[Adipose epicardial tissue association with subclinical systolic dysfunction detected by longitudinal strain in diabetic patients with poor glycemic control]. / Association entre tissu adipeux epicardique et dysfonction systolique infraclinique détectée par strain longitudinal chez les diabétiques mal équilibrés.

OBJECTIVE: The aim of this study is to assess the association between epicardial adipose tissue (EAT) and infraclinical myocardial dysfunction detected by strain imaging in diabetic patients (T2DM) with poor glycemic control. METHODS: 22 patients with T2DM and 22 healthy control subjects of similar age and sex were prospectively recruited. Echocardiographic parameters were investigated. RESULTS: In comparison to controls, diabetic patients had significantly higher body mass index (27.7 vs. 24.6; P<0.01), waist perimeter (103 vs. 84; P<0.001) and usCRP level (5.4 vs. 1.5; P<0.01). On echocardiography; no differences were found in terms of ejection fraction or ventricular mass; however, patients with T2DM had significantly thicker EAT (8.7±0.7 vs. 3.0±1.0; P<0.001) and altered systolic longitudinal strain (-18.8±3.2 vs. 22.3±1.6; P<0.001). On multivariate analysis, EAT was identified as an independent contributor (ß=0,46, P=0.001) to systolic longitudinal strain. CONCLUSION: In patients with T2DM and poor glycemic control; EAT was associated with infraclinical systolic dysfunction evaluated by global longitudinal strain despite normal at rest ejection fraction and no coronary artery disease.

Left ventricles of aging athletes: better untwisters but not more relaxed during exercise.

OBJECTIVE: With an aging population and the increasing prevalence of heart failure with preserved ejection fraction, developing strategies to prevent diastolic dysfunction is crucial. Regular endurance training has been suggested to be one such strategy. However, the underlying mechanisms of training, including the effect on left ventricular (LV) untwist, which promotes LV filling, are unclear and studies exploring the heart during exercise in the aging heart are lacking. METHODS: Cardiopulmonary exercise testing with speckle tracking echocardiography was realized in male subjects: 16 young athletes (YA), 19 young controls (YC), 22 middle-aged athletes (MA) with a lifelong history of endurance training, and 20 middle-aged controls (MC). RESULTS: During exercise, the early filling was lower in MC compared to YC, whereas it was preserved between YA and MA. At exercise, peak untwisting rate/peak twist ratio and the percentage of untwist during isovolumic relaxation time were decreased in senior groups but higher in YA and MA compared to age-matched controls. Early diastolic filling reserve correlated with untwisting rate/peak twist reserve in YA and MA (R 2 = 0.22, p < 0.05) but not in controls. LV relaxation indices in athletes at rest and during exercise were not improved compared to age-matched controls. CONCLUSION: LV intrinsic relaxation was similarly lower with age, independently of training, while the age-related decrease of untwist during exercise was lower with lifelong exercise training. The preservation of untwist mechanics in MA could thus sustain the early filling during exercise. Further studies are needed to confirm the role of exercise training as a preventive strategy for diastolic dysfunction and heart failure.

Exercise-induced cardioprotection: a role for eNOS uncoupling and NO metabolites.

Exercise is an efficient strategy for myocardial protection against ischemia-reperfusion (IR) injury. Although endothelial nitric oxide synthase (eNOS) is phosphorylated and activated during exercise, its role in exercise-induced cardioprotection remains unknown. This study investigated whether modulation of eNOS activation during IR could participate in the exercise-induced cardioprotection against IR injury. Hearts isolated from sedentary or exercised rats (5 weeks training) were perfused with a Langendorff apparatus and IR performed in the presence or absence of NOS inhibitors [N-nitro-L-arginine methyl ester, L-NAME or N5-(1-iminoethyl)-L-ornithine, L-NIO] or tetrahydrobiopterin (BH4). Exercise training protected hearts against IR injury and this effect was abolished by L-NAME or by L-NIO treatment, indicating that exercise-induced cardioprotection is eNOS dependent. However, a strong reduction of eNOS phosphorylation at Ser1177 (eNOS-PSer1177) and of eNOS coupling during early reperfusion was observed in hearts from exercised rats (which showed higher eNOS-PSer1177 and eNOS dimerization at baseline) in comparison to sedentary rats. Despite eNOS uncoupling, exercised hearts had more S-nitrosylated proteins after early reperfusion and also less nitro-oxidative stress, indexed by lower malondialdehyde content and protein nitrotyrosination compared to sedentary hearts. Moreover, in exercised hearts, stabilization of eNOS dimers by BH4 treatment increased nitro-oxidative stress and then abolished the exercise-induced cardioprotection, indicating that eNOS uncoupling during IR is required for exercise-induced myocardial cardioprotection. Based on these results, we hypothesize that in the hearts of exercised animals, eNOS uncoupling associated with the improved myocardial antioxidant capacity prevents excessive NO synthesis and limits the reaction between NO and O2·- to form peroxynitrite (ONOO⁻), which is cytotoxic.

Carbon monoxide exposure in the urban environment: an insidious foe for the heart?

Since Claude Bernard first demonstrated in the 19th century that carbon monoxide (CO) poisoning occurs through hemoglobin binding, CO has proven to be more than simply a toxic gas, and to possess complex biological properties. In this review, we highlight the dual nature of CO in cardiovascular function, from endogenous and therapeutic properties to harmful aspects. Focussing on exposure to low environmental CO levels, the most common but least studied form of exposure, we summarize the pathophysiological effects of CO in vivo and in vitro, from cardiac disorders to phenotypic remodelling of cardiomyocytes, based on clinical observations and experimental studies. While acute exposure to low CO levels is considered beneficial and cardioprotective, prolonged exposure appears deleterious, mainly due to alterations in redox status, ion homeostasis, intracellular Ca(2+) handling, and sympathovagal balance. We emphasize that, despite its fascinating therapeutic potential at low levels, regular exposure to CO may have significant consequences on cardiovascular health and must be considered a cardiovascular risk factor.

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 ß-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.

Vascular reactivity at rest and during exercise in middle-aged obese men: effects of short-term, low-intensity, exercise training.

OBJECTIVE: Although increased blood flow (BF) in exercising muscles is thought to be impaired in obese subjects and may contribute to physical inactivity, data are scarce in this regard and the involvement of endothelium dysfunction remains partly hypothetical. METHODS: A total of 16 middle-aged obese men (body mass index, BMI ≥ 30 kg m(-2)) and 16 normal-weight men (BMI<25 kg m(-2)), matched for age, were recruited. We used ultrasonography to compare intima-media thickness (IMT) and distensibility of the carotid artery, flow-mediated dilation (FMD), nitrate-dependent dilation (NDD) and peak BF during post-ischemic hyperemia in the brachial artery (a conduit artery), and leg BF during knee-extensor exercise (indicative of resistance vessel function) in obese and in normal-weight men. In addition, 10 obese men participated in an 8 week individualized low-intensity training program. RESULTS: Compared with normal-weight men, obese men had higher carotid IMT (0.50 ± 0.01 vs 0.62 ± 0.04 mm, P < 0.05) but lower carotid distensibility (0.26 ± 0.03 vs 0.11 ± 0.03 mm Hg(-1) 10(-2), P < 0.05), FMD (5.7 ± 0.4 vs 3.3 ± 0.5%, P < 0.05) and peak BF during post-ischemic hyperemia (398 ± 52 vs 229 ± 24%, P < 0.05), despite similar maximal shear rate, without NDD differences. Lower limb BF (ml min(-1) 100 g(-1)) increased significantly from rest to maximal exercise in both groups with lower values in obese men (at peak power, 36.9 ± 1.6 vs 31.5+2.2 ml min(-1) 100 g(-1), P < 0.05). Exercise training normalized carotid distensibility (0.14 ± 0.04 before vs 0.23 ± 0.03 mm Hg(-1) 10(-2) after training, P = 0.09) and FMD (2.7 ± 0.4 before vs 4.8 ± 0.5% after training, P < 0.05), but did not improve brachial post-ischemic peak BF or exercising leg BF. CONCLUSIONS: In obese men, conduit and resistance vessel reactivity is depressed, but a short-term low-intensity exercise training improves distensibility and endothelium dependent vasodilation in the large conduit artery, but not post ischemic or exercise muscle BF.

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.

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.

Alteration of endothelium-mediated vasodilator response in the rat hindlimb vasculature consecutive to chronic hypoxic stress: NO and EDHF involvement.

The previously documented impairment of hindlimb blood flow consecutive to chronic hypoxia might be related to endothelial vasomotor dysfunction. The aim of this study was to assess in-vivo the effect of chronic hypoxic stress on endothelium-mediated vasodilator response of hindlimb vascular bed, especially as regards to endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide (NO) pathway contribution. Dark Agouti rats were randomly assigned to live at barometric pressure approximately 760 mmHg (N rats) or approximately 550 mmHg (CH rats). Under anesthesia, catheters were placed in the carotid artery for arterial pressure measurement, and in the saphenous vein and iliac artery for drug delivery. Hindlimb blood flow (HBF) was measured by transit-time ultrasound flowmetry, at baseline and during endothelium-dependent vasodilator response induced by intra-arterial injection of acetylcholine (0.75 ng and 7.5 ng) with and without specific blockers of NOS (L-NAME) and EDHF (Charybdotoxin+Apamin). HBF and hindlimb vascular conductance changes in response to ACh infusion were significantly lower in CH than in N rats. The mechanisms responsible for this blunted response involved impairment in both NO pathway and EDHF. The chronic hypoxia-induced alteration of NO pathway was mainly related to the bioavailability of its substrate l-Arginine, since the infusion of l-Arginine restored the endothelial response to ACh in CH rats to the level of N rats. These results demonstrate that the impairment in endothelium-mediated vasodilator response of the hindlimb vascular tree induced by chronic hypoxic stress involves both NO and EDHF.

Abnormal vascular reactivity at rest and exercise in obese boys.

BACKGROUND: Obese children exhibit vascular disorders at rest depending on their pubertal status, degree of obesity, and level of insulin resistance. However, data regarding their vascular function during exercise remain scarce. The aims of the present study were to evaluate vascular morphology and function at rest, and lower limb blood flow during exercise, in prepubertal boys with mild-to-moderate obesity and in lean controls. MATERIALS AND METHODS: Twelve moderately obese prepubertal boys [Body Mass Index (BMI: 23.9+/-2.6 kg m(-2))] and thirteen controls (BMI:17.4+/-1.8 kg m(-2)), matched for age (mean age: 11.6+/-0.6 years) were recruited. We measured carotid intima-media thickness (IMT) and wall compliance and incremental elastic modulus, resting brachial flow-mediated dilation (FMD) and nitrate-dependent dilation (NDD), lower limb blood flow during local knee-extensor incremental and maximal exercise, body fat content (DEXA), blood pressure, blood lipids, insulin and glucose. RESULTS: Compared to lean controls, obese boys had greater IMT (0.47+/-0.06 vs. 0.42+/-0.03 mm, P<0.05) but lower FMD (4.6+/-2.8 vs. 8.8+/-3.2%, P<0.01) in spite of similar maximal shear rate, without NDD differences. Lower limb blood flow (mL min(-1).100 g(-1)) increased significantly from rest to maximal exercise in both groups, although obese children reached lower values than lean counterparts whatever the exercise intensity. CONCLUSIONS: Mild-to-moderate obesity in prepubertal boys without insulin resistance is associated with impaired endothelial function and blunted muscle perfusion response to local dynamic exercise without alteration of vascular smooth muscle reactivity.

Two months of endurance training does not alter diastolic function evaluated by TDI in 9-11-year-old boys and girls.

OBJECTIVE: Superior global cardiac performance (ie stroke volume) is classically reported after training in children. Current knowledge of the impact of exercise training on myocardial relaxation, a major component of left ventricular (LV) filling and subsequently stroke volume, is, however, limited in the paediatric population. This study aimed to investigate the effect of aerobic training on LV wall motion velocities by tissue Doppler imaging (TDI) in healthy children. METHODS: 25 children (11 girls, 14 boys) were enrolled in a 2 month high-intensity aerobic training programme and 25 (12 girls and 13 boys) served as controls. The children (9-11 years old) performed a graded maximal exercise test on a treadmill to evaluate maximal oxygen uptake. Standard Doppler echocardiography and TDI measurements were performed at baseline and end of the study. Tissue Doppler systolic, early and late myocardial velocities were obtained at the mitral annulus in the septal, lateral, inferior and posterior walls. RESULTS: Maximal oxygen uptake increased by 6.5% (before: 51.6 (SD 4.2), after: 55.0 (4.5) ml/min/kg p<0.001) after training. A modest but significant increase in left ventricular end-diastolic diameter was also noticed (before: 46.1 (3.4), after: 48.3 (4.3) mm.BSA(-1/2), p<0.001), whereas left ventricular wall thickness and mass were unchanged. Neither transmitral inflow velocities nor early and late wall motion (Em: before = 18.4 (2.7), after = 18.0 (2.3) cm/s, Am: before = 6.8 (1.2), after = 6.7 (1.3) cm/s) were affected by training. Shortening fraction and regional systolic function (Sm: before = 10.1 (1.6), after = 10.2 (1.4) cm/s) by TDI were also unchanged. CONCLUSION: High-intensity aerobic sessions repeated over a 2 month period failed to improve regional diastolic function assessed by TDI in healthy young children.

Alteration in left ventricular normal and shear strains evaluated by 2D-strain echocardiography in the athlete's heart.

The contraction of cardiomyocytes induces a systolic increase in left ventricular (LV) normal (radial, circumferential and longitudinal) and shear strains, whose functional consequences have not been evaluated, so far, in athletes. We used 2D ultrasound speckle tracking imaging (STI) to evaluate LV regional strain in high-level cyclists compared to sedentary controls. Sixteen male elite cyclists and 23 sedentary controls underwent conventional, tissue Doppler, and STI echocardiography at rest. We assessed LV long and short axis normal strains and shear strains. We evaluated circumferential-longitudinal shear strain from LV torsion, and circumferential-radial shear strain from the difference between subendocardial and subepicardial torsion. Apical radial strain (42.7 +/- 10.5% versus 52.2 +/- 14.3%, P < 0.05) and LV torsion (6.0 +/- 1.8 deg versus 9.2 +/- 3.2 deg, P < 0.01) were lower in cyclists than in controls, respectively. Rotations and torsion were higher in the subendocardial than in the subepicardial region in sedentary controls, but not in cyclists. Haemodynamic and tissue Doppler based indexes of global LV diastolic and systolic functions were not different between cyclists and controls. Athlete's heart is associated with specific LV adaptation including lower apical strain and lower myocardial shear strains, with no change in global LV diastolic and systolic function. These mechanical alterations could improve the cardiovascular adjustments to exercise by increasing the radial strain and torsional (and thus untwisting) response to exercise, a key element of diastolic filling and thus of cardiac performance in athletes.

Paradoxical effects of endurance training and chronic hypoxia on myofibrillar ATPase activity.

This study aimed to determine the changes in soleus myofibrillar ATPase (m-ATPase) activity and myosin heavy chain (MHC) isoform expression after endurance training and/or chronic hypoxic exposure. Dark Agouti rats were randomly divided into four groups: control, normoxic sedentary (N; n = 14), normoxic endurance trained (NT; n = 14), hypoxic sedentary (H; n = 10), and hypoxic endurance trained (HT; n = 14). Rats lived and trained in normoxia at 760 mmHg (N and NT) or hypobaric hypoxia at 550 mmHg (approximately 2,800 m) (H and HT). m-ATPase activity was measured by rapid flow quench technique; myosin subunits were analyzed with mono- and two-dimensional gel electrophoresis. Endurance training significantly increased m-ATPase (P < 0.01), although an increase in MHC-I content occurred (P < 0.01). In spite of slow-to-fast transitions in MHC isoform distribution in chronic hypoxia (P < 0.05) no increase in m-ATPase was observed. The rate constants of m-ATPase were 0.0350 +/- 0.0023 s(-1) and 0.047 +/- 0.0050 s(-1) for N and NT and 0.033 +/- 0.0021 s(-1) and 0.038 +/- 0.0032 s(-1) for H and HT. Thus, dissociation between variations in m-ATPase and changes in MHC isoform expression was observed. Changes in fraction of active myosin heads, in myosin light chain isoform (MLC) distribution or in MLC phosphorylation, could not explain the variations in m-ATPase. Myosin posttranslational modifications or changes in other myofibrillar proteins may therefore be responsible for the observed variations in m-ATPase activity.

Flow-mediated dilation and exercise-induced hyperaemia in highly trained athletes: comparison of the upper and lower limb vasculature.

AIM: The main purpose of the present study was to assess whether similar vascular adaptive changes could be obtained by long-term intensive training involving predominantly either the lower or the upper limb musculature. METHODS: In 11 cyclists (C), 10 swimmers (S) and 10 sedentary controls (Sed), duplex Doppler ultrasonography was used to measure post-occlusion endothelium-dependent flow-mediated dilation (FMD), endothelium-independent, glycerine trinitrate-induced dilation (GTND) and exercise-induced blood flow changes in the arm (axillary artery) and leg (superficial femoral artery). Limb-specific exercise was achieved by one elbow-flexion or one leg-extension maximal exercise test, thereby allowing assessment of upper and lower limb muscle perfusion, vascular conductance and vasodilatory capacity of resistance vessels during effort. RESULTS: C and S exhibited vascular remodelling associated with improved FMD and GTND in the predominantly trained limbs compared to Sed. Both showed greater muscle perfusion and vascular conductance than Sed during isolated exercise involving the predominantly trained musculature. C showed also higher FMD in the brachial artery and greater peak muscle perfusion and conductance in the non-exercising muscles, whereas S presented only enhanced FMD in the superficial femoral artery. CONCLUSION: Therefore, in the upper as well as in the lower limb vasculature, repetitive exposure to increased shear stress over a long-term period results in improved FMD of large conduit arteries as well as greater vasodilatory capacity during isolated exercise in the predominantly trained muscles. Long-term training involving predominantly the lower limbs also results in enhanced vascular reactivity in upper limb conduit and resistance vessels.

Tissue Doppler imaging reproducibility during exercise.

Tissue Doppler imaging (TDI) is an echocardiographic technique used during exercising to improve the accuracy of a cardiovascular diagnostic. The validity of TDI requires its reproducibility, which has never been challenged during moderate to maximal intensity exercising. The present study was specifically designed to assess the transmitral Doppler and pulsed TDI reproducibility in 19 healthy men, who had undergone two identical semi-supine maximal exercise tests on a cycle ergometer. Systolic (S') and diastolic (E') tissue velocities at the septal and lateral walls as well as early transmitral velocities (E) were assessed during exercise up to maximal effort. The data were compared between the two tests at 40 %, 60 %, 80 % and 100 % of maximal aerobic power. Despite upper body movements and hyperventilation, good quality echocardiographic images were obtained in each case. Regardless of exercise intensity, no differences were noticed between the two tests for all measurements. The variation coefficients for Doppler variables ranged from 3 % to 9 % over the transition from rest to maximal exercise. The random measurement error was, on average, 5.8 cm/s for E' and 4.4 cm/s for S'. Overall, the reproducibility of TDI was acceptable. Tissue Doppler imaging can be used to accurately evaluate LV diastolic and/or systolic function for this range of exercise intensity.

Combined effects of hypoxia and endurance training on lipid metabolism in rat skeletal muscle.

AIM: To determine whether endurance training can counterbalance the negative effects of hypoxia on mitochondrial phosphorylation and expression of the long chain mitochondrial fatty acid transporter muscle carnitine palmitoyl transferase 1 (mCPT-1). METHODS: Male Wistar rats were exposed either to hypobaric hypoxia (at a simulated altitude of approximately 4000 m, PIO(2) approximately 90 mmHg) or to normoxia (sea level) for 5 weeks. In each environment, rats were randomly assigned to two groups. The trained group went through a 5-week endurance training programme. The control group remained sedentary for the same time period. Muscle fatty acid oxidation capacity was evaluated after the 5-week period on isolated mitochondria prepared from quadriceps muscles with the use of palmitoylcarnitine or pamitoylCoA + carnitine. RESULTS: Chronic hypoxia decreased basal (V(0), -31% with pamitoylCoA + carnitine and -21% with palmitoylcarnitine, P < 0.05) and maximal (V(max), -31% with pamitoylCoA + carnitine, P < 0.05) respiration rates, hydroxyacylCoA dehydrogenase activity (-48%, P < 0.05), mCPT-1 activity index (-34%, P < 0.05) and mCPT-1 protein content (-34%, P < 0.05). Five weeks of endurance training in hypoxia brought V(0), mCPT-1 activity index and mCPT-1 protein content values back to sedentary normoxic levels. Moreover, in the group trained in hypoxia, V(max) reached a higher level than in the group that maintained a sedentary lifestyle in normoxia (24.2 nmol O(2). min(-1) . mg(-1) for hypoxic training vs. 19.9 nmol O(2) . min(-1) . mg(-1) for normoxic sedentarity, P < 0.05). CONCLUSION: Endurance training can attenuate chronic hypoxia-induced impairments in mitochondrial fatty acid oxidation. This training effect seems mostly mediated by mCPT-1 activity rather than by mCPT-1 content.

Aortic vasoconstriction related to smooth muscle cells ET-A and ET-B receptors is not involved in hypoxia-induced sustained systemic arterial hypertension in rats.

OBJECTIVES: We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension. METHODS: Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure. RESULTS: Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%). CONCLUSION: This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.

Reproducibility of automated pulse wave velocity measurement during exercise. Running head: pulse wave velocity during exercise.

Pulse wave velocity measurement is used as an index of arterial stiffness. The purpose was to evaluate the reproducibility of pulse wave velocity measurement at rest, during exercise and recovery from exercise, using an automated device. Twelve healthy young adults (mean age 22.0 +/- 3.1 yrs) underwent an upright submaximal cycle test on two separate occasions, one week apart. Pulse wave velocity, systolic and diastolic blood pressures and heart rate were assessed at rest, during the last 2 min of exercise and 10 min later. Pulse wave velocity was measured on the upper limb and the forearm by the cross-correlation function of photoplethysmography and Doppler signals. Brachial artery pulse wave velocity was calculated from upper limb and forearm pulse wave velocities. No significant difference was found on duplicate measurements of heart rate, systolic and diastolic blood pressures at rest, during exercise and recovery, showing that pulse wave velocity was measured under similar conditions. Coefficient of variation for upper limb and forearm pulse wave velocities ranged from 2.9 to 5.9% at rest and during recovery, and were respectively 2.9% and 8.3% during exercise. However, coefficient of variation for brachial pulse wave velocity was 7.7 and 10.3% at rest, 15.7% during exercise, and 5.8% during recovery. During exercise, pulse wave velocity measurements were satisfying, but indirect assessment of brachial artery pulse wave velocity showed poor reproducibility. Thus, upper limb and forearm pulse wave velocities may be used during exercise to assess the effect of training or drugs on arterial wall mechanical properties.

Effects of high-altitude exercise training on contractile function of rat skinned cardiomyocyte.

OBJECTIVE: Previous studies have questioned whether there is an improved cardiac function after high-altitude training. Accordingly, the present study was designed specifically to test whether this apparent blunted response of the whole heart to training can be accounted for by altered mechanical properties at the cellular level. METHODS: Adult rats were trained for 5 weeks under normoxic (N, NT for sedentary and trained animals, respectively) or hypobaric hypoxic (H, HT) conditions. Cardiac morphology and function were evaluated by echocardiography. Calcium Ca2+ sensitivity of the contractile machinery was estimated in skinned cardiomyocytes isolated from the left ventricular (LV) sub-epicardium (Epi) and sub-endocardium (Endo) at short and long sarcomere lengths (SL). RESULTS: Cardiac remodelling was harmonious (increase in wall thickness with chamber dilatation) in NT rats and disharmonious (hypertrophy without chamber dilatation) in HT rats. Contrary to NT rats, HT rats did not exhibit enhancement in global cardiac performance evaluated by echocardiography. Stretch- dependent Ca2+ sensitization of the myofilaments (cellular index of the Frank-Starling mechanism) increased from Epi to Endo in N rats. Training in normoxic conditions further increased this stretch-dependent Ca2+ sensitization. Chronic hypoxia did not significantly affect myofibrilar Ca2+ sensitivity. In contrast, high-altitude training decreased Ca2+ sensitivity of the myofilaments at both SL, mostly in Endo cells, resulting in a loss of the transmural gradient of the stretch-dependent Ca2+ sensitization. Expression of myosin heavy chain isoforms was affected both by training and chronic hypoxia but did not correlate with mechanical data. CONCLUSIONS: Training at sea level increased the transmural gradient of stretch-dependent Ca2+ sensitization of the myofilaments, accounting for an improved Frank-Starling mechanism. High-altitude training depressed myofilament response to Ca2+, especially in the Endo layer. This led to a reduction in this transmural gradient that may contribute to the lack of improvement in LV function via the Frank-Starling mechanism.

Protection against reactive oxygen species injuries in rat isolated perfused hearts: effect of LPBNAH, a new amphiphilic spin-trap derived from PBN.

Numerous strategies have been designed to protect the myocardium against reactive oxygen species (ROS). The present study was designed to test wether LPBNAH, a new amphiphilic spin-trap derived from PBN is able to protect isolated perfused rat hearts against ROS injuries. Following total glola ischemia (30 min), hearts were reperfused in the presence or not of LPBNAH (10 micromol/l), and left ventricular function was continuously monitored. The addition of LPBNAH led to a significant recovery in left ventricular developped pressure (LVDevP, control: 16.5+/- 7.5, p < 0.05). To conclude, the present results strongly suggest that the modification of previous wellknown molecules in order to facilitate their access to intracellular site of ROS production might be of interest to limit oxidative stresses.