Posterior Wall Shortening Velocity Research Articles

Exercise Rehabilitation Preserves Cardiorespiratory Muscle Function Following Doxorubicin Treatment

Doxorubicin (DOX) is a highly effective chemotherapeutic agent. Unfortunately, cancer patients who have completed DOX treatment often experience exercise intolerance, reduced cardiac function, dyspnea and unfavorable changes to body composition, ultimately, leading to increased incidence of heart failure. Exercise has been shown to reduce the risk of developing chemotherapy-induced cardiorespiratory dysfunction; however, the ability of cancer patients to exercise during treatment can be limited by cancer type, stage and fatigue. Therefore, these experiments utilized a chronic DOX-induced cardiotoxicity model to determine the effects of rehabilitative exercise on cardiorespiratory muscle function. Female Sprague-Dawley rats were treated with DOX once every three weeks for four total cycles via intravenous infusion (i.e., cumulative dose of ~160mg/m2). One-week following the completion of DOX treatment, rats remained sedentary (Sed-DOX) or were prescribed 10-weeks of moderate intensity treadmill running at 30m/min, 0% grade, 1-hour/day, and 3x/week (Mod-DOX). Body composition, exercise tolerance and echocardiography were assessed at three timepoints: 1) pre-treatment; 2) post-treatment and; 3) post-rehabilitation. Diaphragm muscle specific force production was measured post-rehabilitation. From pre- to post-treatment each group gained weight and no differences existed between groups. However, from post-treatment to post-rehabilitation body weight of the DOX-treated groups did not change and was significantly reduced compared to sedentary saline-treated (Sed-Sal) rats from week 15 onwards. Although mean body weight did not differ between the DOX-treated groups, lean mass increased in Mod-DOX rats between each timepoint with no change in fat mass, while fat mass increased in Sed-DOX rats and an initial increase in lean mass was attenuated from post-treatment to post-rehabilitation. Exercise time to fatigue did not change between timepoints within each group; however, exercise run time from post-treatment to post-rehabilitation was significantly longer in Mod-DOX rats compared to Sed-DOX and Sed-Sal. Cardiac fractional shortening percentage (FS%) was reduced in Sed-DOX rats at post-treatment and post-rehabilitation compared to pre-treatment. Additionally, posterior wall shortening velocity (PWSV) was reduced in Sed-DOX rats at post-treatment compared to pre-treatment. No differences in FS% or PWSV were seen between any timepoint in the Mod-DOX group. Finally, ex vivo diaphragm muscle function showed significant diaphragm muscle weakness in Sed-DOX rats at 15-60Hz stimulations compared to Sed-Sal. Diaphragm force production did not differ in Mod-DOX rats compared to Sed-Sal at any stimulation frequency. These results demonstrate a beneficial effect of moderate intensity rehabilitation exercise for the maintenance of body composition, cardiac function and diaphragm muscle function following DOX treatment compared to sedentary rats. NIH R01 HL144858, NIH R01 HL146443, NIH HL134621. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exercise Preconditioning Alters Markers of Cellular Senescence and Prevents DOX‐Induced Cardiorespiratory Dysfunction

Doxorubicin (DOX) is a highly effective chemotherapeutic agent; however its clinical use is limited due to cardiorespiratory complications, including the development of dyspnea, exercise intolerance, and cardiomyopathy. While the mechanisms responsible for DOX‐induced cardiorespiratory dysfunction remain unclear, evidence indicates that DOX administration causes DNA damage and promotes oxidative stress‐induced cellular senescence. Factors shown to contribute to DOX‐induced cellular senescence include cell cycle arrest, driven by signaling through the p16INK4a/Rb and p21/p53 pathways, impaired mitochondrial function, upregulation of pro‐survival pathways, increased lysosomal mass, and expression of the proinflammatory senescence‐associated secretory phenotype (SASP). In contrast, exercise has been shown to prevent cellular senescence in several tissues, leading to the hypothesis that endurance exercise preconditioning is sufficient to prevent senescence induced in the heart and diaphragm muscle following DOX chemotherapy treatment. To determine the relationship between DOX‐induced cardiorespiratory impairment, exercise preconditioning and the impact of accelerated cellular senescence, female Sprague‐Dawley rats underwent two weeks of endurance exercise training (treadmill running, 5 days/week, 60 min/day, 30m/min, 0% grade) before receiving a bolus dose of DOX (20mg/kg IP) or saline treatment. Functional measures were evaluated 48 hours after DOX or saline administration, followed by tissue collection for subsequent analysis of cellular senescence markers. Our results revealed that exercise preconditioning prior to DOX administration prevented diastolic and systolic dysfunction in the heart, with marked improvements in fractional shortening, myocardial performance index, and posterior wall shortening velocity compared to sedentary DOX‐treated animals. DOX‐induced weight loss, reduction in grip strength, and diaphragm weakness were partially rescued with exercise as well, with diaphragm specific force production preserved at frequencies of 60‐160Hz. Finally, both exercise and DOX appear to alter expression of proteins associated with the senescent phenotype in the heart and diaphragm. Therefore, the protective effects of exercise against DOX cardiorespiratory dysfunction may be related to changes in muscle cellular senescence.

Dexamethasone and Training-Induced Cardiac Remodeling Improve Cardiac Function and Arterial Pressure in Spontaneously Hypertensive Rats

Dexamethasone (DEX)-induced hypertension and cardiac remodeling are still unclear, especially in spontaneously hypertensive rats (SHR). On the other side, exercise training is a good strategy to control hypertension. Therefore, this study investigated the effects of DEX treatment and physical training on arterial pressure and cardiac remodeling in SHR. SHR underwent treadmill training (5 days/week, 1h/session, at 50-60% of maximal capacity, 0% degree, 75 days) and received low-dose of DEX (50µg/kg, s.c.) during the last 15 days. Sedentary Wistar rats (W) were used as control. Echocardiography and artery catheterization were performed for cardiac remodeling and function, arterial pressure and autonomic nervous system analyses. In addition, left ventricle (LV) capillary density, myocyte diameter and collagen deposition area were analyzed using specific histological staining. Low-dose of DEX treatment did not exacerbate arterial pressure of SHR and trained groups had lower values, regardless of DEX. DEX and training decreased relative left ventricle wall thickness (RWT) and determined LV angiogenesis (+19%) and lower collagen deposition area (-22%). In addition, it determined increased left ventricular diastolic diameter. These changes were followed by improvements on systolic and diastolic function, since it was observed increased posterior wall shortening velocity (PWSV) and reduced isovolumetric relaxation time (IVRT). In conclusion, this study is unique to indicate that low-dose of DEX treatment does not exacerbate arterial pressure in SHR and, when associated with training, it improves LV systolic and diastolic function, which may be due to LV angiogenesis and reduction of wall collagen deposition area.

AT1Receptor Blockade Improves Myocardial Functional Performance in Obesity.

ResumoFundamento A obesidade tem sido associada com ativação crônica do sistema renina-angiotensina-aldosterona e importantes alterações no desempenho cardíaco.Objetivo Avaliar a influência do bloqueio de receptores de angiotensina-II do tipo 1 (AT1) sobre a morfologia e desempenho cardíaco de ratos obesos por dietaMétodos Ratos Wistar (n=48) foram submetidos a dieta controle (2,9 kcal/g) ou hiperlipídica (3,6 kcal/g) durante 20 semanas. Após a 16ª semana, foram distribuídos em quatro grupos: Controle (CO), Obeso (OB), Controle Losartan (CL) e Obeso Losartan (OL). CL e OL receberam losartan (30 mg/kg/dia) na água durante quatro semanas. Posteriormente, foram analisadas composição corporal, pressão arterial sistólica (PAS) e ecocardiograma. A função de músculos papilares foi avaliada em situação basal com concentração de cálcio ([Ca2+]o) de 2,50 mM e após manobras inotrópicas: potencial pós-pausa (PPP), elevação da [Ca2+]o e durante estimulação beta-adrenérgica com isoproterenol. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de comparações apropriado. O nível de significância considerado foi de 5%.Resultados Embora a alteração da PAS não tenha se mantido ao final do experimento, a obesidade se associou com hipertrofia cardíaca e maior velocidade de encurtamento da parede posterior do ventrículo esquerdo.No estudo de músculos papilares em condição basal, CL mostrou menor velocidade máxima de variação negativa da tensão desenvolvida (-dT/dt) do que CO. O PPP de 60s promoveu menor -dT/dt e pico de tensão desenvolvida (TD) em OB e CL, comparados ao CO, e maior variação relativa de TD e velocidade máxima de variação positiva (+dT/dt) no OL em relação a CL e OB. Sob 1,5, 2,0 e 2,5mM de [Ca2+]o, o grupo OL exibiu maior -dT/dt do que CL.Conclusão Losartan melhora a função miocárdica de ratos com obesidade induzida por dieta. (Arq Bras Cardiol. 2020; 115(1):17-28)

Administration of Losartan Improves Myocardial Functional Performance in Rats with High‐Fat Diet‐Induced Obesity

Extensive evidence has shown that high‐fat diet is associated with chronic activation of the renin‐angiotensin system (RAS) and left ventricular remodeling. This study was developed to evaluate the impact of angiotensin‐1 (AT1) receptor antagonism on myocardial function in rats with high‐fat diet‐induced obesity.MethodsMale Wistar rats (n=48) were fed a control (2.9 kcal/g, C) or high‐fat (3.6 kcal/g, O) diet for 20 weeks. After the 16th week, the rats were assigned into four groups: C, O, CL, and OL. CL and OL groups received Losartan (30 mg/kg/day) in drinking water during four weeks. At the end of the experiment, body composition and systolic blood pressure were assessed, and echocardiogram analysis was performed. Mechanical performance of papillary muscles was evaluated under basal condition with 2.5 mM calcium ([Ca+2])o and after inotropic stimulation: post‐rest contraction (PRC) and change in extracellular [Ca+2]o from 1.0 to 2.5 mM.ResultsBoth O and OL groups presented higher body weight and adiposity than their respective controls (p<0.05). Systolic blood pressure did not differ among groups. O and OL groups had greater left ventricular weight‐to‐tibia length ratio and posterior wall shortening velocity (C 42.92±4.45; O 48.72±4.81; CL 42.82±3.60; OL 47.96±4.03 mm/s). In papillary muscles evaluation, CL presented reduced negative tension derivative (‐dT/dt) in comparison to the C group at basal condition. After 60 seconds of PRC, both O and CL had lower relative variations in ‐dT/dt (C 55.9±20.9; O 47.1±13.3; CL 47.7±15.9; OL 51.1±14.5%) and peak developed tension than C. Also, OL had higher relative variation in DT than CL and O (C 65.7±23.6; O 56.3±13.9; CL 58.0±17.4; OL 66.4±17.4%), while variation of positive tension derivative (+dT/dt) was increased in OL compared to CL and O groups. After increasing [Ca2+]o to 2.0 and 2.5 mM, the relative variation in DT and +dT/dt were higher in OL than CL and O, respectively. OL showed increased ‐dT/dt in comparison to CL at extracellular calcium concentrations of 1.5, 2.0, and 2.5 mM.ConclusionAngiotensin II antagonism with losartan improves myocardial functional performance in rats with high‐fat diet induced‐obesity.Support or Funding InformationFinancial support: CAPES; CNPq; FUNDECT/MS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiac function and intracellular Ca2+ handling proteins are not impaired by high-saturated-fat diet-induced obesity.

Obesity is often associated with changes in cardiac function; however, the mechanisms responsible for functional abnormalities have not yet been fully clarified. Considering the lack of information regarding high-saturated-fat diet-induced obesity, heart function, and the proteins involved in myocardial calcium (Ca2+) handling, the aim of this study was to test the hypothesis that this dietary model of obesity leads to cardiac dysfunction resulting from alterations in the regulatory proteins of intracellular Ca2+ homeostasis. Male Wistar rats were distributed into two groups: control (C, n=18; standard diet) and obese (Ob, n=19; high-saturated-fat diet), which were fed for 33 weeks. Cardiac structure and function were evaluated using echocardiographic and isolated papillary muscle analyses. Myocardial protein expressions of sarcoplasmic reticulum Ca2+-ATPase, phospholamban (PLB), PLB serine-16 phosphorylation, PLB threonine-17 phosphorylation, ryanodine receptor, calsequestrin, Na+/Ca2+ exchanger, and L-type Ca2+ channel were assessed by western blot. Obese rats presented 104% increase in the adiposity index (C: 4.5±1.4 vs Ob: 9.2±1.5%) and obesity-related comorbidities compared to control rats. The left atrium diameter (C: 5.0±0.4 vs Ob: 5.5±0.5 mm) and posterior wall shortening velocity (C: 36.7±3.4 vs Ob: 41.8±3.8 mm/s) were higher in the obese group than in the control. The papillary muscle function was similar between the groups at baseline and after inotropic and lusitropic maneuvers. Obesity did not lead to changes in myocardial Ca2+ handling proteins expression. In conclusion, the hypothesis was not confirmed, since the high-saturated-fat diet-induced obese rats did not present cardiac dysfunction or impaired intracellular Ca2+ handling proteins.

Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial β-adrenergic system and does not compromise cardiac function.

Obesity is a worldwide pandemic associated with high incidence of cardiovascular disease. The mechanisms by which the obesity leads cardiac dysfunction are not fully elucidated and few studies have evaluated the relationship between obesity and proteins involved in myocardial β‐adrenergic (βA) system. The purpose of this study was to evaluate the cardiac function and βA pathway components in myocardium of obese rats. Male Wistar rats were distributed into two groups: control (n = 17; standard diet) and obese (n = 17; saturated high‐fat diet) fed for 33 weeks. Nutritional profile and comorbidities were assessed. Cardiac structure and function was evaluated by macroscopic postmortem, echocardiographic and isolated papillary muscle analyzes. Myocardial protein expression of β 1‐ and β 2‐adrenergic receptors, Gαs protein, adenylate cyclase (AC) and protein kinase A (PKA) was performed by Western blot. Cardiac cyclic adenosine monophosphate (cAMP) levels and PKA activity were assessed by ELISA. Obese rats showed increased adiposity index (P < 0.001) and several comorbidities as hypertension, glucose intolerance, insulin resistance, and dyslipidemia compared with control rats. Echocardiographic assessment revealed increased left atrium diameter (C: 4.98 ± 0.38 vs. Ob: 5.47 ± 0.53, P = 0.024) and posterior wall shortening velocity (C: 37.1 ± 3.6 vs. Ob: 41.8 ± 3.8, P = 0.007) in obese group. Papillary muscle evaluation indicated that baseline data and myocardial responsiveness to isoproterenol stimulation were similar between the groups. Protein expression of myocardial AC was higher in obese group than in the control (C: 1.00 ± 0.21 vs. Ob: 1.25 ± 0.10, P = 0.025), whereas the other components were unchanged. These results suggest that saturated high‐fat diet‐induced obesity was not effective in triggering cardiac dysfunction and impair the beta‐adrenergic signaling.

Effects of early aldosterone antagonism on cardiac remodeling in rats with aortic stenosis-induced pressure overload

Aldosterone plays a pivotal role in the pathophysiology of systolic heart failure. However, whether early aldosterone antagonism improves cardiac remodeling during persistent pressure overload is unsettled. We evaluated the effects of aldosterone antagonist spironolactone on cardiac remodeling in rats with ascending aortic stenosis (AS). MethodsThree days after inducing AS, weaning rats were randomized to receive spironolactone (AS-SPR, 20mg/kg/day) or no drug (AS) for 18weeks, and compared with sham-operated rats. Myocardial function was studied in isolated left ventricular (LV) papillary muscles. Statistical analyses: ANOVA or Kruskal–Wallis tests. ResultsEchocardiogram showed that LV diastolic (Sham 8.73±0.57; AS 8.30±1.10; AS-SPR 9.19±1.15mm) and systolic (Sham 4.57±0.67; AS 3.61±1.49; AS-SPR 4.62±1.48mm) diameters, left atrial diameter (Sham 5.80±0.44; AS 7.15±1.22; AS-SPR 8.02±1.17mm), and LV mass were higher in AS-SPR than AS. Posterior wall shortening velocity (Sham 38.5±3.8; AS 35.6±5.6; AS-SPR 31.1±3.8mm/s) was lower in AS-SPR than Sham and AS; E/A ratio was higher in AS-SPR than Sham. Developed tension was lower in AS and AS-SPR than Sham. Time to peak tension was higher in AS-SPR than Sham and AS after post-rest contraction. Right ventricle weight was higher in AS-SPR than AS, suggesting more severe heart failure in AS-SPR than AS. Interstitial collagen fractional area and myocardial hydroxyproline concentration were higher in AS than Sham. Metalloproteinase-2 and -9 activity, evaluated by zymography, did not differ between groups. ConclusionEarly spironolactone administration causes further hypertrophy in cardiac chambers, and left ventricular dilation and dysfunction in rats with AS-induced chronic pressure overload.

Association between Functional Variables and Heart Failure after Myocardial Infarction in Rats.

BackgroundHeart failure prediction after acute myocardial infarction may have important clinical implications.ObjectiveTo analyze the functional echocardiographic variables associated with heart failure in an infarction model in rats.MethodsThe animals were divided into two groups: control and infarction. Subsequently, the infarcted animals were divided into groups: with and without heart failure. The predictive values were assessed by logistic regression. The cutoff values predictive of heart failure were determined using ROC curves.ResultsSix months after surgery, 88 infarcted animals and 43 control animals were included in the study. Myocardial infarction increased left cavity diameters and the mass and wall thickness of the left ventricle. Additionally, myocardial infarction resulted in systolic and diastolic dysfunction, characterized by lower area variation fraction values, posterior wall shortening velocity, E-wave deceleration time, associated with higher values of E / A ratio and isovolumic relaxation time adjusted by heart rate. Among the infarcted animals, 54 (61%) developed heart failure. Rats with heart failure have higher left cavity mass index and diameter, associated with worsening of functional variables. The area variation fraction, the E/A ratio, E-wave deceleration time and isovolumic relaxation time adjusted by heart rate were functional variables predictors of heart failure. The cutoff values of functional variables associated with heart failure were: area variation fraction < 31.18%; E / A > 3.077; E-wave deceleration time < 42.11 and isovolumic relaxation time adjusted by heart rate < 69.08.ConclusionIn rats followed for 6 months after myocardial infarction, the area variation fraction, E/A ratio, E-wave deceleration time and isovolumic relaxation time adjusted by heart rate are predictors of heart failure onset.

Rutin administration attenuates myocardial dysfunction in diabetic rats.

BackgroundOxidative stress plays a major role in diabetic cardiomyopathy pathogenesis. Anti-oxidant therapy has been investigated in preventing or treating several diabetic complications. However, anti-oxidant action on diabetic-induced cardiac remodeling is not completely clear. This study evaluated the effects of rutin, a flavonoid, on cardiac and myocardial function in diabetic rats.MethodsWistar rats were assigned into control (C, n = 14); control-rutin (C-R, n = 14); diabetes mellitus (DM, n = 16); and DM-rutin (DM-R, n = 16) groups. Seven days after inducing diabetes (streptozotocin, 60 mg/kg, i.p.), rutin was injected intraperitoneally once a week (50 mg/kg) for 7 weeks. Echocardiogram was performed and myocardial function assessed in left ventricular (LV) papillary muscles. Serum insulin concentration was measured by ELISA. Statistics: One-way ANOVA and Tukey’s post hoc test.ResultsGlycemia was higher in DM than DM-R and C and in DM-R than C-R. Insulin concentration was lower in diabetic groups than controls (C 2.45 ± 0.67; C-R 2.09 ± 0.52; DM 0.59 ± 0.18; DM-R 0.82 ± 0.21 ng/mL). Echocardiogram showed no differences between C-R and C. DM had increased LV systolic diameter compared to C, and increased left atrium diameter/body weight (BW) ratio and LV mass/BW ratio compared to C and DM-R. Septal wall thickness, LV diastolic diameter/BW ratio, and relative wall thickness were lower in DM-R than DM. Fractional shortening and posterior wall shortening velocity were lower in DM than C and DM-R. In papillary muscle preparation, DM and DM-R presented higher time to peak tension and time from peak tension to 50% relaxation than controls; time to peak tension was lower in DM-R than DM. Under 0.625 and 1.25 mM extracellular calcium concentrations, DM had higher developed tension than C.ConclusionRutin attenuates cardiac remodeling and left ventricular and myocardial dysfunction caused by streptozotocin-induced diabetes mellitus.

Chronic heart failure alters orexin and melanin concentrating hormone but not corticotrophin releasing hormone-related gene expression in the brain of male Lewis rats

ObjectiveThe aim of this study was to investigate the effect of chronic heart failure (HF; 16weeks post left coronary artery ligation) on the brain's orexin (ORX) and related neuropeptide systems. MethodsIndicators of cardiac function, including the percent fractional shortening (%FS) left ventricular posterior wall shortening velocity (LVPWSV) were assessed via echocardiography at 16weeks post myocardial infarction or sham treatment in male Lewis rats (n=5/group). Changes in gene expression in HF versus control (CON) groups were quantified by real-time PCR in the hypothalamus, amygdala and dorsal pons. ResultsHF significantly reduced both the %FS and LVPWSV when compared to CON animals (P<0.02). In the hypothalamus ORX gene expression was significantly reduced in HF and correlated with changes in cardiac function when compared to CON (P<0.02). No significant changes in hypothalamic ORX receptor (type 1 or type 2) gene expression were identified. Alternatively hypothalamic melanin concentrating hormone (MCH) gene expression was significantly upregulated in HF animals and negatively correlated with LVPWSV (P<0.006). In both the amygdala and dorsal pons ORX type 2 receptor expression was significantly down-regulated in HF compared to CON. ORX receptor type 1, CRH and CRH type 1 and type 2 receptor expressions were unchanged by HF in all brain regions analyzed. ConclusionThese observations support previous work demonstrating that cardiovascular disease modulates the ORX system and identify that in the case of chronic HF the ORX system is altered in parallel with changes in MCH expression but independent of any significant changes in the central CRH system. This raises the new possibility that ORX and MCH systems may play an important role in the pathophysiology of HF.

Low Intensity Physical Exercise Attenuates Cardiac Remodeling and Myocardial Oxidative Stress and Dysfunction in Diabetic Rats.

We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary diabetes (DM-Sed), and exercised diabetes (DM-Ex). Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV) papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73 ± 0.49; C-Ex: 5.67 ± 0.53; DM-Sed: 6.41 ± 0.54; DM-Ex: 5.81 ± 0.50 mm; P < 0.05 DM-Sed vs C-Sed and DM-Ex). Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats.

Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling.

Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca(2+)) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca(2+)-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups (n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), calsequestrin, L-type Ca(2+) channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser(16)) and PLB threonine-17 phosphorylation (pPLB Thr(17)) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca(2+). Obesity caused a reduction in cardiac pPLB Ser(16) and the pPLB Ser(16)/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser(16), but does not impair the myocardial Ca(2+) entry and recapture to SR.

Influence of late N‐acetylcysteine administration on cardiac remodeling in long‐term follow‐up postinfarction rats (862.3)

This study aimed to evaluate the influence of late N‐acetylcysteine (NAC) administration on cardiac remodeling in long‐term follow‐up postinfarction rats. Methods: Myocardial infarction (MI) was induced by left coronary occlusion. Four months later, rats were assigned to three groups: Sham (n=13), MI‐C (MI without treatment, n=16), and MI‐NAC (MI treated with N‐acetylcysteine, 120 mg/kg/day, n=16). Six months after surgery, cardiac structures and function were evaluated by transthoracic Doppler echocardiogram and rats were euthanized the next day. Infarct size was measured by histological analysis, and rats with small MI (&lt; 30%) were excluded. Results: MI size did not differ between MI‐C and MI‐NAC groups (p&gt;0.05; Student’s t test). Right ventricle (RV) and lung weight, RV/body weight (BW) and lung/BW ratios were similar between MI‐C and MI‐NAC and higher than Sham. Left ventricle diastolic diameter, left atrium (LA) diameter, and LA/BW ratio were higher in MI‐C than Sham and similar between MI‐C and MI‐NAC. The systolic function variables fractional area shortening and posterior wall shortening velocity were similar between MI‐C and MI‐NAC and both lower than Sham. Concerning diastolic function, E wave‐to‐A wave ratio was higher in MI‐C than in both Sham and MI‐NAC (Sham: 1.47±0.14; MI‐C: 4.83±2.41; MI‐NAC: 3.25±1.85; p&lt;0.001, ANOVA and Bonferroni). Conclusion: Late N‐acetylcysteine treatment attenuates diastolic dysfunction in long‐term follow‐up postinfarction rats.Grant Funding Source: FAPESP and CNPq

Periostin as a modulator of chronic cardiac remodeling after myocardial infarction

OBJECTIVE:After acute myocardial infarction, during the cardiac repair phase, periostin is released into the infarct and activates signaling pathways that are essential for the reparative process. However, the role of periostin in chronic cardiac remodeling after myocardial infarction remains to be elucidated. Therefore, the objective of this study was to investigate the relationship between tissue periostin and cardiac variables in the chronic cardiac remodeling induced by myocardial infarction.METHODS:Male Wistar rats were assigned to 2 groups: a simulated surgery group (SHAM; n = 8) and a myocardial infarction group (myocardial infarction; n = 13). After 3 months, morphological, functional and biochemical analyses were performed. The data are expressed as means±SD or medians (including the lower and upper quartiles).RESULTS:Myocardial infarctions induced increased left ventricular diastolic and systolic areas associated with a decreased fractional area change and a posterior wall shortening velocity. With regard to the extracellular matrix variables, the myocardial infarction group presented with higher values of periostin and types I and III collagen and higher interstitial collagen volume fractions and myocardial hydroxyproline concentrations. In addition, periostin was positively correlated with type III collagen levels (r = 0.673, p = 0.029) and diastolic (r = 0.678, p = 0.036) and systolic (r = 0.795, p = 0.006) left ventricular areas. Considering the relationship between periostin and the cardiac function variables, periostin was inversely correlated with both the fractional area change (r = -0.783, p = 0.008) and the posterior wall shortening velocity (r = -0.767, p = 0.012).CONCLUSIONS:Periostin might be a modulator of deleterious cardiac remodeling in the chronic phase after myocardial infarction in rats.

Early echocardiographic predictors of increased left ventricular end-diastolic pressure three months after myocardial infarction in rats

SummaryBackgroundThe objective of this study was to determine the early echocardiographic predictors of elevated left ventricular end-diastolic pressure (LVEDP) after a long follow-up period in the infarcted rat model.Material/MethodsFive days and three months after surgery, sham and infarcted animals were subjected to transthoracic echocardiography. Regression analysis and receiver-operating characteristic (ROC) curve were performed for predicting increased LVEDP 3 months after MI.ResultsAmong all of the variables, assessed 5 days after myocardial infarction, infarct size (OR: 0.760; CI 95% 0.563–0.900; p=0.005), end-systolic area (ESA) (OR: 0.761; CI 95% 0.564–0.900; p=0.008), fractional area change (FAC) (OR: 0.771; CI 95% 0.574–0.907; p=0.003), and posterior wall-shortening velocity (PWSV) (OR: 0.703; CI 95% 0.502–0.860; p=0.048) were predictors of increased LVEDP. The LVEDP was 3.6±1.8 mmHg in the control group and 9.4±7.8 mmHg among the infarcted animals (p=0.007). Considering the critical value of predictor variables in inducing cardiac dysfunction, the cut-off value was 35% for infarct size, 0.33 cm2 for ESA, 40% for FAC, and 26 mm/s for PWSV.ConclusionsInfarct size, FAC, ESA, and PWSV, assessed five days after myocardial infarction, can be used to estimate an increased LVEDP three months following the coronary occlusion.

Preditores ecocardiográficos de remodelação ventricular após o infarto agudo do miocárdio em ratos

The prediction of the ventricular remodeling process after acute myocardial infarction (AMI) may have important clinical implications. To analyze echocardiographic variables predictors of remodeling in the infarction model in rats. MEHTODS: The animals underwent echocardiography in two moments, five days and three months after infarction (AMI group) or sham surgery (control group). Linear regression was used to identify the echocardiographic variables on the fifth day after the infarction, which were predictive of remodeling after three months of coronary occlusion. We considered as a criterion of remodeling in this study, the values of left ventricular diastolic diameter (LVDD) after three months of infarction. The infarction induced increase in the left chambers, associated with changes in systolic and diastolic functions. The variables body weight, left ventricular wall stress index (LVWSI), systolic area (SA), diastolic area (DA), LVDD, left ventricular systolic diameter (LVSD), area variation fraction (AVF), ejection fraction (EF), percent of endocardial shortening (%Short), posterior wall shortening velocity (PWSV) and infarct size assessed five days after infarction were predictors of LVDD after three months. At the multivariate regression analysis, we included the size of infarction, the LVWSI and PWSV. The LVWSI (coefficient: 4.402, standard error: 2.221, p = 0.05), but not the size of infarction and PWSV, was a predictor of remodeling after three months of infarction. LVPSI was an independent predictor of remodeling three months after the myocardial infarction and could be included in the clinical stratification after the coronary occlusion.

Critical infarct size to induce ventricular remodeling, cardiac dysfunction and heart failure in rats

Ventricular remodeling, decreased left ventricular systolic function, and heart failure have been associated with poor long-term outcomes after myocardial infarction [1,2]. Thus, it is critical to know the pathophysiological alterations involved in these processes for myocardial infarction management. A rat coronary artery ligation leads to a wide range of infarct size, cardiac remodeling and left ventricular dysfunction. In addition, it is accepted that the coronary occlusion consequences are closely related to infarction size, which is a powerful determinant of survival [3], ventricular remodeling [4], and cardiac systolic function [5]. In order to determine the association between infarct size and outcomes after coronary occlusion, the animals were divided into three groups (small, moderate or large infarct size), but this division was not homogeneous among the studies because the animals were randomly placed in the groups. Consequently, the infarct size that is necessary to determine morphological, functional, and clinical alterations after the coronary occlusion, still needs to be determined. The present study was carried out to determine the critical infarct size to induce ventricular remodeling, cardiac dysfunction, and heart failure in a rat model. Myocardial infarction was induced following the method described previously [6]. Six months after surgery, Sham (n=67) and infarcted animals (n=166) were subjected to transthoracic echocardiography, and euthanized the next day. The echocardiographic exams and morphometric analysis were performed as described previously [6,7]. The left ventricular remodeling was defined as the infarcted values of the left ventricular end-diastolic cavity areas with a difference of N2 and standard deviations above Sham group mean. The systolic dysfunction was defined as the infarcted values of posterior wall shortening velocity (PWSV) with a difference of b2 and standard deviations under Sham group mean. The diastolic dysfunction was defined as the infarcted values of E/A ratio with a difference of N2 and standard deviations above Sham group mean. The variables utilized to determine heart failure included pleuropericardial effusion, left atrial thrombi, ascites, or right ventricular hypertrophy (right ventricle weight-to-body weight ratio N0.8 mg/g) [8]. An infarct size cut-off valuewas derived from the receiver-operating characteristic (ROC) curve according to the infarct size value to maximize sensitivity, specificity, and predictivity values in order to anticipate remodeling, cardiac dysfunctions, and heart failure. The bias between histology and echocardiogram in the infarct size assessment was evaluated by Bland & Altman. After a six-month follow-up, the infarct size in the infarcted animals ranged from 18.5% to 57%, with an average of 40±9% assessed by histology, and 42±9% assessed by echocardiogram, and bias between the methods at −1.15%. The infarct size cut-off values were 36% (area under ROC curves (AUC): 0.70; 95% CI: 0.61-0.78; p=0.017) for ventricular remodeling; 38% (AUC: 0.72; 95% CI: 0.64-0.80; p=0.001) for PWSV; 44% (AUC: 0.72; 95% CI: 0.64–0.79; pb0.001) for E/A ratio and 40% (AUC: 0.65; 95% CI: 0.56-0.73; p=0.004) for heart failure. Among the infarcted rats, 93% presented ventricular remodeling; 86% showed systolic dysfunction; 47% presented diastolic dysfunction; and 66% had heart failure. The knowledge of the critical infarct size necessary to induce remodeling, cardiac dysfunction, and heart failure in this model can be extremely useful, since infarct size can be early estimated after the coronary occlusion by non invasive methods, such as echocardiogram. In the present study, the infarct size was determined by histology, even though this measurement had low bias when compared to infarct size measured by echocardiography. In conclusion, the identification of the critical infarct size to induce ventricular remodeling, cardiac dysfunction, and heart failure might be particularly useful in longitudinal studies about therapeutic and pathophysiological aspects following coronary occlusion. Our data indicate that the minimum infarct size to cause these morphological, functional and clinical abnormalities is 36%, 38%, and 40%, respectively. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).

Echocardiographic detection of congestive heart failure in postinfarction rats

In studies of congestive heart failure (CHF) treatment, it is essential to select animals with a similar degree of cardiac dysfunction. However, this is difficult to establish without hemodynamic evaluation in rat postinfarction-induced CHF. This study aimed to diagnose CHF in long-term follow-up postinfarction rats using only echocardiographic criteria through a J-tree cluster analysis and Fisher's linear discriminant function. Two sets of sham and infarcted rats were studied. The first was used to perform cluster analysis and the second to prospectively validate the results. Six months after inducing myocardial infarction (MI), rats were subjected to transthoracic echocardiography. Infarct size was measured by histological analysis. Six echocardiographic variables were used in the cluster analysis: left ventricular (LV) systolic dimension, LV diastolic dimension-to-body weight ratio, left atrial diameter-to-body weight ratio, LV posterior wall shortening velocity, E wave, and isovolumetric relaxation time. Cluster analysis joined the rats into one sham and two MI groups. One MI cluster had more severe anatomical and echocardiographic changes and was called MI with heart failure (MI/HF+, n = 24, infarct size: 42.7 ± 5.8%). The other had less severe changes and was called MI without heart failure (MI/HF-, n = 11, infarct size: 32.3 ± 9.9%; P < 0.001 vs. MI/HF+). Three rats with small infarct size (21.6 ± 2.2%) presenting mild cardiac alterations were misallocated in the sham group. Fisher's linear discriminant function was built using these groups and used to prospectively classify additional groups of sham-operated (n = 20) and infarcted rats (n = 57) using the same echocardiographic parameters. The discriminant function therefore detected CHF with 100% specificity and 80% sensitivity considering allocation in MI/HF+ and sham group, and 100% specificity and 58.8% sensitivity considering MI/HF+ and MI/HF- groups, taking into account pathological criteria of CHF diagnosis. Echocardiographic analysis can be used to accurately predict congestive heart failure in postinfarction rats.

Growth hormone attenuates skeletal muscle changes in experimental chronic heart failure

Objective This study evaluated the effects of growth hormone (GH) on morphology and myogenic regulatory factors (MRF) gene expression in skeletal muscle of rats with ascending aortic stenosis (AAS) induced chronic heart failure. Design Male 90–100 g Wistar rats were subjected to thoracotomy. AAS was created by placing a stainless-steel clip on the ascending aorta. Twenty five weeks after surgery, rats were treated with daily subcutaneous injections of recombinant human GH (2 mg/kg/day; AAS-GH group) or saline (AAS group) for 14 days. Sham-operated animals served as controls. Left ventricular (LV) function was assessed before and after treatment. IGF-1 serum levels were measured by ELISA. After anesthesia, soleus muscle was frozen in liquid nitrogen. Histological sections were stained with HE and picrosirius red to calculate muscle fiber cross-sectional area and collagen fractional area, respectively. MRF myogenin and MyoD expression was analyzed by reverse transcription PCR. Results Body weight was similar between groups. AAS and AAS-GH groups presented dilated left atrium, left ventricular (LV) hypertrophy (LV mass index: Control 1.90 ± 0.15; AAS 3.11 ± 0.44; AAS-GH 2.94 ± 0.47 g/kg; p < 0.05 AAS and AAS-GH vs. Control), and reduced LV posterior wall shortening velocity. Soleus muscle fiber area was significantly lower in AAS than in Control and AAS-GH groups; there was no difference between AAS-GH and Control groups. Collagen fractional area was significantly higher in AAS than Control; AAS-GH did not differ from both Control and AAS groups. Serum IGF-1 levels decreased in AAS compared to Control. MyoD mRNA was significantly higher in AAS-GH than AAS; there was no difference between AAS-GH and Control groups. Myogenin mRNA levels were similar between groups. Conclusion In rats with aortic stenosis-induced heart failure, growth hormone administration increases MyoD gene expression above non-treated animal levels, preserves muscular trophism and attenuates interstitial fibrosis. These results suggest that growth hormone may have a potential role as an adjuvant therapy for chronic heart failure.