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

Abstract

Woodman OL. Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function. Am J Physiol Heart Circ Physiol 304: H729 -H739, 2013. First published December 21, 2012; doi:10.1152/ajpheart.00638.2012.-Rats selectively bred for low (LCR) or high (HCR) intrinsic running capacity simultaneously present with contrasting risk factors for cardiovascular and metabolic disease. However, the impact of these phenotypes on left ventricular (LV) morphology and microvascular function, and their progression with aging, remains unresolved. We tested the hypothesis that the LCR phenotype induces progressive age-dependent LV remodeling and impairments in microvascular function, glucose utilization, and ␤-adrenergic responsiveness, compared with HCR. Hearts and vessels isolated from female LCR (n ϭ 22) or HCR (n ϭ 26) were studied at 12 and 35 wk. Nonselected N:NIH founder rats (11 wk) were also investigated (n ϭ 12). LCR had impaired glucose tolerance and elevated plasma insulin (but not glucose) and body-mass at 12 wk compared with HCR, with early LV remodeling. By 35 wk, LV prohypertrophic and glucose transporter GLUT4 gene expression were up-and downregulated, respectively. No differences in LV ␤-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function was predominantly nitric oxide (NO)-mediated in both phenotypes and remained intact in LCR for both age-groups. In contrast, mesenteric arteries microvascular endothelial function, which was impaired in LCR rats regardless of age. At 35 wk, endothelial-derived hyperpolarizing factor-mediated relaxation was impaired whereas the NO contribution to relaxation is intact. Furthermore, there was reduced ␤2-adrenoceptor responsiveness in both aorta and mesenteric LCR arteries. In conclusion, diminished intrinsic exercise capacity impairs systemic glucose tolerance and is accompanied by progressive development of LV remodeling. Impaired microvascular perfusion is a likely contributing factor to the cardiac phenotype. cardiomyocyte hypertrophy; cardiac fibrosis; insulin resistance; EDHF; low-capacity runner; metabolic syndrome; resistance arteries THE METABOLIC SYNDROME is a polygenic disorder that includes obesity, insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and impaired glycemic control. The prevalence of this disorder is dramatically increasing and is strongly linked to cardiovascular diseases (23). The presence of cardiovascular risk factors that constitute the metabolic syndrome is correlated with impairments in aerobic capacity and vascular endothelial function, as well as increased heart failure risk, all of which are strong independent predictors of mortality (13,30,37,48). Furthermore, the myocardial and vascular abnormalities associated with the metabolic syndrome in general, and the associated impairments in insulin signaling, likely include alterations in myocardial structure (through cardiomyocyte hypertrophy, cardiac fibrosis, and/or impairm...

The Role of Exercise in Cardiac Aging

“…From 1996–2011, selective breeding of a genetically heterogeneous N:NIH rat stock (28 generations, n=11,606 rats) eventually generated two distinct lines that differed in maximal running capacity by approximately 7-fold. Comparative analyses of hearts and isolated cardiomyocytes from aged rats with low and high intrinsic running capacities subsequently identified mitochondrial dysfunction 36 , abnormal calcium (Ca 2+ ) handling 37 , increased hypertrophy, 38 and microvascular dysfunction as key molecular phenotypes in the heart associated with exercise intolerance in aging (Figure 1). …”

Sympathetic Nervous System Signaling in Heart Failure and Cardiac Aging

“…Therefore, such a receptor is expected to play a key role in the reduced vasoreactivity observed in the elderly [ 46 ]. Of interest, the agerelated decline in β 2 AR function and successive cAMP generation is a common factor to several cardiovascular disorders, including hypertension, atherosclerosis, vascular insuffi ciency, and orthostatic hypotension, all conditions with signifi cant mortality and morbidity [ 15 , 47 -49 ].…”

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