E stained slides of myocardium of 2AL, 24AL, and 24CR groups illustrating an increased fibrosis in 24AL and its reduction in 24CR groups; B - Myocardial fibrosis, expressed as a percent of myocardium, in different age groups of AL and CR rats; C – Cardiomyocyte density in different age groups of AL and CR rats; D – Myocyte diameter (short axis) in different age groups of AL and CR rats; E – Total number of cardiomyocytes in different age groups of AL and CR rats; # p<0.05 vs 2AL; * p<0.05 vs 24AL (Bonferroni correction for multiple comparison).

Figure 5

Arterial stiffness. A – representative histological slides of thoracic aorta (Masson trichrome) from different age/diet groups; B, C – content of collagen in the aortic wall expressed as a percent of the total wall area (B) or tunica media (C), # - p<0.05 vs 2AL, * - p<0.05 vs 24AL; D – sonographic measurement of fractional expansion of aortic wall, # - p<0.05 vs 24AL, ˆ0.39 – calculated power of body weight for scaling procedure; E - pulse wave velocity in descending aorta of AL and CR 24-mo old rats. * p<0.05 CR vs AL (Student's t-test).

Figure 6

Myocardial infarction and area at risk 24 hrs after permanent ligation of a coronary artery in the hearts of AL and CR rats. A – representative sections of the hearts after Evans blue parfusion and TTC staining. B – Area at risk and MI sizes in AL and CR rats.

Figure 7

Body weight change, cardiac remodeling (Echo) and MI size (histology) 10 weeks following induction of MI in AL and CR rats. # p<0.05 vs pre MI baseline (0 wks); * p<0.05 vs Sh of the same diet group.