Liraglutide Pretreatment Does Not Improve Acute Doxorubicin-Induced Cardiotoxicity in Rats.

Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2ß did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.

The Role of Oxidative Stress in the Aging Heart.

Medical advances and the availability of diagnostic tools have considerably increased life expectancy and, consequently, the elderly segment of the world population. As age is a major risk factor in cardiovascular disease (CVD), it is critical to understand the changes in cardiac structure and function during the aging process. The phenotypes and molecular mechanisms of cardiac aging include several factors. An increase in oxidative stress is a major player in cardiac aging. Reactive oxygen species (ROS) production is an important mechanism for maintaining physiological processes; its generation is regulated by a system of antioxidant enzymes. Oxidative stress occurs from an imbalance between ROS production and antioxidant defenses resulting in the accumulation of free radicals. In the heart, ROS activate signaling pathways involved in myocyte hypertrophy, interstitial fibrosis, contractile dysfunction, and inflammation thereby affecting cell structure and function, and contributing to cardiac damage and remodeling. In this manuscript, we review recent published research on cardiac aging. We summarize the aging heart biology, highlighting key molecular pathways and cellular processes that underlie the redox signaling changes during aging. Main ROS sources, antioxidant defenses, and the role of dysfunctional mitochondria in the aging heart are addressed. As metabolism changes contribute to cardiac aging, we also comment on the most prevalent metabolic alterations. This review will help us to understand the mechanisms involved in the heart aging process and will provide a background for attractive molecular targets to prevent age-driven pathology of the heart. A greater understanding of the processes involved in cardiac aging may facilitate our ability to mitigate the escalating burden of CVD in older individuals and promote healthy cardiac aging.

Aerobic Exercise During Advance Stage of Uncontrolled Arterial Hypertension.

AIM: To evaluate the influence of physical training on myocardial function, oxidative stress, energy metabolism, and MAPKs and NF-κB signaling pathways in spontaneously hypertensive rats (SHR), at advanced stage of arterial hypertension, which precedes heart failure development. METHODS: We studied four experimental groups: normotensive Wistar rats (W, n = 27), trained W (W-EX, n = 31), SHR (n = 27), and exercised SHR (SHR-EX, n = 32). At 13 months old, the exercise groups underwent treadmill exercise 5 days a week for 4 months. In vitro myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Antioxidant enzyme activity and energy metabolism were assessed by spectrophotometry. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was analyzed by lucigenin reduction and protein expression by Western blot. Statistical analyzes: ANOVA and Tukey or Kruskal-Wallis and Dunn tests. RESULTS: SHR-EX had a lower frequency of heart failure features than SHR. Myocardial function and antioxidant enzyme activity were better in SHR-EX than SHR. Lipid hydroperoxide concentration, and phosphorylated JNK and total IkB protein expression were higher in hypertensive than control groups. Malondialdehyde, NADPH oxidase activity, total JNK, phosphorylated p38, phosphorylated and total p65 NF-κB, and phosphorylated IkB did not differ between groups. Protein expression from total p38, and total and phosphorylated ERK were higher in SHR than W. Lactate dehydrogenase and phosphorylated ERK were lower and citrate synthase and ß-hydroxyacyldehydrogenase were higher in SHR-EX than SHR. CONCLUSION: Exercise improves physical capacity, myocardial function, and antioxidant enzyme activity; reduces the frequency of heart failure features and ERK phosphorylation; and normalizes energy metabolism in SHR.

Effects of Late Aerobic Exercise on Cardiac Remodeling of Rats with Small-Sized Myocardial Infarction. / Efeitos do Exercício Aeróbico Tardio na Remodelação Cardíaca de Ratos com Infarto do Miocárdio Pequeno.

BACKGROUND: Physical exercise has been considered an important non-pharmacological therapy for the prevention and treatment of cardiovascular diseases. However, its effects on minor cardiac remodeling are not clear. OBJECTIVE: To evaluate the influence of aerobic exercise on the 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-AE). The rats exercised on a treadmill three times a week for 12 weeks. An echocardiogram was performed before and after training. The infarction size was evaluated by histology, and gene expression was assessed by RT-PCR. The significance level for statistical analysis was set at 5%. RESULTS: Rats with MI lower than 30% of the LV total area were included in the study. Functional capacity was higher in MI-AE than in Sham and MI-SED rats. The 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. Relative wall thickness was lower in MI-SED than in the MI-AE and Sham groups. Gene expression of the NADPH oxidase subunits NOX2, NOX4, p22phox, and p47phox did not differ between groups. CONCLUSION: Small-sized MI changes cardiac structure and LV systolic function. Late aerobic exercise is able to improve functional capacity and cardiac remodeling by preserving the left ventricular geometry. NADPH oxidase subunits gene expression is not involved in cardiac remodeling or modulated by aerobic exercise in rats with small-sized MI.

FUNDAMENTO: O exercício físico tem sido considerado uma importante terapia não farmacológica para a prevenção e tratamento das doenças cardiovasculares. No entanto, seus efeitos na remodelação cardíaca leve não são claros. OBJETIVO: Avaliar a influência do exercício aeróbico sobre a capacidade funcional, estrutura cardíaca, função ventricular esquerda (VE) e expressão gênica das subunidades da NADPH oxidase em ratos com infarto do miocárdio pequeno (IM). MÉTODOS: Três meses após a indução do IM, ratos Wistar foram divididos em três grupos: Sham; IM sedentário (IM-SED); e IM exercício aeróbico (IM-EA). Os ratos se exercitaram em uma esteira três vezes por semana durante 12 semanas. Um ecocardiograma foi realizado antes e após o treinamento. O tamanho do infarto foi avaliado por histologia e a expressão gênica por RT-PCR. O nível de significância para análise estatística foi estabelecido em 5%. RESULTADOS: Ratos com IM menor que 30% da área total do VE foram incluídos no estudo. A capacidade funcional foi maior no IM-EA do que nos ratos Sham e IM-SED. O tamanho do infarto não diferiu entre os grupos. Ratos infartados apresentaram aumento do diâmetro diastólico e sistólico do VE, diâmetro do átrio esquerdo e massa do VE, com disfunção sistólica. A espessura relativa da parede foi menor no grupo IM-SED do que nos grupos IM-EA e Sham. A expressão gênica das subunidades NADPH oxidase NOX2, NOX4, p22phox e p47phox não diferiu entre os grupos. CONCLUSÃO: Infarto do miocárdio pequeno altera a estrutura cardíaca e a função sistólica do VE. O exercício aeróbico tardio pode melhorar a capacidade funcional e a remodelação cardíaca por meio da preservação da geometria ventricular esquerda. A expressão gênica das subunidades da NADPH oxidase não está envolvida na remodelação cardíaca, nem é modulada pelo exercício aeróbico em ratos com infarto do miocárdio pequeno.

Efeitos do Exercício Aeróbico Tardio na Remodelação Cardíaca de Ratos com Infarto do Miocárdio Pequeno / Effects of Late Aerobic Exercise on Cardiac Remodeling of Rats with Small-Sized Myocardial Infarction

Resumo Fundamento: O exercício físico tem sido considerado uma importante terapia não farmacológica para a prevenção e tratamento das doenças cardiovasculares. No entanto, seus efeitos na remodelação cardíaca leve não são claros. Objetivo: Avaliar a influência do exercício aeróbico sobre a capacidade funcional, estrutura cardíaca, função ventricular esquerda (VE) e expressão gênica das subunidades da NADPH oxidase em ratos com infarto do miocárdio pequeno (IM). Métodos: Três meses após a indução do IM, ratos Wistar foram divididos em três grupos: Sham; IM sedentário (IM-SED); e IM exercício aeróbico (IM-EA). Os ratos se exercitaram em uma esteira três vezes por semana durante 12 semanas. Um ecocardiograma foi realizado antes e após o treinamento. O tamanho do infarto foi avaliado por histologia e a expressão gênica por RT-PCR. O nível de significância para análise estatística foi estabelecido em 5%. Resultados: Ratos com IM menor que 30% da área total do VE foram incluídos no estudo. A capacidade funcional foi maior no IM-EA do que nos ratos Sham e IM-SED. O tamanho do infarto não diferiu entre os grupos. Ratos infartados apresentaram aumento do diâmetro diastólico e sistólico do VE, diâmetro do átrio esquerdo e massa do VE, com disfunção sistólica. A espessura relativa da parede foi menor no grupo IM-SED do que nos grupos IM-EA e Sham. A expressão gênica das subunidades NADPH oxidase NOX2, NOX4, p22phox e p47phox não diferiu entre os grupos. Conclusão: Infarto do miocárdio pequeno altera a estrutura cardíaca e a função sistólica do VE. O exercício aeróbico tardio pode melhorar a capacidade funcional e a remodelação cardíaca por meio da preservação da geometria ventricular esquerda. A expressão gênica das subunidades da NADPH oxidase não está envolvida na remodelação cardíaca, nem é modulada pelo exercício aeróbico em ratos com infarto do miocárdio pequeno.

Abstract Background: Physical exercise has been considered an important non-pharmacological therapy for the prevention and treatment of cardiovascular diseases. However, its effects on minor cardiac remodeling are not clear. Objective: To evaluate the influence of aerobic exercise on the 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-AE). The rats exercised on a treadmill three times a week for 12 weeks. An echocardiogram was performed before and after training. The infarction size was evaluated by histology, and gene expression was assessed by RT-PCR. The significance level for statistical analysis was set at 5%. Results: Rats with MI lower than 30% of the LV total area were included in the study. Functional capacity was higher in MI-AE than in Sham and MI-SED rats. The 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. Relative wall thickness was lower in MI-SED than in the MI-AE and Sham groups. Gene expression of the NADPH oxidase subunits NOX2, NOX4, p22phox, and p47phox did not differ between groups. Conclusion: Small-sized MI changes cardiac structure and LV systolic function. Late aerobic exercise is able to improve functional capacity and cardiac remodeling by preserving the left ventricular geometry. NADPH oxidase subunits gene expression is not involved in cardiac remodeling or modulated by aerobic exercise in rats with small-sized MI.

Effects of aerobic and resistance exercise on cardiac remodelling and skeletal muscle oxidative stress of infarcted rats.

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.

Common bean protein hydrolysate modulates lipid metabolism and prevents endothelial dysfunction in BALB/c mice fed an atherogenic diet.

BACKGROUND AND AIMS: Common beans (Phaseolus vulgaris L.) protein hydrolysate is a source of bioactive peptides with known health benefits. The aim of this study was to evaluate the effect of common bean protein hydrolysate on lipid metabolism and endothelial function in male adult BALB/c mice fed an atherogenic diet for nine weeks. METHODS AND RESULTS: Male adult mice were divided into three experimental groups (n = 12) and fed with normal control diet; atherogenic diet and atherogenic diet added with bean protein hydrolysate (700 mg/kg/day) for nine weeks. Food intake, weight gain, lipid profile, Atherogenic Index of Plasma, inflammation biomarkers and endothelial function were evaluated. APH group presented reduced feed intake, weight gain, lipid profile, tumor necrosis factor-α, angiotensin II (94% and 79%, respectively) and increased endothelial nitric oxide synthase (62%). CONCLUSIONS: Protein hydrolysate showed hypocholesterolemic activity preventing inflammation and dysfunction of vascular endothelium, in addition to decreasing oxidative stress, indicating an adjuvant effect on reducing atherogenic risk.

Low-intensity aerobic exercise improves cardiac remodelling of adult spontaneously hypertensive rats.

We evaluated the influence of aerobic training on cardiac remodeling in untreated spontaneously hypertensive rats (SHR). Four experimental groups were used: sedentary (W-SED, n=27) and trained (WEX, n=31) normotensive Wistar rats, and sedentary (SHR-SED, n=27) and exercised (SHR-EX, n=32) hypertensive rats. At 13 months old, trained groups underwent treadmill exercise five days a week for four months. Statistical analysis: ANOVA or Kruskal-Wallis. Exercised groups had higher physical capacity. Hypertensive groups presented left ventricular (LV) concentric hypertrophy with impaired function. Left atrium diameter, LV posterior wall thickness and relative thickness, and isovolumetric relaxation time were lower in SHR-EX than SHR-SED. Interstitial collagen fraction and Type I-Type III collagen ratio were higher in SHR-SED than W-SED. In SHR-EX these parameters had intermediate values between W-EX and SHRSED with no differences between either group. Myocardial matrix metalloproteinase-2 activity, evaluated by zymography, was higher in SHR-SED than W-SED and SHR-EX. TIMP-2 was higher in hypertensive than normotensive groups. In conclusion, low intensity aerobic exercise reduces left atrium dimension and LV posterior wall thickness, and improves functional capacity, diastolic function, and metalloproteinase-2 activity in adult SHR.

Exercise during transition from compensated left ventricular hypertrophy to heart failure in aortic stenosis rats.

We evaluated the influence of aerobic exercise on cardiac remodelling during the transition from compensated left ventricular (LV) hypertrophy to clinical heart failure in aortic stenosis (AS) rats. Eighteen weeks after AS induction, rats were assigned into sedentary (AS) and exercised (AS-Ex) groups. Results were compared to Sham rats. Exercise was performed on treadmill for 8 weeks. Exercise improved functional capacity. Echocardiogram showed no differences between AS-Ex and AS groups. After exercise, fractional shortening and ejection fraction were lower in AS-Ex than Sham. Myocyte diameter and interstitial collagen fraction were higher in AS and AS-Ex than Sham; however, myocyte diameter was higher in AS-Ex than AS. Myocardial oxidative stress, evaluated by lipid hydroperoxide concentration, was higher in AS than Sham and was normalized by exercise. Gene expression of the NADPH oxidase subunits NOX2 and NOX4, which participate in ROS generation, did not differ between groups. Activity of the antioxidant enzyme superoxide dismutase was lower in AS and AS-Ex than Sham and glutathione peroxidase was lower in AS-Ex than Sham. Total and reduced myocardial glutathione, which is involved in cellular defence against oxidative stress, was lower in AS than Sham and total glutathione was higher in AS-Ex than AS. The MAPK JNK was higher in AS-Ex than Sham and AS groups. Phosphorylated P38 was lower in AS-Ex than AS. Despite improving functional capacity, aerobic exercise does not change LV function in AS rats. Exercise restores myocardial glutathione, reduces oxidative stress, impairs JNK signalling and further induces myocyte hypertrophy.

N-Acetylcysteine Influence on Oxidative Stress and Cardiac Remodeling in Rats During Transition from Compensated Left Ventricular Hypertrophy to Heart Failure.

BACKGROUND/AIMS: To evaluate the effects of the antioxidant N-acetylcysteine (NAC) on cardiac structure and function in rats with long-term ascending aortic stenosis (AS). METHODS: Four months after inducing AS, Wistar rats were assigned into the groups Sham, AS, and AS treated with NAC (AS-NAC) and followed for eight weeks. Cardiac structure and function were evaluated by echocardiogram. Myocardial antioxidant enzymes activity was measured by spectrophotometry and malondialdehyde serum concentration by HPLC. Gene expression of NADPH oxidase subunits NOX2, NOX4, p22 phox, and p47 phox was assessed by real time RT-PCR and protein expression of MAPK proteins by Western blot. Statistical analyzes were performed with Goodman and ANOVA or Mann-Whitney Results: NAC restored myocardial total glutathione (Sham 20.8±3.00; AS 12.6±2.92; AS-NAC 17.6±2.45 nmol/g tissue; p<0.05 AS vs Sham and AS-NAC). Malondialdehyde serum concentration was lower in AS-NAC and myocardial lipid hydroperoxide was higher in AS (Sham 199±48.1; AS 301±36.0; AS-NAC 181±41.3 nmol/g tissue). Glutathione peroxidase activity was lower in AS than Sham. Echocardiogram showed LV concentric hypertrophy with systolic and diastolic dysfunction before and after treatment; no differences were observed between AS-NAC and AS groups. NAC reduced p-ERK and p-JNK protein expression, attenuated myocardial fibrosis, and decreased the frequency of right ventricular hypertrophy. CONCLUSION: N-acetylcysteine restores myocardial total glutathione, reduces systemic and myocardial oxidative stress, improves MAPK signaling, and attenuates myocardial fibrosis in aortic stenosis rats.

Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure.

BACKGROUND: Skeletal muscle wasting is often observed in heart failure (HF). The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis is impaired in HF. In this study, we evaluated the effects of GH on soleus muscle and cardiac remodeling in rats with aortic stenosis (AS)-induced HF. METHODS: AS was created by placing a stainless-steel clip on the ascending aorta. After clinically detecting HF, GH (2 mg/kg/day) was subcutaneously injected for 14 days (AS-GH group). Results were compared with those from Sham and non-treated AS groups. Transthoracic echocardiogram was performed before and after treatment. Protein expression was evaluated by Western blot and satellite cells activation by immunofluorescence. Statistical analyzes: ANOVA and Tukey or Kruskal-Wallis and Student-Newman-Keuls. RESULTS: Before treatment both AS groups presented a similar degree of cardiac injury. GH prevented body weight loss and attenuated systolic dysfunction. Soleus cross-sectional fiber areas were lower in both AS groups than Sham (Sham 3,556±447; AS 2,882±422; AS-GH 2,868±591 µm2; p=0.016). GH increased IGF-1 serum concentration (Sham 938±83; AS 866±116; AS-GH 1167±166 ng/mL; p<0.0001) and IGF-1 muscle protein expression and activated PI3K protein. Neural cell adhesion molecule (NCAM) immunofluorescence was increased in both AS groups. Catabolism-related intracellular pathways did not differ between groups. CONCLUSION: Short-term growth hormone attenuates left ventricular systolic dysfunction in rats with aortic stenosis-induced HF. Despite preserving body weight, increasing serum and muscular IGF-1 levels, and stimulating PI3K muscle expression, GH does not modulate soleus muscle trophism, satellite cells activation or intracellular pathways associated with muscle catabolism.

Effects of late exercise on cardiac remodeling and myocardial calcium handling proteins in rats with moderate and large size myocardial infarction.

BACKGROUND: Physical exercise attenuates myocardial infarction (MI)-induced cardiac remodeling. However, it is unsettled whether late exercise modulates post-infarction cardiac remodeling differentially according to infarct size. We investigated the effects of exercise started at late stage heart failure on cardiac remodeling in rats with moderate and large sized MI. METHODS: Three months after MI, rats were assigned into sedentary and exercise groups. Exercise rats underwent treadmill for three months. After assessing infarct size by histological analysis, rats were subdivided into four groups: moderate MI sedentary (Mod MI-Sed; n=7), Mod MI exercised (Mod MI-Ex; n=7), Large MI-Sed (n=11), and Large MI-Ex (n=10). RESULTS: Before exercise, MI-induced cardiac changes were demonstrated by comparing results to a Sham group; alterations were more intense in rats with large than moderate MI size. Systolic function, evaluated by echocardiogram using the variation in LV fractional area change between after and before exercise, was improved in exercise than sedentary groups. Calsequestrin expression increased in exercised compared to sedentary groups. L-type calcium channel was higher in Mod MI-Ex than Mod MI-Sed. SERCA2a, phospholamban, and Na(+)/Ca(2+) exchanger expression did not differ between groups. CONCLUSION: Late exercise improves systolic function and modulates intracellular calcium signaling proteins in rats with moderate and large MI.

Early Spironolactone Treatment Attenuates Heart Failure Development by Improving Myocardial Function and Reducing Fibrosis in Spontaneously Hypertensive Rats.

BACKGROUND: We evaluated the role of the aldosterone blocker spironolactone in attenuating long-term pressure overload-induced cardiac remodeling and heart failure (HF) in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Thirteen month-old male SHR were assigned to control (SHR-C, n=20) or spironolactone (SHR-SPR, 20 mg/kg/day, n=24) groups for six months. Normotensive Wistar-Kyoto rats (WKY, n=15) were used as controls. Systolic blood pressure was higher in SHR groups and unchanged by spironolactone. Right ventricular hypertrophy, which characterizes HF in SHR, was less frequent in SHR-SPR than SHR-C. Echocardiographic parameters did not differ between SHR groups. Myocardial function was improved in SHR-SPR compared to SHR-C [developed tension: WKY 4.85±0.68; SHR-C 5.22±1.64; SHR-SPR 6.80±1.49 g/mm2; -dT/dt: WKY 18.0 (16.0­19.0); SHR-C 20.8 (18.4­25.1); SHR-SPR 28.9 (24.2­34.6) g/mm2/s]. Cardiomyocyte cross-sectional area and total collagen concentration (WKY 1.06±0.34; SHR-C 1.85±0.63; SHR-SPR 1.28±0.39 µg/mg wet tissue) were greater in SHR-C than WKY and SHR-SPR. Type 3 collagen expression was lower in SHR-C than WKY and unchanged by spironolactone. Soluble collagen, type I collagen, and lysyl oxidase did not differ between groups. CONCLUSION: Early spironolactone treatment decreases heart failure development frequency by improving myocardial systolic and diastolic function and attenuating hypertrophy and fibrosis in spontaneously hypertensive rats.

Long-term low intensity physical exercise attenuates heart failure development in aging spontaneously hypertensive rats.

BACKGROUND: Physical exercise is a strategy to control hypertension and attenuate pressure overload-induced cardiac remodeling. The influence of exercise on cardiac remodeling during uncontrolled hypertension is not established. We evaluated the effects of a long-term low intensity aerobic exercise protocol on heart failure (HF) development and cardiac remodeling in aging spontaneously hypertensive rats (SHR). METHODS: Sixteen month old SHR (n=50) and normotensive Wistar-Kyoto (WKY, n=35) rats were divided into sedentary (SED) and exercised (EX) groups. Rats exercised in treadmill at 12 m/min, 30 min/day, 5 days/week, for four months. The frequency of HF features was evaluated at euthanasia. STATISTICAL ANALYSES: ANOVA and Tukey or Mann-Whitney, and Goodman test. RESULTS: Despite slightly higher systolic blood pressure, SHR-EX had better functional capacity and lower HF frequency than SHR-SED. Echocardiography and tissue Doppler imaging showed no differences between SHR groups. In SHR-EX, however, left ventricular (LV) systolic diameter, larger in SHR-SED than WKY-SED, and endocardial fractional shortening, lower in SHR-SED than WKY-SED, had values between those in WKY-EX and SHR-SED not differing from either group. Myocardial function, assessed in LV papillary muscles, showed improvement in SHR-EX over SHR-SED and WKY-EX. LV myocardial collagen fraction and type I and III collagen gene expression were increased in SHR groups. Myocardial hydroxyproline concentration was lower in SHR-EX than SHR-SED. Lysyl oxidase gene expression was higher in SHR-SED than WKY-SED. CONCLUSION: Exercise improves functional capacity and reduces decompensated HF in aging SHR independent of elevated arterial pressure. Improvement in functional status is combined with attenuation of LV and myocardial dysfunction and fibrosis.