Relationship between microalbuminuria and cardiac structural changes in mild hypertensive patients

The aim of this study was to determine the relationship between urinary albumin excretion (UAE), cardiac structural changes upon echocardiography and 24-h ambulatory blood pressure (ABPM) levels. Twenty mild hypertensive patients (mean age 56.8 ± 9.6 years) were evaluated. After 2 weeks of a washout period of all antihypertensive drugs, all patients underwent an echocardiographic evaluation, a 24-h ABPM and an overnight urine collection. Systolic and diastolic blood pressure during 24-h ABPM was 145 ± 14/91 ± 10 mmHg (daytime) and 130 ± 14/76 ± 8 mmHg (nighttime), respectively. Seven (35%) patients presented UAE > or = 15 µg/min, and for the whole group, the geometric mean value for UAE was 10.2 x/÷ 3.86 µg/min. Cardiac measurements showed mean values of interventricular septum thickness (IVS) of 11 ± 2.3 mm, left ventricular posterior wall thickness (PWT) of 10 ± 2.0 mm, left ventricular mass (LVM) of 165 ± 52 g, and left ventricular mass index (LVMI) of 99 ± 31 g/m². A forward stepwise regression model indicated that blood pressure levels did not influence UAE. Significant correlations were observed between UAE and cardiac structural parameters such as IVS (r = 0.71, P<0.001), PWT (r = 0.64, P<0.005), LVM (r = 0.65, P<0.005) and LVMI (r = 0.57, P<0.01). Compared with normoalbuminuric patients, those who had microalbuminuria presented higher values of all cardiac parameters measured. The predictive positive and negative values of UAE > or = 15 µg/min for the presence of geometric cardiac abnormalities were 75 and 91.6%. These data indicate that microalbuminuria in essential hypertension represents an early marker of cardiac structural damage.

Effects of losartan combined with exercise training in spontaneously hypertensive rats

We investigate whether combined treatment with losartan, an angiotensin II receptor blocker, and exercise training (ET) in spontaneously hypertensive rats (SHR) would have an additive effect in reducing hypertension and improving baroreflex sensitivity when compared with losartan alone. Male SHR (8 weeks old) were assigned to 3 groups: sedentary placebo (SP, N = 16), sedentary under losartan treatment (SL, N = 11; 10 mg kg-1 day-1, by gavage), and ET under losartan treatment (TL, N = 10). ET was performed on a treadmill 5 days/week for 60 min at 50% of peak VO2, for 18 weeks. Blood pressure (BP) was measured with a catheter inserted into the carotid artery, and cardiac output with a microprobe placed around the ascending aorta. The baroreflex control of heart rate was assessed by administering increasing doses of phenylephrine and sodium nitroprusside (iv). Losartan significantly reduced mean BP (178 ± 16 vs 132 ± 12 mmHg) and left ventricular hypertrophy (2.9 ± 0.4 vs 2.5 ± 0.2 mg/g), and significantly increased baroreflex bradycardia and tachycardia sensitivity (1.0 ± 0.3 vs 1.7 ± 0.5 and 2.0 ± 0.7 vs 3.2 ± 1.7 bpm/mmHg, respectively) in SL compared with SP. However, losartan combined with ET had no additional effect on BP, baroreflex sensitivity or left ventricular hypertrophy when compared with losartan alone. In conclusion, losartan attenuates hypertension and improves baroreflex sensitivity in SHR. However, ET has no synergistic effect on BP in established hypertension when combined with losartan, at least at the dosage used in this investigation.

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 µg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 µg kg-1 h-1, sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1ß concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.

The association of ACE gene D/I polymorphism with cardiovascular risk factors in a population from Rio de Janeiro

Our aim was to determine the frequencies of the angiotensin-converting enzyme (ACE) gene alleles D and I and any associations to cardiovascular risk factors in a population sample from Rio de Janeiro, Brazil. Eighty-four adults were selected consecutively during a 6-month period from a cohort subgroup of a previous large cross-sectional survey in Rio de Janeiro. Anthropometric data and blood pressure measurements, echocardiogram, albuminuria, glycemia, lipid profile, and ACE genotype and serum enzyme activity were determined. The frequency of the ACE*D and I alleles in the population under study, determined by PCR, was 0.59 and 0.41, respectively, and the frequencies of the DD, DI, and II genotypes were 0.33, 0.51, and 0.16, respectively. No association between hypertension and genotype was detected using the Kruskal-Wallis method. Mean plasma ACE activity (U/mL) in the DD (N = 28), DI (N = 45) and II (N = 13) groups was 43 (in males) and 52 (in females), 37 and 39, and 22 and 27, respectively; mean microalbuminuria (mg/dL) was 1.41 and 1.6, 0.85 and 0.9, and 0.6 and 0.63, respectively; mean HDL cholesterol (mg/dL) was 40 and 43, 37 and 45, and 41 and 49, respectively, and mean glucose (mg/dL) was 93 and 108, 107 and 98, and 85 and 124, respectively. A high level of ACE activity and albuminuria, and a low level of HDL cholesterol and glucose, were found to be associated with the DD genotype. Finally, the II genotype was found to be associated with variables related to glucose intolerance.

Kinetics of cardiac and vascular remodeling by spontaneously hypertensive rats after discontinuation of long-term captopril treatment

Angiotensin-converting enzyme inhibitors reduce blood pressure and attenuate cardiac and vascular remodeling in hypertension. However, the kinetics of remodeling after discontinuation of the long-term use of these drugs are unknown. Our objective was to investigate the temporal changes occurring in blood pressure and vascular structure of spontaneously hypertensive rats (SHR). Captopril treatment was started in the pre-hypertensive state. Rats (4 weeks) were assigned to three groups: SHR-Cap (N = 51) treated with captopril (1 g/L) in drinking water from the 4th to the 14th week; SHR-C (N = 48) untreated SHR; Wistar (N = 47) control rats. Subgroups of animals were studied at 2, 4, and 8 weeks after discontinuation of captopril. Direct blood pressure was recorded in freely moving animals after femoral artery catheterism. The animals were then killed to determine left ventricular hypertrophy (LVH) and the aorta fixed at the same pressure measured in vivo. Captopril prevented hypertension (105 ± 3 vs 136 ± 5 mmHg), LVH (2.17 ± 0.05 vs 2.97 ± 0.14 mg/g body weight) and the increase in cross-sectional area to luminal area ratio of the aorta (0.21 ± 0.01 vs 0.26 ± 0.02 μm²) (SHR-Cap vs SHR-C). However, these parameters increased progressively after discontinuation of captopril (22nd week: 141 ± 2 mmHg, 2.50 ± 0.06 mg/g, 0.27 ± 0.02 μm²). Prevention of the development of hypertension in SHR by using captopril during the prehypertensive period prevents the development of cardiac and vascular remodeling. Recovery of these processes follows the kinetic of hypertension development after discontinuation of captopril.

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of the hemodynamic overload into myocardial growth are poorly understood. This review summarizes the physiological stimuli that induce concentric and eccentric physiological hypertrophy, and discusses the molecular mechanisms, sarcomeric organization, and signaling pathway involved, also showing that the cardiac markers of pathological hypertrophy (atrial natriuretic factor, β-myosin heavy chain and α-skeletal actin) are not increased. There is no fibrosis and no cardiac dysfunction in eccentric or concentric hypertrophy induced by exercise training. Therefore, the renin-angiotensin system has been implicated as one of the regulatory mechanisms for the control of cardiac function and structure. Here, we show that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotensin II. Recently, microRNAs (miRs) have been investigated as a possible therapeutic approach since they regulate the translation of the target mRNAs involved in cardiac hypertrophy; however, miRs in relation to physiological hypertrophy have not been extensively investigated. We summarize here profiling studies that have examined miRs in pathological and physiological cardiac hypertrophy. An understanding of physiological cardiac remodeling may provide a strategy to improve ventricular function in cardiac dysfunction.

Left Ventricular Diastolic Function in Essential Hypertensive Patients: Influence of Age and Left Ventricular Geometry

PURPOSE - To evaluate diastolic dysfunction (DD) in essential hypertension and the influence of age and cardiac geometry on this parameter. METHODS - Four hundred sixty essential hypertensive patients (HT) underwent Doppler echocardiography to obtain E/A wave ratio (E/A), atrial deceleration time (ADT), and isovolumetric relaxation time (IRT). All patients were grouped according to cardiac geometric patterns (NG - normal geometry; CR - concentric remodeling; CH- concentric hypertrophy; EH - eccentric hypertrophy) and to age (<40; 40 - 60; >60 years). One hundred six normotensives (NT) persons were also evaluated. RESULTS - A worsening of diastolic function in the HT compared with the NT, including HT with NG (E/A: NT - 1.38±0.03 vs HT - 1.27±0.02, p<0.01), was observed. A higher prevalence of DD occurred parallel to age and cardiac geometry also in the prehypertrophic groups (CR). Multiple regression analysis identified age as the most important predictor of DD (r²=0.30, p<0.01). CONCLUSION - DD was prevalent in this hypertensive population, being highly affected by age and less by heart structural parameters. DD is observed in incipient stages of hypertensive heart disease, and thus its early detection may help in the risk stratification of hypertensive patients.

Right ventricular structure and function as possible determinants of surgical outcome 30 years after repair of tetralogy of Fallot

OBJECTIVE: To identify the variables that may be involved in the persistence of symptoms (functional class II, III, or IV vs. I) in patients being followed up for 30 years after surgical repair of tetralogy of Fallot. METHODS: Fifty-three patients (27 women), who underwent corrective surgery for tetralogy of Fallot between 1960 and 1970, were studied. Their ages ranged from 7 months to 26 years. At the end of follow-up, 13 patients were asymptomatic and the remaining were in functional class II (N=24), III (N=15), and IV (N=1). To differentiate asymptomatic from symptomatic patients, the following variables were analyzed: age at surgery, need for widening the pulmonary ring and trunk, need for a second (2nd OP) or 3rd operation, residual defect of the interventricular septum, residual regurgitation of the pulmonary valve, systolic gradient through the right ventricular outflow tract, right ventricular dilation or hypertrophy (RVH), cardiothoracic index (CTI), right and left ventricular ejection fraction (RVEF/LVEF), and arrhythmias. RESULTS: The univariate analysis showed an association between the presence of symptoms and the 2nd OP (P=0.03), an increase in the CTI (P=0.0001), moderate to severe RVH (P=0.002), and dilation (P=0.0003). In the logistic regression model, the combination of the 2nd OP (P=0.008), the RVH (P=0.002), and the reduction in RVEF (P=0.01) determined the presence of symptoms. CONCLUSION: Despite the surgical treatment, right ventricular remodeling and performance were the major determinants in the late follow-up of tetralogy of Fallot.

Reproducibility of Left Ventricular Mass by Echocardiogram in the ELSA-Brasil

Background: Echocardiography, though non-invasive and having relatively low-cost, presents issues of variability which can limit its use in epidemiological studies. Objective: To evaluate left ventricular mass reproducibility when assessed at acquisition (online) compared to when assessed at a reading center after electronic transmission (offline) and also when assessed by different readers at the reading center. Methods: Echocardiographers from the 6 ELSA-Brasil study investigation centers measured the left ventricular mass online during the acquisition from 124 studies before transmitting to the reading center, where studies were read according to the study protocol. Half of these studies were blindly read by a second reader in the reading center. Results: From the 124 echocardiograms, 5 (4%) were considered not measurable. Among the remaining 119, 72 (61%) were women, mean age was 50.2 ± 7.0 years and 2 had structural myocardial abnormalities. Images were considered to be optimal/ good by the reading center for 110 (92.4%) cases. No significant difference existed between online and offline measurements (1,29 g, CI 95% −3.60-6.19), and the intraclass correlation coefficient between them was 0.79 (CI 95% 0.71-0.85). For images read by two readers, the intraclass correlation coefficient was 0.86 (CI 95% 0.78-0.91). Conclusion: There were no significant drifts between online and offline left ventricular mass measurements, and reproducibility was similar to that described in previous studies. Central quantitative assessment of echocardiographic studies in reading centers, as performed in the ELSA-Brasil study, is feasible and useful in clinical and epidemiological studies performed in our setting.

Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure

Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased ß-adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased ß-adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of ß-adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence. ß-Adrenergic receptor density was determined by [³H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25% reduction in mean I Ca(L) density (5.7 ± 0.28 vs 7.6 ± 0.32 pA/pF) and a 19% reduction in mean peak [Ca2+]i transients (0.13 ± 0.007 vs 0.16 ± 0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6 ± 4.3 vs 123.3 ± 0.9% in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups. ß-Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89 ± 20.22 vs 271.5 ± 31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to ß-adrenergic stimulation was also reduced and was probably related to ß-adrenergic receptor down-regulation and not to changes in adenylate cyclase activity.

Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

HEART ANEURYSM IN CHAGAS' DISEASE

This prospective study on 41 autopsy collected human hearts concerns the "apical" lesion in Chagas' disease. Previous report did not show a correlation between lesion frequency and heart weight then discarding a vascular factor in its pathogenesis. The present paper involves other variables besides the heart weight to evaluate the relative coronary insufficiency. Distinct colored gel (green and red) injected through the capillary beds of both coronary arteries defined the extent of both vessels before separating the atria and removing the sub-epicardium fat. The Right Ventricle (RV) and Left Ventricle (LV) free walls furnished the RV/LV mass ratio. The myocardium mass colored green (right coronary artery - RC) and the whole Ventricular Weight (VW) determined the RC/VW mass ratio. The heart weight plus these mass ratios, graded and added, composed a score inversely proportional to the myocardium irrigation condition. It intended to be a more sensitive morphologic evaluation of the relative ischaemia to correlate to the apical lesion. This study showed a right deviation for the relative accumulated frequency of lesions plotted as a score function and a significant difference for higher scores in hearts with aneurysm. It suggests a ischaemic factor intervening in the apical lesion pathogenesis in Chagas' cardiopathy.

EXPERIMENTAL INFECTION WITH Toxocara cati IN PIGS: MIGRATORY PATTERN AND PATHOLOGICAL RESPONSE IN EARLY PHASE

Experimental inoculations of approximately 100,000 infective Toxocara cati larval eggs were done in twelve pigs. The T. cati eggs used for inoculation were collected from cat's feces. Another group of three pigs served as an uninfected control. Groups of infected pigs were euthanized at seven, 14, 21, and 28 days post-inoculation (dpi). Tissue samples were taken for digestion and histopathology changes in early phase. The number of larvae recovered from the lungs peaked at seven and 14 dpi and were also present at 21, and 28 dpi. Larvae of T. cati were present in the lymph nodes of the small and large intestine at seven, 14, and 28 dpi and at seven, 14, 21, and 28 dpi respectively. In other studied tissues, no larvae or less than one larva per gram was detected. The pathological response observed in the liver and lungs at seven and 14 dpi, showed white spots on the liver surface and areas of consolidation were observed in the lungs. The lungs showed an inflammatory reaction with larvae in center at 28 dpi. In the liver we observed periportal and perilobular hepatitis. The lymph nodes of the intestines displayed eosinophil lymphadenitis with reactive centers containing parasitic forms in some of them. The granulomatous reaction was not observed in any tissues. The role of the other examined tissues had less significance. The relevance of this parasite as an etiological agent that leads to disease in paratenic hosts is evident.

PREDICTIVE FACTORS FOR THE PROGRESSION OF CHRONIC CHAGAS CARDIOMYOPATHY IN PATIENTS WITHOUT LEFT VENTRICULAR DYSFUNCTION

The identification of predictors for the progression of chronic Chagas cardiomyopathy (CCC) is essential to ensure adequate patient management. This study looked into a non-concurrent cohort of 165 CCC patients between 1985 and 2010 for independent predictors for CCC progression. The outcomes were worsening of the CCC scores and the onset of left ventricular dysfunction assessed by means of echo-Doppler cardiography. Patients were analyzed for social, demographic, epidemiologic, clinical and workup-related variables. A descriptive analysis was conducted, followed by survival curves based on univariate (Kaplan-Meier and Cox’s univariate model) and multivariate (Cox regression model) analysis. Patients were followed from two to 20 years (mean: 8.2). Their mean age was 44.8 years (20-77). Comparing both iterations of the study, in the second there was a statistically significant increase in the PR interval and in the QRS duration, despite a reduction in heart rates (Wilcoxon < 0.01). The predictors for CCC progression in the final regression model were male gender (HR = 2.81), Holter monitoring showing pauses equal to or greater than two seconds (HR = 3.02) increased cardiothoracic ratio (HR = 7.87) and time of use of digitalis (HR = 1.41). Patients with multiple predictive factors require stricter follow-up and treatment.