Exercise training decreases myocardial collagen III and heart failure signs rate, and improves physical performance in spontaneously hypertensive rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Obesity does not lead to imbalance between myocardial phospholamban phosphorylation and dephosphorylation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Direct effects of colchicine on myocardial function: studies in hypertrophied and failing spontaneously hypertensive rats

The aging spontaneously hypertensive rat (SHR) is a model in which the transition from chronic stable left ventricular hypertrophy to overt heart failure can be observed. Although the mechanisms for impaired function in hypertrophied and failing cardiac muscle from the SHR have been studied, none accounts fully for the myocardial contractile abnormalities. The cardiac cytoskeleton has been implicated as a possible cause for myocardial dysfunction. If an increase in microtubules contributes to dysfunction, then myocardial microtubule disruption by colchicine should promote an improvement in cardiac performance. We studied the active and passive properties of isolated left ventricular papillary muscles from 18- to 24-month-old SHR with evidence of heart failure (SHR-F, n=6), age-matched SHR without heart failure (SHR-NF, n=6), and age-matched normotensive Wistar-Kyoto rats (WKY, n=5). Mechanical parameters were analyzed before and up to 90 minutes after the addition of colchicine (10(-5), 10(-4), and 10(-3) mol/L). In the baseline state, active tension (AT) developed by papillary muscles from the WKY group was greater than for SHR-NF and SHR-F groups (WKY 5.69+/-1.47 g/mm2 [mean+/-SD], SHR-NF 3.41+/-1.05, SHR-F 2.87+/-0.26; SHR-NF and SHR-F P<0.05 versus WKY rats). The passive stiffness was greater in SHR-F than in the WKY and SHR-NF groups (central segment exponential stiffness constant, Kcs: SHR-F 70+/-25, SHR-NF 44+/-17, WKY 41+/-13 [mean+/-SD]; SHR-F P<0.05 versus SHR-NF and WKY rats). AT did not improve after 10, 20, and 30 minutes of exposure to colchicine (10(-5), 10(-4), and 10(-3) mol/L) in any group. In the SHR-F group, AT and passive stiffness did not change after 30 to 90 minutes of colchicine exposure (10(-4) mol/L). In summary, the data in this study fail to demonstrate improvement of intrinsic muscle function in SHR with heart failure after colchicine. Thus, in the SHR there is no evidence that colchicine-induced cardiac microtubular depolymerization affects the active or passive properties of hypertrophied or failing left ventricular myocardium.

Myocardial contractility impairment with racemic bupivacaine, non-racemic bupivacaine and ropivacaine. A comparative study

To study racemic bupivacaine, non-racemic bupivacaine and ropivacaine on myocardial contractility. Isolated Wistar papillary muscles were submitted to 50 and 100 mM racemic bupivacaine (B50 and B100), non-racemic bupivacaine (NR50 and NR100) and ropivacaine (R50 and R100) intoxication. Isometric contraction data were obtained in basal condition (0.2 Hz), after increasing the frequency of stimulation to 1.0 Hz and after 5, 10 and 15 min of local anesthetic intoxication. Data were analyzed as relative changes of variation. Developed tension was higher with R100 than B100 at D1 (4.3 ± 41.1 vs -57.9 ± 48.1). Resting tension was altered with B50 (-10.6 ± 23.8 vs -4.7 ± 5.0) and R50 (-14.0 ± 20.5 vs -0.5 ± 7.1) between D1 and D3. Maximum rate of tension development was lower with B100 (-56.6 ± 38.0) than R50 (-6.3 ± 37.9) and R100 (-1.9 ± 37.2) in D1. B50, B100 and NR100 modified the maximum rate of tension decline from D1 through D2. Time to peak tension was changed with NR50 between D1 and D2. Racemic bupivacaine depressed myocardial contractile force more than non-racemic bupivacaine and ropivacaine. Non-racemic and racemic bupivacaine caused myocardial relaxation impairment more than ropivacaine.

Rutin administration attenuates myocardial dysfunction in diabetic rats

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

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.

Metalloproteinases-2 and -9 predict left ventricular remodeling after myocardial infarction

Background: The role of serum metalloproteinases (MMP) after myocardial infarction (MI) is unknown. Objective: The aim of this study was to evaluate the role of serum MMP-2 and -9 as predictors of ventricular remodeling six months after anterior MI. Methods: We prospectively enrolled patients after their first anterior MI. MMP activity was assayed 12 to 72 hours after the MI. An echocardiogram was performed during the hospitalization and six months later. Results: We included 29 patients; 62% exhibited ventricular remodeling. The patients who exhibited remodeling had higher infarct size based on creatine phosphokinase (CPK) peak values (p = 0.037), higher prevalence of in-hospital congestive heart failure (p = 0.004), and decreased ejection fraction (EF) (p = 0.007). The patients with ventricular remodeling had significantly lower serum levels of inactive MMP-9 (p = 0.007) and significantly higher levels of the active form of MMP-2 (p = 0.011). In a multivariate logistic regression model, adjusted by age, CPK peak, EF and prevalence of heart failure, MMP-2 and -9 serum levels remained associated with remodeling (p = 0.033 and 0.044, respectively). Conclusion: Higher serum levels of inactive MMP-9 were associated with the preservation of left ventricular volumes, and higher serum levels of the active form of MMP-2 were a predictor of remodeling 6 months after MI. (Arq Bras Cardiol. 2013;100(4):315-321).

In Patients With Acute Myocardial Infarction, the Impact of Hyperglycemia as a Risk Factor for Mortality Is Not Homogeneous Across Age-Groups

OBJECTIVE To assess the impact of hyperglycemia in different age-groups of patients with acute myocardial infarction (AM I). RESEARCH DESIGN AND METHODS A total of 2,027 patients with AMI were categorized into one of five age-groups: <50 years (n = 301), >= 50 and <60 (n = 477),>= 60 and <70 (n = 545), >= 70 and <80 (n = 495), and years (n = 209). Hyperglycemia was defined as initial glucose >= 115 mg/dL. RESULTS The adjusted odds ratios for hyperglycemia predicting hospital mortality in groups 1-5 were, respectively, 7.57 (P = 0.004), 3.21 (P 0.046), 3.50 (P = 0.003), 3.20 (P < 0.001.), and 2.16 (P = 0.021). The adjusted P values for correlation between glucose level (as a continuous variable) and mortality were 0.007, <0.001, 0.043, <0.001, and 0.064. The areas under the ROC curves (AUCs) were 0.785, 0.709, 0.657, 0.648, and 0.613. The AUC in group 1 was significantly higher than those in groups 3-5. CONCLUSIONS The impact of hyperglycemia as a risk factor for hospital mortality in AMI is more pronounced in younger patients.

Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes

BACKGROUND Vorapaxar is a new oral protease-activated receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5010 vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.)

Renal Function at Hospital Admission and Mortality Due to Acute Kidney Injury after Myocardial Infarction

Background: The role of an impaired estimated glomerular filtration rate (eGFR) at hospital admission in the outcome of acute kidney injury (AKI) after acute myocardial infarction (AMI) has been underreported. The aim of this study was to assess the influence of an admission eGFR<60 mL/min/1.73 m(2) on the incidence and early and late mortality of AMI-associated AKI. Methods: A prospective study of 828 AMI patients was performed. AKI was defined as a serum creatinine increase of >= 50% from the time of admission (RIFLE criteria) in the first 7 days of hospitalization. Patients were divided into subgroups according to their eGFR upon hospital admission (MDRD formula, mL/min/1.73 m(2)) and the development of AKI: eGFR >= 60 without AKI, eGFR<60 without AKI, eGFR >= 60 with AKI and eGFR<60 with AKI. Results: Overall, 14.6% of the patients in this study developed AKI. The admission eGFR had no impact on the incidence of AKI. However, the admission eGFR was associated with the outcome of AMI-associated AKI. The adjusted hazard ratios (AHR, Cox multivariate analysis) for 30-day mortality were 2.00 (95% CI 1.11-3.61) for eGFR, 60 without AKI, 4.76 (95% CI 2.45-9.26) for eGFR >= 60 with AKI and 6.27 (95% CI 3.20-12.29) for eGFR, 60 with AKI. Only an admission eGFR of <60 with AKI was significantly associated with a 30-day to 1-year mortality hazard (AHR 3.05, 95% CI 1.50-6.19). Conclusions: AKI development was associated with an increased early mortality hazard in AMI patients with either preserved or impaired admission eGFR. Only the association of impaired admission eGFR and AKI was associated with an increased hazard for late mortality among these patients.

Twelve-month clinical outcomes after coronary stenting with the Genous Bio-engineered R Stent in patients with a bifurcation lesion: from the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) registry

Background The e-Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth (e-HEALING) registry was designed to capture clinical data on the use of the endothelial progenitor cell capture stent (ECS) in routine clinical practice. In this analysis, we investigated the 12-month clinical outcomes in patients treated with an ECS for a bifurcation lesion. Methods The worldwide, prospective, nonrandomized e-HEALING registry aimed to enrol 5000 patients treated for coronary artery disease with one or more ECS between October 2005 and October 2007. Clinical follow-up was obtained at 1, 6, and 12 months. The primary endpoint was target vessel failure (TVF), defined as the composite of cardiac death, myocardial infarction, and target vessel revascularization at 12 months. Results A total of 573 patients were treated for at least one bifurcation lesion and were assessed in the current analysis. Baseline characteristics showed a median age of 65 years; 21% were diabetic patients and 36% had unstable angina. A total of 63% of the bifurcation lesions were located in the left artery descending and the mean stent length was 20.7 +/- 12.6 mm. At 12 months, TVF was 12.7% and target lesion revascularization was 7.5%. Definite or probable stent thrombosis occurred in 1.7% of the patients. Moreover, one or more stents per lesion [hazard ratio (HR): 2.79, 95% confidence interval (CI): 1.60-4.86, P < 0.001], predilatation (HR: 0.39, 95% CI: 0.17-0.87, P = 0.023), and lesions located in the right coronary artery (HR: 4.56, 95% CI: 1.07-19.5, P = 0.041) were independent predictors of TVF. Conclusion In the e-HEALING registry, coronary bifurcation stenting with the ECS results in favorable clinical outcomes and low incidences of repeat revascularization and stent thrombosis. Coron Artery Dis 23:201-207 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Glucose Control in Acute Myocardial Infarction: A Pilot Randomized Study Controlled by Continuous Glucose Monitoring System Comparing the Use of Insulin Glargine with Standard of Care

Background: This pilot study aimed to verify if glycemic control can be achieved in type 2 diabetes patients after acute myocardial infarction (AMI), using insulin glargine (iGlar) associated with regular insulin (iReg), compared with the standard intensive care unit protocol, which uses continuous insulin intravenous delivery followed by NPH insulin and iReg (St. Care). Patients and Methods: Patients (n = 20) within 24 h of AMI were randomized to iGlar or St. Care. Therapy was guided exclusively by capillary blood glucose (CBG), but glucometric parameters were also analyzed by blinded continuous glucose monitoring system (CGMS). Results: Mean glycemia was 141 +/- 39 mg/dL for St. Care and 132 +/- 42 mg/dL for iGlar by CBG or 138 +/- 35 mg/dL for St. Care and 129 +/- 34 mg/dL for iGlar by CGMS. Percentage of time in range (80-180 mg/dL) by CGMS was 73 +/- 18% for iGlar and 77 +/- 11% for St. Care. No severe hypoglycemia (<= 40 mg/dL) was detected by CBG, but CGMS indicated 11 (St. Care) and seven (iGlar) excursions in four subjects from each group, mostly in sulfonylurea users (six of eight patients). Conclusions: This pilot study suggests that equivalent glycemic control without increase in severe hyperglycemia may be achieved using iGlar with background iReg. Data outputs were controlled by both CBG and CGMS measurements in a real-life setting to ensure reliability. Based on CGMS measurements, there were significant numbers of glycemic excursions outside of the target range. However, this was not detected by CBG. In addition, the data indicate that previous use of sulfonylurea may be a potential major risk factor for severe hypoglycemia irrespective of the type of insulin treatment.

Early detection of doxorubicin myocardial injury by ultrasonic tissue characterization in an experimental animal model

In the clinical setting, the early detection of myocardial injury induced by doxorubicin (DXR) is still considered a challenge. To assess whether ultrasonic tissue characterization (UTC) can identify early DXR-related myocardial lesions and their correlation with collagen myocardial percentages, we studied 60 rats at basal status and prospectively after 2mg/Kg/week DXR endovenous infusion. Echocardiographic examinations were conducted at baseline and at 8,10,12,14 and 16 mg/Kg DXR cumulative dose. The left ventricle ejection fraction (LVEF), shortening fraction (SF), and the UTC indices: corrected coefficient of integrated backscatter (IBS) (tissue IBS intensity/phantom IBS intensity) (CC-IBS) and the cyclic variation magnitude of this intensity curve (MCV) were measured. The variation of each parameter of study through DXR dose was expressed by the average and standard error at specific DXR dosages and those at baseline. The collagen percent (%) was calculated in six control group animals and 24 DXR group animals. CC-IBS increased (1.29 +/- 0.27 x 1.1 +/- 0.26-basal; p=0.005) and MCV decreased (9.1 +/- 2.8 x 11.02 +/- 2.6-basal; p=0.006) from 8 mg/Kg to 16mg/Kg DXR. LVEF presented only a slight but significant decrease (80.4 +/- 6.9% x 85.3 +/- 6.9%-basal, p=0.005) from 8 mg/Kg to 16 mg/Kg DXR. CC-IBS was 72.2% sensitive and 83.3% specific to detect collagen deposition of 4.24%(AUC=0.76). LVEF was not accurate to detect initial collagen deposition (AUC=0.54). In conclusion: UTC was able to early identify the DXR myocardial lesion when compared to LVEF, showing good accuracy to detect the initial collagen deposition in this experimental animal model.

Duration of dual antiplatelet therapy and outcomes after coronary stenting with the genous (TM) bio-engineered R stent (TM) in patients from the e-healing registry

Objective: We investigated the relation between duration of dual antiplatelet therapy (DAPT) and clinical outcomes up to 12 months after Genous (TM) endothelial progenitor cell capturing R stent (TM) placement in patients from the e-HEALING registry. Background: Cessation of (DAPT) has been shown to be associated with the occurrence of stent thrombosis (ST). After Genous placement, 1 month of DAPT is recommended. Methods: Patients were analyzed according to continuation or discontinuation of DAPT at a 30-day and 6-month landmark, excluding patients with events before the landmark. Each landmark was a new baseline, and outcomes were followed up to 12 months after stenting. The main outcome for our current analysis was target vessel failure (TVF), defined as target vessel-related cardiac death or myocardial infarction and target vessel revascularization. Secondary outcomes included ST. (Un)adjusted hazard ratios (HR) for TVF were calculated with Cox regression. Results: No difference was observed in the incidence of TVF [HR: 1.03; 95% confidence intervals (CI): 0.651.65, P = 0.89] in patients continuing DAPT (n = 4,249) at 30 days versus patients stopped (n = 309), and HR: 0.82 (95% CI: 0.551.23, P = 0.34) in patients continuing DAPT (n = 2,654) at 6 months versus patients stopped [n = 1,408] DAPT). Furthermore, no differences were observed in ST. Even after addition of identified independent predictors for TVF, adjusted TVF hazards were comparable. Conclusions: In a post-hoc analysis of e-HEALING, duration of DAPT was not associated with the occurrence of the outcomes TVF or ST. The Genous stent may be an attractive treatment especially in patients at increased risk for (temporary) cessation of DAPT or bleeding. (C) 2011 Wiley Periodicals, Inc.