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Exercise capacity and cardiac hemodynamic response in female ApoE/LDLR(-/-) mice: a paradox of preserved V'O2max and exercise capacity despite coronary atherosclerosis.

ABSTRACT: We assessed exercise performance, coronary blood flow and cardiac reserve of female ApoE/LDLR(-/-) mice with advanced atherosclerosis compared with age-matched, wild-type C57BL6/J mice. Exercise capacity was assessed as whole body maximal oxygen consumption (V'O2max), maximum running velocity (vmax) and maximum distance (DISTmax) during treadmill exercise. Cardiac systolic and diastolic function in basal conditions and in response to dobutamine (mimicking exercise-induced cardiac stress) were assessed by Magnetic Resonance Imaging (MRI) in vivo. Function of coronary circulation was assessed in isolated perfused hearts. In female ApoE/LDLR(-/-) mice V'O2max, vmax and DISTmax were not impaired as compared with C57BL6/J mice. Cardiac function at rest and systolic and diastolic cardiac reserve were also preserved in female ApoE/LDLR(-/-) mice as evidenced by preserved fractional area change and similar fall in systolic and end diastolic area after dobutamine. Moreover, endothelium-dependent responses of coronary circulation induced by bradykinin (Bk) and acetylcholine (ACh) were preserved, while endothelium-independent responses induced by NO-donors were augmented in female ApoE/LDLR(-/-) mice. Basal COX-2-dependent production of 6-keto-PGF1α was increased. Concluding, we suggest that robust compensatory mechanisms in coronary circulation involving PGI2- and NO-pathways may efficiently counterbalance coronary atherosclerosis-induced impairment in V'O2max and exercise capacity.

SUBMITTER: Wojewoda M

PROVIDER: S-EPMC4842974 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Project description:BackgroundExercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF.MethodsThirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20 Watts (W), and peak exercise during both placebo and nitroglycerin conditions.ResultsPCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (-1±2 mm Hg), 20W (-5±5 mm Hg), and peak exercise (-7±6 mm Hg; drug × exercise stage P=0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug × exercise P=0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (-8±13 mL) and 20W (-7±11 mL), but not peak exercise (0±10 mL).ConclusionsSublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT04068844.

Project description:Atherosclerosis is the preliminary cause of coronary artery disease, one of the diseases that ac-count for the largest number of fatal mortalities. Physical activity is an effective strategy to restrain atherosclerosis from deterioration. Evidence indicated that the changes of proteomic profile is highly associated with the atherosclerosis development, but the mechanism behind the exercise for atherosclerosis amelioration has not yet been investigated from the proteomics perspective. Hence, the proteomic profiles could further elucidate the systematic effects of exercise interven-tion on ApoE knockout atherosclerotic model and high fat diet intervention. In current study, Apoeem1Narl/Narl mice were randomly allocated into a normal diet (ND), western diet (WD) and WD with 12 weeks exercise intervention (WD EX) groups. The plasm proteome between WD and WD EX demonstrate the significant difference, and ten major pathways, including cardiovascular disease (CVD)–hematological disease, cellular compromise–inflammatory response, protein synthesis, connective tissue disorders, cellular movement–immune cell tracking, inflammatory response, etc., were generated by the IPA analysis. The fourteen proteins (PROS, PROZ, C2, F5, C5, SERPINA 10, FGB, FGG, CFB, F12, CRP, CFHR1, HABP2, and PPIA) critically involved in CVD–hematological disease pathway showed significant difference among groups. The PROS, F5, C5, FGG, and CFB levels associated with thrombosis and atherosclerosis induced by WD were significantly decreased by exercise intervention in WD EX. Furthermore, the F5 and FGG were well-demonstrated the important roles for thrombosis of atherosclerotic pathogenesis but the complement factor C5 in the development of atherosclerosis is not fully understood. In current study, the exercise could significantly alleviate the significantly elevated C5 and inflammation induced by WD group in accordance to amelioration of atherosclerosis. Therefore, exercise could mitigate chemotaxis through the modulation of the C5 level and innate immunity, thereby alle-viating the pathogenesis of atherosclerosis in western-diet induced obese mice.

Project description:Key pointsHealthy older adults exhibit lower cardiorespiratory fitness ( V̇O2peak ) than young in the absence of any age-related difference in skeletal muscle mitochondrial capacity, suggesting central haemodynamics plays a larger role in age-related declines in V̇O2peak . Total physical activity did not differ by age, but moderate-to-vigorous physical activity was lower in older compared to young adults. Moderate-to-vigorous physical activity is associated with V̇O2peak and muscle oxidative capacity, but physical inactivity cannot entirely explain the age-related reduction in V̇O2peak .AbstractDeclining fitness ( V̇O2peak ) is a hallmark of ageing and believed to arise from decreased oxygen delivery and reduced muscle oxidative capacity. Physical activity is a modifiable lifestyle factor that is critical when evaluating the effects of age on parameters of fitness and energy metabolism. The objective was to evaluate the effects of age and sex on V̇O2peak , muscle mitochondrial physiology, and physical activity in young and older adults. An additional objective was to assess the contribution of skeletal muscle oxidative capacity to age-related reductions in V̇O2peak and determine if age-related variation in V̇O2peak and muscle oxidative capacity could be explained on the basis of physical activity levels. In 23 young and 52 older men and women measurements were made of V̇O2peak , mitochondrial physiology in permeabilized muscle fibres, and free-living physical activity by accelerometry. Regression analyses were used to evaluate associations between age and V̇O2peak , mitochondrial function, and physical activity. Significant age-related reductions were observed for V̇O2peak (P < 0.001), but not muscle mitochondrial capacity. Total daily step counts did not decrease with age, but older adults showed lower moderate-to-vigorous physical activity, which was associated with V̇O2peak (R2 = 0.323, P < 0.001) and muscle oxidative capacity (R2 = 0.086, P = 0.011). After adjusting for sex and physical activity, age was negatively associated with V̇O2peak but not muscle oxidative capacity. Healthy older adults exhibit lower V̇O2peak but preserved mitochondrial capacity compared to young. Physical activity, particularly moderate-to-vigorous, is a key factor in observed age-related changes in fitness and muscle oxidative capacity, but cannot entirely explain the age-related reduction in V̇O2peak .

Project description:BackgroundArterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise.Methods and resultsA total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52-3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption.ConclusionsExercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular-vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.

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Exercise capacity and cardiac hemodynamic response in female ApoE/LDLR(-/-) mice: a paradox of preserved V'O2max and exercise capacity despite coronary atherosclerosis.

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