Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction

Abstract

The statistical association between endurance exercise capacity and cardiovascular disease suggests that impaired aerobic metabolism underlies the cardiovascular disease risk in men and women. To explore this connection, we applied divergent artificial selection in rats to develop low-capacity runner (LCR) and high-capacity runner (HCR) rats and found that disease risks segregated strongly with low running capacity. Here, we tested if inborn low aerobic capacity promotes differential sex-related cardiovascular effects. Compared with HCR males (HCR-M), LCR males (LCR-M) were overweight by 34% and had heavier retroperitoneal, epididymal, and omental fat pads; LCR females (LCR-F) were 20% heavier than HCR females (HCR-F), and their retroperitoneal, but not perireproductive or omental, fat pads were heavier as well. Unlike HCR-M, blood pressure was elevated in LCR-M, and this was accompanied by left ventricular (LV) hypertrophy. Like HCR-F, LCR-F exhibited normal blood pressure and LV weight as well as increased spontaneous cage activity compared with males. Despite normal blood pressures, LCR-F exhibited increased myocardial interstitial fibrosis and diastolic dysfunction, as indicated by increased LV stiffness, a decrease in the initial filling rate, and an increase in diastolic relaxation time. Although females exhibited increased arterial stiffness, ejection fraction was normal. Increased interstitial fibrosis and diastolic dysfunction in LCR-F was accompanied by the lowest protein levels of phosphorylated AMP-actived protein kinase [phospho-AMPK (Thr(172))] and silent information regulator 1. Thus, the combination of risk factors, including female sex, intrinsic low aerobic capacity, and overweightness, promote myocardial stiffness/fibrosis sufficient to induce diastolic dysfunction in the absence of hypertension and LV hypertrophy.

Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function

“…Given the extent of cardiac remodeling already evident at 12 wk of age in LCR rats, we speculate that the age of onset of cardiac dysfunction may occur earlier than first thought, particularly if the extent of microvascular dysfunction evident in the coronary vascular bed at this age mirrors that in the mesenteric circulation. The reduced cardiac index and coronary flow rates reported in LCR even in the absence of a significant LV systolic fraction (6,16) indicate that interrogation of myocardial perfusion abnormalities particularly at the level of the microvasculature (analogous to our work here in mesenteric arteries) is warranted. While our findings of impaired mesenteric microvascular function cannot necessarily be extrapolated to changes at the level of coronary microvascular function, such abnormalities could account for the impairments in myocardial perfusion often evident in metabolic syndrome.…”

“…Confirmation of morphological changes specifically on LV histology, protein content, or gene expression using real-time PCR or other semiquantitative approaches was not available. Recent work has now suggested that more mature LCR rats (ϳ30 wk of age) exhibit upregulated cardiac collagen deposition (6). Following enzymatic isolation, cardiomyocytes from older LCR also tend to be shorter and wider than those from their HCR counterparts (4,19).…”

“…This evidence, like that for cardiac remodeling, has largely been obtained in older animals (20 -30 wk of age) and whether LV dysfunction is impaired in younger animals remains to be determined. Often, changes at the level of LV diastolic function are more marked than systolic parameters (6,15), suggesting that LCR, like other models of metabolic syndrome and type 2 diabetes, may predispose to earlier onset of abnormalities in myocardial relaxation rather than contractile dysfunction (39). If permitted to proceed to senescence (Ն2 yr of age), marked dysfunction in both systolic and diastolic function are evident (21).…”

“…When compared with HCR, LCR rats have reduced whole body insulin sensitivity, glucose tolerance, and hyperlipidemia, indicative of poor metabolic health (26,43,46,49). Furthermore, LCR rats exhibit modest but significantly higher systolic blood pressure (SBP) compared with HCR, particularly in males (6,49). While this may be a result of concomitant impairments in endothelial nitric oxide (NO)-dependent relaxation (49), endothelial function has yet to be studied in the LCR microvasculature.…”

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain

“…Female LCR and HCR rats were not different in their overall weights. Prior studies have shown clear differences in body weight in female rats, though less pronounced compared to their male counterparts (DeMarco et al., 2012; Ritchie et al., 2013). It is likely that examination of aged female rats would have revealed differences in overall body weight.…”