angiotensinogen and Myocardial-Infarction

It has been suggested that the a. A significant association between

Topics: Alleles; Angiotensinogen; Asian People; Genetic Predisposition to Disease; Humans; Myocardial Infarction; Polymorphism, Genetic; Risk Factors; White People

To investigate if there is an association between M235T polymorphism of angiotensinogen gene and myocardial infarction (MI) risk and perform a meta-analysis and an in silico approach.. This case-control study included 340 participants (155 MI patients and 185 controls) examined at Kashan University of Medical Sciences (Kashan, Iran) between 2013 and 2015. Meta-analysis included 25 studies with 6334 MI patients and 6711 controls. Bioinformatics tools were applied to evaluate the impact of M235T polymorphism on angiotensinogen function and structure.. Genetic association study revealed a significant association between TT genotype (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.08-4.00, P=0.029) and T allele (OR 1.45, 95% CI 1.06-1.99, P=0.021) and MI risk. Meta-analysis also revealed a significant association between M235T polymorphism and MI risk in allelic (OR 1.55, 95% CI 1.10-2.18, P=0.012) and recessive (OR 1.69, 95% CI 1.13-2.53, P=0.010) models within Asian population. In silico-analysis revealed that M235T fundamentally changed the function of angiotensinogen (score 32; expected accuracy 66%).. Our study suggests that M235T polymorphism might be a helpful biomarker for screening of susceptible individuals for MI in Asian population.

Topics: Aged; Alleles; Angiotensinogen; Asian People; Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Polymorphism, Genetic; Risk Factors

Numerous studies have evaluated the association between the T174M polymorphism in the angiotensinogen (AGT) gene and myocardial infarction (MI) risk. However, the specific association remains controversial because of small sample sizes and varied study designs among different studies. We performed a meta-analysis to assess this correlation. A comprehensive search was conducted to identify all published articles regarding the association between the AGT gene T174M polymorphism and MI risk from different databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and heterogeneity and publication bias were assessed. A total of 1032 patients with lung cancer and 1286 controls from 6 comparative studies were included in this meta-analysis. The results revealed a significant association between the AGT gene T174M polymorphism and MI risk (MM vs TT: OR = 2.87, 95%CI = 1.71-4.83; dominant model: OR = 1.57, 95%CI = 1.10-2.25; recessive model: OR = 0.41, 95%CI = 0.25-0.66). In subgroup analysis by nationality, we observed a significant association between the AGT gene T174M polymorphism and susceptibility to MI in both Caucasian and Asian populations. In conclusion, the T174M polymorphism in the AGT gene may be related to an increased risk of MI. Further larger studies are needed to confirm these conclusions.

Topics: Amino Acid Sequence; Angiotensinogen; Case-Control Studies; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Myocardial Infarction; Polymorphism, Genetic; Risk

The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI), but previous studies have been inconsistent. The present study aimed at assessing the association of M235T polymorphism in the AGT gene with MI using a meta-analysis.. We retrieved literature in Google Scholar, PubMed, Cochrane Library and the China National Knowledge Infrastructure database (January 1990-December 2011) for the relevant studies on the AGT polymorphism M235T and risk of MI. Statistical analyses were carried out using Stata 10.0 for combining all the relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Begg's test was used to measure publication bias.. A total of 21 case-control studies containing 5887 patients and 6164 controls were enrolled into this meta-analysis. Overall, significant association was found between the AGT gene M235T polymorphism and risk of MI in the subgroup analysis for TT vs MT in Asians (OR 1.47, 95% CI: 1.01-2.12; p = 0.04). No associations were detected between AGT M235T and the risk of MI in total population and Caucasians.. This meta-analysis demonstrated that the AGT M235T polymorphism could be a prediction marker for risk of MI in Asians. Conclusive evidence on the effects of the variants in MI should be addressed in further studies.

Topics: Adult; Angiotensinogen; Asian People; Genetic Predisposition to Disease; Humans; Myocardial Infarction; Odds Ratio; Polymorphism, Single Nucleotide; Publication Bias; Risk Factors

Angiotensinogen, one of the most important proteins in the renin-angiotensin system, plays a key role in the progress of coronary heart disease and myocardial infarction (MI). Many studies have investigated the association between angiotensinogen gene M235T polymorphism and MI risk, but the results were inconsistent. We performed a meta-analysis of 22 studies on M235T polymorphism and MI risk published before November 2012. This meta-analysis included a total of 4,606 MI cases and 4,918 controls. Overall, the per-allele odds ratio (OR) of the 235T variant for total MI risk was 1.04 (95 % CI 0.92-1.17). When a recessive model was evaluated, the OR was 1.06 (95 % CI 0.96-1.17) and under a dominant model, the OR was 0.96 (95 % CI 0.82-1.11). Under pairwise comparisons, non-significant associations were found between M235T polymorphism and MI risk (MT vs. MM, OR, 0.96, 95 % CI 0.87-1.06; TT vs. MM, OR, 1.03, 95 % CI 0.83-1.28). Subgroup analyses in the different ethnic groups and different control sources were performed and no significant association was found also. Based on the available evidence, no association between M235T polymorphism and MI risk was observed, even in the sub-analysis concerning different races and control sources. The direction of further research should focus not only on the simple relationship of M235T polymorphism and MI risk, but also on gene-gene and gene-environment interaction.

Topics: Alleles; Amino Acid Substitution; Angiotensinogen; Codon; Genetic Predisposition to Disease; Humans; Myocardial Infarction; Odds Ratio; Polymorphism, Genetic; Publication Bias; Renin-Angiotensin System; Risk

The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI) and brain infarction (BI), but the results remain inconclusive. This meta-analysis was designed to clarify these controversies. Electronic databases were systematically searched before February 2013. A total of 38 studies with 17304 subjects met our inclusion criteria. In East Asian group, significant association was found between AGT M235T polymorphism and risk of MI (for dominant model: OR=1.79; 95% CI=1.04-3.06; for recessive model OR=2.01; 95% CI=1.21-3.36; for additive model OR=1.79; 95% CI=1.14-2.86) as well as BI (for dominant model: OR=1.66; 95% CI=1.22-2.27; for recessive model OR=1.78, 95% CI=1.29-2.46; for additive model: OR=1.64, 95% CI=1.34-2.00), while the M235T polymorphism did not impact the risk of MI in total population and other ethnicity. In the subgroup analyses by gender and age, there was lack of evidence for the association. This meta-analysis suggested an association between the M235T polymorphism and MI as well as BI in East Asian population. Further studies with larger numbers of worldwide participants are needed to understand the genetic basis of MI and BI.

Topics: Angiotensinogen; Asia, Eastern; Asian People; Brain Infarction; Humans; Myocardial Infarction; Polymorphism, Genetic; Risk Factors; White People

The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations.. One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%; P=0.0004) in MT heterozygotes and 11% (7% to 15%; P<0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.. Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.

Topics: Angiotensinogen; Asian People; Black People; Blood Pressure; Genotype; Heterozygote; Homozygote; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Polymorphism, Genetic; Stroke; White People

The importance of genetics to the pathogenesis of myocardial infarction is suggested by the frequent familial clustering of premature disease. Yet, studies associating myocardial infarction with gene polymorphisms of vascular proteins (angiotensinogen, angiotensin converting enzyme, angiotensin II type 1 receptor, endothelial nitric oxide synthase) and haemostatic factors (fibrinogen, coagulation factors II, V, VII and XIII, plasminogen activator inhibitor-1, tissue-type plasminogen activator, platelet glycoproteins IIb/IIIa, Ia/IIa and Ib-IX-V, or methylenetetrahydrofolate reductase) have revealed conflicting results. This is hardly surprising, given: 1) the multigenic nature of myocardial infarction, whereby single polymorphisms are bound to play at best only a limited role in the global risk of disease; 2) the multiple pathogenetic mechanisms of infarction (e.g., atheromatous obstruction, plaque rupture, thrombosis, vasospasm), each of which is likely influenced by a number of genes and by several environmental factors. The simultaneous investigation of a set of polymorphisms--and of their interactions with environmental factors--in extremely homogeneous sets of patients should offer a better understanding of the contribution of specific genes to the risk of myocardial infarction.

Topics: Angiotensinogen; Blood Coagulation Factors; Blood Platelets; Factor VII; Fibrinogen; Fibrinolysis; Humans; Myocardial Infarction; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Platelet Membrane Glycoproteins; Polymorphism, Genetic; Receptors, Angiotensin

Topics: Alleles; Angiotensinogen; Apolipoproteins; Aryldialkylphosphatase; Carrier Proteins; Cholesterol Ester Transfer Proteins; Esterases; Fibrinogen; Glycoproteins; Humans; Lipoprotein Lipase; Myocardial Infarction; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Risk Factors; Selectins

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Collagen; Myocardial Infarction; Myocardium; Peptidyl-Dipeptidase A; Rats; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Tissue Distribution; Wound Healing

Angiotensin-converting enzyme inhibitors have proven to be uniquely effective in inducing regression, or preventing the occurrence, of ventricular hypertrophy associated with systemic hypertension. This has pointed, for many years, to a possible direct involvement of the renin-angiotensin system in the pathogenesis of cardiac hypertrophy. Over the last 10 years further supporting evidence has been forthcoming about direct trophic effects of angiotensin II in several experimental systems. Additionally, we now have rather conclusive evidence for the existence of a local, intracardiac renin-angiotensin system, which is capable of synthesis of all components of the system, and of cleaving, via the classic pathway, angiotensin peptides from the precursor, angiotensinogen. Moreover, a number of studies have demonstrated the capacity of regulatory response and modulation of activity of the local system in response to a variety of pharmacologic perturbations as well as differential expression of specific components under pathologic conditions, including compensatory hypertrophy and remodeling after myocardial infarction, pressure overload hypertrophy, and volume overload hypertrophy. Continued research into the role of the cardiac renin-angiotensin system in the pathogenesis of cardiac hypertrophy and failure will provide us with the tools to devise more specific, targeted strategies for therapeutic intervention or prevention.

Topics: Adaptation, Physiological; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cardiomegaly; Humans; Hypertension; Myocardial Infarction; Myocardium; Renin-Angiotensin System

On the basis of recent advances in molecular biology and statistical genetics, it has become possible to search for chromosome regions that contain genes predisposing to hypertension and to directly link specific mutations on candidate genes to hypertension. As the human genome has been extensively mapped, highly informative, polymorphic markers are available, which can be used to detect genes in their proximity with 'hypertensinogenic' alleles. Some of these markers have been shown to be tightly linked to the genes of the renin-angiotensin system. Furthermore, the coding and regulatory regions of the genes encoding for renin, ACE, angiotensinogen and the AT1 receptor have been partially characterized. This provides a basis for further definition of specific polymorphisms within these genes that are of functional importance and that can be used to examine their contribution to the inheritance of primary hypertension. The first studies of these links have already emerged and have been reviewed in this article. Several problems arise in performing such linkage studies in human primary hypertension, however. It is difficult to define the genetic background of heterogeneous, multigenetic and multifactorial diseases such as human hypertension. Extensive studies of population genetics, including the analysis of large numbers of generations and controlled breeding experiments, cannot be performed, for obvious reasons. Blood pressure is not a convenient study trait, because it exhibits great intraindividual variance and also because of the relatively low reliability of just a few indirect measurements obtained under loosely controlled environmental conditions. Twenty-four-hour ambulatory blood pressure measurements may improve such investigations in the near future. Ravogli et al (1990) reported that the 24-hour ambulatory systolic blood pressure is higher in normotensive subjects of hypertensive parents than in normotensive subjects of normotensive parents--a finding that had not been previously reported using the conventional method of measurement. Hypertension as a trait per se is also problematic: its classification (above 140/90 mmHg) is purely artefactual, and its aetiology is highly heterogeneous. Thus, we have to keep in mind that even strong gene effects, if present in only a small subgroup of hypertensives, may not be detected in these studies. Attempts are being made to strengthen the analysis by characterizing physiologically distinct subgroups. In ad

Topics: Angiotensin II; Angiotensinogen; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Infarction; Peptidyl-Dipeptidase A; Pre-Eclampsia; Pregnancy; Receptors, Angiotensin; Renin; Renin-Angiotensin System

The renin-angiotensin system is an important regulator of vascular resistance in many patients with hypertension and congestive heart failure. To quantitatively evaluate this contribution requires correlation of markers of the renin-angiotensin system with haemodynamic parameters, notably blood pressure, cardiac output, and calculated systemic vascular resistance. In addition, to determine ventricular loading properties, assessment of cardiac filling pressures is also required. The availability of specific pharmacological inhibitors of the renin-angiotensin system greatly enhances such correlation, as the haemodynamic consequence of blocking the renin-angiotensin system can then more fully identify its contribution. In the last decade, highly specific pharmacological inhibitors have become available to serve such a purpose. Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin. However, this method of blockade is still at the early stages of investigation. More readily available are converting enzyme inhibitors which block the formation of angiotensin II, the potent vasoconstrictor which mediates increased systemic vascular resistance, and angiotensin II analogues which compete with endogenous angiotensin II for vascular and adrenal receptors. Although hypertension and chronic congestive heart failure are clinically distinct entities in many respects, their common bond is the fact that both pathological mechanisms are mediated by an increase of systemic vascular resistance. The implications of blocking the resulting vasoconstriction in both entities are therefore quite similar. This review summarises our present knowledge of the contribution of the renin-angiotensin system to the vasoconstriction of hypertension and congestive heart failure, and also summarises the haemodynamic consequences of such inhibition. The implications of the response to these specific pharmacological probes, as well as their limitations, are discussed. Their importance rests not only in their therapeutic application, but also in their contribution as probes for pathophysiological mechanisms of vasoconstriction in cardiovascular disease.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Dipeptides; Enalapril; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Kinetics; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin; Renin-Angiotensin System; Teprotide

This study sought to evaluate whether genetic variants in the renin-angiotensin-aldosterone system (RAAS) have an impact on long-term mortality after acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era. We investigated the impacts of individual and combinations of 4 major RAAS genetic variants, angiotensinogen (AGT) T1311C, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensin 2 type 1 receptor A1166C, and aldosterone synthase T4660C on 5-year mortality in 3149 post-AMI patients using multivariate Cox regression analysis. The predictive accuracy of all possible RAAS genetic combinations was evaluated using Cox regression analysis, and the best combination that affected prognosis was determined based on the minimal Akaike Information Criterion. There were 220 deaths during a median follow-up of 4.9 years. Independent analyses of any single RAAS variant did not show significant impacts on 5-year mortality. However, analyses in combination revealed that absence of both AGT CC genotype and ACE D allele was associated with lower 5-year mortality (log-rank P = 0.005). Patients with at least either of the AGT CC or ACE D allele had increased mortality with adjusted hazard ratios of 2.07 (95% confidence interval 1.18-3.65, P = 0.012), compared with those with neither the AGT CC nor ACE D allele. Among the 4 RAAS genetic variants examined, a combination of AGT and ACE polymorphisms was associated with 5-year mortality after AMI.

Topics: Aged; Angiotensinogen; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Japan; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Retrospective Studies; Risk Factors; Survival Rate; Survivors; Time Factors

We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg(-1)·day(-1), n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

Topics: Angiotensinogen; Animals; Cell Line; Electrocardiography; Heart Failure; Hemodynamics; Immunohistochemistry; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle, Skeletal; Myocardial Infarction; NADPH Oxidases; Oncogene Protein v-akt; Oxidative Stress; Oxygen Consumption; Phosphorylation; Prorenin Receptor; Receptors, Cell Surface; Renin-Angiotensin System; RNA, Small Interfering; Signal Transduction

The development of left ventricular remodelling after acute myocardial infarction is a predictor of heart failure and mortality. The purpose of the present study was to assess whether the polymorphism of angiotensinogen (AGT) gene with threonine (T) instead of methionine (M) at amino acid 235 in exon 2 (M235T) had effects on cardiac remodelling after acute myocardial infarction.. One hundred and forty-one patients (mean age 56.4±11.1 years) with a first acute myocardial infarction were enrolled. Within 24-72 hours of the onset of the symptoms and at a four month period two-dimensional echocardiography was performed. Remodelling was defined as a 20% increase from the baseline in left ventricular end-diastolic volume. The genotypes of the study group were compared with the reference group (n=1010) genotypes. AGT M235T polymorphism was determined using polymerase chain reaction amplification.. At follow-up, 49 patients (34.7%) were classified as having left ventricular remodelling. Anterior localization of the infarct (p=0.008), leucocyte count at admission (p=0.040), global left ventricular longitudinal strain (p=0.021) and MM genotype of AGT (p=0.024) were independent predictors of ventricular remodelling after myocardial infarction.. Anterior wall infarction, increased leucocyte count, decreased longitudinal strain of left ventricular and polymorphism of AGT M235T may predict remodelling after myocardial infarction.

Topics: Angiotensinogen; Echocardiography; Feasibility Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Ventricular Remodeling

The aim of the study was to determine whether the presence of angiotensin II type 1 receptor 1166A/C gene polymorphism and two polymorphisms of angiotensinogen, namely Met235Thr and Thr174Met, pointed at the culprit artery in patients with ST-segment elevation myocardial infarction (STEMI).. The AGTR1 1166A/C polymorphism and two AGT gene polymorphisms, Met235Thr and Thr174Met, were assessed in 100 patients with STEMI.. The odds ratio (OR) of circumflex artery (CRX) responsible for STEMI was 3.49 (95% CI: 1.1-10.8, p<0.05) for MetThr genotype for AGT Met235Thr gene and 4.54 (95% CI: 1.5-14.2, p<0.01) for ThrMet genotype for AGT Thr174Met gene. Homozygous ThrThr genotype for AGT Thr174Met gene reduced OR of CRX as culprit artery in STEMI (OR=0.29, 95% CI: 0.1-0.9, p<0.05). However, the highest OR that increased up to 13.71 (95% CI: 1.58-119.3) was shown in case of right coronary artery and C/C genotype for AGTR1 1166A/C gene.. Polymorphism of AGTR1 1166A/C gene can point at the right coronary artery as infarct-related artery in STEMI. Polymorphisms of AGT Met235Thr and AGT Thr174Met genes are able to mark increased or reduced odds ratio of circumflex artery as culprit artery in STEMI.

Topics: Adult; Aged; Angiotensinogen; Female; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1

The objective of the study was to explore the role of a genetic variant of angiotensinogen (AGT), M235T, as an independent risk factor for acute myocardial infarction (AMI) and to investigate the possible association with the severity of coronary artery disease (CAD), estimated on the basis of the number of coronary stenoses and critical arterial occlusions.. 123 AMI patients were compared to 144 healthy controls. AGT genotypes were determined by PCR.. A significant association was found between AGT M235T polymorphism and AMI (p = .021). By logistic regression, the TT genotype appeared to confer 1.9-fold increased risk for AMI in both the univariate and the multivariate model. The frequencies of the TT genotype and T allele increased with the number of stenoses in coronary vessels. Moreover, the TT genotype and the T allele were more frequent in the subgroup of patients with stenoses in at least four coronary vessels than in other patients, including subjects with one- to three-vessel disease. Furthermore, the TT genotype and the T allele were significantly more frequent in patients with critical arterial occlusions (> 90%) than in subjects without critical stenoses.. The AGT M235T polymorphism associates with AMI risk and influences CAD severity.

Topics: Alleles; Angiotensinogen; Coronary Occlusion; Coronary Stenosis; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide

Recent advances in molecular biology have made it possible to identify numerous polymorphisms of the renin-angiotensin system, which play an important role in the etiology of cardiovascular disease.. The aims of the study were (i) to assess the distribution of the angiotensin II type 1 receptor (AGTR1) gene 1166A/C polymorphism and two polymorphisms of the angiotensinogen (AGT) gene (Met235Thr and Thr174Met) in patients with ST-segment-elevation myocardial infarction (STEMI) who underwent coronary angiography, compared with healthy volunteers; (ii) to determine if there was any correlation between these polymorphisms and risk of STEMI; and (iii) to assess the association of the examined polymorphisms with such classic cardiovascular risk factors as hypertension, diabetes mellitus, obesity (based on a body mass index ≥25 kg/m2), smoking, dyslipidemia, and family history of cardiovascular disease.. A total of 100 patients (mean age 57 ± 10 years [range 31-76 years]; 21% women) with diagnosed STEMI and a control group consisting of 95 healthy volunteers (mean age 38 ± 11 years [range 17-60 years]; 20% women) were investigated for the AGTR1 1166A/C polymorphism and two variants of AGT (Met235Thr and Thr174Met). All patients received standard therapy for STEMI.. There were significant differences in the distribution of genotypes and the AGT Met174 allele for AGT Thr174Met polymorphism between patients and healthy subjects (p < 0.05). The AGTR1 1166A/C polymorphism genotype frequencies were significantly different in patients with hypertension compared with normotensive individuals. Specifically, the AGTR1 1166 AA genotype was twice as common in patients with hypertension as in those without (67% vs 33%), while the AC and CC genotypes were found predominantly in normotensive patients (p = 0.0016). The variant 1166C allele was much more common in patients without hypertension (67%) than in patients with hypertension (33%; p = 0.0006). The variant AGT Thr235 allele was more common in patients without a family history of cardiovascular disease than in patients with this risk factor (p < 0.05). The odds ratio (OR) for STEMI in patients with the heterozygous AGT 174 Thr/Met genotype was increased to 1.884 (95% confidence interval [CI] 1.03, 3.446; p < 0.05), while the OR calculated for carriers of the AGT Met174 allele was 2.038 (95% CI 1.129, 3.68; p = 0.0182). Significant genotypic associations of combinations of renin-angiotensin system gene polymorphisms in STEMI were not observed.. The most powerful predictive value for STEMI was represented by the Thr/Met genotype and the Met174 allele of the AGT Thr174Met gene polymorphism. In our study, in contrast to observations reported by other authors, the AA genotype of the AGTR1 1166A/C gene polymorphism - much more than other genotypes - was associated with hypertension.

Topics: Adult; Aged; Angiotensinogen; Coronary Artery Disease; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

We assessed the association between (CA)n repeat polymorphism of angiotensinogen (AGT), 250 base pair (bp) insertion/deletion (I/D) of angiotensin-converting enzyme (ACE), tetranucleotide repeat polymorphism (TCTG)n of renin (REN), (CT)n repeat polymorphism of the natriuretic peptide receptor A (NPRA) genes, and the presence and extent of coronary artery disease (CAD) in Greek patients with a history of myocardial infarction (MI). A total of 158 post-MI patients referred for coronary angiography were compared with 144 controls. The SS genotype of the AGT gene was related with an increased risk for 3-vessel CAD (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.05-3.61; P = .041), whereas the SL genotype was related with a decreased risk (OR, 0.44; 95% CI, 0.22-0.87; P = .019). Moreover, there was a trend for the SL genotype of the REN gene toward increased risk for CAD. There was a significant association between (CA)n polymorphism of the AGT gene and the extent of CAD in Greek patients with a history of MI.

Topics: Aged; Angiotensinogen; Coronary Artery Disease; Female; Greece; Humans; Male; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Atrial Natriuretic Factor; Renin

AGT*M235T polymorphism has been associated with high serum angiotensinogen (AGT) levels, systemic hypertension and cardiac dysfunction (CD).. To test the hypothesis of AGT*M235T polymorphism being associated with the risk of developing cardiac dysfunction (heart failure or asymptomatic left ventricular systolic dysfunction) after acute coronary syndrome (ACS) during hospitalization.. A total of 363 patients (mean age of 62 ± 12 years), of whom 233 (64%) were men and 130 (36%) were women, all from the same cohort and hospitalized for ACS, were studied. Clinical and genetic data from the 117 (32.2%) patients who developed cardiac dysfunction (case group) were compared to those of the 246 (67.8%) who did not develop this condition (control group). The AGT*M235T polymorphism was determined by sequence analysis and was in Hardy-Weinberg equilibrium.. There was a significant difference in the distribution of genotypes among women, with a predominance of the *235MM genotype in the control group (p = 0.001) and of the *235T allele in the case group. In the logistic regression models, the diagnosis of anterior wall myocardial infarction at admission was related to an increased risk of CD in both genders, whereas unstable angina at admission.; absence of the *235T allele; blood glucose <100 mg/dl; use of betablocker; serum creatinine level < 1.5 mg/dl;heart rate range > 60 and < 90 bpm; and current cigarette smoking were related to a lower risk of CD.. This study suggests that the absence of the AGT *235T allele contributes to a reduced risk of cardiac dysfunction after acute coronary syndrome.

Topics: Acute Coronary Syndrome; Adult; Alleles; Angiotensinogen; Case-Control Studies; Echocardiography; Female; Genotype; Humans; Hypertension; Logistic Models; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Young Adult

The balance between norepinephrine (NE) synthesis, release, and reuptake is disrupted after acute myocardial infarction, resulting in elevated extracellular NE. Stimulation of sympathetic neurons in vitro increases NE synthesis and the synthetic enzyme tyrosine hydroxylase (TH) to a greater extent than it increases NE reuptake and the NE transporter (NET), which removes NE from the extracellular space. We used TGR(ASrAOGEN) transgenic rats, which lack postinfarct sympathetic hyperactivity, to test the hypothesis that increased cardiac sympathetic nerve activity accounts for the imbalance in TH and NET expression in these neurons after myocardial infarction. TH and NET mRNA levels were identical in the stellate ganglia of unoperated TGR(ASrAOGEN) rats compared with Sprague Dawley (SD) controls, but the threefold increase in TH and twofold increase in NET mRNA seen in the stellate ganglia of SD rats 1 wk after ischemia-reperfusion was absent in TGR(ASrAOGEN) rats. Similarly, the increase in TH and NET protein observed in the base of the SD ventricle was absent in the base of the TGR (ASrAOGEN) ventricle. Neuronal TH content was depleted in the left ventricle of both genotypes, whereas NET was unchanged. Basal heart rate and cardiac function were similar in both genotypes, but TGR(ASrAOGEN) hearts were more sensitive to the beta-agonist dobutamine. Tyramine-induced release of endogenous NE generated similar changes in ventricular pressure and contractility in both genotypes, but postinfarct relaxation was enhanced in TGR(ASrAOGEN) hearts. These data support the hypothesis that postinfarct sympathetic hyperactivity is the major stimulus increasing TH and NET expression in cardiac neurons.

Topics: Adrenergic beta-Agonists; Angiotensinogen; Animals; Animals, Genetically Modified; Coronary Vessels; Disease Models, Animal; Dobutamine; Female; Heart; Heart Rate; Ligation; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Norepinephrine Plasma Membrane Transport Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stellate Ganglion; Sympathetic Nervous System; Sympathomimetics; Tyramine; Tyrosine 3-Monooxygenase; Up-Regulation; Ventricular Function, Left

The neuropeptide galanin is elevated in the cardiac sympathetic innervation after myocardial infarction (MI). Galanin inhibits vagal transmission and may support the regeneration of sympathetic nerves, thereby contributing to the development of arrhythmia and sudden cardiac death after MI. The reason for increased galanin production in sympathetic neurons after myocardial infarction is not known. Cardiac sympathetic neurons are activated chronically after cardiac ischemia-reperfusion, and activation of sympathetic neurons in culture stimulates galanin expression. Therefore, we tested the hypothesis that increased sympathetic nerve activity stimulates galanin expression in cardiac sympathetic neurons after myocardial infarction. To test this hypothesis we used TGR(ASrAOGEN) transgenic rats, which lack brain angiotensinogen and do not exhibit post-infarct sympathetic hyperactivity. Hearts and stellate ganglia were collected 1 week after ischemia-reperfusion. Galanin mRNA was quantified by real-time PCR and peptide content was assayed by enzyme-linked immunosorbent assay. Galanin mRNA increased approximately 3-fold after MI in cardiac sympathetic neurons of both genotypes compared to unoperated and sham controls. Left ventricular galanin content, however, increased after MI only in Sprague-Dawley rats and not in AOGEN rats. These data suggest that post-infarct cardiac sympathetic hyperactivity stimulates galanin peptide production but is not required for increased galanin mRNA expression.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Galanin; Gene Expression Regulation; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Rats; Rats, Sprague-Dawley; Stellate Ganglion; Sympathetic Nervous System

There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi2=31.6, P=0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.

Topics: Aged; Angiography; Angiotensinogen; Coronary Artery Disease; Epistasis, Genetic; Female; Humans; Linkage Disequilibrium; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Taiwan

Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and beta-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or beta-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension , aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in The Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of beta-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cohort Studies; Comorbidity; Female; Genetic Predisposition to Disease; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Netherlands; Pharmacogenetics; Polymorphism, Genetic; Prospective Studies; Renin-Angiotensin System; Risk Factors; Stroke

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Gene Transfer Techniques; Heart Failure; Infusions, Parenteral; Interleukin-10; Models, Cardiovascular; Models, Neurological; Myocardial Infarction; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; RNA, Antisense; RNA, Messenger; Spironolactone; Supraoptic Nucleus; Sympathetic Nervous System; Ventricular Remodeling

The M235T mutation of the human angiotensinogen gene has been shown to be associated with elevated circulating angiotensinogen concentrations and essential hypertension. The frequencies of the 235T allele are significantly different in black and white subjects. We analyzed the independent contribution of the angiotensinogen M235T mutation to the development of recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) in a cohort of 916 black (n=145) and white (n=771) postmyocardial infarction patients who were prospectively studied during an average follow-up of 28 months. The frequency of the 235T allele was significantly higher among black (82%) than among white (44%) patients (P<0.001). There was no evidence for Hardy-Weinberg disequilibrium. During follow-up, 41 cardiac events (28%) occurred in blacks and 197 (26%) in whites (P=0.49). Multivariate Cox proportional hazards regression analysis demonstrated that 235T homozygosity was independently associated with increased risk of coronary events among black (hazard ratio: 2.37; P=0.04) but not white (hazard ratio: 0.93; P=0.68) patients, with a significant ethnic-related interaction effect (P for the difference=0.04). Among hypertensive black patients, the TT genotype was associated with a 3.3-fold (P=0.02) increase in the risk of coronary events. Our findings suggest that homozygosity for the 235T mutation in the angiotensinogen gene is an independent risk factor for coronary events in black postmyocardial infarction patients. The presence of hypertension significantly augments the risk associated with this genetic mutation.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Black People; Cardiovascular Diseases; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Homozygote; Humans; Hypertension; Male; Methionine; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Prospective Studies; Recurrence; Threonine; White People

The brain renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiac remodeling after myocardial infarction (MI). To assess the contribution of the brain RAAS in the activation of the cardiac RAAS post-MI, transgenic (TG) rats deficient in brain angiotensinogen and Wistar rats with intracerebroventricular (ICV) infusion of spironolactone were studied. An MI was induced by acute coronary artery ligation. TG and control Sprague-Dawley (SD) rats were followed for 8 weeks and Wistar rats for 6 weeks. Infarct sizes, % of left ventricle (LV) area, were in the 30-33% range. In SD rats at 8 weeks post-MI, internal circumference, interstitial and perivascular fibrosis, cardiomyocyte diameter in the LV and right ventricle (RV), laminin and fibronectin in the LV, and lung weights were increased. Aldosterone was increased markedly in both the LV and RV at 8 weeks post-MI. In TG rats, the MI-induced increases of RV internal circumference and weight were prevented and increases of lung weight and LV internal circumference were significantly inhibited. In TG rats, the post-MI increases of interstitial fibrosis and cardiomyocyte diameter were prevented in septum and RV and significantly inhibited in the peri-infarct zone of the LV. The increases in perivascular fibrosis, laminin and fibronectin were prevented in the LV. In TG rats, cardiac aldosterone did not increase. In Wistar rats at 6 weeks post-MI, aldosterone was markedly increased in the LV, but not in the RV. This increase was prevented by ICV infusion of spironolactone. These findings support the pivotal role of locally produced angiotensin II in the brain in cardiac remodeling post-MI. The brain RAAS appears to activate a cascade of events, among others an increase in cardiac aldosterone, which play a major role in cardiac remodeling post-MI.

Topics: Aldosterone; Angiotensinogen; Animals; Animals, Genetically Modified; Brain; Cell Size; Fibronectins; Fibrosis; Heart Ventricles; Immunohistochemistry; Laminin; Male; Myocardial Infarction; Myocytes, Cardiac; Organ Size; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Spironolactone; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Three-gene interactions among the genetic polymorphisms of the renin-angiotensin system (RAS) associated with acute myocardial infarction (AMI) have not been examined in a single population. We hypothesized that all types of gene-to-gene associations may occur in AMI, but that some will have a higher risk, depending on the gene frequencies.. Polymorphisms of the AGT (M235T), ACE (I/D) and AGTR1 (A1166C) genes in AMI patients and controls were analyzed using the polymerase chain reaction. Classic coronary risk factors were analyzed in all individuals.. Logistic regression analysis of these factors and the genetic polymorphisms demonstrated that smoking, family history of CAD, arterial hypertension and total cholesterol were the most significant contributors to AMI. The genotypic frequencies for all three genes alone were similar between the infarction and control groups, with no increased risk of developing AMI. Double homozygous combinations for normal alleles (MM of AGT, II of ACE and AA of AGTR1) had a lower risk of AMI (odds ratio<0.38), indicating a protective effect in these individuals. In genotypic combinations that included at least one unfavorable allele, the risk (odds ratio) of developing AMI was 2.92, 2.63 and 2.68 for AGT vs. ACE, AGT vs. ATR1 and ACE vs. AGTR1, respectively. The positive interaction among the three genes and the risk of AMI had an odds ratio of 3.78 with a 95% CI of 0.88-12.85.. The risk of developing AMI is higher whenever there are unfavorable alleles in gene-to-gene associations in the RAS.

Topics: Adolescent; Alleles; Angiotensinogen; Biomarkers; DNA; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Male; Mutation; Myocardial Infarction; Odds Ratio; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

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

Topics: Adult; Angiotensinogen; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Coronary Angiography; Coronary Disease; Endothelium, Vascular; Genotype; Heat-Shock Proteins; Hemodynamics; Humans; Hypertension; Male; Myocardial Infarction; Nitric Oxide; Platelet Aggregation; Risk Factors; Vasodilation

The ThrThr genotype of the angiotensinogen (AGT) Met235Thr polymorphism has been associated with elevated AGT levels, hypertension, increased heart disease risk, and improved blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitors. We hypothesized that risk of stroke or myocardial infarction (MI) associated with ACE inhibitor use varies by AGT genotype, with a larger protective effect of ACE inhibitors in individuals with the ThrThr genotype than individuals who are carriers of the Met allele.. We conducted a population-based case-control study. Participants were health maintenance organization members aged 30 to 79 years with treated hypertension. Those who survived incident stroke (n = 116) or MI (n = 208) during the study period were designated as cases. Control subjects (n = 717) were randomly sampled and frequency-matched to MI cases on age, sex, and calendar year. Health history, medication use, and AGT genotype were assessed.. ThrThr genotype was present in 21% of stroke cases, 26% of MI cases, and 19% of control subjects. Compared with nonuse, ACE inhibitor use was associated with lower stroke risk among Thr homozygotes (odds ratio [OR] = 0.37, 95% CI = 0.14 to 0.99) than among Met carriers (OR = 1.4, 95% CI = 0.88 to 2.4; P for interaction =.02). Compared with nonuse, ACE inhibitor use was associated with similar MI risk among Thr homozygotes (OR = 0.90, 95% CI = 0.62 to 1.3) and among Met carriers (OR = 1.2, 95% CI = 0.60 to 2.5; P for interaction = 0.5).. In this hypertensive population, the association of ACE inhibitor use with risk of nonfatal stroke varied by genotype. The protective association between ACE inhibitor use and nonfatal stroke risk among individuals with ThrThr genotype was not observed for nonfatal MI.

Topics: Adult; Aged; Alleles; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Case-Control Studies; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Risk; Stroke

Topics: Age of Onset; Angiotensinogen; Humans; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Turkey

Genetic polymorphisms/mutations associated with venous thrombosis have largely been confined to the genes that encode for proteins in either the coagulant or the anticoagulant pathway. Although genetic alterations in the renin-angiotensin system have been reported to have a role in myocardial infarction and hypertension, there is recent evidence to suggest that there may also be an association with venous thrombosis. To extend our earlier observation of an association between the ACE DD genotype in African-American males and venous thrombosis, other genes in the renin-angiotensin pathway were investigated for possible disease association and were compared with African-Americans with myocardial infarction. African-American patients with a documented history of venous thrombosis or a history of myocardial infarction were eligible for participation as cases in the study. Control subjects were African-American outpatients attending a clinical laboratory for routine blood tests who had comparable age and gender distributions to the cases. Persons with a history of myocardial infarction, stroke, or thrombosis were excluded. Genes that were analyzed for known polymorphisms included angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin II type I receptor. Our results showed that the ACE DD genotype was also associated with MI in African-American males but not in females. Racial/ethnic and sex differences were also found with respect to the genotype distribution of the ACE 4656(CT)(2/3) polymorphism. It was observed that the 2/2 genotype had a protective effective in males for myocardial infarction and venous thrombosis. The data also demonstrated that the allele frequencies of the A1166C variant of the angiotensin II type I receptor were different in African-Americans as compared to Caucasians.

Topics: Angiotensinogen; Black or African American; Black People; Female; Gene Frequency; Genotype; Humans; Male; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Reference Values; Renin-Angiotensin System; Sex Characteristics; Thromboembolism; Venous Thrombosis

Topics: Angiotensinogen; Brain Ischemia; Case-Control Studies; Denmark; Female; Heterozygote; Homozygote; Humans; Male; Mutation; Myocardial Infarction; Myocardial Ischemia; Risk Factors

The renin-angiotensin system is involved in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI). The authors investigated the association of genetic variability in the renin-angiotensin system (RAS) with premature MI and interactive effects between gene polymorphisms and metabolic risk factors on MI risk. Their study compared 142 patients with MI younger than 55 years with 142 healthy subjects. Polymorphisms of angiotensin-I converting enzyme (ACE) gene (insertion/deletion), angiotensinogen gene (M235T), and angiotensin-II type-1 receptor (AGT1R) gene (A1166C) were tested. The ACE-DD (deletion/deletion) genotype conferred a twofold independent risk for MI (confidence interval [CI] = 1.1-3.7; p = 0.01) after adjustment for cardiovascular risk factors, whereas angiotensinogen-TT genotype and AGT1R-AA genotype were not independent risk factors for MI. An interactive effect on MI risk was found between ACE-DD and AGT1R-AA genotypes (odds ratio [OR]=2, 95% CI= 1-3.9), between ACE-DD and angiotensinogen-TT genotypes (OR = 2.7, 95% CI = 1-7.3), as well as among ACE-DD, angiotensinogen-TT, and AGT1R-AA genotypes (OR=4.8, 95% CI = 1-22.8). Similarly, metabolic risk factors interacted with angiotensinogen-TT genotype (OR= 2, 95% CI = 1.1-3.9) on MI risk. The ACE-DD genotype is an independent risk factor for MI in patients younger than 55 years. Additionally, the authors provide evidence of an interactive effect on MI risk between risk genotypes of RAS, as well as between the angiotensinogen-TT genotype and metabolic risk factors.

Topics: Angiotensinogen; Female; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors

We examined the relationship between the angiotensinogen (AGT) gene M235T polymorphism, the variant promoter of the AGT gene A(-6)G and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary heart disease (CHD) in native Gran Canaria Island habitants, who have the highest rates of CHD in Spain.. Some studies subject that the ACE (I/D) polymorphism could be associated with CHD, while AGT (M235T) has been related to essential hypertension.. We studied 304 subjects with angiographic evidence of coronary artery disease and a clinical diagnosis of myocardial infarction or unstable angina and 315 age- and gender-matched controls. Blood was drawn and DNA extracted. Angiotensin-converting enzyme (I/D) gene polymorphism was analyzed by polymerase chain reaction (PCR) and AGT gene polymorphisms by restriction fragment length polymorphism-PCR and mutagenically-separated PCR.. The ACE (I/D) polymorphism showed no association with CHD, whereas the frequency distribution of AGT (M235T) genotypes among patients and controls (235T: 29.1% and 19.0%; M235T: 48.5% and 50.2%; M235: 22.4% and 30.8%, respectively) was statistically different (p = 0.005) and not related to the presence of essential hypertension. Similar results were observed with the AGT A(-6)G polymorphism. In multiple logistic regression analysis, CHD odds ratio associated with 235T and M235 homozygotes were 1.7 (1.1 to 2.6) and 0.54 (0.36 to 0.82), respectively.. This study shows that genetic variation of the AGT (M235T), but not the ACE (I/D), genotypes contributes to the presence of CHD independently of blood pressure profile in a subset of the Spanish population with a high prevalence of cardiovascular disease.

Topics: Adult; Aged; Angina, Unstable; Angiotensinogen; Case-Control Studies; Coronary Disease; Female; Gene Deletion; Gene Frequency; Genetic Markers; Genetic Variation; Genotype; Homozygote; Humans; Logistic Models; Male; Middle Aged; Mutagenesis, Insertional; Myocardial Infarction; Odds Ratio; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Prevalence; Promoter Regions, Genetic; Radiography; Renin-Angiotensin System; Risk Factors; Spain

The M235T and T174M angiotensinogen mutations have been linked to increased risk for ischemic heart and cerebrovascular disease.. To determine whether angiotensinogen mutations are associated with ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease.. Six case-control studies from the Copenhagen City Heart Study.. Copenhagen, Denmark.. Participants in the Copenhagen City Heart Study and patients from the same hospital with ischemic heart disease (n = 866 and n = 943, respectively), myocardial infarction (n = 519 and n = 493, respectively), or ischemic cerebrovascular disease (n = 489 and n = 434, respectively) and 7975 controls without these conditions.. Genotypes for the M235T and T174M angiotensinogen mutations were compared between controls and Copenhagen City Heart Study participants with ischemic heart disease, myocardial infarction, and cerebrovascular disease (studies 1a, 1b, and 1c) and patients from Copenhagen University Hospital with the same conditions (studies 2a, 2b, and 2c).. Relative allele frequencies of 235T and 174M in the general population were 0.41 and 0.12, respectively. Genotype was not associated with increased risk for ischemic heart or ischemic cerebrovascular disease in studies of either mutation alone or combined in women or men. Among compound heterozygotes (235MT /174TM ), women in case-control study 2a had decreased risk for ischemic heart disease in age-adjusted analysis; however, this decreased risk was not seen in multifactorial-adjusted or matched analyses, in men, or in case-control study 1a. Among double homozygotes (235TT /174MM ), women in case-control study 2b had increased risk for myocardial infarction in matched analysis; however, this increased risk was not seen in age- or multifactorial-adjusted analyses, in men, or in case-control study 1b. Among single homozygotes (235TT /174TT ), men in case-control study 2b had increased risk for myocardial infarction in multifactorial-adjusted and matched analyses. This risk was not present in age-adjusted analysis, in women, or in case-control study 1b. In addition, male single homozygotes had decreased risk for ischemic cerebrovascular disease in case-control study 2c in age- and multifactorial-adjusted analyses, but this finding was not seen in matched analysis, in women, or in case-control study 1c.. In six large case-control studies, the M235T and T174M angiotensinogen mutations were not consistently associated with increased (or decreased) risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease. Statistically significant associations may represent chance findings rather than real phenomena.

Topics: Aged; Angiotensinogen; Brain Ischemia; Case-Control Studies; Female; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Male; Middle Aged; Mutation; Myocardial Infarction; Myocardial Ischemia; Regression Analysis; Risk Factors

Topics: Angiotensinogen; Brain Ischemia; Genetic Predisposition to Disease; Humans; Mutation; Myocardial Infarction; Myocardial Ischemia; Risk Factors

Molecular variants of the angiotensinogen (AGT) and the angiotensin II type 1 receptor (ATR) genes have been associated with the risk of coronary artery disease (CAD) and myocardial infarction (MI), but data so far available are conflicting. The primary object of the paper is to verify this possible association by a rigorous, angiographically controlled study in a large sample of patients with or without multi-vessel CAD.. We designed a large case-control study in Italian patients candidates for coronary artery bypass grafting, with angiographically documented multi-vessel CAD, compared to subjects with angiographically documented normal coronary arteries.. AGT M235T and ATR A1166C gene polymorphisms were analysed in 699 subjects; 454 patients were candidates for coronary artery bypass grafting, having angiographically documented (mainly multi-vessel) CAD. An appropriate documentation of previous MI was obtained from 404/454 (89%, 247 with and 157 without MI). Subjects (n = 245) with angiographically documented normal coronary arteries, were included as control group (CAD-free group). CAD patients had a substantial burden of conventional risk factors as compared with controls free of coronary atherosclerosis. Age, gender, smoking habit and number of stenosed vessels were the only differences between patients with or without previous myocardial infarction, who were similarly exposed to the other conventional risk factors (including hypertension). AGT M235T and ATR A1166C allele and genotype frequencies were similar between CAD and CAD-free patients. In the CAD group, AGT 235T allele was found more frequently in subjects with a previous myocardial infarction (0.494 versus 0.414; P < or = 0.05). By logistic regression, homozygosity for AGT 235T variant appeared to confer 1.9-fold increased risk for MI in both the univariate and the multivariate (adjusted for age, gender, smoking habit and number of stenosed vessels) model.. AGT 235 T homozygous patients with multivessel CAD have an increased risk of myocardial infarction as compared with subjects with clinically similar phenotype but different genotype.

Topics: Aged; Angiotensinogen; Coronary Disease; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Homozygote; Humans; Male; Middle Aged; Myocardial Infarction; Phenotype

Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium.. We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 micromol/L), an AT(1) blocker, or with tyrphostin AG490 (5 micromol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium.. These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.

Topics: Angiotensinogen; Animals; DNA-Binding Proteins; Enzyme Inhibitors; In Vitro Techniques; Janus Kinase 2; Male; Milk Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; RNA, Messenger; Signal Transduction; STAT5 Transcription Factor; STAT6 Transcription Factor; Trans-Activators; Tyrphostins; Up-Regulation

We have studied the role of three polymorphic genes of the renin-angiotensin system (RAS) as independent risk factors for myocardial infarction (MI) and their correlation with three of the major coronary risk factors: serum cholesterol (CH), hypertension (HT) and smoking (SM). A population of 392 men was genotyped for the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion of the angiotensin-converting enzyme (ACE) and the all66c of the angiotensin-II type 1 receptor (AT1R), by means of polymerase chain reaction (PCR) and restriction enzyme analysis. It was observed that the T allele frequency increased significantly in the MI with HT, CH, and SM subgroup (0.58 vs 0.31) (p<0.01). In contrast, the M allele frequency was higher in the MI without HT, CH, and SM (0.69 vs 0.42) (p<0.01). A strong association between the MM genotype and MI (p<0.001, odds ratio=4.29, confidence interval=1.95-9.42) was found when age-matched MM control subjects were compared to MI individuals with none of the other known major coronary risk factors. Futhermore, subjects with the MM genotype showed a significantly higher plasma renin activity (PRA) profile than those with the TT genotype (p<0.001). It can be concluded that the M allele is an independent risk factor for MI and the T allele modified the risk when other major risk factors are present.

Topics: Adult; Alleles; Amino Acid Substitution; Angiotensinogen; Cholesterol; DNA; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Risk Factors; Smoking

The aim of this study was to estimate the frequencies of some DNA polymorphisms of two genes of the renin-angiotensin system (RAS), M235T angiotensinogen gene and insertion-deletion polymorphism in angiotensin-converting enzyme gene, in older (>55 years old) myocardial infarction survival and control groups. For this purpose 198 myocardial infarction (MI) patients and 152 randomly selected healthy persons have been analyzed. We have not found any differences in allele and genotype distribution in the above-mentioned genes for either group. However, statistical research showed a significant increase of double homozygotes IITT in the group of MI patients as compared with those in the control group. In this respect we suggested that gene-gene interaction in the RAS system may be considered to be a predisposing factor for MI development.

Topics: Adolescent; Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Angiotensinogen; Child; Epistasis, Genetic; Gene Frequency; Genetic Predisposition to Disease; Homozygote; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Russia; Sequence Deletion

Several studies based on different populations worldwide have described an association between cardiovascular diseases and genetic variations in the apolipoprotein E (A:POE), angiotensinogen (A:GT), angiotensin receptor type 1 (A:T1R), and angiotensin-converting enzyme (A:CE) genes. In addition, there is growing evidence of an interaction between hypercholesterolemia and the renin-angiotensin system in the risk for hypertension and atherosclerosis.. To determine whether the DNA polymorphisms in A:POE (epsilon2, epsilon3, and epsilon4 alleles), A:GT (M235T), A:T1R (1166 A:/C:), and ACE (I:/D:) are associated with early onset of myocardial infarction (MI), we genotyped 220 patients and 200 controls <55 years of age. Patients and controls were males from the same homogeneous Caucasian population. Data concerning hypertension, diabetes, and tobacco consumption were recorded. The lipid profiles of patients and controls were also determined.. APOE, ACE, AGT, and AT1R allele and genotype frequencies did not differ between patients and controls. None of these polymorphisms was related to the biochemical values in patients or controls. The frequency of individuals who were both APOE epsilon4 allele carriers and AGT-TT homozygotes was significantly higher in patients than in controls (11% vs 3.5%; P: = 0.0037). In patients, the frequency of epsilon4 carriers was significantly higher (P: <0.00001) in those who were AGT-TT (46%) than those who were AGT-MT/MM (14%). Mean cholesterol was significantly higher in AGT-TT + APOE epsilon34/44 patients than in the TM/MM + epsilon34/44 or TT + epsilon23/33 genotypes (P: = 0. 029).. Our data suggest a synergistic effect between the APOE and AGT polymorphisms and early MI. The increased risk could be mediated in part through higher cholesterol concentrations among individuals who are AGT-TT + APOE epsilon4 allele carriers.

Topics: Adult; Age of Onset; Angiotensin II; Angiotensinogen; Apolipoproteins E; Cholesterol; Genotype; Humans; Lipoproteins, HDL; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Risk Factors; Triglycerides

Genes encoding components of the renin-angiotensin system have been associated with elevated blood pressure (BP) and an increased risk of coronary artery disease. To explore the role of the angiotensinogen (AGT) gene in coronary atherosclerosis and thrombosis, we studied the effect of the AGT M235T gene variant on plasma AGT levels and BP in patients with coronary artery disease and in the subgroup of survivors of myocardial infarction as compared with angiographically defined control subjects.. This was a case-control study of 301 white male subjects examined at Frankfurt University medical center. Plasma AGT levels increased stepwise according to the number of T235 alleles present (no T235 allele, 14.8 +/- 3.9 nmol/L; 1 allele, 15.7 +/- 5.1 nmol/L; 2 alleles, 17.3 +/- 4.7 nmol/L; P =.006). In a multivariate model, circulating AGT emerged as the most important predictor of diastolic pressure (P =.001). In addition, AGT M235T gene polymorphism remained a significant predictor of diastolic BP in a multivariate model adjusted for age, body mass index, fasting glucose, apolipoprotein B, presence of coronary artery disease, and treatment with antihypertensive agents ( P <.05). Finally, homozygosity for T235 was associated with increased univariate risk of coronary artery disease and myocardial infarction (odds ratio estimates 1.5; 95% confidence intervals 1.1 to 2.1, P =.03, and 1.0 to 2.1, P =.05, respectively).. The significant relations observed between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating AGT in the pathogenesis of coronary artery disease.

Topics: Alleles; Angiotensinogen; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Coronary Artery Disease; Coronary Thrombosis; Gene Frequency; Genotype; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors

The renin-angiotensin system promotes cardiac hypertrophy after myocardial infarction. The purpose of this study was to measure renin and angiotensinogen in plasma and myocardium 10 days after myocardial infarction. Infarction involving 45 +/- 4% of left ventricular circumference with accompanying hypertrophy was induced in rats (n = 14). Plasma and myocardial renin were increased after infarction compared with sham controls (n = 8) (27.4 +/- 3.2 vs. 7.5 +/- 1.8 ng ANG I. ml plasma. h-1, P < 0.0002; and 8.8 +/- 1.6 vs. 2. 5 +/- 0.1 ng ANG I. g myocardium-1. h-1, P < 0.008, respectively). After infarction, myocardial renin was correlated with infarct size (r = 0.62, P < 0.02) and plasma renin (r = 0.55, P < 0.04). Plasma angiotensinogen decreased in infarct animals, but myocardial angiotensinogen was not different from shams (1.1 +/- 0.08 vs. 2.03 +/- 0.06 nM/ml plasma, P < 0.002; and 0.081 +/- 0.008 vs. 0.070 +/- 0.004 nM/g myocardium, respectively). In conclusion, myocardial renin increased after infarction in proportion to plasma renin and infarct size, and myocardial angiotensinogen was maintained after infarction despite decreased plasma angiotensinogen and increased levels of myocardial renin.

Topics: Angiotensinogen; Animals; Extracellular Space; Male; Myocardial Infarction; Myocardium; Nephrectomy; Osmolar Concentration; Protein Isoforms; Rats; Rats, Sprague-Dawley; Renin

We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of myocardial infarction (MI) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with MI into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and MI groups showed that the MM genotype frequency increased in MI men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the MI > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for MI. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for MI in case-control studies, since data from isolated age-matched groups can be misinterpreted.

Topics: Adult; Aged; Alleles; Angiotensinogen; Case-Control Studies; DNA; DNA Transposable Elements; Female; Gene Frequency; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Myocardial Infarction; Oxidoreductases Acting on CH-NH Group Donors; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

The groups of patients with myocardial infarction (MI) and hypertrophy of the left ventricle (HLV) (n = 45 and n = 53, respectively) and a sample of healthy individuals from the Moscow population (n = 60) were examined for T174M polymorphism of AGT gene (replacement of methionine for threonine at position 174 of the correspondent amino acid sequence). In MI patients the content of TT genotypes and T allele was significantly lower than in the control group (57.8% against 80% and 67.9 against 89.2%, respectively), whereas the proportion of M allele and TM heterozygotes was increased (32.1 against 10.8% and 37.8 against 18.3%, respectively). In patients with HLV, the proportion of TT genotype (64.2%) and T allele (77.4%) was also lower than in the control group, whereas the frequency of M allele was increased (22.6%). Our results suggest that the T174M polymorphism of AGT gene is associated with MI and HLV in the Moscow population.

Topics: Adult; Angiotensinogen; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Moscow; Myocardial Infarction; Polymorphism, Genetic

To investigate a possible involvement of polymorphisms of the renin-angiotensin system in predisposition to moderate and severe hypertension and their relationship to parental histories of myocardial infarction and stroke.. Hypertensive cases (453 men, 326 women) were patients followed up by general practitioners for established hypertension. Inclusion criteria were an age of onset of hypertension < or = 60 years and a diastolic blood pressure > or = 105 mmHg without antihypertensive medication or > or = 100 mmHg under treatment. Normotensive controls were selected from population-based samples (362 men) and during a preventative medicine visit (170 women). Polymorphisms of the angiotensinogen gene (AGT M235T and T174M), the angiotensin I converting enzyme gene (ACE I/D), and the angiotensin II type 1 receptor gene (AGT1R A1166C) were investigated.. The AGTT235 allele prevalence was higher among male hypertensive cases than it was among controls (0.46 versus 0.40, P = 0.01) and a similar trend was observed with female cases whose hypertension had been diagnosed before they were aged 45 years (0.44 versus 0.38, P = 0.20). The AGT1R C1166 allele prevalence was higher among female hypertensives than it was among controls (0.30 versus 0.23, P = 0.03) but no such difference was observed for men. The AGT T174M and ACE I/D polymorphisms were not associated with hypertension. Hypertensive patients reporting a parental history of myocardial infarction before age 60 years had a higher prevalence of the ACE D allele than did those without such a parental history (0.68 versus 0.56, P = 0.01). The ACE D allele prevalence was also greater among patients reporting a parental history of stroke incidence before age 65 years (0.66 versus 0.57, P = 0.05).. These results support the hypothesis that the AGT gene plays a role in predisposition to hypertension and that the ACE gene plays a role in predisposition to acute ischemic events.

Topics: Adult; Alleles; Angiotensinogen; Cerebrovascular Disorders; Female; France; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Parents; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors

We have previously reported that production of endothelin (ET)-1 is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET-1 in the left ventricle (LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore, we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-1 production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.

Topics: Angiotensinogen; Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Enzyme Induction; Heart Failure; Hemodynamics; Male; Metalloendopeptidases; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

A molecular variant of the angiotensinogen(AGT) gene with threonine instead of methionine at position 235(i.e.,with M235T polymor- phism) has been shown to be associated with essential hypertension, preeclampsia, coronary atherosclerosis, coronary heart disease(CHD), myocardial infarction(MI) in Caucasians and in Japanese. The purpose of the present study was to assess whether the M235T polymorphism was associated with MI in a Chinese population.. M235T polymorphism in exon 2 of AGT gene was determined by polymerase chain reaction(PCR) and restriction endonuclease analysis in a study of 57 patients with MI and 76 non-CHD individuals as control.. The frequencies of T235 allele(0.82) and 235TT genotype (0.70) in the MI group were higher than those in the control subjects(0.63 and 0.42 respectively, P=0.013 and P<0.025). AGT gene 235TT genotype was at significantly increased risk of MI(odds ratio 3.65, P=0.016) in analysis adjusted for several main CHD risk factors.. There is a significant association between AGT gene 235TT genotype and MI, this genotype might be an independent risk for MI in Chinese population.

Topics: Aged; Angiotensinogen; Female; Humans; Male; Middle Aged; Myocardial Infarction; Polymerase Chain Reaction; Polymorphism, Genetic

Both myocardial and plasma endothelin-1 (ET-1) are elevated in congestive heart failure (CHF). However, the role played by endogenous ET-1 in the progression of CHF remains unknown. The aim of the present study was to investigate and correlate myocardial gene expression programs and left ventricular (LV) remodeling during chronic ET-receptor antagonism in CHF rats. After ligation of the left coronary artery, rats were randomized to oral treatment with a nonselective ET-receptor antagonist (bosentan, 100 mg . kg-1 . day-1, n = 11) or vehicle (saline, n = 13) for 15 days, starting 24 h after induction of myocardial infarction. Bosentan substantially attenuated LV dilatation during postinfarction failure as evaluated by echocardiography. Furthermore, bosentan decreased LV systolic and end-diastolic pressures and increased fractional shortening. Myocardial expression of preproET-1 mRNA and a fetal gene program characteristic of myocardial hypertrophy were increased in the CHF rats and were not affected by bosentan. Consistently, right ventricular-to-body weight ratios, diameters of cardiomyocytes, and echocardiographic analysis demonstrated a sustained hypertrophic response and a normalized relative wall thickness after intervention with bosentan. Thus the modest reduction of preload and afterload provided by bosentan substantially attenuates LV dilatation, causing improved pressure-volume relationships. However, the compensatory hypertrophic response was not altered by ET-receptor antagonism. Therefore, ET-1 does not appear to play a crucial role in the mechanisms of myocardial hypertrophy during the early phase of postinfarction failure.

Topics: Angiotensinogen; Animals; Bosentan; Coronary Vessels; Endothelin Receptor Antagonists; Gene Expression; Heart Failure; Hypertrophy, Left Ventricular; Ligation; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Ventricular Function, Left

Rats with congestive heart failure demonstrate striking intrarenal vasoconstriction that contributes to reduced renal excretory function. We previously demonstrated that inhibition of angiotensin action reverses intrarenal vasoconstriction in rats 4-6 wk after coronary artery ligation. In the present study we tested the hypothesis that abnormalities in the expression and regulation of glomerular angiotensin receptors contribute to the intrarenal vasoconstriction. Because glomerular angiotensin type 1 (AT1) receptors normally downregulate in response to high local ANG II concentrations, we anticipated that glomerular AT1-receptor expression would be reduced in rats after myocardial infarction (MI). To our surprise, the density of glomerular AT1 receptors was nearly double (97% increase, P < 0.002) that of controls, indicating an acquired abnormality in angiotensin receptor regulation. This was specific for renal glomeruli, because the density of angiotensin receptors on renal vasculature was decreased in rats after MI compared with normal controls. Glomerular AT1-receptor expression was downregulated by an acute pharmacological infusion of ANG II and upregulated by acute angiotensin-converting enzyme inhibition to a similar extent in MI and control rats. Renal cortical mRNA expression showed an increase in the renin mRNA-to-actin ratio and angiotensinogen-to-actin ratio, indicating stimulation of the intrarenal angiotensin system in rats after MI. The data indicate a specific dysregulation of AT1 receptors in glomeruli but not blood vessels after MI.

Topics: Actins; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Down-Regulation; Gene Expression Regulation; Kidney Cortex; Kidney Glomerulus; Kinetics; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Reference Values; Renal Circulation; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic; Up-Regulation

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 aim of this study was to analyze sequential change of angiotensinogen (Ao) mRNA expression in rat liver and noninfarcted myocardium after myocardial infarction (MI). Female sprague-Dawley rats were subjected either to left coronary artery occlusion or sham operation. Three weeks after MI, coronary artery ligation resulted in comparable infarct sizes. A hypokinetic thin anterior wall and remarkable dilatation of the left ventricle, as well as decreased contractility (left ventricular end-systolic dimension = 6.0+/-0.4, 3.3+/-0.2, LV end-diastolic dimension = 7.9+/-0.3, 5.9+/-0.2 mm, and fractional shortening = 25.3+/-3.1%, 45.1+/-3.3%) were shown in the MI and sham group, respectively, by echocardiography (P < 0.01). Experimental MI caused a significant fall in systolic blood pressure (MI 90+/-5.0, vs sham 130+/-7.5 mmHg; P< 0.01) and significantly higher left ventricular end-diastolic pressure (MI 21+/-1.5, vs sham 11+/-1.0 mmHg: P < 0.01). At 4, 18, and 24h after MI, liver Ao mRNA levels, as shown by Northern blot analysis, had increased by up to four times (Ao/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) = 1.4+/-0.1 and 6.0+/-0.2 at baseline and 4h after MI, respectively (P < 0.01). After sham surgery, however, the corresponding increase was slight (maximal 1.5-fold). Three days after MI, liver mRNA had returned to the baseline level. In contrast, ATG mRNA expression in noninfarcted myocardium, as shown by reverse transcription-polymerase chain reaction and Southern blotting, decreased transiently during the acute phase. It returned to its baseline level within 3 days, and then increased further (Ao/ GAPDH = 2.9+/-0.6, 0.3+/-0.1, 3.2+/-0.8, and 3.7+/-0.8 at baseline, 24h, 3 days, and 3 weeks after MI, respectively). In conclusion, it can be stated that after MI, the Ao gene contributes, acutely in the liver and chronically in the myocardium, to the maintenance of hemodynamic homeostasis during the acute phase and ventricular remodeling during the chronic phase.

Topics: Angiotensinogen; Animals; Blotting, Northern; Female; Liver; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Genetic polymorphisms of the renin-angiotensin system (RAS) have been associated with coronary artery disease (CAD) but no relation between these polymorphisms and coronary atherosclerosis has yet been systematically evaluated. The CORGENE study is a cross-sectional study involving 463 Caucasians who underwent standardized coronary angiography for established or suspected CAD [156 patients with a previous myocardial infarction (MI), 307 without MI]. Four angiographic scores assessing the extent and severity of the coronary lesions were obtained from a double visual analysis of each angiogram, arbitration being achieved by a quantitative measurement. Three different genotypes were analyzed: the angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism, the Met to Thr change at position 235 of the angiotensinogen gene (AGT M235T) and the A to C transition at position 1166 of the angiotensin II type-1 receptor gene (AT1R A1166C). No significant association was observed between these polymorphisms and the clinical characteristics of MI and non-MI subjects. While most classical risk factors were positively correlated with the angiographic scores, no significant relationship could be established with the three genotypes (r ranging from -0.08 to 0.05). Only one significant correlation was observed: between the presence of the AGT 235T allele and the extent of the coronary lesions (r = -0.19, P = 0.04) in patients with low-risk status. These overall results are not in favor of a role of these RAS genetic polymorphisms in the development of coronary atherosclerosis.

Topics: Angiotensinogen; Coronary Angiography; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus; DNA Transposable Elements; Family; Female; France; Gene Frequency; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Risk Assessment; Sequence Deletion; White People

Angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) are major components of the renin-angiotensin systems. An association between myocardial infarction (MI) and the ACE DD genotype of the insertion/deletion (ID) polymorphism in intron 16 of the ACE gene has been reported. However, other similarly designed studies have not found such an association. Angiotensin II, the product of AGT, has a direct effect on vascular tone; and a variant in the AGT gene has been found to be associated with MI in the Japanese. This case-control study was initiated to investigate whether the ACEI/D and AGT M235T polymorphisms are associated with an increased risk for coronary heart disease (CHD) and MI. Our study groups were composed of participants in the National Heart Lung Blood Institute (NHLBI) Family Heart Study (FHS) selected from three population-based studies: two Atherosclerosis Risk in Communities (ARIC) centers (Forsyth County, NC, and Minneapolis, MN), and the Framingham Heart Study. In multivariate analysis within ARIC Caucasians, a significant positive association was found between CHD (controls = 230, cases = 232) and the AGT TT genotype (P = 0.022; OR = 1.84, 1.09-3.10 95% CI). When we restricted the analysis to a low-risk group for CHD (controls = 70, cases = 35) an interaction between the ACE DD and AGT TT genotypes was significant (P = 0.025; OR = 5.02 1.22-20.6 95% CI). After further subsetting low-risk cases to those with a definite MI (controls = 74, cases = 16), we found that the associations with the ACE DD genotype was also significant (P = 0.013, OR = 3.94, 1.28-12.2 95% CI). Comparable tests in the Framingham sample failed to support an association of these markers with CHD. In conclusion, within selected groups the ACE D and AGT 235T alleles are statistically associated with CHD and MI, and there is a synergistic interaction between the two alleles. These results and those from previous studies together suggest that the association of these two loci is neither strong nor consistent and involves a complex interaction among risk factors and genotypes.

Topics: Angiotensinogen; Black People; Body Mass Index; Case-Control Studies; Coronary Disease; Female; Gene Deletion; Genotype; Humans; Logistic Models; Male; Massachusetts; Minnesota; Myocardial Infarction; North Carolina; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; White People

Aim of this study is to carry out a genetic analysis of polymorphisms of the renin-angiotensin system in a genetically homogeneous population, in patients with and without myocardial infarction (AMI) expansion and to evaluate the influence of non genetic, mechanical factors. The study was conducted on 299 patients with first AMI. Ecocardiography studies were performed on all patients on day 1 and 3 from the onset of AMI and before discharge. Eighty-four patients were excluded because of inadequate quality of echocardiograms and 215 (163 males, 52 females) were admitted. Of these, 157 had no evidence of AMI expansion (EXP-) while 58 had expansion (EXP+). DNA was extracted by standard methods from blood samples. Age and gender had no influence on AMI expansion. Anterior infarction (p < 0.000001) and Q-wave infarction (p < 0.00002) were found more frequently in EXP+. Peak of creatine phosphokinase was higher in EXP+ than in EXP- (p < 0.00001). The percent of patients treated with thrombolysis or with hypertension and/or left ventricular hypertrophy was not significantly different in the two groups. AGT MT235 polymorphism of angiotensinogen gene, I/D polymorphism of ACE gene and AT1 A1166C of AT1 receptor of angiotensin II were not significantly different in two groups. Stratified analysis showed that in patients with anterior AMI (n = 87), with a higher risk of AMI expansion, there is a significant difference (p < 0.02) in ACE genotype between EXP- and EXP+. Odds ratio assuming the dominant effect of I allele (II+ ID < DD) was 3.35 (confidence interval 1.41-7.56) with increased risk of expansion. More extension studies are need to verify if these results can contribute to early identification of patients at higher risk and to optimize therapeutic approach.

Topics: Aged; Alleles; Angiotensin II; Angiotensinogen; Causality; Confidence Intervals; Echocardiography; Female; Genes; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System

1. It has been suggested that local tissue renin-angiotensin systems may be activated in heart failure and that effects on such systems may, at least partially, explain the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in this syndrome. To investigate these hypotheses, we examined expression of renin-angiotensin system components in several tissues in a rodent model of post-myocardial infarction (MI) heart failure, and analysed whether such expression is modified by ACE inhibitor treatment. 2. Four groups of rats (n = 8 - 12 per group) were studied 30 days after surgery: (A) sham-operated rats with no treatment, (B) rats with post-MI heart failure induced by ligation of the left coronary artery, (C) sham-operated rats treated with the ACE inhibitor perindopril (1.5 mg day-1 kg-1), and (D) rats as per B, but treated with perindopril. Expression of renin, angiotensinogen, ACE and angiotensin subtype 1 receptor was assessed by quantification of their respective mRNAs by Northern blotting. 3. Renal renin mRNA increased 2-fold in animals with MI (group B) compared with controls (group A) (P < 0.05) and between 50 and 100-fold after ACE inhibitor treatment (P < 0.001). No change in renin gene expression was found in any extra-renal site either following MI or after ACE inhibitor treatment. Hepatic angiotensinogen mRNA level was similar in all groups, but kidney angiotensinogen mRNA level was increased 1.6-fold (P < 0.01) in the groups receiving perindopril. ACE mRNA level in the lung was not affected by ACE inhibitor treatment but decreased by 50% following MI (groups B and D, P < 0.01). This was associated with a similar (50%, P < 0.01) fall in lung ACE activity and was correlated with the severity of heart failure. Angiotensin subtype 1 receptor mRNA level was not affected in any tissue by either MI or ACE inhibitor treatment. 4. We did not find a systematic activation of tissue renin-angiotensin systems, as assessed by steady-state mRNA levels of key components of the system in experimental post-MI heart failure, or a major effect of ACE inhibitor treatment on expression of these components. However, we observed tissue-specific changes in expression of selected components of the renin-angiotensin system in the kidney and the lung in post-MI heart failure and after ACE inhibitor treatment, which may be of relevance to the pathophysiology of the syndrome and the effects of ACE inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blotting, Northern; Heart Failure; Indoles; Kidney; Liver; Lung; Male; Myocardial Infarction; Peptidyl-Dipeptidase A; Perindopril; Rats; Rats, Wistar; Renin

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

Wistar-Kyoto rats underwent myocardial infarction (MI) or sham surgery. At different time points after surgery (1-90 days), hearts were removed and divided into infarcted left ventricle (LV), noninfarcted septum, and right ventricle. The tissues were used for total RNA isolation or Formalin fixation for in situ hybridization (ISH). Renin and angiotensinogen mRNA contents were quantified by the competitive reverse transcriptase polymerase chain reaction. We found a 4-, 14-, and 8-fold increase (P < 0.05, n = 6) in renin mRNA in the infarcted LV at 2, 4, and 7 days after MI, respectively. No differences were observed between angiotensinogen mRNA levels in sham and infarcted hearts. ISH at 4 days after surgery revealed a dense renin mRNA labeling around the infarcted area, whereas ISH of angiotensinogen displayed an overall low density in the myocardium with somewhat higher levels in the epicardium of sham and MI animals. Atrial natriuretic factor mRNA, a marker for cardiac hypertrophy, was approximately twofold higher in all compartments of the hearts after MI. The low amounts of renin and angiotensinogen mRNA in the noninfarcted hypertrophied myocardium indicate that the intracardiac synthesis of these components does not play a dominant role in the development of cardiac hypertrophy in the rat heart after MI. In addition, the increased renin mRNA expression in the border zone of the infarcted LV suggests a role for intracardiac angiotensin II in infarct healing.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; In Situ Hybridization; Male; Myocardial Infarction; Myocardium; Polymerase Chain Reaction; Rats; Rats, Inbred WKY; Renin; RNA, Messenger; Transcription, Genetic

To study the association between polymorphisms of the angiotensinogen (AGT) gene and blood pressure in population-based samples, and to determine whether genetic variation at the AGT locus is involved in the susceptibility to myocardial infarction.. The study population comprised 630 cases who survived a myocardial infarction, recruited from the World Health Organization Monitoring Cardiovascular Diseases registers in Belfast, Lille, Strasbourg and Toulouse, and 741 controls drawn from the corresponding populations. The AGT polymorphisms investigated were T174M and M235T. High blood pressure was defined as diastolic blood pressure > 100 mmHg or the use of antihypertensive medication, or both.. In the controls the mean +/- SEM frequency of the M174 allele was 0.116 +/- 0.008, and that of the T235 allele was 0.401 +/- 0.013. In the whole population blood pressure levels and prevalence of high blood pressure did not vary according to T174M and M235T genotypes. However, obesity appeared as a crucial factor influencing the relationship between high blood pressure and T174M. In subjects with body mass index < 26 kg/m2 there was a 2.4-fold increase of the prevalence of high blood pressure in carriers of the M174 allele compared with in homozygotes for the T174 allele, whereas no association was detected in subjects with body mass index > 26 kg/m2. The association between high blood pressure and M235T was not significant in either group. The T174M and M235T genotype distributions did not differ between survivors of myocardial infarction and controls.. These data suggest that the AGT gene could be involved in the predisposition to high blood pressure in non-overweight, but not in overweight men, possibly reflecting genetically different types of hypertension. No significant impact of the AGT locus in the risk of non-fatal myocardial infarction was detected.

Topics: Adult; Alleles; Angiotensinogen; Base Sequence; Blood Pressure; DNA; Genotype; Humans; Male; Middle Aged; Molecular Sequence Data; Myocardial Infarction; Polymerase Chain Reaction; Polymorphism, Genetic; World Health Organization

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

Extrahepatic synthesis and localization of angiotensinogen (ATN) have been described in animals, thus establishing the tissue renin-angiotensin (RA) system. However, there had been no reports of tissue RA systems in human organs, including the heart. In earlier, we have reported the possibility of ATN synthesis in the human heart using ribonuclease protection assay system. ATN mRNA was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that ATN is synthesized in the human heart. In this report, we looked for the distribution of ATN in diseased human heart. Northern blot hybridization of cDNA with total RNA extracted from human liver, brain, kidney, atrial and ventricular tissues revealed that ATN mRNA exists in cardiac ventricule. Immunohistochemical studies using a specific antibody to ATN revealed a stronger reaction in the endocardial layer of the human left ventricle, than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. This distribution pattern was similar to that of human atrial natriuretic peptide (hANP), which functions a smooth muscle relaxant. Double immunostaining of ATN and hANP demonstrated that all myocytes in the right atrium had immunopositive reactions to ATN, hANP or both of ATN and hANP. Double immunoelectron staining enabled us to show more detailed localization of ATN and hANP; hANP only existed in the specific granules and ATN existed in the myofibril, but not in the granule. Furthermore, our experiments provide evidence of ATN in healthy human hearts and also reveal a widespread immunopositive reaction for ATN in the left ventricle of diseased hearts.

Topics: Angiotensinogen; Antibodies, Monoclonal; Blotting, Northern; Heart Atria; Heart Conduction System; Heart Diseases; Heart Ventricles; Humans; Myocardial Infarction; Myocardium

Activation of the intrarenal renin-angiotensin system may contribute to the pathophysiology of heart failure by accelerating the generation of angiotensin II at local sites within the kidneys. Activation of the local intrarenal renin-angiotensin system occurs in rats and with mild heart failure. The aim of the present study was to examine components of the circulating as well as the intrarenal renin-angiotensin system in rats with severe heart failure.. Six weeks after experimental myocardial infarction (heart failure, HF; n = 8) or sham operation (control, C; n = 6), haemodynamics and the circulating and intrarenal components of the renin-angiotensin system were studied.. HF rats were characterised by large infarctions (scar tissue > 40% of the left ventricular circumference). In comparison to sham operated controls, large myocardial infarctions resulted in severe heart failure with decreased systolic [108(SEM 3) mm Hg v 132(3) in C; p < 0.001] and diastolic arterial blood pressure [83(3) mm Hg v 95(2) in C; p < 0.05], decreased left ventricular systolic pressure [109(3) mm Hg v 132(3) in C; p < 0.005] and increased left ventricular end diastolic pressure [27(2) mm Hg v 5(1) in C; p < 0.0001]. In rats with severe heart failure, the circulating renin-angiotensin system was activated, with an increase in plasma renin activity (3.5-fold, p < 0.05) and plasma angiotensin II concentration (threefold, p < 0.01). In parallel, the intrarenal renin-angiotensin system was activated in severe heart failure. Increases occurred in renal renin mRNA level (1.7-fold, p < 0.01), renal angiotensinogen mRNA level (1.8-fold, p < 0.05), and renal angiotensin II concentration (twofold, p < 0.05) compared to C. Intrarenal angiotensin II concentrations exceeded plasma levels by a factor of 50 and were positively correlated with renal angiotensinogen mRNA levels (r = 0.874, p < 0.001), suggesting that local synthesis is the major source of angiotensin II found in the kidney.. The intrarenal renin-angiotensin system may be selectively activated in mild heart failure, while both circulating and intrarenal renin-angiotensin systems are induced as the extent of left ventricular function worsens.

Topics: Angiotensin II; Angiotensinogen; Animals; Blotting, Northern; Disease Models, Animal; Heart Failure; Kidney; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System

Recent studies in both experimental animals and man have demonstrated the unique efficacy of converting enzyme inhibitors to prevent or attenuate ventricular remodeling after myocardial infarction. Concomitantly, evidence for a trophic role of the renin-angiotensin system (RAS), as well as for the existence of an intracardiac tissue-resident RAS, has been presented, raising the question whether altered regulation of this cardiac RAS may be associated with the process of ventricular remodeling. We conducted the present study to examine whether cardiac angiotensinogen gene expression is altered after myocardial infarction. Experiments were performed in rats 5 and 25 days after ligation of the left coronary artery or sham operation. Coronary artery ligation resulted in relative infarct sizes averaging 29% and 36% of total left ventricular mass at 5 and 25 days and in marked elevations of left ventricular end-diastolic pressure (LVEDP). Angiotensinogen mRNA levels, measured by solution hybridization assay and confirmed in a second, independent experimental group by RNAse protection assay, were significantly elevated in the non-infarcted portion of the left ventricle at 5 days after infarction when compared to the sham group (22.1 + 3.3 vs. 13.4 +/- 2.0 fg/microgram total RNA; ratio of densitometric absorbance for angiotensinogen/beta-actin: 0.356 +/- 0.041 vs. 0.156 +/- 0.02), and showed a significant correlation with infarct size (r = 0.93). At 25 days, angiotensinogen gene expression had returned to control values. Similarly, no significant differences in angiotensinogen mRNA levels between animals with and without infarction were found in other cardiac tissues (atria, right ventricle). Plasma renin activity was significantly increased over baseline in the infarct group at 5, but not at 25 days. Our results demonstrate that acute hemodynamic embarrassment early after LV infarction is associated with augmented angiotensinogen gene expression. The potential significance of this finding is discussed.

Topics: Angiotensinogen; Animals; Constriction; Coronary Vessels; Gene Expression; Heart Ventricles; Hemodynamics; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger

Topics: Adult; Aged; Angiotensin II; Angiotensinogen; Endopeptidases; Enzyme Activation; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Renin; Shock, Cardiogenic