A administração precoce de hormônio de crescimento resulta em efeitos deletérios na remodelação ventricular após o infarto agudo do miocárdio

Objective: To assess the effect of growth hormone (GH) on myocardial remodeling in infarcted rats. Methods: This study comprised 24 Wistar rats divided into 3 groups as follows: 1) AMI-GH group - comprising 8 rats that underwent infarction and were treated with GH; 2) AMI group - comprising 8 rats that underwent infarction and received only the diluent of the GH solution; and 3) control group (C group) - comprising 8 rats that underwent simulated infarction. After 30 days, the animals underwent functional study through echocardiography, and the changes in myocardial contractility of the isolated left ventricular (LV) papillary muscle were studied. Results: The echocardiography identified an increase in the diastolic (C=7.32±0.49; AMI=8.50±0.73; AMI-GH=9.34±0.73; P<0.05) and systolic (C=3.38±0.47, AMI=5.16±1.24; AMI-GH=5.96±1.54; P<0.05) diameters (mm) in the LV of the infarcted animals. The AMI-GH group animals had a lower ejection fraction (%) (C=0.9±0.03; AMI=0.76±0.12; AMI-GH=0.72± 0.14; P<0.05 for C vs AMI-GH) compared with those in controls. The study of the isolated left ventricular papillary muscle showed that the AMI-GH group had changes (C=1.50±0.59; AMI= 1.28±0.38; AMI-GH=1.98±0.41; P<0.05 for C vs AMI-GH) only in the tension at rest (TR - g/mm2) and in the time delta for a 50% decrease in the tension developed (TR50, ms) after stimulation with calcium (C=23.75±9.16; AMI=-16.56±14.82; AMI-GH=-4.69±8.39; P<0.05 for C vs AMI-GH) and in the delta of tension developed (TD, g/mm2) after stimulation with isoproterenol (C=0.99±0.17; AMI=0.54±0.62; AMI-GH=0.08±0.75; P<0.05 for C vs AMI-GH) compared with those in control animals. Conclusion: The early administration of GH in the experimental infarction model in rats may result in adverse effects on the process of ventricular remodeling.

Retinoic acid supplementation attenuates ventricular remodeling after myocardial infarction in rats

The objective of this study was to evaluate the role of retinoic acid in experimental postinfarction myocardial remodeling. Wistar rats were subjected to myocardial infarction (MI) and treated with retinoic acid (RA), 0.3 mg/(kg · d) (MI-RA, n = 29), or fed a control diet (MI, n = 34). After 6 mo, the surviving rats (MI-RA = 18 and MI = 22) underwent echocardiograms, and isolated hearts were tested for function in vitro. The cross-sectional area of the myocyte (CSA) and interstitial collagen fraction (IC) were measured in a cross section of the heart stained by hematoxylin-eosin and picrosirius red, respectively. The CSA was smaller in the MI-RA group [229 (220, 234) μm 2] [medians (lower quartile, upper quartile)] than in the MI group [238 (232, 241) μm 2] (P = 0.01) and IC was smaller in the MI-RA group [2.4 (1.7, 3.1)%] than in the MI group [3.5 (2.6, 3.9)%] (P = 0.05). The infarct size did not differ between the groups [MI = 44.6 (40.8, 48.4)%, MI-RA = 45 (38.6, 47.2)%]. Maximum rate of rise of left ventricular pressure (+dp/dt) was greater in the MI-RA group (2645 ± 886 mm Hg/s) than in the MI group (2081 ± 617 mm Hg/s) (P = 0.05). The other variables tested did not differ between groups. Retinoic acid supplementation of rats for 6 mo attenuates the ventricular remodeling process after MI. © 2005 American Society for Nutrition.

Ventricular systolic reserve in asymptomatic children previously treated with low doses of anthracyclines: A longitudinal, prospective exercise echocardiography study

Background: The time course of mild cardiotoxicity induced by anthracycline remains unknown. The aim of this study was to evaluate the long-term evolution of decreased myocardial reserve in children previously treated with a cumulative dose of anthracycline up to 100mg/m 2. Patients and Methods: Twenty-seven asymptomatic cancer survival patients (25 with lymphoblastic leukemia), in continuous remission and off treatment for >12 months with no alterations in conventional echocardiograms were evaluated by exercise echocardiography at 37±15.4 months (T1) and 101±24 months (T2) after finishing treatment (ADRIA group). This group was compared with 25 healthy individuals (control group) similar to the ADRIA group with respect to age and body surface area (BSA). All individuals underwent treadmill exercise testing according to Bruce protocol. Echocardiograms were performed before and immediately after exercise. Results: The groups were similar regarding cardiac structure and left ventricular (LV) systolic function at rest at T1 and T2. The growth of LV posterior wall thickness related to BSA was lower in the ADRIA group at T2. Post exercise, smaller LV ejection indexes and attenuated changes in the afterload in ADRIA group were observed at T1 and T2. Conclusion: The decreased systolic reserve induced by a low dose of anthracycline in asymptomatic children and adolescents remains unaffected over a 5-year period, suggesting that positive outcomes in chronic cardiotoxicity would be expected in patients with mild impairment after anthracycline treatment. © 2011 Wiley Periodicals, Inc.

Impacto do padrão geométrico ventricular na remodelação cardíaca após o infarto do miocárdio

BACKGROUND: The relevance of left ventricular (LV) geometric pattern after myocardial infarction is not known. OBJECTIVES: To analyze the presence of different LV geometric patterns and teir impact as a predictor of remodeling in patients with myocardial infarction. METHODS: Patients with anterior acute myocardial infarction (n = 80) were divided according to the geometric pattern: normal (normal left ventricular mass index [LVMI] and normal relative wall thickness [RWT]), concentric remodeling (normal LVMI and increased RWT), concentric hypertrophy (increased LVMI and RWT) and eccentric hypertrophy (increased LVMI and normal RWT). After six months, echocardiographic assessment was repeated. RESULTS: Four patients died. Of the survivors, 41 showed remodeling (R +), whereas 39 did not (R-). Considering the geometric pattern, the cases were distributed as follows: 24 patients with normal pattern, 13 with concentric remodeling, 29 with concentric hypertrophy and 14 with eccentric hypertrophy. Patients who showed remodeling had larger infarction sizes analyzed by peak CPK (R + = 4,610 (1,688-7,970), R- = 1,442 (775-4247), p <0.001) and CK-MB (R + = 441 (246 - 666), R- = 183 (101-465), p <0.001), trend towards higher prevalence of concentric remodeling (R+ = 10, R- = 3, p = 0.08) and lower prevalence of eccentric hypertrophy (R + = 2 R- = 12, p = 0.006). In the multivariate regression analysis, infarction size was a predictor (OR = 1.01, p = 0.020) and eccentric hypertrophy was a protective factor (OR = 0.189, p = 0.046) of ventricular remodeling after coronary occlusion. CONCLUSION: The LV geometric pattern of can have an impact on the remodeling process in patients with myocardial infarction.

Pretransplant pulmonary hypertension and long-term allograft right ventricular function

Graft right ventricular (RV) function is compromised directly posttransplant, especially in heart transplantation (HTx) recipients with pretransplant pulmonary hypertension (PH). Graft RV size and systolic function, and the effect of the recipient's pulmonary haemodynamics on the graft extracellular matrix are not well characterised in the patients long-term after HTx.

Reversal of myocyte hypertrophy by ventricular unloading: cardiac improvement without adrenergic receptor up-regulation and relocalization.

In previous studies, we found that the improved contractile ability of cardiac myocytes from patients who have had left ventricular assist device (LVAD) support was due to a number of beneficial changes, most notably in calcium handling (increased sarcoplasmic reticulum calcium binding and uptake), improved integrity of cell membranes due to phospholipid reconstruction (reduced lysophospholipid content), and an upregulation of adrenoreceptors (increased adrenoreceptor numbers). However, in the case presented here, there was no increase in adrenoreceptor number, which is something that we usually find in core tissue at the time of LVAD removal or organ transplantation; also, there was no homogeneous postassist device receptor distribution. However, the patient was well maintained for 10 months following LVAD implantation, until a donor organ was available, regardless of the lack of adrenoreceptor improvement. We conclude from these studies that cardiac recovery is the result of the initiation of multiple repair mechanisms, and that the lack of expected changes, in this case increased adrenoreceptors, is not always an accurate indicator of anticipated outcome. We suggest that interventions and strategies have to consider multiple, beneficial changes due to unloading and target a number of biochemical and structural areas to produce improvement, even if not all of these improvements occur.

Estudo ecocardiográfico da função ventricular esquerda em pacientes com lúpus eritematoso sistêmico juvenil através da técnica de Speckle-Tracking bidimensional

Objetivo: O principal propósito do estudo foi pesquisar a disfunção ventricular esquerda subclínica em pacientes com lúpus eritematoso sistêmico juvenil (LESJ) através da técnica de speckle-tracking bidimensional. Foi investigada ainda uma possível correlação entre o comprometimento da deformação miocárdica e o SLEDAI-2K (Systemic Lupus Erithematosus Disease Activity Index 2000), bem como a presença de fatores de risco cardiovascular, tanto tradicionais como ligados à doença. Métodos: 50 pacientes assintomáticos do ponto de vista cardiovascular e 50 controles saudáveis (14,74 vs. 14,82 anos, p=0.83) foram avaliados pelo ecocardiograma convencional e pelo speckle-tracking bidimensional. Resultados: Apesar da fração de ejeção normal, os pacientes apresentaram redução de todos os parâmetros de deformação miocárdica longitudinal e radial, quando comparados aos controles: strain de pico sistólico longitudinal [-20,3 (-11 a -26) vs. -22 (-17,8 a -30.4) %, p < 0,0001], strain rate de pico sistólico longitudinal [-1,19 ± 0,21 vs. -1,3 ± 0,25 s-1, p=0,0005], strain rate longitudinal na diástole precoce [1,7 (0,99 a 2,95) vs. 2 (1,08 a 3,00) s-1 , p=0,0034], strain de pico sistólico radial [33,09 ± 8,6 vs. 44,36 ± 8,72%, p < 0,0001], strain rate de pico sistólico radial [1,98 ± 0,53 vs. 2,49 ± 0,68 s-1, p < 0,0001] e strain rate radial na diástole precoce [-2,31 ± 0,88 vs. -2,75 ± 0,97 s-1, p=0,02]. O strain de pico sistólico circunferencial [-23,67 ± 3,46 vs. - 24,6 ± 2,86%, p=0,43] e o strain rate circunferencial na diástole precoce [2 (0,88 a 3,4) vs. 1,99 (1,19 a 3,7) s-1, p=0,88] foram semelhantes em pacientes e controles. Apenas o strain rate de pico sistólico circunferencial [-1,5 ± 0,3 vs. -1,6 ± 0,3 s-1, p=0,036] mostrou-se reduzido no LESJ. Uma correlação negativa foi identificada entre o strain de pico sistólico longitudinal e o SLEDAI-2K (r = - 0,52; p < 0,0001) e também o número de fatores de risco cardiovascular por paciente (r = -0,32, p=0,024). Conclusões: Foi evidenciada disfunção sistólica e diastólica subclínica de ventrículo esquerdo no LESJ através da técnica de speckle-tracking bidimensional. A atividade da doença e a exposição aos fatores de risco cardiovascular provavelmente contribuíram para o comprometimento da deformação miocárdica nesses pacientes

Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. METHODS AND RESULTS: To better understand the role of beta(3)ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human beta(3)AR (TGbeta(3) mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous beta(1)- and beta(2)ARs, isoproterenol resulted in an increase in contractility in the TGbeta(3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta(3)AR agonist L-755,507 significantly increased contractility in the TGbeta(3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGbeta(3) mice was investigated in terms of beta(3)AR-G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGbeta(3) mice with L-755,507 resulted in a pertussis toxin-insensitive 1.33-fold increase in [(35)S]GTPgammaS loading and a 1.6-fold increase in adenylyl cyclase activity. CONCLUSIONS: Cardiac overexpression of human beta(3)ARs results in positive inotropy only on stimulation with a beta(3)AR agonist. Overexpressed beta(3)ARs couple to G(s) and activate adenylyl cyclase on agonist stimulation.

Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

Transgenic overexpression (40- to 100-fold) of the wild-type human beta2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) activity inherent in the receptor. Here we report that transgenic mice expressing a mutated constitutively active form of the receptor (CAM) show no such phenotype, owing to its modest expression (3-fold above endogenous cardiac beta-adrenergic receptor levels). Surprisingly, treatment of the animals with a variety of beta-adrenergic receptor ligands leads to a 50-fold increase in CAM beta2-adrenergic receptor expression, by stabilizing the CAM beta2-adrenergic receptor protein. Receptor up-regulation leads in turn to marked increases in adenylate cyclase activity, atrial tension determined in vitro, and indices of cardiac contractility determined in vivo. These results illustrate a novel mechanism for regulating physiological responses, i.e., ligand-induced stabilization of a constitutively active but inherently unstable protein.