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.

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.

Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity. Wistar-Kyoto (n = 40) rats were subjected to control (C; 3.2 kcal/g) and hypercaloric diets (OB; 4.6 kcal/g) for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day) for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE), and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP), echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2), c-Jun amino-terminal kinases (JNK), insulin receptor subunit β (βIR), and phosphatidylinositol 3-kinase (PI3K) by Western Blot. Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated βIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-βRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group. Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes.

Background/Aims: Although increased oxidative stress plays a role in heart failure (HF)-induced skeletal myopathy, signaling pathways involved in muscle changes and the role of antioxidant agents have been poorly addressed. We evaluated the effects of N-acetylcysteine (NAC) on intracellular signaling pathways potentially modulated by oxidative stress in soleus muscle from HF rats. Methods and Results: Four months after surgery, rats were assigned to Sham, myocardial infarction (MI)-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. Oxidative stress was evaluated in serum and soleus muscle; malondialdehyde was higher in MI-C than Sham and did not differ between MI-C and MI-NAC. Oxidized glutathione concentration in soleus muscle was similar in Sham and MI-C, and lower in MI-NAC than MI-C (Sham 0.168 ± 0.056; MI-C 0.223 ± 0.073; MI-NAC 0.136 ± 0.023 nmol/mg tissue; p = 0.014). Western blot showed increased p-JNK and decreased p38, ERK1/2, and p-ERK1/2 in infarcted rats. NAC restored ERK1/2. NF-κB p65 subunit was reduced; p-Ser276 in p65 and IκB was increased; and p-Ser536 unchanged in MI-C compared to Sham. NAC did not modify NF-κB p65 subunit, but decreased p-Ser276 and p-Ser536. Conclusion: N-acetylcysteine modulates MAPK and NF-κB signaling pathways in soleus muscle of HF rats.

The role of tissue vitamin-A insufficiency on post-infarction ventricular remodeling is unknown. We tested the hypothesis that cardiac vitamin A insufficiency on post-infarction is associated with adverse myocardial remodeling. After infarction, rats were allocated into two groups: C (controls, n=25); VA (dietary vitamin A restriction, n= 26). After 3 months, the animals were submitted to echocardiogram, morphometric and biochemical analysis. Rats fed the vitamin-A-deficient diet had lower heart and liver retinol concentration and normal plasma retinol. There were no differences in infarct size between the groups. VA showed higher diastolic left ventricular area normalised by body weight (C= 1.81 ± 0.4 cm2/kg, VA= 2.15 ± 0.3 cm2/kg; p=0.03), left ventricular diameter (C= 9.4 ± 1.4 mm, VA= 10.5 ± 1.2 mm; p=0.04), but similar systolic ventricular fractional area change (C= 33.0 ± 10.0 %, VA= 32.1 ± 8.7 %; p=0.82). VA showed decreased isovolumetric relaxation time normalised by heart rate (C= 68.8 ± 11.4 ms, VA= 56.3 ± 16.8 ms; p=0.04). VA showed higher interstitial collagen fraction (C= 2.8 ± 0.9 %, VA= 3.7 ± 1.1 %; p=0.05). There were no differences in myosin heavy chain expression, metalloproteinase 2 and 9 activation, or IFN-γ and TNF-α cardiac levels. Local tissue vitamin A insufficiency intensified ventricular remodeling after MI, worsening diastolic dysfunction.