Sandrine Gayrard

Two-Dimensional Strain and Twist by Vector Velocity Imaging in Adolescents With Severe Obesity

The prevalence of severe obesity is increasing worldwide in adolescents. Whether it is associated with functional myocardial abnormalities remains largely unknown, potentially because of its frequent association with other cardiovascular risk factors and also use of insensitive techniques to detect subclinical changes in myocardial function. We used 2D vector velocity imaging (VVI) to investigate early changes in left ventricular (LV) myocardial function in youths with isolated severe obesity. Thirty‐seven asymptomatic severely obese adolescents free of diabetes and hypertension, and 24 lean controls were enrolled. LV longitudinal, basal, and apical circumferential strain, strain rate (SR), rotations, and LV twist were measured. Obese adolescents had greater LV mass and reduced systolic and early diastolic tissue Doppler imaging (TDI) velocities than lean counterparts. L strain (−24%) and systolic and early diastolic SR were also diminished in the obese, whereas no intergroup differences existed for the circumferential deformation indexes. LV twist was more pronounced in the obese (+1.7°, P < 0.01) on account of greater apical rotation only (4.1 ± 0.9 vs. 5.2 ± 1.2°, P < 0.01), potentially compensating for the loss in longitudinal function. Systolic—diastolic coupling, an important component of early filling and diastolic function, was maintained with severe obesity. No intergroup differences were reported regarding time to peak values for all VVI indexes highlighting that dynamics of strain and twist/untwist along the cardiac cycle was preserved with severe obesity. Isolated severe obesity in adolescents, at a preclinical stage, is associated with changes in myocardial deformation and torsional mechanics that could be in part related to alterations in relaxation and contractility properties of subendocardial fibers.

β-Adrenergic receptors desensitization is not involved in exercise-induced cardiac fatigue: NADPH oxidase-induced oxidative stress as a new trigger

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that β-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the β-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to β-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

Simulated urban carbon monoxide air pollution exacerbates rat heart ischemia-reperfusion injury

Myocardial damages due to ischemia-reperfusion (I/R) are recognized to be the result of a complex interplay between genetic and environmental factors. Epidemiological studies suggested that, among environmental factors, carbon monoxide (CO) urban pollution can be linked to cardiac diseases and mortality. The aim of this work was to evaluate the impact of exposure to CO pollution on cardiac sensitivity to I/R. Regional myocardial I/R was performed on isolated perfused hearts from rats exposed for 4 wk to air enriched with CO (30-100 ppm). Functional variables, reperfusion ventricular arrhythmias (VA) and cellular damages (infarct size, lactate dehydrogenase release) were assessed. Sarcomere length shortening and Ca(2+) handling were evaluated in intact isolated cardiomyocytes during a cellular anoxia-reoxygenation protocol. The major results show that prolonged CO exposure worsens myocardial I/R injuries, resulting in increased severity of postischemic VA, impaired recovery of myocardial function, and increased infarct size (60 +/- 5 vs. 33 +/- 2% of ischemic zone). The aggravating effects of CO exposure on I/R could be explained by a reduced myocardial enzymatic antioxidant status (superoxide dismutase -45%; glutathione peroxidase -49%) associated with impaired intracellular Ca(2+) handling. In conclusion, our results are consistent with the idea that chronic CO pollution dramatically increases the severity of myocardial I/R injuries.

Moderate exercise prevents impaired Ca2+ handling in heart of CO-exposed rat: implication for sensitivity to ischemia-reperfusion

Sustained urban carbon monoxide (CO) exposure exacerbates heart vulnerability to ischemia-reperfusion via deleterious effects on the antioxidant status and Ca(2+) homeostasis of cardiomyocytes. The aim of this work was to evaluate whether moderate exercise training prevents these effects. Wistar rats were randomly assigned to a control group and to CO groups, living during 4 wk in simulated urban CO pollution (30-100 parts/million, 12 h/day) with (CO-Ex) or sedentary without exercise (CO-Sed). The exercise procedure began 4 wk before CO exposure and was maintained twice a week in standard filtered air during CO exposure. On one set of rats, myocardial ischemia (30 min) and reperfusion (120 min) were performed on isolated perfused rat hearts. On another set of rats, myocardial antioxidant status and Ca(2+) handling were evaluated following environmental exposure. As a result, exercise training prevented CO-induced myocardial phenotypical changes. Indeed, exercise induced myocardial antioxidant status recovery in CO-exposed rats, which is accompanied by a normalization of sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a expression and then of Ca(2+) handling. Importantly, in CO-exposed rats, the normalization of cardiomyocyte phenotype with moderate exercise was associated with a restored sensitivity of the myocardium to ischemia-reperfusion. Indeed, CO-Ex rats presented a lower infarct size and a significant decrease of reperfusion arrhythmias compared with their sedentary counterparts. To conclude, moderate exercise, by preventing CO-induced Ca(2+) handling and myocardial antioxidant status alterations, reduces heart vulnerability to ischemia-reperfusion.

Endothelial function does not improve with high-intensity continuous exercise training in SHR: implications of eNOS uncoupling.

Exercise training is a well-recognized way to improve vascular endothelial function by increasing nitric oxide (NO) bioavailability. However, in hypertensive subjects, unlike low- and moderate-intensity exercise training, the beneficial effects of continuous high-intensity exercise on endothelial function are not clear, and the underlying mechanisms remain unknown. The aim of this study was to investigate the impact of high-intensity exercise on vascular function, especially on the NO pathway, in spontaneous hypertensive rats (SHR). These effects were studied on WKY, sedentary SHR and SHR that exercised at moderate (SHR-MOD) and high intensity (SHR-HI) on a treadmill (1 h per day; 5 days per week for 6 weeks at 55% and 80% of their maximal aerobic velocity, respectively). Endothelial function and specific NO contributions to acetylcholine-mediated relaxation were evaluated by measuring the aortic ring isometric forces. Endothelial nitric oxide synthase (eNOS) expression and phosphorylation (ser1177) were evaluated by western blotting. The total aortic and eNOS-dependent reactive oxygen species (ROS) production was assessed using electron paramagnetic resonance in aortic tissue. Although the aortas of SHR-HI had increased eNOS levels without alteration of eNOS phosphorylation, high-intensity exercise had no beneficial effect on endothelium-dependent vasorelaxation, unlike moderate exercise. This result was associated with increased eNOS-dependent ROS production in the aortas of SHR-HI. Notably, the use of the recoupling agent BH4 or a thiol-reducing agent blunted eNOS-dependent ROS production in the aortas of SHR-HI. In conclusion, the lack of a positive effect of high-intensity exercise on endothelial function in SHR was mainly explained by redox-dependent eNOS uncoupling, resulting in a switch from NO to O2− generation.

Effects of a Lifestyle Program on Vascular Reactivity in Macro- and Microcirculation in Severely Obese Adolescents

CONTEXT AND OBJECTIVE This study aimed to comprehensively assess the macro- and microcirculation of severely obese adolescents (SOA) and normal-weight counterparts and to determine the longitudinal effects of weight loss on vascular function in SOA. DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Seventeen SOA (body mass index z-score = 4.22 ± 0.73) and 19 puberty-matched normal-weight counterparts (body mass index z-score = -0.02 ± 1.04) were included. The SOA participated in a 4 month weight loss program. Brachial artery flow-mediated dilation and response to sublingual nitrate (nitrate-mediated dilation [NMD]) were assessed by high-resolution ultrasound. Microvascular reactivity was evaluated by laser Doppler flowmetry in response to NMD, iontophoresis of acetylcholine and sodium nitroprusside, and local hyperthermia. Plasma insulin, leptin, resistin, C-reactive protein, myeloperoxidase, and tissue plasminogen activator were measured. RESULTS At baseline, SOA had similar flow-mediated dilation and impaired NMD in the brachial artery compared to normal-weight adolescents. Similarly, peak responses to acetylcholine and sodium nitroprusside iontophoresis and to local hyperthermia were unaltered, whereas cutaneous blood flow after NMD was lower in the forearm microcirculation of SOA. All plasma measurements were significantly higher in SOA. After the 4-month program, SOA presented a weight reduction of 7.4 ± 3.1%, but neither brachial artery nor microvascular reactivity variables were improved. Significant decreases were detected in plasma leptin, myeloperoxidase, and tissue plasminogen activator. CONCLUSIONS Macro- and microvascular endothelial function are preserved in adolescents with severe obesity. Conversely, weight loss does not improve their impaired smooth muscle response to exogenous organic nitrate in both vascular beds, despite reducing plasma markers adversely related to vascular homeostasis.

Impact of diet and exercise training-induced weight loss on myocardial mechanics in severely obese adolescents.

Recent findings indicated silent incipient myocardial dysfunction in juvenile obesity despite normal global cardiac function. The present study investigated whether lifestyle intervention is able to favorably impact these obesity‐related myocardial abnormalities and whether improvements are related to changes in insulin resistance and cardiac remodeling.

Carbon Monoxide Pollution Impairs Myocardial Perfusion Reserve: Implication of Coronary Endothelial Dysfunction

Chronic exposure to simulated urban CO pollution is reported to be associated with cardiac dysfunction. Despite the potential implication of myocardial perfusion alteration in the pathophysiology of CO pollution, the underlying mechanisms remain today still unknown. Therefore, the aim of this work was to evaluate the effects of prolonged exposure to simulated urban CO pollution on the regulation of myocardial perfusion. Cardiac hemodynamics and myocardial perfusion were assessed under basal conditions and during the infusion of a β-Adrenergic agonist. The effects of CO exposure on capillary density, coronary endothelium-dependent vasodilatation, eNOS expression and eNOS uncoupling were also evaluated. Our main results were that prolonged CO exposure was associated with a blunted myocardial perfusion response to a physiological stress responsible for an altered contractile reserve. The impairment of myocardial perfusion reserve was not accounted for a reduced capillary density but rather by an alteration in coronary endothelium-dependent vasorelaxation (−45% of maximal relaxation to ACh). In addition, though chronic CO exposure did not change eNOS expression, it significantly increased eNOS uncoupling. Therefore, the present work underlines the fact that chronic CO exposure, at levels found in urban air pollution, is associated with reduced myocardial perfusion reserve. This phenomenon is explained at the coronary-vessel level by deleterious effects of CO exposure on the endothelium NO-dependent vasorelaxation via eNOS uncoupling.

Stress-induced protein S-glutathionylation and phosphorylation crosstalk in cardiac sarcomeric proteins - Impact on heart function

BACKGROUND The interplay between oxidative stress and other signaling pathways in the contractile machinery regulation during cardiac stress and its consequences on cardiac function remains poorly understood. We evaluated the effect of the crosstalk between β-adrenergic and redox signaling on post-translational modifications of sarcomeric regulatory proteins, Myosin Binding Protein-C (MyBP-C) and Troponin I (TnI). METHODS AND RESULTS We mimicked in vitro high level of physiological cardiac stress by forcing rat hearts to produce high levels of oxidized glutathione. This led to MyBP-C S-glutathionylation associated with lower protein kinase A (PKA) dependent phosphorylations of MyBP-C and TnI, increased myofilament Ca2+ sensitivity, and decreased systolic and diastolic properties of the isolated perfused heart. Moderate physiological cardiac stress achieved in vivo with a single 35 min exercise (Low stress induced by exercise, LSE) increased TnI and cMyBP-C phosphorylations and improved cardiac function in vivo (echocardiography) and ex-vivo (isolated perfused heart). High stress induced by exercise (HSE) altered strongly oxidative stress markers and phosphorylations were unchanged despite increased PKA activity. HSE led to in vivo intrinsic cardiac dysfunction associated with myofilament Ca2+ sensitivity defects. To limit protein S-glutathionylation after HSE, we treated rats with N-acetylcysteine (NAC). NAC restored the ability of PKA to modulate myofilament Ca2+ sensitivity and prevented cardiac dysfunction observed in HSE animals. CONCLUSION Under cardiac stress, adrenergic and oxidative signaling pathways work in concert to alter myofilament properties and are key regulators of cardiac function.

0301 : Effects of low and high polyphenols content lettuces consumption on high fat diet induced metabolic syndrome and endothelial dysfunction

Consumption of vegetables has been recommended to reduce the risk of cardiovascular disease. The protection against disease is partly due to bioactive molecules including polyphenols. In order to evaluate the effects of such polyphenols, we supplemented High Fat diet rats with low and high polyphenolic content lettuces. 32 Wistar rats were divided in 4 groups, a control group (Ctrl), a high fat and sucrose diet group (HFS, 60% fat+10%sucrose) and 2 groups that after 6 weeks of HFS diet were supplemented 8 weeks with both HFS diet and either a low or high polyphenol content lettuces (HFS-LP; Blond Oak Leaf, 30g/day vs. HFS-HP; Red Oak Leaf, 30g/day). After 14 weeks of HF diet including 8 weeks of supplementation, we performed a glucose tolerance test and an evaluation of arterial blood pressure (BP) by tail cuff method. Then, aortic endothelial function and eNOS dependent vasodilatation were evaluated ex vivo on isolated rings. Firstly, we observed a higher body weight in HFS group (502±21g) compared to Ctrl group (417±14g) without any effect of both supplementations. Regarding glycemic control, HFS group presented increased fasting blood glucose (1,37g/l vs. 1,20g/l) as well as an impairment of glucose tolerance. Interestingly, both groups with lettuces intake displayed healthy fasting blood glucose values (1.14g/l and 1.15g/l) and an improvement of glucose tolerance. Moreover, both lettuces treatments managed to normalize the increase in mean BP observed in HFS group (HFS; 131mmHg; HFS-LP 120 mmHg; HFS-HP, 117mmHg). However, no effect of lettuce consumption was observed on endothelial dysfunction and impaired eNOS dependent vasodilatation observed in HFS rats. In conclusion, we observed in this study a major effect of lettuce intake on glycemic control as well as arterial BP. However, no effect regarding the difference in polyphenols content has been reported here underlying that the effects were independent of the specific polyphenols contained in the HP lettuce.