Endurance training-induced cardiac remodeling in a guinea pig athlete's heart model.

Besides the health benefits of regular exercise, high-level training-above an optimal level-may have adverse effects. In this study, we investigated the effects of long-term vigorous training and its potentially detrimental structural-functional changes in a small animal athlete's heart model. Thirty-eight 4-month-old male guinea pigs were randomized into sedentary and exercised groups. The latter underwent a 15-week-long endurance-training program. To investigate the effects of the intense long-term exercise, in vivo (echocardiography, electrocardiography), ex vivo, and in vitro (histopathology, patch-clamp) measurements were performed. Following the training protocol, the exercised animals exhibited structural left ventricular enlargement and a significantly higher degree of myocardial fibrosis. Furthermore, resting bradycardia accompanied by elevated heart rate variability occurred, representing increased parasympathetic activity in the exercised hearts. The observed prolonged QTc intervals and increased repolarization variability parameters may raise the risk of electrical instability in exercised animals. Complex arrhythmias did not occur in either group, and there were no differences between the groups in ex vivo or cellular electrophysiological experiments. Accordingly, the high parasympathetic activity may promote impaired repolarization in conscious exercised animals. The detected structural-functional changes share similarities with the human athlete's heart; therefore, this model might be useful for investigations on cardiac remodeling.

Future scope and challenges for congestive heart failure: moving toward development of pharmacotherapy.

Heart failure is invariably associated with cardiac hypertrophy and impaired cardiac performance. Although several drugs have been developed to delay the progression of heart failure, none of the existing interventions have shown beneficial effects in reducing morbidity and mortality. To determine specific targets for future drug development, we have discussed different mechanisms involving both cardiomyocytes and nonmyocyte extracellular matrix (ECM)) alterations for the transition of cardiac hypertrophy to heart failure as well as for the progression of heart failure. We have emphasized the role of oxidative stress, inflammatory cytokines, metabolic alterations, and Ca2+-handling defects in adverse cardiac remodeling and heart dysfunction in hypertrophied myocardium. Alterations in the regulatory process due to several protein kinases, as well as the participation of mitochondrial Ca2+ overload, activation of proteases and phospholipases, and changes in gene expression for subcellular remodeling have also been described for the occurrence of cardiac dysfunction. Association of cardiac arrhythmia with heart failure has been explained as a consequence of catecholamine oxidation products. Since these multifactorial defects in ECM and cardiomyocytes are evident in the failing heart, it is a challenge for experimental cardiologists to develop appropriate combination drug therapy for improving cardiac function in heart failure.

Impact of aerobic training periodisation on global and regional right ventricular strain in coronary heart disease.

Linear aerobic training periodisation (LP) is recommended for patients with coronary heart disease (CHD). However, the effects of training periodisation on the right heart mechanics in patients with CHD have never been examined. This study aimed to explore the effects of LP and non-linear periodisation (NLP) on right heart mechanics. We prospectively randomised CHD patients to 12 weeks of aerobic training with LP or NLP. While there was a weekly increase in energy expenditure with LP, there was a steeper increase during the first 3 weeks, followed by a decrease in the fourth week with NLP. Echocardiography was performed at baseline and after the training period to assess the right ventricular free wall (RVFW) and right atrial strain. Thirty patients with CHD were included (NLP, n = 16; LP, n = 14). The traditional right and left heart parameters showed no significant time effects. There was a decrease of RVFW strain with time in both groups (+1.3 ± 0.9% with NLP, and +1.5 ± 0.8% with LP; p = 0.033). Mid-ventricular RVFW strain changed significantly with time (+2.0 ± 1.3% with NLP, and from +2.3 ± 1.2% with LP; p = 0.025). There was no time effect on the right atrial strain. In stable CHD patients, LP and NLP resulted in right ventricular strain decrements with a segment-specific pattern. This study was registered at ClinicalTrials.gov (identifier number: NCT03414996). Novelty: In stable coronary heart disease patients, both linear and non-linear aerobic training periodisation programs result in right ventricular strain decrements with time, particularly in the mid-ventricular segment. Traditional right and left heart parameters and right atrial strain showed no significant time effect in both 12 weeks aerobic training periodisation programs.

Impact of 2 different aerobic periodization training protocols on left ventricular function in patients with stable coronary artery disease: an exploratory study.

We compared the impacts of linear (LP) and nonlinear (NLP) aerobic training periodizations on left ventricular (LV) function and geometry in coronary artery disease (CAD) patients. Thirty-nine CAD patients were randomized to either a 3-month isoenergetic supervised LP or NLP. All underwent standard echocardiography with assessment of 3D LV ejection fraction (LVEF), diastolic function, strain (global longitudinal, radial, and circumferential), and strain rate at baseline and study end. Training was performed 3 times/week and included high-intensity interval and moderate-intensity continuous training sessions. Training load was progressively increased in the LP group, while it was deeply increased and intercepted with a recovery week each fourth week in the NLP group. For the 34 analyzed patients, we found similar improvements for 3D LVEF (effect size (ES): LP, 0.29; NLP, 0.77), radial strain (ES: LP, 0.58; NLP, 0.48), and radial strain rate (ES: LP, 0.87; NLP, 0.17) in both groups (time for all: p ≤ 0.01). All other parameters of cardiac function remained similar. In conclusion, NLP and LP led to similar improvements in 3D LVEF and radial strain, suggesting a favourable positive cardiac remodelling through myofibers reorganization. These findings must be investigated in patients with more severe cardiac dysfunction. The study was registered on ClinicalTrials.gov (NCT03443193). Novelty: Linear and nonlinear periodization programs improved radial strain, accompanied by improvement of ejection fraction. Both aerobic periodization programs did not negatively impact cardiac function in coronary artery disease patients.

Mechanisms for the transition from physiological to pathological cardiac hypertrophy.

The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, Ca2+-handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy.

The effect of folic acid administration on cardiac tissue matrix metalloproteinase activity and hepatorenal biomarkers in diabetic rats 1.

Diabetes mellitus (DM) is a metabolic disorder that causes severe complications. Thus, the aims of this study were to investigate the influence of DM and folic acid treatment on liver and renal biomarkers, and heart remodeling through evaluation of cardiac matrix metalloproteinase (MMP) activity. There were 4 groups: control (physiological saline 1 mL/kg, i.p., 28 days), DM (streptozotocin [STZ] 100 mg/kg in physiological saline, i.p., 1 day), folic acid (FA; 5 mg/kg, i.p., 28 days), and DM+FA (STZ 100 mg/kg, i.p., 1 day and folic acid 5 mg/kg, i.p., 28 days). Our results demonstrated increased aminotransferase and alkaline phosphatase activity, urea and creatinine concentration, and decreased albumin and fibrinogen concentration in the DM group. MMP-2 relative activity was elevated in the DM and FA groups; MMP-9 was decreased in the DM and increased in the FA group. The folic acid treatment of diabetic rats did not change aminotransferase activity; it alleviated the increase in alkaline phosphatase and the decrease in albumin and fibrinogen concentration, and reduced MMP-2 activity; however, it increased urea and creatinine concentration. In conclusion, folic acid treatment of diabetic rats has cardio- and hepato-protective effects. However, its dosing should be carefully considered because of possible renal damage.

Excessive exercise in endurance athletes: Is atrial fibrillation a possible consequence?

Moderate physical activity levels are associated with increased longevity and lower risk of atrial fibrillation (AF). However, the relative risk of lone AF is 3-5-fold higher in intensive endurance-trained athletes compared with healthy adults. There is growing concern that "excessive" endurance exercise may promote cardiac remodelling, leading to long-term adverse consequences. The pathogenesis of exercise-induced AF is thought to arise from an interplay of multiple acute and chronic factors, including atrial enlargement, pro-fibrotic tendency, high vagal tone, and genotypic profile, which collectively promote adverse atrial remodelling. Clinical management of athletes with AF, while challenging, can be achieved using various strategies that may allow continued, safe exercise. Based on the overall risk-benefit evidence, it is premature to suggest that excessive exercise is unsafe or should be curtailed. Evidence-based assessment and treatment guidelines are required to ensure optimal and safe exercise among the growing number of endurance athletes with AF.

Cardiovascular remodeling and the peripheral serotonergic system.

Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3, 5-HT1B/1D, 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5-HT2A/2B) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system.

Cardiopulmonary reflex, cardiac cytokines, and nandrolone decanoate: response to resistance training in rats.

This study evaluated the effects of nandrolone associated with resistance training (RT) on cardiac cytokines, angiotensin-converting enzyme activity (ACEA), and the sensitivity of the Bezold-Jarisch reflex (BJR). Male Wistar rats were divided into 3 groups: CONT (received vehicle, no training); EXERC (RT: after one week of water adaptation, rats were exercised by jumping into water twice a week for 4 weeks), and ND+EXERC (received nandrolone decanoate 10 mg/kg, twice/week, i.m, associated with RT). The BJR was analysed by measuring bradycardic and hypotensive responses elicited by serotonin administration. Myocyte hypertrophy and matrix collagen deposition were determined by morphometric analysis of H&E and picrosirius red-stained samples, respectively. TNF-α and ACEA were also studied. RT promoted physiological myocyte hyrpertrophy but did not cause changes in the other parameters. The association of ND with RT increased myocyte hypertrophy, deposition of matrix type I collagen, TNF-α and ACEA; decreased IL-10, and impairment in the BJR were observed in ND+EXERC compared with CONT and EXERC. ND is associated with alterations in cardiac structure and function as a result of the development of pathological cardiac hypertrophy (cardiac cytokine imbalance, elevation of ACEA) and cardiac injury, even when combined with resistance training.

[Sodium restriction prevents cardiovascular remodeling associated with insulin-resistance in the rat]. / La restriction sodée prévient le remodelage cardiovasculaire dans l'insulinorésistance chez le rat.

AIM OF THE STUDY: In the present work, the objective was to evaluate the influence of a dietary sodium restriction on cardiovascular morphology changes associated with insulin-resistance. ANIMALS AND PROTOCOL: At 8 weeks of age, rats were fed for 12 weeks a 60%-fructose diet containing a regular sodium content (0.64%) or totally lacking in sodium chloride (<0.01%). A group of rats fed a wheat starch-based diet with regular sodium content served as control group. RESULTS: Elevated HOMA index and plasma insulin confirm the presence of insulin-resistance in fructose-fed rats. Concomitantly, an increase in cardiac mass and in cardiac collagen (Sirius red staining) was detected without obvious change in arterial pressure or cardiac aldosterone synthase mRNA expression. In addition, cross-sectional area of the carotid artery was higher in fructose-fed rats. Production of superoxide anion, equated with dihydroethidium (DHE) staining, was enhanced in cardiac tissue of rats with insulin-resistance. Withdrawal of sodium from the fructose diet prevented all the cardiovascular effects of fructose consumption, including DHE staining. CONCLUSION: These results are in favor of the participation of oxidative stress normalization in the beneficial influence of dietary sodium deprivation on cardiovascular remodeling in this model of insulin-resistance in rats.