Prior resistance training exerts cardioprotection against cardiac remodelling after myocardial infarction

Background Skeletal muscle changes contribute to reduced physical performance after myocardial infarction (MI). Exercise has been recommended to stable patients. However, the effects of resistance exercise after MI are not clear. We compared the effects of aerobic and resistance exercise initiated during compensated cardiac remodeling in infarcted rat gastrocnemius muscle. Methods Three months after MI induction, Wistar rats were divided into four groups: Sham (n=20); sedentary MI (MI-S, n=9); aerobic exercised MI (MI-A, n=9); and resistance exercised MI (MI-R, n=13). Exercised rats trained three times a week for 12 weeks on a treadmill or ladder. Energy metabolism, oxidative stress markers, and antioxidant enzyme activities were assessed by spectrophotometry. Satellite cells activation markers (MyoD, NCAM, and myosin heavy chain neonatal isoform) were assessed by immunofluorescence or Western blot (Pax-7). Statistical analysis: ANOVA or Mann Whitney. Results Physical aerobic capacity was greater in MI-A and strength gain higher in MI-R. Cardiac structures and left ventricular function evaluated by echocardiogram did not differ between infarcted groups. Histological analysis showed that MI size and gastrocnemius cross sectional area did not differ between infarcted groups. Oxygen reactive species production was higher in MI-S than Sham and lipid hydroperoxide concentration was lower in MI-A than the other groups. Catalase activity was higher and glutathione peroxidase lower in infarcted groups than Sham. Superoxide dismutase activity was higher in Sham and MI-R than MI-S. Skeletal muscle metabolism enzyme activity did not differ between groups, except for increase pyruvate kinase in MI-S against the other groups, and β-hydroxyacyl CoA dehydrogenase in MI-S against Sham. Satellite cell activation and protein expression of MAPK and NF-kB did not differ between groups. Conclusion Aerobic and resistance exercise respectively improves physical capacity and muscle strength without changing echocardiographic parameters of infarcted rats. Myocardial infarction increases oxygen reactive species production and changes antioxidant enzyme activity and glucose and fatty acid metabolism. Aerobic exercise is superior to resistance exercise against oxidative stress reducing muscle lipid hydroperoxide concentration and attenuating change in glutathione peroxidase activity. Acknowledgement/Funding Financial support: Fapesp, CNPq, Capes, and UNESP

Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis. Article p 2127 These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9 Understanding the components of remodeling …

Background Physical exercise has been highlighted as an important non-pharmacological therapy for prevention and treatment of several cardiovascular diseases. However, its effects on hearts with minor cardiac remodeling are not clear. Purpose To evaluate the influence of aerobic physical exercise on functional capacity, cardiac structure, left ventricular (LV) function, and gene expression of NADPH oxidase subunits in rats with small-sized myocardial infarction (MI). Methods Three months after MI induction, Wistar rats were divided into three groups: Sham; sedentary MI (MI-SED); and aerobic exercised MI (MI-EA). Rats exercised three times a week for 12 weeks on a treadmill. Echocardiogram was performed before and after experimental period. Infarction size and cardiomyocyte diameters were evaluated by histology. Gene expression was assessed by RT-PCR. Results Only rats with MI size lower than 30% of LV total area were included in the study. Functional capacity was higher in MI-AE than the other groups. Infarction size did not differ between groups. Infarcted rats had increased LV diastolic and systolic diameter, left atrial diameter, and LV mass, with systolic dysfunction. LV diastolic posterior wall thickness was higher in MI-AE than Sham, and relative wall thickness was lower in MI-SED than MI-AE and Sham groups. Cardiomyocyte diameter was smaller in infarcted groups than Sham. Myocardial gene expression of the NADPH oxidase subunits NOX2, NOX4, p22phox, and p47phox did not differ between groups. Conclusion Small-sized myocardial infarction changes cardiac structures and left ventricular systolic function. Late aerobic physical exercise improves functional capacity and cardiac remodeling by preserving left ventricular geometry. NADPH oxidase subunits gene expression is not involved in cardiac remodeling or modulated by aerobic exercise in rats with small myocardial infarction. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): CNPq; CAPES

The changing anatomic reference base of evolving myocardial infarction. Underestimation of myocardial collateral blood flow and overestimation of experimental anatomic infarct size due to tissue edema, hemorrhage and acute inflammation.

Although current guidelines recommend resistance exercise in combination with aerobic training to increase muscle strength and prevent skeletal muscle loss during cardiac remodeling, its effects are not clear. In this study, we evaluated the effects of resistance training on cardiac remodeling and the soleus muscle in long-term myocardial infarction (MI) rats. Methods: Three months after MI induction, male Wistar rats were assigned to Sham (n = 14), MI (n = 9), and resistance exercised MI (R-MI, n = 13) groups. The rats trained three times a week for 12 weeks on a climbing ladder. An echocardiogram was performed before and after training. Protein expression of the insulin-like growth factor (IGF)-1/protein kinase B (Akt)/rapamycin target complex (mTOR) pathway was analyzed by Western blot. Results: Mortality rate was higher in MI than Sham; in the R-MI group, mortality rate was between that in MI and Sham and did not differ significantly from either group. Exercise increased maximal load capacity without changing cardiac structure and left ventricular function in infarcted rats. Infarction size did not differ between infarcted groups. Catalase activity was lower in MI than Sham and glutathione peroxidase lower in MI than Sham and R-MI. Protein expression of p70S6K was lower in MI than Sham and p-FoxO3 was lower in MI than Sham and R-MI. Energy metabolism did not differ between groups, except for higher phosphofrutokinase activity in R-MI than MI. Conclusion: Resistance exercise is safe and increases muscle strength regardless structural and functional cardiac changes in myocardial-infarcted rats. This exercise modality attenuates soleus glycolytic metabolism changes and improves the expression of proteins required for protein turnover and antioxidant response.

We compared the influence of aerobic and resistance exercise on cardiac remodelling, physical capacity and skeletal muscle oxidative stress in rats with MI‐induced heart failure. Three months after MI induction, Wistar rats were divided into four groups: Sham; sedentary MI (S‐MI); aerobic exercised MI (A‐MI); and resistance exercised MI (R‐MI). Exercised rats trained three times a week for 12 weeks on a treadmill or ladder. Statistical analysis was performed by ANOVA or Kruskal‐Wallis test. Functional aerobic capacity was greater in A‐MI and strength gain higher in R‐MI. Echocardiographic parameters did not differ between infarct groups. Reactive oxygen species production, evaluated by fluorescence, was higher in S‐MI than Sham, and lipid hydroperoxide concentration was lower in A‐MI than the other groups. Glutathione peroxidase activity was higher in A‐MI than S‐MI and R‐MI. Superoxide dismutase was lower in S‐MI than Sham and R‐MI. Gastrocnemius cross‐sectional area, satellite cell activation and expression of the ubiquitin‐proteasome system proteins did not differ between groups. In conclusion, aerobic exercise and resistance exercise improve functional capacity and maximum load carrying, respectively, without changing cardiac remodelling in infarcted rats. In the gastrocnemius, infarction increases oxidative stress and changes antioxidant enzyme activities. Aerobic exercise reduces oxidative stress and attenuates superoxide dismutase and glutathione peroxidase changes.

Introduction Exercise is an important therapeutic strategy for heart failure (HF). However, the myocardial effects of resistance exercise during HF are not completely understood. In this study, we investigated the influence of resistance exercise on cardiac remodeling and molecular myocardial changes of rats with myocardial infarction (MI)-induced HF. Methods Three months after MI induction or simulated surgery, Wistar rats were divided into three groups: Sham (n=14); MI (n=9); and MI subjected to resistance exercise (MI-R, n=13). Exercised rats trained 3 times a week during 12 weeks performing four climbs in a ladder with progressive loads. Cardiac structure and left ventricular function were assessed by echocardiogram. Myocyte diameters were measured in histological sections. Energy metabolism, lipid hydroperoxide, antioxidant enzymes activity, malondialdehyde, and protein carbonylation were evaluated by spectrophotometry. NADPH oxidase subunits (Nox2, Nox4, p22phox and p47phox) gene expression was assessed by RT-PCR. Statistical analysis: ANOVA and Tukey test or Dunn's test. Results Mortality did not differ between MI-R and MI groups. MI-R and MI presented dilated left atrium and left ventricle with systolic and diastolic dysfunction. Exercise improved maximum carrying load with no changes in cardiac structure or left ventricle function. Myocyte diameter was lower in MI than Sham and MI-R. Lactate dehydrogenase and creatine kinase activities were lower in MI than Sham. Activity of citrate synthase and catalase was lower in MI and MI-R than Sham. Lipid hydroperoxide concentration was lower in MI-R than MI. Nox2 and p22phox gene expression was higher in MI-R than Sham. Gene expression of Nox4 was higher in both infarcted groups and gene expression of p47phox was lower in MI than Sham. Conclusion Resistance exercise is safe and well tolerated by infarcted rats. Exercise increases maximum carrying load and reduces myocardial oxidative stress with no changes in cardiac structure or left ventricle function of infarcted rats. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): CNPq - National Council for Scientific and Technological Development

This study aims to explore the role and the mechanism of Parkin protein in cardiac function and ventricular remodeling in myocardial infarction (MI) rats, and to provide a new sight for the treatment of myocardial infarction. Fifty Sprague- Dawley (SD) male rats were randomly divided into 5 groups: sham operation group (Sham group), model group (MI group), low-dose Parkin group (L-Parkin group), middle-dose Parkin group (M-Parkin group) and high-dose Parkin group (H-Parkin group). The rat model of myocardial infarction was established by ligation of the anterior descending branch. Small animal ultrasound was used to measure cardiac function. The myocardial infarct size was observed by triphenyltetrazolium chloride (TTC) staining. The pathological changes of myocardial tissues were observed by hematoxylin-eosin (HE) staining. The myocardial cell apoptosis was detected by TUNEL assay. The mRNA expression of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), tissue inhibitor of matrix metalloproteinase 1 (TIMP1), tissue inhibitor of matrix metalloproteinase 2 (TIMP2) were detected by qRT-PCR. The expression of Parkin protein in myocardial tissue of rats was detected by Western-blot. Compared with MI group, left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) in Parkin overexpressing group were significantly decreased (p<0.05), while the value of left ventricular short axis shortening (FS) and left ventricular ejection fraction (EF %) in Parkin overexpression group were significantly increased (p<0.05). Overexpression of Parkin improved abnormal structure of myocardial tissue, reduced the size of myocardial infarct, made the arrangement of myocardium fibers more neatly and made the stain of myocardial cells more uniformly. Apoptosis index (AI) values were significantly decreased (p<0.05), and MMP2, MMP9, TIMP1 and TIMP2 mRNA levels were significantly decreased (p<0.05), while Parkin protein expression was significantly elevated in a dose-dependent manner (p<0.05). After treatment with Parkin in myocardial infarction rats, the relevant mRNA levels decreased, the number of apoptotic cells decreased, the myocardial fiber morphology returned to normal, the myocardial infarct size decreased, and the cardiac function of rats improved. Therefore, Parkin therapy plays an active role in cardiac function and ventricular remodeling in myocardial infarction rats.

Introduction: Exercise is an important therapeutic strategy for preventing and treating myocardial infarction (MI)-induced cardiac remodeling and heart failure. However, the myocardial effects of resistance exercise on infarcted hearts are not completely established. In this study, we investigated the effects of resistance exercise on structural, functional, and molecular cardiac alterations in infarcted rats. Methods: Three months after MI induction or simulated surgery, Wistar rats were assigned into three groups: Sham (n = 14); MI (n = 9); and exercised MI (MI-Ex, n = 13). Exercised rats performed, 3 times a week for 12 weeks, four climbs on a ladder with progressive loads. Cardiac structure and left ventricle (LV) function were analyzed by echocardiogram. Myocyte diameters were evaluated in hematoxylin- and eosin-stained histological sections as the smallest distance between borders drawn across the nucleus. Myocardial energy metabolism, lipid hydroperoxide, malondialdehyde, protein carbonylation, and antioxidant enzyme activities were evaluated by spectrophotometry. Gene expressions of NADPH oxidase subunits were evaluated by RT-PCR. Statistical analyses were performed using ANOVA and Tukey or Kruskal–Wallis and Dunn’s test. Results: Mortality did not differ between the MI-Ex and MI groups. MI had dilated left atrium and LV, with LV systolic dysfunction. Exercise increased the maximum load-carrying capacity, with no changes in cardiac structure or LV function. Myocyte diameters were lower in MI than in Sham and MI-Ex. Lactate dehydrogenase and creatine kinase activity were lower in MI than in Sham. Citrate synthase and catalase activity were lower in MI and MI-Ex than in Sham. Lipid hydroperoxide concentration was lower in MI-Ex than in MI. Nox2 and p22phox gene expressions were higher in MI-Ex than in Sham. Gene expression of Nox4 was higher in MI and MI-Ex than in Sham, and p47phox was lower in MI than in Sham. Conclusion: Late resistance exercise was safe in infarcted rats. Resistance exercise improved maximum load-carrying capacity, reduced myocardial oxidative stress, and preserved myocardial metabolism, with no changes in cardiac structure or left ventricle function in infarcted rats.

Introduction Resistance exercise (RE) provides several benefits for healthy individuals. However, its effects during heart failure are unclear. The aim of this study was to evaluate the effects of RE on functional capacity, cardiac remodeling, and soleus muscle molecular and biochemical features in rats with myocardial infarction (MI). Methods Three months after MI or simulated surgery (Sham), Wistar rats were divided into three groups: Sham (n=14), MI (n=13), and MI subjected to RE (RE-MI, n=14). Exercised rats trained 3 times a week performing four climbs with progressive loads on a ladder over 12 weeks. Functional capacity was assessed by maximum carrying capacity test in the ladder and exercise tolerance test in treadmill. Echocardiogram was performed at the end of the study. Energy metabolism and antioxidant enzyme activities were assessed by spectrophotometry in the soleus muscle. Oxidative stress markers were analyzed in soleus muscle (lipid hydroperoxide) or serum (malondialdehyde and protein carbonylation). Protein expression of insulin type-1 growth factor-like pathway, protein kinase B, and rapamycin target complex was analyzed by Western-blot. Statistical analysis: ANOVA and Bonferroni or Dunn, Student's t and Goodman tests; p&amp;lt;0.05. Results Mortality was higher in MI than Sham. Infarction size did not differ between groups. Resistance exercise increased maximum load carrying capacity, without changing functional capacity or cardiac remodeling. Catalase activity was lower in MI than Sham and glutathione peroxidase activity was lower in MI than Sham and RE-MI. Protein carbonylation was higher in RE-MI than MI. Energy metabolism did not differ between groups, except for lower phosphofructokinase activity in RE-MI than MI. Expression of p70s6K, p-FoxO3a, and p-FoxO3a-to-FoxO3a ratio was lower, and p-p70s6K-to-p70s6K ratio was higher in MI than Sham. Conclusion The practice of resistance exercise is safe, attenuates mortality, and improves maximum load carrying capacity regardless of changes in cardiac remodeling in infarcted rats. In soleus muscle, resistance exercise preserves phosphofructokinase and antioxidant enzyme activity and expression of the proteins involved in muscle trophism. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): CNPq UNESP

In ST-segment–elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI), the myocardial salvage index (MSI) provides a more sensitive measure for assessing the efficacy of novel cardioprotective therapies, than an absolute reduction in myocardial infarct (MI) size. Knowledge of the MI size and the size of the area at risk (AAR) are prerequisites for measuring the MSI, and both may be obtained by cardiovascular magnetic resonance (CMR) in reperfused STEMI patients, with the MSI shown to predict clinical outcomes after PPCI.1 CMR is considered the gold standard imaging modality for quantifying MI size, and it can also delineate the edema-based AAR, with T2- and T1-mapping CMR emerging as the most robust techniques,2 although no consensus has yet been reached. See Article by Garg et al In this issue of Circulation: Cardiovascular Imaging , Garg et al3 report on a potentially novel approach for quantifying the AAR, chronic MI size, and MSI in a study of 50 STEMI patients reperfused by PPCI, based on extracellular volume fraction (ECV) maps from an acute CMR scan. The study derived specific ECV cutoff values on an acute CMR scan (performed at a median of 48 hours post-PPCI) in a subset of 10 patients, to delineate the AAR (when compared with T2-STIR imaging), and chronic MI size (when compared with late gadolinium enhancement [LGE]) on a follow-up scan performed at 3 months post-PPCI). Using acute ECV cutoff values of >33% to delineate the AAR and >46% to delineate chronic MI size, they concluded that acute ECV maps could be used to reliably quantify AAR, chronic MI size, and MSI. Being able to accurately quantify MI size using a …

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Background Patients with anterior MI experience worse LV remodeling and dysfunction than non-anterior MI patients. It remains unclear whether this difference is due to larger MI size or whether infarct location plays a role beyond MI size. Study aim To assess the relationship between myocardial infarction (MI) location and size and their reciprocal influences on post-infarction left ventricular (LV) remodeling. Methods A cohort of 260 reperfused ST-segment elevation MI patients was studied with cardiovascular magnetic resonance (CMR) at 1-week (baseline) and 4-month (followup). Area at risk (AAR) and MI size were quantified by T2-weighted and late gadolinium enhancement imaging, respectively. Adverse LV remodeling was defined as increase in LV end-systolic volume ≥15% at follow-up. Results One-hundred twenty-seven(49%) patients had anterior MI and 133(51%) patients had non-anterior MI. Although the degree of myocardial salvage was similar between groups (p=0.74), anterior MI patients had larger AAR and MI size than non-anterior MI patients yielding worse regional and global LV function at baseline and follow-up. At univariable analysis, anterior MI was associated with increased risk of adverse LV remodeling (p=0.017) and lower LV ejection-fraction at follow-up (p=0.001), but not when accounted for baseline MI size. Accordingly, at multivariable analysis baseline MI size but not its location was an independent predictor of adverse LV remodeling (OR=1.061, p<0.001) and ejection-fraction at follow-up (Beta-coefficient=-0.255, p<0.001).

We investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

Summary : Lifelong exercise training maintains a youthful compliance of the left ventricle (LV), whereas a year of exercise training started later in life fails to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products. Alagebrium is a novel drug that breaks advanced glycation end product crosslinks and improves LV stiffness in aged animals. In this study, the authors prescribed alagebrium (200 mg daily) or placebo combined with aerobic exercise training or contact control in healthy, sedentary older individuals for 1 year. The authors evaluated overall cardiac function by the use of several modalities, including invasive pressure–volume measurements, exercise testing, and cardiac MRI before and after the training. To the authors’ knowledge, this is the first study to evaluate the effects of alagebrium and exercise training in healthy aged humans. After intervention, exercise training significantly increased exercise capacity, LV mass, and LV end-diastolic volume. Conversely, alagebrium had little effect on exercise capacity or LV geometry. However, alagebrium showed a modest improvement in LV stiffness compared with placebo. This favorable effect of alagebrium on LV stiffness was most prominent in individuals with combined alagebrium and exercise training. Conclusions : Alagebrium had no effect on hemodynamics, LV geometry, or exercise capacity in healthy, previously sedentary seniors. However, it did show a modestly favorable effect on age-associated LV stiffening.1 Summary : Maximum oxygen consumption (peak VO2) and efficiency of ventilation (VE) during exercise (VE/VCO2 slope) are known to stratify adults in heart failure for 1-year survival. On the basis of adult data, a recent American Heart Association scientific statement suggested that peak VO2<50% predicted for age and sex should be considered substantial impairment in exercise performance in children with heart disease and therefore a class I indication for heart transplant listing. This single-center study examined the association of …