An ethically guided preclinical device for phenotyping H2 production in laboratory rodents.

BACKGROUND: Dihydrogen (H2) is produced endogenously by the intestinal microbiota through the fermentation of diet carbohydrates. Over the past few years, numerous studies have demonstrated the significant therapeutic potential of H2 in various pathophysiological contexts, making the characterization of its production in laboratory species of major preclinical importance. METHODS: This study proposes an innovative solution to accurately monitor H2 production in free-moving rodents while respecting animal welfare standards. The developed device consisted of a wire rodent cage placed inside an airtight chamber in which the air quality was maintained, and the H2 concentration was continuously analyzed. After the airtightness and efficiency of the systems used to control and maintain air quality in the chamber were checked, tests were carried out on rats and mice with different metabolic phenotypes, over 12 min to 1-h experiments and repeatedly. H2 production rates (HPR) were obtained using an easy calculation algorithm based on a first-order moving average. RESULTS: HPR in hyperphagic Zucker rats was found to be twice as high as in control Wistar rats, respectively, 2.64 and 1.27 nmol.s-1 per animal. In addition, the ingestion of inulin, a dietary fiber, stimulated H2 production in mice. HPRs were 0.46 nmol.s-1 for animals under control diet and 1.99 nmol.s-1 for animals under inulin diet. CONCLUSIONS: The proposed device coupled with our algorithm enables fine analysis of the metabolic phenotype of laboratory rats or mice with regard to their endogenous H2 production.

Hydrogen inhalation: in vivo rat genotoxicity tests.

Preclinical and clinical studies have shown that molecular hydrogen (H2) has anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Safety data are available in the literature and acute toxicity has been tested in isolated cells and laboratory animals. We have evaluates the genotoxicity of H2 in vivo in rats after 72 h exposure, following the International Council for Harmonization guidelines ICH S2 (R1). The study was conducted on three groups of male Wistar rats: a negative control group, a positive control group receiving methyl methanesulfonate, and a H2-treated group receiving a 3.1% H2 gas mixture for 72 h. Alkaline comet, formamidopyrimidine DNA glycosylase (Fpg)-modified comet and bone marrow micronucleus assays were performed. H2 exposure increased neither comet-tail DNA intensity (DNA damage) nor frequency of "hedgehogs" in blood, liver, lungs, or bronchoalveolar lavage fluid. No increase in Fpg-sensitive sites in lungs, no induction of micronucleus formation, and no imbalance of immature erythrocyte to total erythrocyte ratio (IME%) was observed in rats exposed to H2. The ICH S2 (R1) test-battery revealed no in vivo genotoxicity in Wistar rats after 72 h inhalation of a mixture containing 3.1% H2.

Flow simulations of rectal evacuation: towards a quantitative evaluation from video defaecography.

Mechanistic understanding of anorectal (patho)physiology is missing to improve the medical care of patients suffering from defaecation disorders. Our objective is to show that complex fluid dynamics modelling of video defaecography may open new perspectives in the diagnosis of defaecation disorders. Based on standard X-ray video defaecographies, we developed a bi-dimensional patient-specific simulation of the expulsion of soft materials, the faeces, by the rectum. The model quantified velocity, pressure and stress fields during the defaecation of a neostool with soft stool-like rheology for patients showing normal and pathological defaecatory function. In normal defaecation, the proximal-distal pressure gradient resulted from both the anorectal junction which formed a converging channel and the anal canal. The flow of the neostool through these anatomical parts was dominated by its shear-thinning viscous properties, rather than its yield stress. Consequently, the evacuation flow rate was significantly affected by variations in pressure applied by the rectum, and much less by the geometry of the anorectal junction. Lastly, we simulated impaired defaecations in the absence of obvious obstructive phenomena. Comparison with normal defaecation allowed us to discuss critical elements which should lead to effective medical management.

Abdominal cardiovascular sound recording and analysis using cardio-microphones.

In view of using abdominal microphones for fetal heart rate (FHR) monitoring, the analysis of the obtained abdominal phonocardiogram (PCG) signals is complex due to many interferential noises including blood flow sounds. In order to improve the understanding of abdominal phonocardiography, a preliminary study was conducted in one healthy volunteer and designed to characterize the PCG signals all over the abdomen. Acquisitions of PCG signals in different abdominal areas were realized, synchronously with one thoracic PCG signal and one electrocardiogram signal. The analysis was carried out based on the temporal behavior, amplitude and mean pattern of each signal. The synchronized rhythmic signature of each signal confirms that the PCG signals obtained on the abdominal area are resulting from heart function. However, the abdominal PCG patterns are totally different from the thoracic PCG one, suggesting the recording of vascular blood flow sounds on the abdomen instead of cardiac valve sounds. Moreover, the abdominal signal magnitude depends on the sensor position and therefore to the size of the underlying vessel. The sounds characterization of abdominal PCG signals could help improving the processing of such signals in the purpose of FHR monitoring.

Towards an assessment of rectal function by coupling X-ray defecography and fluid mechanical modelling.

Despite the numerous available clinical investi-gation tests, the associated alteration of quality of life and the socio-economic cost, it remains difficult for physicians to identify the pathophysiological origins of defecation disorders and therefore to provide the appropriate clinical care. Based on standardized dynamic X-ray defecography, we developed a 2D patient-specific computational fluid dynamic model of rectal evacuation. X-ray defecography was carried out in a sitting position with a standardized paste whose yield stress matched that of soft human feces. The flow was simulated with lattice-Boltzmann methods for yield stress fluids and moving boundary conditions. The model was applied for a patient with a normal recto-anal function. We deduced from the flow field that the main flow resistance during the defecation was due to the extrusion of the paste through the anal canal. We calculated also from pressure and stress fields the spatio-temporal evolution of the wall normal stress. This latter highlighted a gradient from the proximal to the distal part of the rectum. We discussed how this new set of hydrodynamical and biome-chanical parameters could be interpreted to gain new insights on the physiology of defecation and to diagnose underlying evacuation disorders. Clinical relevance - If confirmed, our approach should allow clinicians to obtain other parameters from a classic clinical examination and thus better adapt the response of clinicians to the defecation disorders observed in patients.

A new multimodal device for atrial fibrillation detection: ECG quality analysis in healthy volunteers.

In the context of increase in cardiovascular diseases in the aging population, including a high prevalence of atrial fibrillation (AF), the development of medical devices to ensure patient follow-up is of major interest. The purpose of this study is to assess the ECG signal quality of a one-lead in a new miniaturized device on healthy volunteers submitted to several conditions reflecting daily life activity. Our results show that the P wave identification is not enough reliable to consider the detection of its potential disappearance in case of AF. However, we show that the ECG signals can be used to robustly detect the RR intervals. To conclude, for rhythm disturbance detection, an automatic and specific analysis of RR variability has now to be integrated in this new multimodal device. Clinical relevance - This study confirms the potential interest of implantable medical device in the management of cardiac arrhythmias notably in the context of the individual follow up of aging patients.

Inductive Plethysmography for aortic Pulse Wave Velocity.

Aortic stiffening is a process that is linked to cardiovascular risk factor increase. Then, aortic stiffness evaluation is considered as a good index of the evolution of pathophysiological situations, including myocardial infarction, heart failure, atherosclerosis or stroke. Today, pulse wave velocity (PWV) measurement is considered as the gold standard for evaluation of arterial stiffness. However, most of the current measurement techniques of PWV consider the time for the blood pressure pulse to propagate through a combined length of arteries and give access to arterial PWV. Therefore, none of the available techniques focuses only on the aorta. In the present context of smart clothes development, Inductive Plethsymography (IP) can be an interesting alternative for aortic PWV measure, since it has recently been shown that combination of thoracic and abdominal IP recordings can give cardiac information. We therefore investigate the potential of IP for aortic PWV measurement. In this preliminary study, a comparative analysis of PWV estimated from IP and PWV evaluated from the arm has been carried out on 11 healthy volunteers. Results show a significant linear correlation between both measures (r = 0.86, p<0.001), promising for future investigations on pathological populations.

Cardiopulmonary responses during the cooling and the extracorporeal life support rewarming phases in a porcine model of accidental deep hypothermic cardiac arrest.

BACKGROUND: This study aimed to assess cardiac and pulmonary pathophysiological responses during cooling and extracorporeal life support (ECLS) rewarming in a porcine model of deep hypothermic cardiac arrest (DHCA). In addition, we evaluated whether providing a lower flow rate of ECLS during the rewarming phase might attenuate cardiopulmonary injuries. METHODS: Twenty pigs were cannulated for ECLS, cooled until DHCA occurred and subjected to 30 min of cardiac arrest. In order to assess the physiological impact of ECLS on cardiac output we measured flow in the pulmonary artery using Doppler echocardiography as well as a modified thermodilution technique using the Swan-Ganz catheter (injection site in the right ventricle). The animals were randomized into two groups during rewarming: a group with a low blood flow rate of 1.5 L/min (LF group) and a group with a normal flow rate of 3.0 L/min (NF group). The ECLS temperature was adjusted to 5 °C above the central core. Cardiac output, hemodynamics and pulmonary function parameters were evaluated. RESULTS: During the cooling phase, cardiac output, heart rhythm and blood pressure decreased continuously. Pulmonary artery pressure tended to increase at 32 °C compared to the initial value (20.2 ± 1.7 mmHg vs. 29.1 ± 5.6 mmHg, p = 0.09). During rewarming, arterial blood pressure was higher in the NF than in the LF group at 20° and 25 °C (p = 0.003 and 0.05, respectively). After rewarming to 35 °C, cardiac output was 3.9 ± 0.5 L/min in the NF group vs. 2.7 ± 0.5 L/min in LF group (p = 0.06). At the end of rewarming under ECLS cardiac output was inversely proportional to the ECLS flow rate. Moreover, the ECLS flow rate did not significantly change pulmonary vascular resistance. DISCUSSION: Using a newly developed experimental model of DHCA treated by ECLS, we assessed the cardiac and pulmonary pathophysiological response during the cooling phase and the ECLS rewarming phase. Despite lower metabolic need during hypothermia, a low ECLS blood flow rate during rewarming did not improved cardiopulmonary injuries after rewarming. CONCLUSION: A low ECLS flow rate during the rewarming phase did not attenuate pulmonary lesions, increased blood lactate level and tended to decrease cardiac output after rewarming. A normal ECLS flow rate did not increase pulmonary vascular resistance compared to a low flow rate. This experimental model on pigs contributes a number of pathophysiological findings relevant to the rewarming strategy for patients who have undergone accidental DHCA.

Exercise does not activate the ß3 adrenergic receptor-eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice.

Obesity and diabetes are associated with higher cardiac vulnerability to ischemia-reperfusion (IR). The cardioprotective effect of regular exercise has been attributed to ß3-adrenergic receptor (ß3AR) stimulation and increased endothelial nitric oxide synthase (eNOS) activation. Here, we evaluated the role of the ß3AR-eNOS pathway and NOS isoforms in exercise-induced cardioprotection of C57Bl6 mice fed with high fat and sucrose diet (HFS) for 12 weeks and subjected or not to exercise training during the last 4 weeks (HFS-Ex). HFS animals were more sensitive to in vivo and ex vivo IR injuries than control (normal diet) and HFS-Ex mice. Cardioprotection in HFS-Ex mice was not associated with increased myocardial eNOS activation and NO metabolites storage, possibly due to the ß3AR-eNOS pathway functional loss in their heart. Indeed, a selective ß3AR agonist (BRL37344) increased eNOS activation and had a protective effect against IR in control, but not in HFS hearts. Moreover, iNOS expression, nitro-oxidative stress (protein s-nitrosylation and nitrotyrosination) and ROS production during early reperfusion were increased in HFS, but not in control mice. Exercise normalized iNOS level and reduced protein s-nitrosylation, nitrotyrosination and ROS production in HFS-Ex hearts during early reperfusion. The iNOS inhibitor 1400 W reduced in vivo infarct size in HFS mice to control levels, supporting the potential role of iNOS normalization in the cardioprotective effects of exercise training in HFS-Ex mice. Although the ß3AR-eNOS pathway is defective in the heart of HFS mice, regular exercise can protect their heart against IR by reducing iNOS expression and nitro-oxidative stress.

The impact of cardiac ischemia/reperfusion on the mitochondria-cytoskeleton interactions.

Cardiac ischemia-reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation (OxPhos) and compartmentalized intracellular energy transfer via the phosphocreatine/creatine kinase (CK) network. The restriction of ATP/ADP diffusion at the level of the mitochondrial outer membrane (MOM) is an essential element of compartmentalized energy transfer. In adult cardiomyocytes, the MOM permeability to ADP is regulated by the interaction of voltage-dependent anion channel with cytoskeletal proteins, particularly with ß tubulin II. The IR-injury alters the expression and the intracellular arrangement of cytoskeletal proteins. The objective of the present study was to investigate the impact of IR on the intracellular arrangement of ß tubulin II and its effect on the regulation of mitochondrial respiration. Perfused rat hearts were subjected to total ischemia (for 20min (I20) and 45min (I45)) or to ischemia followed by 30min of reperfusion (I20R and I45R groups). High resolution respirometry and fluorescent confocal microscopy were used to study respiration, ß tubulin II and mitochondrial arrangements in cardiac fibers. The results of these experiments evidence a heterogeneous response of mitochondria to IR-induced damage. Moreover, the intracellular rearrangement of ß tubulin II, which in the control group colocalized with mitochondria, was associated with increased apparent affinity of OxPhos for ADP, decreased regulation of respiration by creatine without altering mitochondrial CK activity and the ratio between octameric to dimeric isoenzymes. The results of this study allow us to highlight changes of mitochondrial interactions with cytoskeleton as one of the possible mechanisms underlying cardiac IR injury.

Deep Hypothermic Cardiac Arrest Treated by Extracorporeal Life Support in a Porcine Model: Does the Rewarming Method Matter?

OBJECTIVES: Extracorporeal life support (ECLS) is the reference rewarming technique of accidental deep hypothermic cardiac arrest (DHCA). This study was designed to examine the impact of different rewarming blood flow rates and temperature setting of ECLS on cardiopulmonary lesions after DHCA in a porcine model of accidental hypothermia. METHODS: Twenty-four pigs were cannulated for ECLS, cooled until DHCA occurred, and subjected to 30 minutes of cardiac arrest. During the rewarming phase, we compared a low blood flow rate of 1.5 L/min versus a high flow rate of 3.0 L/min as well as two-temperature-setting rewarming strategies: a temperature during ECLS adjusted to 5°C above the central core temperature versus 38°C maintained throughout the rewarming phase. Cardiac output, hemodynamics and pulmonary function parameters were evaluated. Biologic markers of ischemia-reperfusion injuries were analyzed at baseline and at the end of the experiment. RESULTS: DHCA occurred at 21.2 ± 2°C. There was a trend for better cardiac output in groups with high blood flow (p = 0.053), with no interaction between ECLS flow and temperature (p = 0.63), a trend toward lower pulmonary vascular resistance (PVR; p = 0.075) and a significant decrease in arterial PVR in groups with high blood flow (p = 0.013) with no interaction (p = 0.47 and p = 0.60 for PVR and arterial PVR, respectively). Serum interleukin-6, tumor necrosis factor-α, receptor for advanced glycation end products (RAGE), and neuron-specific enolase were significantly increased between baseline and endpoint. The increase in the serum RAGE concentration was higher in the 38°C rewarming temperature groups compared to 5°C above adjusted temperature. There were no other significant differences in biomarkers. CONCLUSIONS: We developed a porcine model of DHCA treated by ECLS. Our data suggest that cardiac output tended to improve with a high-flow-rate rewarming strategy while a high-temperature delta between core temperature and ECLS increased the RAGE markers of lung injury.

Non-invasive cardiac output monitoring in pharmacology: A plethysmographie solution in rats.

Cardiovascular monitoring is of great importance in pharmacology but there is a lack of convenient non-invasive alternatives. Hence, we aim to evaluate the relevance of inductive plethysmography (IP) in preclinical cardiac studies. An IP system was specifically designed for rat. Its evaluation carried out using a mechanical test bench has shown appropriate instrumental performances for cardiac monitoring in rats. Measurements were also performed during a volume overload hemodynamic challenge in vivo in rats. The cardiac output variation has similar kinetic and amplitude when compared to results of previous studies. This suggests that our system is suitable for cardiac output monitoring in rat.

Carbon monoxide increases inducible NOS expression that mediates CO-induced myocardial damage during ischemia-reperfusion.

We investigated the role of inducible nitric oxide (NO) synthase (iNOS) on ischemic myocardial damage in rats exposed to daily low nontoxic levels of carbon monoxide (CO). CO is a ubiquitous environmental pollutant that impacts on mortality and morbidity from cardiovascular diseases. We have previously shown that CO exposure aggravates myocardial ischemia-reperfusion (I/R) injury partly because of increased oxidative stress. Nevertheless, cellular mechanisms underlying cardiac CO toxicity remain hypothetical. Wistar rats were exposed to simulated urban CO pollution for 4 wk. First, the effects of CO exposure on NO production and NO synthase (NOS) expression were evaluated. Myocardial I/R was performed on isolated perfused hearts in the presence or absence of S-methyl-isothiourea (1 µM), a NOS inhibitor highly specific for iNOS. Finally, Ca(2+) handling was evaluated in isolated myocytes before and after an anoxia-reoxygenation performed with or without S-methyl-isothiourea or N-acetylcystein (20 µM), a nonspecific antioxidant. Our main results revealed that 1) CO exposure altered the pattern of NOS expression, which is characterized by increased neuronal NOS and iNOS expression; 2) cardiac NO production increased in CO rats because of its overexpression of iNOS; and 3) the use of a specific inhibitor of iNOS reduced myocardial hypersensitivity to I/R (infarct size, 29 vs. 51% of risk zone) in CO rat hearts. These last results are explained by the deleterious effects of NO and reactive oxygen species overproduction by iNOS on diastolic Ca(2+) overload and myofilaments Ca(2+) sensitivity. In conclusion, this study highlights the involvement of iNOS overexpression in the pathogenesis of simulated urban CO air pollution exposure.

Cardiac dysfunction in rats with dietary-induced insulin resistance associated with pharmacologically-induced dyslipidemia.

Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. The present study proposes a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function. Male rats were fed a western-type diet (65% fat; 15% fructose; WD). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407; 0.2 mg/kg, 3 times/wk; P-407). A chow diet was used as control. At 11 and 14 weeks, cardiac function was assessed by echocardiography. Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in P-407 treated rats. Echocardiographic data showed no significant difference in cardiac geometry under basal conditions. Diastolic dysfunction was evidenced at 14 weeks by a significant decrease in E/A ratio in the P-407 group. Moreover, fractional shortening was significantly depressed under dobutamine stress in WD group at 14 weeks whereas systolic dysfunction appeared as early as 11 weeks and worsened at 14 weeks in P-407 animals. Finally, myocardial TNF-alpha tissue content increased in P-407 group. In conclusion, DL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments.

Diet modulates endogenous thrombin generation, a biological estimate of thrombosis risk, independently of the metabolic status.

OBJECTIVE: High endogenous thrombin potential (ETP) is associated with venous and arterial thrombosis. Better knowledge of environmental influences on ETP may help to prevent thrombosis. METHODS AND RESULTS: Weaning rats exhibited high ETP values that decreased in low-fat diet and remained elevated on high-fat diet. In adult rats, high-fat diet-induced ETP increase was independent of coagulation factors, obesity, and insulin resistance and negatively associated with polyunsaturated fatty acid levels. Switching from high-fat diet to low-fat diet reversed the procoagulant phenotype with a slower kinetic than the normalization of hyperinsulinemia. In humans, ETP was independent of body weight whereas it was negatively associated with nutritional markers such as the percentage of energy provided by proteins, the protein:fat ratio, circulating phenolic compounds, and omega-3 polyunsaturated fatty acid. A recommended 3-month healthy diet with reduced energy density, including lipids, decreased ETP (-21%; P<0.0001). Changes in ETP were not associated with body weight, insulin sensitivity, or coagulation factor variations, but correlated negatively with plasma docosahexaenoic acid, a nutritional status sensitive fatty acid, and compounds reflecting vegetable intake. CONCLUSIONS: Diet plays a pivotal role in regulating ETP, independently of obesity and insulin resistance. Global nutritional recommendations could be useful in primary prevention of venous thrombosis.

Impact of dietary selenium intake on cardiac health: experimental approaches and human studies.

Selenium, a dietary trace mineral, essential for humans and animals, exerts its effects mainly through its incorporation into selenoproteins. Adequate selenium intake is needed to maximize the activity of selenoproteins, among which glutathione peroxidases have been shown to play a major role in cellular defense against oxidative stress initiated by excess reactive oxygen species. In humans, a low selenium status has been linked to increased risk of various diseases, including heart disease. The main objective of this review is to present current knowledge on the role of selenium in cardiac health. Experimental studies have shown that selenium may exert protective effects on cardiac tissue in animal models involving oxidative stress. Because of the narrow safety margin of this mineral, most interventional studies in humans have reported inconsistent findings. Major determinants of selenium status in humans are not well understood and several nondietary factors might be associated with reduced selenium status. In this review, we discuss recent studies regarding the role of selenoproteins in the cardiovascular system, the effect of dietary intake on selenium status, the impact of selenium status on cardiac health, and the cellular mechanisms that can be involved in the physiological and toxic effects of selenium.

ß-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 ß-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 ß-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 ß-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

Dietary selenium intake influences Cx43 dephosphorylation, TNF-α expression and cardiac remodeling after reperfused infarction.

SCOPE: Post-infarct left ventricular dysfunction and cardiac remodeling are the primary causes of chronic heart failure in industrialized countries. In the present study, we examined the influence of dietary selenium intake on cardiac remodeling after reperfused myocardial infarction and explored one of the possible mechanisms. METHODS AND RESULTS: Rats were fed a diet containing either 0.05 mg/kg (Low-Se, group of rats receiving the low-selenium diet) or 1.50 mg/kg (group of rats receiving the high-selenium diet) selenium. At the end of the 5th week of the diet, rats were subjected to transient (1 h) coronary ligation followed by 8 days of reperfusion. Infarct size and cardiac passive compliance were increased in the Low-Se group compared with group of rats receiving the high-selenium diet. Similarly, indices of cardiac remodeling (thinning index and expansion index) were more altered in Low-Se hearts. These adverse effects of the Low-Se diet on cardiac remodeling were accompanied by an increase in cardiac TNF-α content, a decreased activity of antioxidant seleno-enzymes and an increase in connexin-43 dephosphorylation. CONCLUSION: Dietary selenium intake influences post-infarct cardiac remodeling even when provided within the range of physiological values. Our data suggest that the cardioprotective effect of selenium might be mediated by a reduced oxidative stress, a lower connexin-43 dephosphorylation, and a decreased TNF-α expression.

Carbon monoxide pollution promotes cardiac remodeling and ventricular arrhythmia in healthy rats.

RATIONALE: Epidemiologic studies associate atmospheric carbon monoxide (CO) pollution with adverse cardiovascular outcomes and increased cardiac mortality risk. However, there is a lack of data regarding cellular mechanisms in healthy individuals. OBJECTIVES: To investigate the chronic effects of environmentally relevant CO levels on cardiac function in a well-standardized healthy animal model. METHODS: Wistar rats were exposed for 4 weeks to filtered air (CO < 1 ppm) or air enriched with CO (30 ppm with five peaks of 100 ppm per 24-h period), consistent with urban pollution. Myocardial function was assessed by echocardiography and analysis of surface ECG and in vitro by measuring the excitation-contraction coupling of single left ventricular cardiomyocytes. MEASUREMENTS AND MAIN RESULTS: Chronic CO pollution promoted left ventricular interstitial and perivascular fibrosis, with no change in cardiomyocyte size, and had weak, yet significant, effects on in vivo cardiac function. However, both contraction and relaxation of single cardiomyocytes were markedly altered. Several changes occurred, including decreased Ca(2+) transient amplitude and Ca(2+) sensitivity of myofilaments and increased diastolic intracellular Ca(2+) subsequent to decreased SERCA-2a expression and impaired Ca(2+) reuptake. CO pollution increased the number of arrhythmic events. Hyperphosphorylation of Ca(2+)-handling and sarcomeric proteins, and reduced responses to beta-adrenergic challenge were obtained, suggestive of moderate CO-induced hyperadrenergic state. CONCLUSIONS: Chronic CO exposure promotes a pathological phenotype of cardiomyocytes in the absence of underlying cardiomyopathy. The less severe phenotype in vivo suggests a role for compensatory mechanisms. Arrhythmia propensity may derive from intracellular Ca(2+) overload.

Alteration in left ventricular strains and torsional mechanics after ultralong duration exercise in athletes.

BACKGROUND: Numerous studies have reported evidence of cardiac injury associated with transient left ventricular (LV) systolic and diastolic dysfunction after prolonged and strenuous exercise. We used 2D ultrasound speckle tracking imaging to evaluate the effect of an ultralong-duration exercise on LV regional strains and torsion. We speculated that systolic dysfunction after exercise is associated with depressed LV strains and torsion, and diastolic dysfunction results from decreased and delayed untwisting, a key factor of LV suction and early filling. METHODS AND RESULTS: Twenty-three triathletes underwent conventional and speckle tracking imaging echocardiography at rest before and immediately after an ultralong distance triathlon. Measurements included LV longitudinal, circumferential and radial strains, LV rotations, and LV torsion. After the race, LV systolic dysfunction was characterized by a decrease in LV longitudinal, radial, and circumferential strains, especially for apical radial strains (44.6+/-15.1% versus 31.1+/-13.8%, P<0.001). Peak torsion was slightly decreased (8.3+/-5.1 degrees versus 6.4+/-3.9 degrees , respectively, P=0.09) and significantly delayed (91+/-18% versus 128+/-31% of systolic duration, P<0.001) beside end-ejection. Peak untwisting was also depressed and delayed beside isovolumic relaxation. CONCLUSIONS: This study documented major alterations in cardiac strains and torsion after an ultralong distance triathlon. LV systolic strains were depressed but not delayed, whereas twisting was decreased and delayed. This altered pattern hampered the rapid untwisting during isovolumic relaxation phase, reducing LV diastolic suction and early filling.