angiotensinogen and Heart-Failure

The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen-the precursor substrate of the RAAS pathway-remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.

Topics: Angiotensinogen; Cardiovascular Diseases; Heart Failure; Humans; Hypertension; Oligonucleotides, Antisense; Peptide Hormones; Renin-Angiotensin System; RNA

Corona virus disease-19 (covid-19) is caused by a coronavirus that is also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and is generally characterized by fever, respiratory inflammation, and multi-organ failure in susceptible hosts. One of the first things during inflammation is the response by acute phase proteins coupled with coagulation. The angiotensinogen (a substrate for hypertension) is one such acute phase protein and goes on to explain an association of covid-19 with that of angiotensin-converting enzyme-2 (ACE2, a metallopeptidase). Therefore, it is advisable to administer, and test the efficacy of specific blocker(s) of angiotensinogen such as siRNAs or antibodies to covid-19 subjects. Covid-19 activates neutrophils, macrophages, but decreases T-helper cells activity. The metalloproteinases promote the activation of these inflammatory immune cells, therefore; we surmise that doxycycline (a metalloproteinase inhibitor, and a safer antibiotic) would benefit the covid-19 subjects. Along these lines, an anti-acid has also been suggested for mitigation of the covid-19 complications. Interestingly, there are three primary vegetables (celery, carrot, and long-squash) which are alkaline in their pH-range as compared to many others. Hence, treatment with fresh juice (without any preservative) from these vegies or the antioxidants derived from purple carrot and cabbage together with appropriate anti-coagulants may also help prevent or lessen the detrimental effects of the covid-19 pathological outcomes. These suggested remedies might be included in the list of putative interventions that are currently being investigated towards mitigating the multi-organ damage by Covid-19 during the ongoing pandemic.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; COVID-19; COVID-19 Drug Treatment; Heart; Heart Failure; Humans; Inflammation; Neutrophils; Pandemics; RNA, Small Interfering; SARS-CoV-2

Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF).. Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Chymases; Heart Failure; Humans; Hypertension; Peptide Fragments; Receptors, Angiotensin; Renin-Angiotensin System

Chronic renal diseases and congestive heart failure are progressive disorders, which cannot be completely controlled by established therapies. It has been argued that intracrine biology involving the formation of self-sustaining intracrine regulatory loops accounts for the progression of these disorders and for the inability of standard therapies to stop disease spread. The renin-angiotensin system is a prime candidate to be involved in any such process, and an amplifying role for mineralocorticoid activation is also consistent with this view. Here, the notion of intracrine participation in congestive heart failure and chronic renal disease is expanded to include consideration of the participation of other intracrines including transforming growth factor beta 1, parathyroid hormone-related protein and vascular endothelial growth factor among others. The possibility that intracrine expression patterns account for disease phenotypes is explored. The therapeutic implications of this view are discussed.

Topics: Angiotensin II; Angiotensinogen; Cardio-Renal Syndrome; Disease Progression; Heart Failure; Humans; Parathyroid Hormone-Related Protein; Peptidyl-Dipeptidase A; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Signal Transduction; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

The angiotensinogen (AGT) gene M235T polymorphism has been suggested to be linked to risk of heart failure (HF). However, association studies on the M235T polymorphism and HF risk have shown conflicting results. PubMed and China Biology Medicine (CBM) databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 1,281 HF cases and 1,376 controls were included in the analysis. The pooled data showed that there was no significant associations between the AGT M235T polymorphism and HF risk for TT vs. MM (OR = 1.17, 95%CI = 0.62-2.19, P = 0.635), MT vs. MM (OR = 0.97, 95%CI = 0.77-1.22, P = 0.776), MT/TT vs. MM (OR = 1.07, 95%CI = 0.67-1.69, P = 0.781), and TT vs. MM/MT (OR = 1.23, 95%CI = 0.86-1.76, P = 0.259). In contrast, in the HF subgroup analysis by ethnicity, the AGT M235T polymorphism had a decreased risk of HF among Asians (MT vs. MM, OR = 0.39, 95%CI = 0.17-0.92, P = 0.032). Our results suggest that the AGT M235T polymorphism is a low-penetrant risk factor for the development of HF among Asians.

Topics: Alleles; Angiotensinogen; Asian People; Case-Control Studies; Genetic Predisposition to Disease; Genotype; Heart Failure; Humans; Odds Ratio; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Publication Bias

The aim of the present study was to assess the association between M235T polymorphism and heart failure using a meta-analysis.. A literature search of Google Scholar, PubMed, the Cochrane Library and the China National Knowledge Infrastructure database (January 1990-April 2012) was performed for relevant studies. Statistical analyses were carried out using the Stata 12.0 to combine all the relevant studies. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model and a random-effects model when appropriate. The pooled ORs were performed under the allelic contrast (T vs M), the dominant (TT + MT vs. MM) and the recessive models (TT vs MT + MM). Begg's test was used to measure publication bias.. A total of six case-control studies including 842 patients and 1054 controls were enrolled in this meta-analysis. Overall, there was a significant association between angiotensinogen (AGT) gene M235T polymorphism and risk of heart failure in the subgroup analysis under the allelic contrast (T vs M: OR = 1.48, 95% CI: 1.04-2.11) and the dominant model (TT+MT vs MM: OR=1.67, 95% CI: 1.13-2.46) in the Caucasian population.. The current meta-analysis suggests that M235T polymorphism might be associated with increased risk of heart failure in Caucasians.

Topics: Alleles; Angiotensinogen; Asian People; Black People; Case-Control Studies; Genes, Dominant; Genes, Recessive; Heart Failure; Humans; Polymorphism, Genetic; Risk; White People

Recent studies have shown that the JAK-STAT signaling pathway plays a central role in cardiac pathophysiology. JAK-STAT signaling has been implicated in pressure overload-induced cardiac hypertrophy and remodeling, ischemic preconditioning, and ischemia/reperfusion-induced cardiac dysfunction. The different STAT family members expressed in cardiac myocytes appear to be linked to different, and at times, opposite responses, such as cell growth/survival and apoptosis. Thus, differential activation and/or selective inhibition of the STAT proteins by agonists for G-protein coupled receptors, such as angiotensin II, may contribute to cardiac dysfunction during ischemia and heart failure. In addition, JAK-STAT signaling may represent one limb of an autocrine loop for angiotensin II generation, that serves to amplify the actions of angiotensin II on cardiac muscle. The purpose of this article is to provide an overview of recent findings that have been made for JAK-STAT signaling in cardiac myocytes and to highlight some unresolved issues for future investigation. The central focus of this review is on recent studies suggesting that modulation or activation of JAK-STAT signaling by ANG II has pathological consequences for heart function.

Topics: Angiotensinogen; Apoptosis; Autocrine Communication; Cardiomegaly; Cytokines; DNA-Binding Proteins; Heart; Heart Diseases; Heart Failure; Janus Kinase 1; Janus Kinase 2; MAP Kinase Signaling System; Milk Proteins; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Protein-Tyrosine Kinases; Proteins; Proto-Oncogene Proteins; Renin-Angiotensin System; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; STAT6 Transcription Factor; Trans-Activators; TYK2 Kinase

Congestive heart failure (CHF) patients share several similar features, such as reduced cardiac contractility and neurohumoral activation to compensate the impaired cardiac function. In CHF patients, the cardiac renin-angitensin (RA) system, receptors, GTP-binding proteins, and their effector molecules are inevitably exposed to chronically elevated neurohumoral stimulation. A widely recognized concept is that a chronic increase in such stimulation can desensitize target cell receptors and the post-receptor signal transducing pathway. Recently, reports of several studies have indicated that the inhibitory GTP-binding protein (Gi) can be increased in CHF patients and animal models. Although direct evidence for a change in catalytic protein of adenylyl cyclase has not been found, limited information has suggested a reduced catalytic activity in terminally failing hearts. In this paper, we have assessed the changes in beta AR, GTP-binding protein, catalytic protein and beta ARK. We also examined angiotensinogen mRNA expression in failing heart. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies 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. Our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. In the non-diseased heart, ACE and AT1 receptor RNA are present in ventricular muscles. Renin and Ao mRNA could not be detected in the subendocardium of non-diseased left ventricle, but both were present in the left ventricle of diseased hearts. These data indicate that the cardiac RA system plays an important role in the deterioration of cardiac function.

Topics: Angiotensinogen; Animals; beta-Adrenergic Receptor Kinases; Collagen; Cricetinae; Cyclic AMP-Dependent Protein Kinases; GTP-Binding Proteins; Heart Failure; Humans; Rats; Receptors, Adrenergic, beta; Renin-Angiotensin System; RNA, Messenger; Signal Transduction

Several well controlled multicenter trials demonstrated the great value of ACE-inhibitors in the treatment of heart failure. Interestingly, the mechanisms by which ACE-inhibitors improve survival of patients with heart failure are ony poorly understood. Interesting new aspects regarding the role of the renin angiotensin system in the pathophysiology of heart failure emerged from modern methods of molecular biology. For example, several alleles of the angiotensin converting enzyme or angiotensinogen genes were related to hypertension and myocardial infarction in both clinical and experimental studies. Furthermore, local renin angiotensin systems have been demonstrated in various cardiovascular tissues. These tissue renin angiotensin systems are independently regulated and may be activated in heart failure or cardiac hypertrophy. Finally, it has been shown that inhibition of angiotensin converting enzyme affects also the metabolism of bradykinin and aldosterone which may contribute to the overall pharmacodynamic profile of ACE-inhibitors in heart failure.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Bradykinin; Gene Expression Regulation; Heart Failure; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Peptidyl-Dipeptidase A; Renin-Angiotensin System

The renin-angiotensin and cardiac natriuretic systems were studied by measuring plasma renin activity, plasma concentrations of active renin, angiotensinogen, atrial natriuretic hormone and urinary cyclic GMP in 37 patients with moderate to severe cardiac failure. The plasma sodium and osmolality were chosen as markers of hydroelectrolytic imbalance and plasma concentrations of préalbumin and retinol-binding protein as indicators of the degree of hepatocellular dysfunction. Plasma renin activity (PRA) plasma concentration of active renin, atrial natriuretic hormone and urinary cyclic GMP were higher in patients in NYHA Class IV than in those in Classes II-III, whilst plasma sodium, angiotensinogen, prealbumin and retinol-binding protein concentrations were lower in Class IV patients than in patients in Classes II-III. The plasma angiotensinogen concentrations were negatively correlated with PRA (r = -0.41, p less than 0.02), active renin (r = -0.45, p = 0.005), the atrial natriuretic factor (r = -0.36, p less than 0.05) and positively correlated with prealbumin (r = 0.54, p less than 0.001) and retinol-binding protein (r = 0.60, p less than 0.0001). In NYHA Class IV patients the decreased circulating renin substrate led to an underestimation of plasma concentrations of active renin by measurement of PRA. On the other hand, direct radio-immunometric measurement of active renin allows true estimation of circulating active renin, independently of plasma angiotensinogen concentrations and thereby reliably reflects activation of the renin system. The serum sodium was negatively correlated with active renin (r = -0.66, p less than 0.0001) in these patients not receiving converting enzyme inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Arginine Vasopressin; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Renin; Renin-Angiotensin System; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Sodium

The review will cover the chemistry and biochemistry of angiotensin-converting enzyme inhibitors with emphasis on data published since the publication of previous reviews. The relative merits of each contribution will be evaluated, as well as their potential for leading to new discoveries. The biology of angiotensin-converting enzyme inhibitors will be brought up-to-date to give the reader an appreciation of the medical implications of this new type of antihypertensive agent.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Disease Models, Animal; Heart Failure; Humans; Hypertension; Kidney; Oligopeptides; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin; Structure-Activity Relationship; Substrate Specificity

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

Recently, the availability of a number of specific inhibitors of the renin-angiotensin system has made it possible to address certain critical questions concerning the role of angiotensin II in physiologic homeostasis and in a number of pathologic states. These studies indicate that angiotensin II does not have an obligatory role in blood pressure maintenance in the normal, sodium replete individual, but it is essential following sodium depletion. The role of angiotensin II in feedback control of renin secretion is confirmed as is its importance in aldosterone stimulation both in relation to posture and sodium depletion. Angiotensin II is responsible for the initial pressor response of experimental renovascular hypertension and appears to be important in the initiation of chronic renovascular hypertension. Converting enzyme blockers and competitive inhibitors of angiotensin II are helpful in the diagnosis of clinical renovascular hypertension and in the identification of renin dependent hypertensives. Homeostatic mechanisms leading to maintenance of blood pressure and accumulation of edema in experimental congestive heart failure appear to be dependent on angiotensin II.

Topics: Angiotensin II; Angiotensinogen; Animals; Antibodies; Blood Pressure; Cardiovascular Physiological Phenomena; Dogs; Feedback; Heart Failure; Homeostasis; Humans; Hypertension, Renal; Posture; Rats; Renin; Water-Electrolyte Balance

Activation of the reninangi otens in-aldosterone system has an important role in the pathophysiology of heart failure with reduced ejection fraction. While the effects of systemic reninangi otens in-aldosterone system activation on heart failure with reduced ejection fraction are well known, the impact of the local reninangi otens in-aldosterone system on heart failure with reduced ejection fraction is not fully understood because of limited clinical research. This study aimed to investigate the effect of urinary angiotensinogen level, an accepted indicator of local reninangi otens in-aldosterone system activation, on all-cause mortality in patients with heart failure with reduced ejection fraction.. This retrospective, single-center study included 60 patients with baseline urinary angiotensinogen data and survival/mortality data at 4 years. Urinary angiotensinogen values were standardized to the urinary creatinine value measured from the same urine sample. The median urinary angio tensi nogen /urin ary creatinine value among all patients (114 μg/g) was used as a cutoff to divide the patients into 2 groups. Mortality data were obtained from the national registry systems or by telephone.. Comparison of all-cause mortality in the 2 groups showed that 22 deaths (71%) occurred in the group with a urinary angio tensinogen/urinary creatinine ratio above the median and 10 deaths (35.5%) occurred in the group of patients with urinary angio tensinogen/urinary creatinine equal to or below the median value (P =.005).. Our study suggests that urinary angiotensinogen can be used as a new biomarker in the prognosis and follow-up of heart failure patients.

Topics: Aldosterone; Angiotensinogen; Creatinine; Heart Failure; Humans; Prognosis; Renin-Angiotensin System; Retrospective Studies; Stroke Volume

We investigated oxidative stress and RAAS biomarkers, as well as their association, in chronic heart failure (CHF) patients on optimized medical therapy, stratified by disease severity or by renal function. Since vitamin D has been shown to attenuate RAAS activation and oxidative stress, we further evaluated the relationship between vitamin D, RAAS and oxidative stress in CHF patients with or without renal impairment. Sixty CHF outpatients were included and stratified by disease severity or by renal function. We quantified urinary hydrogen peroxide, plasma and urinary isoprostanes, plasma total antioxidant status, urinary angiotensinogen (intrarenal RAAS activation biomarker) and plasma angiotensinogen, plasma renin and aldosterone concentration, serum angiotensin-converting enzyme (ACE) activity, plasma angiotensin peptides, and serum total 25-hydroxyvitamin D (S-total 25(OH)D). Severe CHF patients had higher urinary isoprostanes (p = 0.002) and lower S-total 25(OH)D (p = 0.006) compared to mild-to-moderate patients, but no differences were observed for other redox or RAAS biomarkers. Patients with impaired renal function (iRF) had higher urinary angiotensinogen (p = 0.003) and lower S-total 25(OH)D (p = 0.028) compared to those with normal renal function (nRF), while no differences were observed for the remaining RAAS and redox parameters. Several positive correlations between oxidative stress and RAAS biomarkers were detected in iRF patients, while in patients with nRF these correlations were primarily inverse. In CHF-iRF patients, S-25(OD)D was inversely associated with urinary isoprostanes, which in turn were positively associated with plasma angiotensinogen and serum ACE. In conclusion, CHF patients with renal function impairment have increased intrarenal RAAS activation and lower vitamin D values and might benefit from the combination of RAAS blockers with vitamin D and/or antioxidants.

Topics: Aged; Angiotensinogen; Biomarkers; Chronic Disease; Female; Glomerular Filtration Rate; Heart Failure; Humans; Isoprostanes; Kidney; Kidney Diseases; Male; Middle Aged; Oxidative Stress; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Severity of Illness Index; Vitamin D

To investigate the relationship between the cardiotonic activity of Fuzi (Radix Aconiti Lateralis Preparata, RALP) and its fingerprint determined by liquid chromatography-mass spectrometry (LC-MS).. First, the fingerprints of six processed products of RALP were established by high performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS) followed by analysis of the principal component of the relative peak area of its common peaks. Next, the scores of the first five principal components were used as input for an artificial neural network (ANN). Additionally, the therapeutic effect of RALP was assessed by measuring the hemodynamic indexes of heart failure model rats. Subsequently, fluorescence semi-quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay kit were used to determine the effects of RALP-processed products on the serum levels of noradrenaline (NA), angiotensin-Ⅰ (Ang-Ⅰ), and the expression of β-norepinephrine receptor mRNA (β-NRm) in the rat cardiac tissues. P < 0.05 was used as the output of the ANN. Finally, a network was constructed to display the relationship between the LC-MS fingerprints and the cardiotonic activity of the RALP-processed products.. Several types of RALPs can improve diastolic function, systolic function and heart rate. On the basis of the findings from the principal component analysis (PCA) of 16 common peaks of fingerprints of six RALP-processed products, it was revealed that the first five principal components may include 100% of the information of the original data. As observed from the multilayer perceptron neural network analysis, principal component 4 presented with the strongest effects on serum levels of NA and Ang-Ⅰ in rats, while principal component 1 exerted the greatest effect on β-NRm expression in cardiac tissue.. The key findings obtained from this study indicated that the network constructed by the PCA-ANN may predict pharmacodynamic effects of the main ingredients of Traditional Chinese Medicine (TCM). This method may serve as a new approach to identify the relationship between LC-MS fingerprints and the pharmacodynamic effects of TCM ingredients.

Topics: Aconitum; Angiotensinogen; Animals; Cardiotonic Agents; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Heart Failure; Humans; Male; Mass Spectrometry; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic

[Figure: see text].

Topics: Angiotensin II; Angiotensinogen; Animals; Heart Failure; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Myocardium; NLR Family, Pyrin Domain-Containing 3 Protein; Sepsis

This prospective cohort study evaluated the association between the renin angiotensin aldosterone system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC = 16%, CT = 48%, and TT = 36%. Frequencies for CYP11B2 rs1799998 were: TT = 33%, TC = 50%, and CC = 17%. After 6 months of spironolactone treatment, change in the left ventricular ejection fraction (LVEF) differed by AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; P = 2.1E-26), and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; P = 0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (P = 0.001), 63% of variability in serum potassium increase (P = 2.25E-08), and 39% of the variability in improvement in quality of life (P = 2.3E-04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.

Topics: Adult; Aged; Angiotensinogen; Cytochrome P-450 CYP11B2; Egypt; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Potassium; Prognosis; Prospective Studies; Quality of Life; Renin-Angiotensin System; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Young Adult

Objective Home care is important in patients with heart failure (HF) in order to maintain their quality of life. A biomarker that can be measured noninvasively is needed to optimize the home care of patients with HF. Urinary angiotensinogen (uAGT) is an indicator of the intrarenal renin-angiotensin system activity, which may be augmented in HF. We hypothesized that uAGT might be a urinary biomarker in HF. Methods We measured uAGT by an enzyme-linked immunosorbent assay and uAGT normalized by urinary creatinine (uCr)-designated uAGT/uCr-at admission and discharge in 45 patients hospitalized for HF. Results We found that both uAGT/uCr [median (interquartile range): 65.5 (17.1-127.7) μg/g Cr at admission; 12.1 (6.0-37.0) μg/g Cr at discharge; p<0.01] and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels [5,422 (2,280-9,907) pg/mL at admission; 903 (510-1,729) pg/mL at discharge; p<0.01] significantly decreased between admission and discharge along with an improvement in patient's clinical status [New York Heart Association scores: 3 (3-4) at admission; 1 (1-1) at discharge; p<0.01]. The generalized least squares model revealed that the time course changes in uAGT/uCr also correlated with those in NT-proBNP levels between admission and readmission in five patients readmitted for HF. Conclusion The results indicated that the time course changes in uAGT/uCr correlated with those in the NT-proBNP levels in patients with HF who showed a clinical improvement. Further investigation and development of a kit for the rapid measurement of uAGT are needed to evaluate the clinical utility of uAGT as a biomarker in HF.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Biomarkers; Female; Heart Failure; Humans; Japan; Male; Middle Aged; Monitoring, Physiologic; Natriuretic Peptide, Brain; Peptide Fragments; Renin-Angiotensin System; Time Factors

Topics: Angiotensinogen; Biomarkers; Heart Failure; Humans; Renin; Renin-Angiotensin System

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

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

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.

Topics: Administration, Oral; Angiotensinogen; Animals; Arrhythmias, Cardiac; Blood Pressure; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Echocardiography; Heart Failure; Heart Ventricles; Humans; Isolated Heart Preparation; Male; Morpholines; Pyrimidines; Rats; Rats, Transgenic; Renin; Soluble Guanylyl Cyclase; Stroke Volume; Survival Rate; Treatment Outcome

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

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

Despite the progress in the treatment of HF, its prognosis remains disappointing primarily due to the fact that important subgroups of patients with HF are not sufficiently investigated. This also applies to patients with HF and background metabolic disorders, in particular, type 2 diabetes. It is known that the polymorphism of the rs699 marker of the M235T ATG gene is associated with a tendency to arterial hypertension, coronary heart disease and atrial fibrillation. A relationship was found between the polymorphism of M235T and the risk of HF development. One of the promising new biomarkers is the fibrosis marker ST2. The purpose of our study was to evaluate the role of the biomarker ST2 and the genetic polymorphism of the AT2 gene M235T in the progression of CHF and the development of adverse events in patients with concomitant type 2 diabetes. We found that patients with HFpEF and T2DM with ATG TT + MT genotype have a higher level of ST2 and a higher probability of unfavorable cardiovascular events during 24 months of observation compared with MM genotype carriers.

Topics: Aged; Angiotensinogen; Biomarkers; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Disease Progression; Female; Fibrosis; Follow-Up Studies; Gene Expression; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Survival Analysis; Triglycerides; Walk Test

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3'-untranslated region (3'-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT

Topics: 3' Untranslated Regions; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Cell Line, Tumor; Heart Failure; Kidney; Losartan; Male; MicroRNAs; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Topics: Acute Kidney Injury; Acute-Phase Proteins; Angiotensinogen; Biomarkers; Creatinine; Disease Progression; Heart Failure; Humans; Lipocalins; Proto-Oncogene Proteins

Although several risk factors for acute kidney injury (AKI) have been identified, early detection of AKI in acute decompensated heart failure patients remains a challenge. The aim of this study was to develop and validate a risk score for early prediction of AKI in acute decompensated heart failure patients.. A total of 676 consecutive acute decompensated heart failure participants were prospectively enrolled from 6 regional central hospitals. Data from 507 participants were analyzed. Participants from 4 of the 6 hospitals (n=321) were used to develop a risk score and conduct internal validation. External validation of the developed risk score was conducted in participants from the other 2 hospitals (n=186). Sequential logistic regression was used to develop and validate the risk score. The c statistic and calibration plot were used to assess the discrimination and calibration of the proposed risk score. The overall occurrence of AKI was 33.1% (168/507). The risk score, ranging from 0 to 55, demonstrated good discriminative power with an optimism-corrected c statistic of 0.859. Similar results were obtained from external validation with c statistic of 0.847 (95% CI 0.819-0.927). The risk score had good calibration with no apparent over- or under-prediction observed from calibration plots.. The novel risk score is a simple and accurate tool that can help clinicians assess the risk of AKI in acute decompensated heart failure patients, which in turn helps them plan and initiate the most appropriate disease management for patients in time.

Topics: Acute Disease; Acute Kidney Injury; Aged; Aged, 80 and over; Angiotensinogen; Cardio-Renal Syndrome; China; Cohort Studies; Female; Heart Failure; Humans; Lipocalin-2; Logistic Models; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Assessment; Risk Factors

Refractory hyperaldosteronism is frequently observed in heart failure patients on up-to-date treatment, and holds prognostic value. Our aim was to identify which factors, either genetic or nongenetic, are associated with refractory hyperaldosteronism.. We enrolled 109 consecutive patients with left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) 32 ± 10%; 86% males; age 65 ± 13 years (mean ± standard deviation)] on optimized adrenergic and renin-angiotensin-aldosterone system (RAAS) antagonism, undergoing clinical and neuroendocrine characterization, and genotyping for six polymorphisms in key RAAS-regulating genes [angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE-240A>T and I/D), angiotensin II type I receptor (AGTR1 1166A>C), aldosterone synthase (CYP11B2-344C>T) and renin (REN rs7539596)].. Patients with refractory hyperaldosteronism (n = 41, 38%, with plasma concentration >180 ng/l, URL, median 283 ng/l, interquartile range 218-433), when compared with those without (106 ng/l, 74-144; P < 0.001), were not different either for treatment or LVEF, while presented with different AGT M235T genotype distribution (P = 0.047). After adjustment for several humoral, instrumental, functional and therapeutical variables, only plasma renin activity (PRA) (P < 0.001) and potassium (P = 0.027) were independently associated with refractory hyperaldosteronism. Among polymorphisms, only AGT M235T (P = 0.038) was associated with refractory hyperaldosteronism, after adjustment for nongenetic variables.. In conclusion, refractory hyperaldosteronism in heart failure may be influenced by AGT M235T polymorphism, among RAAS candidate genes, and by PRA, which may represent, respectively, a constitutive (genotype dependent) and a nongenetic (phenotype-dependent) trigger for aldosterone elevation.

Topics: Aged; Angiotensinogen; Biomarkers; Cardiovascular Agents; Female; Follow-Up Studies; Gene Frequency; Genetic Predisposition to Disease; Heart Failure; Humans; Hyperaldosteronism; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Prospective Studies; Renin; Renin-Angiotensin System

A major challenge in prevention and early treatment of acute cardiorenal syndrome (CRS) is the lack of high-performance predictors. To test the hypothesis that urinary angiotensinogen (uAGT) is an early predictor for acute CRS and 1-year prognosis in patients with acute decompensated heart failure (ADHF), we performed a prospective, two-stage, multicenter cohort study in patients with ADHF. In stage I (test set), 317 patients were recruited from four centers. In stage II (validation set), 119 patients were enrolled from two other centers. Daily uAGT levels were analyzed consecutively. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. In stage I, 104 (32.8%) patients developed AKI during hospitalization. Daily uAGT peaked on the first hospital day in patients who subsequently developed AKI. After multivariable adjustment, the highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared with the lowest quartile. For predicting AKI, uAGT (area under the receiver-operating characteristic curve [AUC]=0.84) outperformed urinary neutrophil gelatinase-associated lipocalin (AUC=0.78), the urinary albumin/creatinine ratio (AUC=0.71), and the clinical model (AUC=0.77). Survivors in stage I were followed prospectively for 1 year after hospital discharge. The uAGT level independently predicted the risk of 1-year mortality (adjusted odds ratio, 4.5; 95% confidence interval, 2.1 to 9.5) and rehospitalization (adjusted odds ratio, 3.6; 95% confidence interval, 1.6 to 5.7). The ability of uAGT in predicting AKI was validated in stage II (AUC=0.79). In conclusion, uAGT is a strong predictor for acute CRS and 1-year prognosis in ADHF.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Angiotensinogen; Biomarkers; China; Female; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies

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

To study the impact of angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1) gene polymorphisms on the development and course of chronic heart failure (CHF) in patients with coronary heart disease (CHD).. Two hundred and twenty-six patients (149 men and 77 women; mean age 55.9 +/- 5.8 years) with CHF were examined. Genotypes were identified by the restriction fragment length polymorphism analysis of polymerase chain reaction products. A control group comprised 136 subjects (63 men and 73 women; mean age 53.6 +/- 4.8 years) without signs of cardiovascular diseases, as evidenced by the examination.. The T allele of the M235T polymorphism in the AGT gene was found to be associated with the development and unfavorable course of CHF in patients with CHD. At the same time, carriage of the M allele of the M235T polymorphism in the AGT gene reflected the favorable course of this disease. That of the C allele and A/C genotype of the A1166C polymorphism in the AGTR1 gene was associated with the development of CHF and the A allele and A/A genotype manifested themselves as protective factors. According to the severity of CHF and the nature of its course, the distribution of frequencies of the genotypes and alleles of the A1166C polymorphism in the AGTR1 gene showed no significant differences between the patient groups.. There were associations of the polymorphisms of the AGT gene (the M235T polymorphic marker) and the AGTR1 gene (the A1166C polymorphic marker) with the development of CHF in patients with CHD.

Topics: Aged; Alleles; Angiotensinogen; Disease Progression; DNA; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Heart Failure; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1). TG1306/R1 mice develop ANG II-mediated left ventricular hypertrophy, and at one year of age approximately half of the mice present heart failure associated with reduced expression of regulatory proteins of fatty acid oxidation and reduced palmitate oxidation during ex vivo working heart perfusion. Hypertrophied hearts from TG1306/R1 mice without heart failure adapted to high-fat feeding, similarly to hearts from wild-type mice, with upregulation of regulatory proteins of fatty acid oxidation and enhancement of palmitate oxidation. There was no myocardial lipid accumulation or contractile dysfunction. In contrast, hearts from TG1306/R1 mice presenting heart failure were unable to respond to high-fat feeding by upregulation of fatty acid oxidation proteins and enhancement of palmitate oxidation. This resulted in accumulation of triglycerides and ceramide in the myocardium, and aggravation of contractile dysfunction. In conclusion, hearts with ANG II-induced contractile failure have lost the ability to enhance fatty acid oxidation in response to increased fatty acid supply. The ensuing accumulation of lipid compounds may play a role in the observed aggravation of contractile dysfunction.

Topics: Angiotensin II; Angiotensinogen; Animals; Diet, High-Fat; Dietary Fats; Fatty Acids; Heart Failure; Hypertrophy, Left Ventricular; Lipid Metabolism; Male; Mice; Mice, Transgenic; Models, Animal; Myocardial Contraction; Myocardium; Oxidation-Reduction; Palmitates; Triglycerides; Ventricular Remodeling

Topics: Angiotensinogen; Atherosclerosis; Female; Gene Frequency; Haplotypes; Heart Failure; Humans; Male

The aim of the present study was to determine whether carvedilol-treated chronic heart failure patients have a different prognosis when stratified for a specific combination of a gain-of-function genotype of the adrenergic β-1 receptor gene (ADRB1) (Arg389-homozygous), two gain-of-function genotypes of the angiotensinogen gene (AGT) (Thr174-homozygous and Thr235-homozygous), and a downregulated genotype of the adrenergic β-2 receptor gene (ADRB2) (Gln27-carrier).. Genotyping of 618 patients was carried out using the Sequenoms MassARRAY genotyping system. Outcome was all-cause mortality and statistics were calculated using a multivariable Cox proportional hazards model. Internal validation was performed using the bootstrap procedure.. Eighty-seven of the 618 patients included in the study were treated with carvedilol. There was a significant interaction between the outcome of carvedilol treatment and the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous) and the gain-of-function AGT genotype (Thr174-homozygous) (P(interaction)=0.003; hazard ratio 2.19, 95% confidence interval 1.26-3.78, P=0.005). There was also a significant interaction when the downregulated ADRB2 genotype (Gln27-carrier) was added to the ADRB1/AGT combination (P(interaction)=0.0005; hazard ratio 2.67, 95% confidence interval 1.51-4.72, P=0.0007). Two hundred and four patients were treated with metoprolol. There was no interaction between metoprolol treatment and the specific genotype combinations as there was no difference in the overall survival. The validity of the results was supported by the bootstrap procedure.. We found a doubling of the hazard of mortality in carvedilol-treated patients with the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous), the gain-of-function AGT genotype (Thr174-homozygous), and the downregulated ADRB2 genotype (Gln27-carrier). This might be valuable when stratifying chronic heart failure patients to the right β-blocker therapy.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Angiotensinogen; Carbazoles; Carvedilol; Chronic Disease; Female; Genotype; Heart Failure; Humans; Male; Middle Aged; Phenotype; Propanolamines; Proportional Hazards Models; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Retrospective Studies; Survival Analysis

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Clinical Trials Data Monitoring Committees; Congresses as Topic; Diabetes Mellitus, Type 2; Endpoint Determination; Fumarates; Heart Failure; Humans; Randomized Controlled Trials as Topic; Rats; Renin; Renin-Angiotensin System

Numerous association studies have been involved in studying the angiotensinogen (AGT) variants, AGT plasma levels and relations to cardiovascular diseases, such as hypertension, myocardial infarction, coronary heart disease. To investigate a role of AGT G(-6)A and M235T genetic variants for chronic heart failure (CHF) and advanced atherosclerosis (AA), a total of 240 patients with CHF and 200 patients with AA of the Czech origin were evaluated for the study. The study shows the role of polymorphism AGT G(-6)A in genetic background among advanced atherosclerosis patients and chronic heart failure patients (Pg=0.001). This difference was also observed in comparison of AA patients with subgroup of CHF with dilated cardiomyopathy (Pg=0.02; Pa=0.009), and ischemic heart disease (Pg=0.007). The greatest difference between triple-vessel disease and chronic heart failure groups was observed in frequency of GT haplotype (P<0.001) and GGMT associated genotype (P<0.001). Retrospectively, we found the same trend when the subgroups of CHF were compared to AA group (AA vs. IHD with CHF P<0.001; AA vs. DCM P<0.001). These results suggest AGT genetic variants as a risk factor for chronic heart failure compared to advanced atherosclerosis disease without heart failure, with a strong difference between IHD patients and chronic heart failure patients with ischemic heart disease, especially in haplotypes and associated genotypes.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Atherosclerosis; Coronary Disease; Female; Gene Frequency; Genotype; Haplotypes; Heart Failure; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

To identify patient-specific factors associated with spironolactone-induced potassium level elevation in patients with heart failure.. Prospective cohort study.. Two adult heart failure clinics.. Sixty-two adult (mean +/- SD age 54 +/- 16 yrs) aldosterone antagonist-naïve patients with heart failure.. Patients received spironolactone 12.5 mg/day, titrated to 25 mg/day if tolerated.. Blood samples were obtained at baseline, 1 week after spironolactone initiation, and 1 week after spironolactone dose titration for assessment of baseline aldosterone level, serum chemistry, and angiotensinogen (AGT) c.-6G>A and p.M268T and mineralocorticoid receptor (NR3C2) c.215C>G and p.I180V genotypes. Patient characteristics, laboratory values, and genotypes were compared between those whose potassium levels increased by more than 0.5 mEq/L (15 patients) and those with lower potassium level elevations (47 patients) after spironolactone initiation and dose titration. Patients with a greater potassium level elevation had a higher mean +/- SD aldosterone concentration (178 +/- 92 vs 102 +/- 57 pg/ml, p=0.007) and NR3C2 215G allele frequency (50% vs 22%, p<0.01). Aldosterone concentrations positively correlated with diuretic dose (r=0.313, p=0.014) and negatively correlated with serum potassium level (r= -0.319, p=0.012). On regression analysis, factors predictive of potassium level increases greater than 0.5 mEq/L with spironolactone were aldosterone level greater than 150 pg/ml (odds ratio [OR] 30, 95% confidence interval [CI] 3.2-287] and NR3C2 215G carrier status (OR 17, 95% CI 1.6-167).. Our data suggest that potassium should be monitored with particular caution when spironolactone is started in patients with heart failure who have evidence of elevated aldosterone levels, such as high diuretic requirements, or the NR3C2 215G allele.

Topics: Adult; Aged; Aldosterone; Angiotensinogen; Black or African American; Cohort Studies; Diuretics; Female; Genotype; Heart Failure; Humans; Hyperkalemia; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Receptors, Mineralocorticoid; Spironolactone; Statistics as Topic; White People

Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg(-1)) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P=0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage.

Topics: Angiotensin II; Angiotensinogen; Animals; bcl-2-Associated X Protein; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Heart; Heart Failure; Heart Rate; Humans; Hydrazones; Hypertension; Major Histocompatibility Complex; Male; Pyridazines; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan

Recent studies have revealed that (pro)renin receptor ((P)RR), a newly identified member of the renin-angiotensin system, was associated with organ damage in the kidney. However, there has been little information for (P)RR in hearts. To investigate the regulation of (P)RR in heart failure, we examined the expression of (P)RR in hearts and kidneys of rats with congestive heart failure (CHF) due to coronary ligation by quantitative RT-PCR and immunohistochemistry. Significantly increased levels of (P)RR mRNA were found in the atrium, right ventricle, non-infarcted part of left ventricle, infarcted part of left ventricle and kidney of CHF rats, when compared with sham operated rats (about 1.6-fold, 1.4-fold, 1.6-fold, 1.7-fold and 1.5-fold, respectively). Expression levels of mRNAs encoding renin and angiotensinogen in these heart and kidney tissues were also increased in the CHF rats. Immunohistochemistry showed positive (P)RR immunostaining in the myocardium, the renal tubular cells, and vascular smooth muscle and endothelial cells in the heart and the kidney. The renal tubular cells were more intensely immunostained in CHF rats than in sham operated rats. These findings suggest that the expression of (P)RR is increased in the hearts and kidneys of rats with heart failure, and that (P)RR may contribute to heart failure.

Topics: Angiotensinogen; Animals; Blotting, Western; Heart Failure; Immunohistochemistry; Kidney; Male; Myocardium; Prorenin Receptor; Rats; Rats, Inbred WKY; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking alpha(2A) and alpha(2C) adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, alpha(2A)/alpha(2C)ARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT(1) receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Heart Failure; Heart Rate; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Genetic; Myocytes, Cardiac; Norepinephrine; Physical Conditioning, Animal; Receptors, Adrenergic, alpha-2; Renin-Angiotensin System; Sympathetic Nervous System

Angiotensinogen M235T and T174M polymorphisms have individually been associated with elevated levels of plasma angiotensinogen, hypertension, and left ventricular hypertrophy. In this study, heart failure patients (n=451) were genotyped for the angiotensinogen M235T and T174M polymorphisms to investigate association with survival (recorded over 4 years of follow-up) and prognostic hormone markers. Patients carrying the 235TT genotype (n=86) were 3 years younger at admission (P=0.011), and, in those with hypertension, diagnosis was made approximately 10 years earlier than other patients. Patients carrying >or=1 174M allele (n=94) were more likely to have a previous history of heart failure (P=0.044) and increased mortality during follow-up (risk ratio: 1.69, 95% CI: 1.03 to 2.79; P=0.038) compared with 174TT homozygotes (n=355), despite having a higher left ventricular ejection fraction (P=0.009). "High-risk" genotype combinations (defined a priori as 235TT and/or >or=1 174M allele; n=144; 32%) were independently predictive of mortality, conferring a 2-fold greater risk of dying during the follow-up period (odds ratio: 2.0; 95% CI: 1.3 to 3.0; P=0.001). This study suggested that angiotensinogen gene variants M235T and T174M may provide prognostic information for long-term survival in heart failure patients.

Topics: Aged; Alleles; Angiotensinogen; Female; Follow-Up Studies; Genotype; Heart Failure; Homozygote; Humans; Male; Medical Records; Methionine; Middle Aged; Polymorphism, Genetic; Prognosis; Risk Assessment; Stroke Volume; Survival Analysis; Threonine

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

Heart failure is associated with downregulation of the fatty acid oxidation pathway in the ventricular myocardium. Since angiotensin II plays a critical role in myocardial phenotypic changes associated with heart failure, we investigated the effect of chronic angiotensin II stimulation on the fatty acid oxidation pathway in transgenic (TG) mice with targeted overexpression of angiotensinogen in the myocardium (TG1306/1R mice). TG1306/R1 mice progressively developed left ventricular hypertrophy. After 12 months, approximately half of the mice exhibited signs of heart failure including increased lung weight index [>+2 SD of age-matched wild-type (WT) mice] and 5-fold increase of myocardial brain natriuretic peptide expression. Myocardial mRNA and protein expression of peroxisome proliferator-activated receptor alpha (PPARalpha) progressively decreased in both WT and TG1306/R1 mice during the 12 months observation period, but much more pronounced in TG1306/R1 mice. Concomitantly, mRNA expression of enzymes of fatty acid oxidation (medium-chain acyl CoA dehydrogenase, MCAD; carnitine palmitoyl transferase I, CPT-I) was reduced in TG1306/R1 compared with age-matched WT mice. However, protein expression of MCAD and CPT-I was decreased concomitantly only in TG mice with criteria of heart failure. Correspondingly, myocardial oxidation of palmitate, measured during ex vivo working heart perfusion, was reduced by 25% in TG1306/R1 mice with heart failure. These results demonstrate that angiotensin II-induced cardiac hypertrophy is associated with reduction of PPARalpha and of mRNA expression of enzymes of fatty acid metabolism relative to age-matched WT mice. However, both protein expression of fatty acid oxidation enzymes and the rate of fatty acid oxidation remain unchanged unless heart failure occurs, suggesting the involvement of posttranscriptional mechanisms in the metabolic changes associated with heart failure.

Topics: Angiotensinogen; Animals; Biological Transport; Down-Regulation; Fatty Acids; Heart Failure; Hypertrophy; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Phenotype; PPAR alpha; RNA, Messenger

The aim of the study was to focus on the relationship between the angiotensinogen (AGT) gene polymorphisms, M235T and promoter G(-6)A, and chronic heart failure in the Czech population. A total of 158 patients with chronic heart failure (functional class NYHA II-IV, ejection fraction <40%, cardiothoracic index >50%) were compared with a control group of 200 subjects of similar age and sex distribution, without any personal history of cardiovascular diseases. The AGT gene polymorphisms were detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. No significant differences in distributions of AGT genotypes between patients with chronic heart failure (CHF) and controls were found. The differences in distributions of alleles in AGT M235T (P(a)=0.02) and genotypes in AGT G(-6)A (P(g)=0.017) were found within women groups. Within CHF patients the distribution of AGT G(-6)A genotypes was not consistent with Hardy-Weinberg equilibrium (P=0.0001). We found significant relative risk of CHF in the GGMT genotype, OR=2.63 with 95% CI 1.39-4.95, P(corr)=0.01 (in the male group OR=1.83, 95% CI 0.92-3.66, P(corr)=0.3; in the female group OR=15.5, 95% CI 1.86-129.42, P(corr)=0.008). We provide evidence of increased risk in subjects with the GGMT variant of associated genotype of AGT gene for CHF, especially of fifteen-fold risk of this variant in women.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Case-Control Studies; Chronic Disease; Czech Republic; Female; Heart Failure; Humans; Male; Middle Aged; Polymorphism, Genetic; Sex Factors

In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental.. In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6- and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3- and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal's survival without additional decreases in systolic pressure.. The pathophysiological roles in the myocardium during the transition to CHF differ qualitatively between Ang II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Disease Progression; Endothelin-1; Endothelins; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hemodynamics; Hypertrophy, Left Ventricular; Male; Organ Size; Peptidyl-Dipeptidase A; Protein Precursors; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Survival Analysis; Thiazepines; Time Factors

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

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

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

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

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 spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components.

Topics: Aging; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Atrial Natriuretic Factor; Captopril; Cardiomegaly; Gene Expression Regulation; Heart; Heart Failure; Hypertension; Male; Myosin Heavy Chains; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta

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

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

Angiotensin converting enzyme (ACE) inhibitor therapy elicits beneficial responses from patients with heart failure. We hypothesized that a major site of action of these drugs is tissue ACE and that ACE inhibitors might differ in their ability to inhibit tissue ACE. To test this hypothesis, we assessed the effects of captopril and enalapril on blood pressure and renal function and on serum and tissue ACE activities in sham-operated rats and rats with heart failure induced by coronary artery ligation.. During short-term (1-week) treatment, captopril (200 mg.kg-1.day-1) and enalapril (25 mg.kg-1.day-1) elicited equipotent effects on blood pressure and inhibition of serum ACE activity (85%). The effects of long-term treatment (47 days) were then studied beginning 45 +/- 5 days after coronary ligation in four treatment groups: sham-operated, vehicle (n = 14); heart failure, vehicle (n = 10); heart failure, captopril (n = 8); and heart failure, enalapril rats (n = 7). During long-term treatment, captopril and enalapril caused comparable falls of 12-18 mm Hg in blood pressure (p < 0.01 compared with vehicle treatment). There was no change in urine volume or sodium or potassium excretion in vehicle- or captopril-treated heart failure rats; in contrast, enalapril-treated heart failure rats demonstrated 83% and 10% increases in urine volume and daily sodium excretion, respectively, compared with vehicle-treated rats (both p < or = 0.01). No significant changes in blood urea nitrogen or creatinine were observed with either treatment. Enalapril but not captopril elicited a significant decrease in serum and lung ACE activities. Captopril but not enalapril inhibited aortic ACE activity. Both agents caused a comparable inhibition of renal ACE activity. The magnitude of inhibition of renal ACE activity but not serum and vascular (aortic) ACE activities correlated with the long-term blood pressure response. Enalapril but not captopril normalized renal angiotensinogen expression; the magnitude of this effect correlated with the increase in daily urinary sodium excretion (r = -0.43; p < or = 0.005).. These data suggest that chronic treatment with these two agents elicits differential effects on tissue ACE activities and renal angiotensinogen regulation. The differential renal effects of these agents may be important in the treatment of heart failure.

Topics: Angiotensinogen; Animals; Blood Pressure; Captopril; Enalapril; Heart Failure; Kidney; Male; Natriuresis; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger; Time Factors

The intrarenal renin-angiotensin system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in the circulating counterpart in this model of experimental heart failure, and they support the concept that the intrinsic renal RAS may contribute to the pathophysiology in this syndrome.

Topics: Angiotensinogen; Animals; Chronic Disease; Enalapril; Heart Failure; Kidney; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; RNA, Messenger

To compare the determination of plasma renin activity (PRA) and the direct measurement of active renin by immunoradiometric assay (IRMA) as methods of assessing the renin system in patients with congestive heart failure.. The status of the renin-angiotensin system in congestive heart failure was assessed by measuring the plasma renin substrate concentration, PRA, and plasma concentration of active renin in 37 patients with mild to severe congestive heart failure. Natremia and plasma levels of atrial natriuretic factor (ANF) were determined as biologic indexes of the severity of heart failure, and concentrations of prealbumin and retinol-binding protein were used as indexes of liver dysfunction.. The PRA and the concentrations of active renin and ANF were markedly higher in patients with New York Heart Association class IV heart failure than in patients with class II to III heart failure, while natremia and the concentrations of renin substrate, prealbumin, and retinol-binding protein were markedly lower in the class IV patients than in the class II to III patients. Plasma renin substrate concentration was negatively correlated with active renin concentration (n = 37, r = -0.45, p = 0.005), and positively related to natremia (r = 0.56, p less than 0.0005), prealbumin (r = 0.54, p less than 0.001), and retinol-binding protein (r = 0.60, p less than 0.0001).. Low levels of plasma renin substrate can be considered as an indirect index of the severity of heart failure that reflects both the high level of circulating active renin and the decrease in hepatic protein output. In patients with class IV heart failure, low levels of renin substrate led to a marked underestimation of active renin concentration from measurements of PRA. In contrast, direct IRMA of active renin measures the true plasma active renin concentration, independent of plasma renin substrate, and closely reflects renin secretion.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Atrial Natriuretic Factor; Female; Heart Failure; Humans; Hypernatremia; Immunoradiometric Assay; Liver; Male; Middle Aged; Prealbumin; Renin; Renin-Angiotensin System; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Severity of Illness Index

We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.

Topics: Adult; Angiotensinogen; Female; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Liver Cirrhosis; Male; Middle Aged; Pregnancy; Renin

There has been considerable interest in the existence of an intrarenal renin-angiotensin system and its physiological implications. Recent demonstrations of renin, angiotensinogen and angiotensin converting enzyme messenger (m)RNAs in the kidney have provided strong evidence for the presence of an independent local system. This has been further supported by the demonstration of tissue-specific regulation of renin and angiotensinogen mRNA expression which may lead to differential systemic and intrarenal angiotensin activities. Using in situ hybridization, we have localized the intrarenal sites of gene expression and possible angiotensin production. One major site appears to be the proximal tubule, where local angiotensin can regulate sodium reabsorption and urine pH. Renin and angiotensinogen mRNA expressions are regulated by several common factors. In particular, sodium depletion stimulates the expression of both genes in the kidney, increasing the production of intrarenal angiotensin that is important in maintaining sodium homeostasis. Renal renin and angiotensinogen mRNA levels are altered in experimental heart failure and the spontaneously hypertensive rat (SHR). These changes in intrarenal renin and angiotensinogen mRNA expression may be important in the renal pathophysiology of these diseases.

Topics: Angiotensin II; Angiotensinogen; Animals; Blotting, Northern; Gene Expression; Heart Failure; Hypertension, Renal; Kidney; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Renin-Angiotensin System; RNA, Messenger

Topics: Adult; Aged; Angiotensin II; Angiotensinogen; Angiotensins; Blood Pressure; Captopril; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Proline; Renin; Time Factors; Vasopressins

A moderate elevation of the daily excretion of free noradrenaline and adrenalin is observed in chronic circulatory insufficiency, beginning with Stage IIA. The catecholamines metabolism is elevated, as shown by the daily excretion of normethanpherine and methanpherine and of vanillyl-mandelic acid. The activity of renin and angiotensinases was growing along with the progressing cardiac insufficiency. The blood level of angiotensinogen was decreasing, especially in patients with Stage IIB and III of decompensation. The daily excretion of aldosterone was growing along with the development of cardiac insufficiency. The functional state of the glucocorticoid function of the adrenal cortex was of a phased nature in cases of circulatory insufficiency. The study of the functional state of the epiphysis was conducted by way of determining the blood level of melatonine and of its daily excretion. In Stages I and IIA the level of this hormone was clearly elevated, in Stages IIB and III -- decreased as compared with the initial and normal levels. The plasma level of the antidiuretic hormone was distinctly growing, beginning with Stage IIB, reaching its maximal values in Stage III.

Topics: 17-Ketosteroids; Adult; Aged; Aldosterone; Angiotensinogen; Coronary Disease; Cortisone; Endopeptidases; Epinephrine; Female; Heart Failure; Humans; Hydrocortisone; Hypertension; Male; Melatonin; Metanephrine; Middle Aged; Norepinephrine; Normetanephrine; Renin; Tetrahydrocortisol; Tetrahydrocortisone; Vanilmandelic Acid