Andréa Somolanji Vanzelli

Intracellular mechanisms of specific β-adrenoceptor antagonists involved in improved cardiac function and survival in a genetic model of heart failure

beta-blockers, as class, improve cardiac function and survival in heart failure (HF). However, the molecular mechanisms underlying these beneficial effects remain elusive. In the present study, metoprolol and carvedilol were used in doses that display comparable heart rate reduction to assess their beneficial effects in a genetic model of sympathetic hyperactivity-induced HF (alpha(2A)/alpha(2C)-ARKO mice). Five month-old HF mice were randomly assigned to receive either saline, metoprolol or carvedilol for 8 weeks and age-matched wild-type mice (WT) were used as controls. HF mice displayed baseline tachycardia, systolic dysfunction evaluated by echocardiography, 50% mortality rate, increased cardiac myocyte width (50%) and ventricular fibrosis (3-fold) compared with WT. All these responses were significantly improved by both treatments. Cardiomyocytes from HF mice showed reduced peak [Ca(2+)](i) transient (13%) using confocal microscopy imaging. Interestingly, while metoprolol improved [Ca(2+)](i) transient, carvedilol had no effect on peak [Ca(2+)](i) transient but also increased [Ca(2+)] transient decay dynamics. We then examined the influence of carvedilol in cardiac oxidative stress as an alternative target to explain its beneficial effects. Indeed, HF mice showed 10-fold decrease in cardiac reduced/oxidized glutathione ratio compared with WT, which was significantly improved only by carvedilol treatment. Taken together, we provide direct evidence that the beneficial effects of metoprolol were mainly associated with improved cardiac Ca(2+) transients and the net balance of cardiac Ca(2+) handling proteins while carvedilol preferentially improved cardiac redox state.

Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function

Heart failure is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. Chronic neurohumoral excitation (i.e., sympathetic hyperactivity) has been considered to be a hallmark of heart failure and is associated with a poor prognosis, cardiac dysfunction and remodeling, and skeletal myopathy. Aerobic exercise training is efficient in counteracting sympathetic hyperactivity and its toxic effects on cardiac and skeletal muscles. In this review, we describe the effects of aerobic exercise training on sympathetic hyperactivity, skeletal myopathy, as well as cardiac function and remodeling in human and animal heart failure. We also discuss the mechanisms underlying the effects of aerobic exercise training.

Integrative Effect of Carvedilol and Aerobic Exercise Training Therapies on Improving Cardiac Contractility and Remodeling in Heart Failure Mice

The use of β-blockers is mandatory for counteracting heart failure (HF)-induced chronic sympathetic hyperactivity, cardiac dysfunction and remodeling. Importantly, aerobic exercise training, an efficient nonpharmacological therapy to HF, also counteracts sympathetic hyperactivity in HF and improves exercise tolerance and cardiac contractility; the latter associated with changes in cardiac Ca2+ handling. This study was undertaken to test whether combined β–blocker and aerobic exercise training would integrate the beneficial effects of isolated therapies on cardiac structure, contractility and cardiomyocyte Ca2+ handling in a genetic model of sympathetic hyperactivity-induced HF (α2A/α2C- adrenergic receptor knockout mice, KO). We used a cohort of 5–7 mo male wild-type (WT) and congenic mice (KO) with C57Bl6/J genetic background randomly assigned into 5 groups: control (WT), saline-treated KO (KOS), exercise trained KO (KOT), carvedilol-treated KO (KOC) and, combined carvedilol-treated and exercise-trained KO (KOCT). Isolated and combined therapies reduced mortality compared with KOS mice. Both KOT and KOCT groups had increased exercise tolerance, while groups receiving carvedilol had increased left ventricular fractional shortening and reduced cardiac collagen volume fraction compared with KOS group. Cellular data confirmed that cardiomyocytes from KOS mice displayed abnormal Ca2+ handling. KOT group had increased intracellular peak of Ca2+ transient and reduced diastolic Ca2+ decay compared with KOS group, while KOC had increased Ca2+ decay compared with KOS group. Notably, combined therapies re-established cardiomyocyte Ca2+ transient paralleled by increased SERCA2 expression and SERCA2:PLN ratio toward WT levels. Aerobic exercise trained increased the phosphorylation of PLN at Ser16 and Thr17 residues in both KOT and KOCT groups, but carvedilol treatment reduced lipid peroxidation in KOC and KOCT groups compared with KOS group. The present findings provide evidence that the combination of carvedilol and aerobic exercise training therapies lead to a better integrative outcome than carvedilol or exercise training used in isolation.

Effect of exercise training and carvedilol treatment on cardiac function and structure in mice with sympathetic hyperactivity-induced heart failure

The present investigation was undertaken to study the effect of beta-blockers and exercise training on cardiac structure and function, respectively, as well as overall functional capacity in a genetic model of sympathetic hyperactivity-induced heart failure in mice (alpha(2A)/alpha(2C)ArKO). alpha(2A)/alpha(2C)ArKO and their wild-type controls were studied for 2 months, from 3 to 5 months of age. Mice were randomly assigned to control (N = 45), carvedilol-treated (N = 29) or exercise-trained (N = 33) groups. Eight weeks of carvedilol treatment (38 mg/kg per day by gavage) or exercise training (swimming sessions of 60 min, 5 days/week) were performed. Exercise capacity was estimated using a graded treadmill protocol and HR was measured by tail cuff. Fractional shortening was evaluated by echocardiography. Cardiac structure and gastrocnemius capillary density were evaluated by light microscopy. At 3 months of age, no significant difference in fractional shortening or exercise capacity was observed between wild-type and alpha(2A)/alpha(2C)ArKO mice. At 5 months of age, all alpha(2A)/alpha(2C)ArKO mice displayed exercise intolerance and baseline tachycardia associated with reduced fractional shortening and gastrocnemius capillary rarefaction. In addition, alpha(2A)/ alpha(2C)ArKO mice presented cardiac myocyte hypertrophy and ventricular fibrosis. Exercise training and carvedilol similarly improved fractional shortening in alpha(2A)/alpha(2C)ArKO mice. The effect of exercise training was mainly associated with improved exercise tolerance and increased gastrocnemius capillary density while beta-blocker therapy reduced cardiac myocyte dimension and ventricular collagen to wild-type control levels. Taken together, these data provide direct evidence for the respective beneficial effects of exercise training and carvedilol in alpha(2A)/alpha(2C)ArKO mice preventing cardiac dysfunction. The different mechanisms associated with beneficial effects of exercise training and carvedilol suggest future studies associating both therapies.

Association of physical training with beta-blockers in heart failure in mice

BACKGROUND Currently there are several types of interventions for the treatment of heart failure (HF). Among these are beta-blocker therapy (BB) and physical training (PT). However, the effects of the combination of these therapies are poorly studied. OBJECTIVE To investigate the effects of BB treatment with metoprolol (M) and carvedilol (C) associated with PT in mice with HF. METHODS We used a genetic model of sympathetic hyperactivity-induced heart failure in mice. Initially, we divided the HF animals into three groups: sedentary (S); trained (T); treated with M (138 mg/kg) (M); or C (65 mg/kg) (C). In the second part, we divided the groups into three subgroups: sedentary (S); trained and treated with M (TM); and trained and treated with C (CT). The PT consisted of aerobic training on a treadmill for 8 weeks. Exercise tolerance was assessed by maximal graded test, and fractional shortening (FS) was assessed by echocardiography. Cardiomyocyte diameter and collagen volume fraction were evaluated by histological analysis. Data were compared by one way ANOVA and post hoc Duncan test. The significance level was set at p ≤ 0.05. RESULTS As to FS and cardiac remodeling, we found that, in isolation, T, M, and C showed an improvement of the variables analyzed. As to therapy combination, after the intervention period, we observed an increase in exercise tolerance in MT and CT (43.0% and 33.0% respectively). There was also a reduction in cardiomyocyte diameter (10.0% and 9.0% respectively) and in collagen volume fraction (52.0% and 63.0%) after the intervention. However, only CT significantly improved FS. CONCLUSION The association of PT with M or C therapies provided benefits on cardiac function and remodeling in HF mice.FUNDAMENTO: O tratamento da insuficiencia cardiaca (IC) conta atualmente com diversos tipos de intervencoes. Dentre elas, destacam-se a terapia com betabloqueadores (BB) e o treinamento fisico (TF). Contudo, os efeitos da associacao dessas terapias sao pouco estudados. OBJETIVO: Verificar os efeitos do tratamento com BB, metoprolol (M) e carvedilol (C) associados ao TF na IC em camundongos. METODOS: Utilizamos modelo genetico de IC induzida em camundongos por hiperatividade simpatica. Inicialmente, dividimos os animais com IC em: sedentarios (S); treinados (T); tratados com M (138 mg/kg) (M) ou C (65 mg/kg) (C). Na segunda parte, dividimos os grupos em S; treinado e tratado com M (MT) e treinado e tratado com C (CT). O TF consistiu em treinamento aerobico em esteira por 8 semanas. A tolerância ao esforco foi avaliada por teste progressivo maximo e a fracao de encurtamento foi avaliada (FE) por ecocardiografia. O diâmetro dos cardiomiocitos e a fracao de colageno foram avaliados por meio de analise histologica. Os dados foram comparados por ANOVA de um caminho com post hoc de Duncan. O nivel de significância foi considerado p < 0,05. RESULTADOS: Destacando FE e remodelacao cardiaca, verificamos que, isoladamente, T, M e C apresentaram melhora das variaveis. Na associacao, apos o periodo de intervencao, observamos aumento da tolerância ao esforco em MT e CT (43,0% e 33,0%, respectivamente). Houve tambem reducao do diâmetro dos cardiomiocitos (10,0% e 9,0%, respectivamente) e da fracao de colageno (52,0% e 63,0%), apos a intervencao. Porem, somente CT melhorou significantemente a FE. CONCLUSAO: A associacao do TF as terapias com M ou C proporcionou beneficios sobre a funcao e remodelacao cardiaca em camundongos com IC.

Associação de betabloqueadores e treinamento físico na insuficiência cardíaca de camundongos

BACKGROUND Currently there are several types of interventions for the treatment of heart failure (HF). Among these are beta-blocker therapy (BB) and physical training (PT). However, the effects of the combination of these therapies are poorly studied. OBJECTIVE To investigate the effects of BB treatment with metoprolol (M) and carvedilol (C) associated with PT in mice with HF. METHODS We used a genetic model of sympathetic hyperactivity-induced heart failure in mice. Initially, we divided the HF animals into three groups: sedentary (S); trained (T); treated with M (138 mg/kg) (M); or C (65 mg/kg) (C). In the second part, we divided the groups into three subgroups: sedentary (S); trained and treated with M (TM); and trained and treated with C (CT). The PT consisted of aerobic training on a treadmill for 8 weeks. Exercise tolerance was assessed by maximal graded test, and fractional shortening (FS) was assessed by echocardiography. Cardiomyocyte diameter and collagen volume fraction were evaluated by histological analysis. Data were compared by one way ANOVA and post hoc Duncan test. The significance level was set at p ≤ 0.05. RESULTS As to FS and cardiac remodeling, we found that, in isolation, T, M, and C showed an improvement of the variables analyzed. As to therapy combination, after the intervention period, we observed an increase in exercise tolerance in MT and CT (43.0% and 33.0% respectively). There was also a reduction in cardiomyocyte diameter (10.0% and 9.0% respectively) and in collagen volume fraction (52.0% and 63.0%) after the intervention. However, only CT significantly improved FS. CONCLUSION The association of PT with M or C therapies provided benefits on cardiac function and remodeling in HF mice.FUNDAMENTO: O tratamento da insuficiencia cardiaca (IC) conta atualmente com diversos tipos de intervencoes. Dentre elas, destacam-se a terapia com betabloqueadores (BB) e o treinamento fisico (TF). Contudo, os efeitos da associacao dessas terapias sao pouco estudados. OBJETIVO: Verificar os efeitos do tratamento com BB, metoprolol (M) e carvedilol (C) associados ao TF na IC em camundongos. METODOS: Utilizamos modelo genetico de IC induzida em camundongos por hiperatividade simpatica. Inicialmente, dividimos os animais com IC em: sedentarios (S); treinados (T); tratados com M (138 mg/kg) (M) ou C (65 mg/kg) (C). Na segunda parte, dividimos os grupos em S; treinado e tratado com M (MT) e treinado e tratado com C (CT). O TF consistiu em treinamento aerobico em esteira por 8 semanas. A tolerância ao esforco foi avaliada por teste progressivo maximo e a fracao de encurtamento foi avaliada (FE) por ecocardiografia. O diâmetro dos cardiomiocitos e a fracao de colageno foram avaliados por meio de analise histologica. Os dados foram comparados por ANOVA de um caminho com post hoc de Duncan. O nivel de significância foi considerado p < 0,05. RESULTADOS: Destacando FE e remodelacao cardiaca, verificamos que, isoladamente, T, M e C apresentaram melhora das variaveis. Na associacao, apos o periodo de intervencao, observamos aumento da tolerância ao esforco em MT e CT (43,0% e 33,0%, respectivamente). Houve tambem reducao do diâmetro dos cardiomiocitos (10,0% e 9,0%, respectivamente) e da fracao de colageno (52,0% e 63,0%), apos a intervencao. Porem, somente CT melhorou significantemente a FE. CONCLUSAO: A associacao do TF as terapias com M ou C proporcionou beneficios sobre a funcao e remodelacao cardiaca em camundongos com IC.

Asociación de betabloqueantes y entrenamiento físico en la insuficiencia cardíaca de ratones

BACKGROUND Currently there are several types of interventions for the treatment of heart failure (HF). Among these are beta-blocker therapy (BB) and physical training (PT). However, the effects of the combination of these therapies are poorly studied. OBJECTIVE To investigate the effects of BB treatment with metoprolol (M) and carvedilol (C) associated with PT in mice with HF. METHODS We used a genetic model of sympathetic hyperactivity-induced heart failure in mice. Initially, we divided the HF animals into three groups: sedentary (S); trained (T); treated with M (138 mg/kg) (M); or C (65 mg/kg) (C). In the second part, we divided the groups into three subgroups: sedentary (S); trained and treated with M (TM); and trained and treated with C (CT). The PT consisted of aerobic training on a treadmill for 8 weeks. Exercise tolerance was assessed by maximal graded test, and fractional shortening (FS) was assessed by echocardiography. Cardiomyocyte diameter and collagen volume fraction were evaluated by histological analysis. Data were compared by one way ANOVA and post hoc Duncan test. The significance level was set at p ≤ 0.05. RESULTS As to FS and cardiac remodeling, we found that, in isolation, T, M, and C showed an improvement of the variables analyzed. As to therapy combination, after the intervention period, we observed an increase in exercise tolerance in MT and CT (43.0% and 33.0% respectively). There was also a reduction in cardiomyocyte diameter (10.0% and 9.0% respectively) and in collagen volume fraction (52.0% and 63.0%) after the intervention. However, only CT significantly improved FS. CONCLUSION The association of PT with M or C therapies provided benefits on cardiac function and remodeling in HF mice.FUNDAMENTO: O tratamento da insuficiencia cardiaca (IC) conta atualmente com diversos tipos de intervencoes. Dentre elas, destacam-se a terapia com betabloqueadores (BB) e o treinamento fisico (TF). Contudo, os efeitos da associacao dessas terapias sao pouco estudados. OBJETIVO: Verificar os efeitos do tratamento com BB, metoprolol (M) e carvedilol (C) associados ao TF na IC em camundongos. METODOS: Utilizamos modelo genetico de IC induzida em camundongos por hiperatividade simpatica. Inicialmente, dividimos os animais com IC em: sedentarios (S); treinados (T); tratados com M (138 mg/kg) (M) ou C (65 mg/kg) (C). Na segunda parte, dividimos os grupos em S; treinado e tratado com M (MT) e treinado e tratado com C (CT). O TF consistiu em treinamento aerobico em esteira por 8 semanas. A tolerância ao esforco foi avaliada por teste progressivo maximo e a fracao de encurtamento foi avaliada (FE) por ecocardiografia. O diâmetro dos cardiomiocitos e a fracao de colageno foram avaliados por meio de analise histologica. Os dados foram comparados por ANOVA de um caminho com post hoc de Duncan. O nivel de significância foi considerado p < 0,05. RESULTADOS: Destacando FE e remodelacao cardiaca, verificamos que, isoladamente, T, M e C apresentaram melhora das variaveis. Na associacao, apos o periodo de intervencao, observamos aumento da tolerância ao esforco em MT e CT (43,0% e 33,0%, respectivamente). Houve tambem reducao do diâmetro dos cardiomiocitos (10,0% e 9,0%, respectivamente) e da fracao de colageno (52,0% e 63,0%), apos a intervencao. Porem, somente CT melhorou significantemente a FE. CONCLUSAO: A associacao do TF as terapias com M ou C proporcionou beneficios sobre a funcao e remodelacao cardiaca em camundongos com IC.