angiotensinogen and Ventricular-Dysfunction--Left

The angiotensinogen M235T polymorphism is positively associated with plasma angiotensinogen, hypertension, and coronary heart disease. However, the association of M235T polymorphism with left ventricular (LV) mass and function is not well defined at the population level. We investigated whether 2 tightly linked polymorphisms of angiotensinogen gene, M235T and G-6A, are associated with LV mass and function in a large population-based sample, composed mostly of patients with hypertension.. Two-dimensional guided M-mode and pulsed Doppler scan echocardiograms were performed in 605 participants. The angiotensinogen M235T was analyzed with a standard polymerase chain reaction test, and the G-6A variant was measured with mass spectrophotometry.. The association of angiotensinogen gene to LV mass and LV mass indexed to body surface area (LVMI) differed significantly between subjects with normotensive and hypertensive conditions with respect to the direction of association (P <.005). The methionine-threonine/threonine-threonine genotype was negatively associated with LV mass and LVMI in patients with hypertension after adjustment for blood pressure, antihypertensive medication use, weight, and other covariates (P <.001), and patients with normotensive conditions with the methionine-threonine/threonine-threonine genotype had higher LV mass and LVMI (P =.04, for LV mass; P =.14, for LVMI). The association in patients with normotensive conditions was not influenced by blood pressure but was partly confounded by weight.. Variation in the angiotensinogen gene was modestly associated with LV mass independently of covariates in patients with hypertensive conditions. The direction of the association was opposite to that observed in patients with normotensive conditions, probably because of the influence of other risk factors or antihypertensive medication use or both.

Topics: Analysis of Variance; Angiotensinogen; Cross-Sectional Studies; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Polymorphism, Genetic; Ventricular Dysfunction, Left

Left ventricular (LV) diastolic dysfunction characterizes heart failure with a preserved ejection fraction. Although it is recognized that the renin-angiotensin-aldosterone system (RAAS) decreases LV diastolic function, whether systemic angiotensinogen (AGT) contributes to these effects is uncertain. Hence, the aim was to determine the relationship between systemic AGT concentrations and LV diastolic function.. LV diastolic function was determined from the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (average e') and from the ratio of early transmitral blood flow velocity (E) to average e' (E/e') in 445 Black African participants from a community sample.. In multivariate regression models with adjustments for age, sex, waist circumference diabetes mellitus, alcohol and tobacco use, hypertension treatment, systolic blood pressure (BP), and relative wall thickness, the square root of serum AGT concentrations was independently associated with E/e' (partial r (95% confidence interval [CI]) = 0.11 (0.02-0.21), P = 0.04), but not with average e' (partial r (95% CI) = -0.06 (-0.15 to 0.04), P = 0.25). There was no association between plasma renin concentrations and markers of diastolic function (all P > 0.05).. Circulating AGT concentrations are associated with LV diastolic function beyond BP and other confounders in an African population. Hence, through circulating AGT, the systemic RAAS may play an important role in contributing to LV diastolic function in Black Africans.

Topics: Angiotensinogen; Blood Flow Velocity; Blood Pressure; Echocardiography; Female; Heart Failure; Humans; Male; Middle Aged; Renin; Renin-Angiotensin System; South Africa; Stroke Volume; Ventricular Dysfunction, Left

Heart failure (HF) is a clinical syndrome resulting from structural or functional damages. Although clinical trials have shown that the plasma renin-angiotensin system (RAS) activation decreases HF functional status and increases hospitalization for HF patients, the effect of intrarenal RAS activity is still unknown. In this study, we investigated the relationship between the New York Heart Association (NYHA) class, duration, and number of hospitalizations in the previous year and urinary angiotensinogen (UAGT) in patients with HF with reduced ejection fraction (HFrEF).. This study included 85 patients who had an ejection fraction of <40% and were receiving optimal medical treatment. Among these, 22 were excluded from the study for various reasons. Demographically and biochemically, the remaining 63 patients were compared according to the NYHA functional classes and re-hospitalization status.. When the groups were compared in terms of N-terminal pro-B-type natriuretic peptide (NT-proBNP), UAGT, and high-sensitivity C-reactive protein (Hs-CRP), it was found that these parameters were significantly higher in patients who were hospitalized more than two times in the previous year [p<0.001; p=0.007; p<0.001, respectively]. There was a significant correlation between number of hospitalizations and NT-proBNP (r=0.507, p<0.001), Hs-CRP (r=0.511, p<0.001), hemoglobin (r=-0.419, p=0.001), serum sodium (r=-0.26, p=0.04), and systolic blood pressure (r=-0.283, p=0.02). When the independence of multiple correlations was assessed using multiple linear regression analysis, NT-proBNP, Hs-CRP, and hemoglobin levels were independent predictors of re-hospitalization, but this was not the same for UAGT.. Although UAGT levels are high in patients with poor NYHA functional class and repeated hospitalizations, this marker is not valuable for predicting repeated hospitalization in patients with HFrEF.

Topics: Aged; Angiotensinogen; Biomarkers; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Renin-Angiotensin System; Stroke Volume; Turkey; Ventricular Dysfunction, Left

High salt intake is an environmental factor that promotes increased blood pressure. We previously demonstrated that high salt diet causes aggravation of hypertension and impaired vasodilation in response to nitric oxide (NO) in young spontaneously hypertensive rats (SHR), which exhibit low sensitivity to salt in adulthood. Changes in offspring blood pressure and cardiovascular structures have been reported. However, it remains unclear to what extent a maternal high salt intake may affect cardiac and/or vascular function in offspring. Therefore, we investigated influence of exposure to a maternal high salt diet during gestation and lactation on offspring's cardiac and arterial functions in SHR.. SHR dams were fed either a high salt diet or a control diet. After weaning, the offspring were fed the high salt diet or control diet for 8weeks.. Compared with offspring of control diet-fed dams, at 12weeks of age, offspring of the high-salt diet-fed dams had lower blood pressure, heart rate, indices of both left ventricular systolic and diastolic function, and a decreased aortic vasodilation response to NO. Postnatal high salt intake did not affect blood pressure, vasodilatory response, or cardiac function in offspring of high-salt diet-fed dams. Neither maternal nor postnatal dietary salt altered levels of lipid peroxide, superoxide dismutase, or angiotensinogen mRNA in serum and ventricle of the offspring.. Exposure to high maternal dietary salt induces cardiac and vascular dysfunction in offspring. These results point to the possible importance of avoiding excess dietary salt during gestation and lactation.

Topics: Angiotensinogen; Animals; Aorta, Abdominal; Blood Pressure; Diet; Female; Hypertension, Pregnancy-Induced; Maternal Nutritional Physiological Phenomena; Mesenteric Arteries; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats, Inbred SHR; Sodium Chloride, Dietary; Thiobarbituric Acid Reactive Substances; Vasodilation; Ventricular Dysfunction, Left

We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Angiotensinogen; Animals; Animals, Genetically Modified; Brain; Cardiomegaly; Consciousness; Heart Rate; Hypertrophy, Left Ventricular; Isoproterenol; Male; Metoprolol; Myocardial Contraction; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left

To provide evidence for the role of angiotensin II locally produced in the brain in the development of sympathetic hyperactivity and heart failure after myocardial infarction (MI), transgenic rats (TGR) were used, which express an antisense RNA against angiotensinogen. In TGR and control Sprague-Dawley (SD) rats, an MI was induced by acute coronary artery ligation. At 8 weeks after MI, MI sizes were similar in TGR and SD rats. In the groups with MI > or =25% of left ventricle (LV), LV peak systolic pressure decreased in SD rats but not in TGR. LV end-diastolic pressure increased substantially more in SD-MI than TGR-MI rats (from 2+/-1 to 15+/-2 mm Hg, and 2+/-1 to 8+/-1 mm Hg, respectively; P<0.05). LV dP/dtmax decreased from approximately 5400 to 3573+/-187 in SD-MI rats, but only to 4353+/-180 mm Hg/sec in TGR-MI (P<0.05). LV pressure volume curves in vitro showed a marked shift to the right in SD-MI rats. This shift was significantly attenuated by -70% in TGR versus SD rats with MI. Both RV weight and interstitial fibrosis in the LV increased clearly in the SD-MI rats, but not or significantly less in the TGR-MI rats. In SD-MI rats, arterial baroreflex control of heart rate and renal sympathetic nerve activity was markedly impaired but was not affected in the TGR-MI. Plasma angiotensin II levels tended to be higher in SD versus TGR rats, both in sham and MI-groups. This study provides the major new finding that in rats after MI, angiotensin II locally produced in the brain plays a dominant role in the development of LV dysfunction after MI, possibly through its effects on sympathetic function and on circulatory/cardiac renin-angiotensin system.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Baroreflex; Brain; DNA, Antisense; Genes, Synthetic; Glial Fibrillary Acidic Protein; Heart Rate; Hypothalamus; Injections, Intraventricular; Male; Myocardial Infarction; Organ Size; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Reflex, Abnormal; Renin-Angiotensin System; Stress, Psychological; Stroke Volume; Sympathetic Nervous System; Transgenes; Ventricular Dysfunction, Left; Ventricular Remodeling

An association between the DD allele of the angiotensin-converting enzyme gene and a poorer outcome in patients with heart failure has been found in whites. The DD allele frequency is lower in Chinese, but the M235T variant of the angiotensinogen gene is more common in Chinese than whites; it is not known to what extent polymorphisms of the renin-angiotensin system affect clinical status or prognosis in Chinese patients with heart failure.. We assessed the relations among polymorphism of the angiotensin-converting enzyme gene, angiotensinogen M235T (AGT) gene, and angiotensin type I receptor A1166C gene with left ventricular systolic function, left and right ventricular diastolic function, serum angiotensin-converting enzyme, plasma aldosterone and atrial natriuretic peptide levels at presentation, and clinical outcome at 1 year (survival, hospital admissions) in a cohort of Chinese patients with typical systolic heart failure (n = 82).. We confirmed the low prevalence of the angiotensin-converting DD and the angiotensin type I receptor CC genotypes, and high prevalence of the AGT TT genotype in Chinese subjects compared with whites. There was no relation between the various gene polymorphisms and survival at 1 year assessed by multiple regression or Cox regression survival analysis. The AC variant of the angiotensin type I receptor gene was associated with morbidity over a 1-year period (hospital admissions) and increased baseline aldosterone levels, but none of the other polymorphisms correlated with systolic or diastolic function, aldosterone or atrial natriuretic peptide levels. By multiple regression for effects on mortality rate, only atrial natriuretic peptide and age were significant.. In Chinese patients with heart failure, polymorphisms of the renin-angiotensin system do not appear to be related to survival or severity, probably because of the different prevalence of these genotypes in the Chinese. Thus this study illustrates that large interethnic differences in the frequencies of genotype polymorphisms of the renin-angiotensin system exist and results from one ethnic group cannot be extrapolated to another.

Topics: Aldosterone; Angiotensinogen; Asian People; Atrial Natriuretic Factor; Cohort Studies; Female; Gene Frequency; Genotype; Heart Failure; Hong Kong; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prevalence; Receptors, Angiotensin; Renin-Angiotensin System; Survival Analysis; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right

To date, the human angiotensinogen (AGT) gene and some of its variants represent the best examples of genetic influences that are involved in the determination of essential hypertension (EH) and associated cardiovascular diseases (CVDs). To assess the value of genotyping AGT in a genetically homogeneous population, we carried out a retrospective, case control study of variants M235T and T174M for putative correlations with CVDs among nationals from the United Arab Emirates (Emirati)--an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 229 Emirati (119 males and 110 females), comprising groups of controls and patients with clinical diagnoses of EH, left ventricular hypertrophy (LVH), ischaemic heart disease (IHD) and myocardial infarction (MI). M235T and T174M alleles were determined via assays based on the polymerase chain reaction. T174M showed no correlation with any of the four clinical entities included in this study. T235 alleles, however, occurred more frequently in the EH group and less frequently in the group of MI survivors. We also found that T235 allele frequencies decreased with age, indicating that in the Emirati population, T235 alleles are associated with a reduced life span and that this effect could occur through independent mechanisms underlying genetic susceptibilities to both EH and MI.

Topics: Adult; Aged; Alleles; Amino Acid Substitution; Angiotensinogen; Body Mass Index; Case-Control Studies; Cholesterol; DNA Mutational Analysis; Female; Genes; Genetic Testing; Genotype; Humans; Hypertension; Male; Middle Aged; Mutation; Myocardial Infarction; Myocardial Ischemia; Phenotype; Pilot Projects; Retrospective Studies; Statistics as Topic; United Arab Emirates; Ventricular Dysfunction, Left

The purpose of the present study was to assess whether the insertion (I)/deletion (D) polymorphism of the angiotensin converting enzyme (ACE) gene, and the polymorphism of angiotensinogen (AGT) gene with threonine (T) instead of methionine (M) at amino acid 235 in exon 2 (M235T) were associated with left ventricular dilatation after myocardial infarction. In 103 patients with myocardial infarction, the left ventricular (LV) end-diastolic volume index (EDVI) and the end-systolic volume index (ESVI) were assessed by echocardiography at two time points, namely at 7 +/- 4 days and at 3.9 +/- 1.3 months (mean +/- S.D.) after the infarction. The increases in the LVEDVI and LVESVI on the second echocardiogram were significantly higher in subjects with the DD and ID genotypes than in patients with the II genotype (P < 0.05 and P < 0.005, respectively). Multiple regression analysis revealed that the LVESVI at the first echocardiographic examination and the ACE I/D genotype were significant predictors of the LVEDVI and LVESVI at the second echocardiographic examination. However, the AGT M235T genotype was eliminated. In conclusion, the DD and ID genotypes of the ACE gene were significantly associated with the progression of the LVEDVI and LVESVI after myocardial infarction. The presence of the deletion allele of the ACE gene may be a risk factor of congestive heart failure after a myocardial infarction.

Topics: Analysis of Variance; Angiotensinogen; Echocardiography; Female; Genotype; Heart Failure; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Regression Analysis; Ventricular Dysfunction, Left

Experimental myocardial infarction is a model of cardiac overload in which part of the cardiac muscle is removed. The resulting left ventricle insufficiency depends on the size of the infarct and time. The infarcted area remodels, due to proteolytic activity of inflammatory cells and collagenogenesis from fibroblast activity. The phenotype of the residual healthy cardiac muscle undergoes modification, and there are peripheral vascular changes which are partly dependent on the activation of pressor systems and/or inactivation of dilator systems. The changes are proportional to the infarct size at any given time after induction of the model. The degree of right ventricular hypertrophy and the drop in arterial pressure are upstream and downstream markers of the loss of left ventricular function and therefore indicate the extent of the remodelling. The increase of type V3isomyosin, the amount of subendocardial collagen, and the biosynthesis, storage and secretion of atrial natriuretic factor (ANF) are all proportional to the infarct size and the degree of cardiac overload. The level of urinary cGMP is also correlated with infarct size. These indices show ventricular remodelling, increased stress and energy restriction of the residual healthy cardiac muscle. The activation of peripheral pressor systems also depends on infarct size. They reflect the influence of defective cardiac pumping on the kidney, liver, brain and endothelium. Massive infarcts are accompanied by an increase in circulating renin and in renal renin content, by a decrease in angiotensinogen due to its consumption by renin, and to its insufficient hepatic synthesis, and by an increase in vasopressin secretion and biosynthesis in the hypothalamus. Converting enzyme inhibition has beneficial effect in this model by lowering cardiac load. It reduces arterial pressure, reverses bi-atrial and right ventricular hypertrophy, reduces the changes in the myosin isoenzyme patterns, and normalizes subendocardial fibrosis and the level of ANF. Although the effects of converting enzyme inhibition are beneficial in this model, they are restricted by their inability to normalize the load and stress when the initial loss of cardiac contractile material exceeds 40%.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Atrial Natriuretic Factor; Collagen; Cyclic GMP; Hypertrophy, Left Ventricular; Indoles; Isoenzymes; Kidney; Myocardial Infarction; Myocardium; Myosins; Perindopril; Rats; Rats, Wistar; Renin; Vasopressins; Ventricular Dysfunction, Left