angiotensinogen and Cardiomyopathy--Dilated

Although several genes or genetic loci that are either responsible for or confer susceptibility to familial hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial HCM or DCM remain to be characterized. An allelic association study for the angiotensin converting enzyme (ACE) and angiotensinogen genes has now been performed with 71 patients with nonfamilial HCM, 88 patients with nonfamilial DCM, and 122 healthy control subjects in the Japanese population. The distribution of ACE genotypes for an insertion/deletion (I/D) polymorphism in intron 16 did not differ significantly among control subjects and patients with HCM or DCM. Similarly, the distributions of angiotensinogen genotypes for methionine-235-threonine (M235T) and threonine-174-methionine (T174M) polymorphisms did not differ significantly among the three groups. Echocardiographic parameters that are indicators of the severity or progression of disease did not differ significantly among ACE I/D or angiotensinogen M235T and T174M genotypes in the two patient groups. Finally, no additive or synergistic effect of any combined genotypes or haplotypes of the ACE and angiotensinogen polymorphisms on the association with HCM or DCM was detected. Results indicate that the ACE I/D and angiotensinogen M235T and T174M polymorphisms are not related to HCM or DCM in the Japanese population, and that variants of these polymorphisms do not contribute to the genesis or progression of these cardiomyopathies.

Topics: Angiotensinogen; Cardiomegaly; Cardiomyopathy, Dilated; Echocardiography; Genotype; Humans; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

The renin-angiotensin (RAS) pathway has an important role in the etiology of heart failure and given the importance of RAS as a therapeutic target in various cardiomyopathies, genetic polymorphisms in the RAS genes may modulate the risk and severity of disease in cardiomyopathy patients. In the present study, we examined the association of RAS pathway gene polymorphisms, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin receptor type 1 (AGTR1) with risk and disease severity in Asian Indian idiopathic cardiomyopathy patients. The case-control study was conducted in 400 cardiomyopathy patients diagnosed with HCM, DCM, or restrictive cardiomyopathy (RCM) and 235 healthy controls. Genotyping of patients and controls was done by PCR-RFLP assays. Left ventricular wall thickness and left ventricular ejection fraction were measured by means of M-mode echocardiography. We observed significantly higher prevalence of ACE DD and AGTR1 1166CC genotypes in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) patients. Also, 235TT genotype of AGT (M235T) was significantly associated with enhanced risk of the disease phenotype in HCM, DCM, and RCM.

Topics: Adult; Angiotensinogen; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Female; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The influence of intracellular renin plus angiotensinogen (Ao) as well as angiotensin (Ang) II on cell volume was investigated in myocytes isolated from the heart of four-month-old cardiomyopathic hamsters (TO-2) and normal hamsters (F1B). Measurements of cell width and cell length were performed on quiescent cells using a Px-it imaging and computer system. The cell volume was calculated assuming the cells as elliptical cylinders and taking the cell depth equal to one third of cell width. For measurements of sodium pump current, the cells were voltage clamped (holding potential -40 mV) using the whole cell configuration. Cells were exposed to K-free solution to inhibit the pump and then to normal Krebs solution to reactivate the pump. In other experiments the cells were voltage clamped (holding potential -40 mV) and changes in the background current elicited by renin plus Ao or by Ang II were monitored. The results indicated that: a) intracellular dialysis of renin (128 pmol Ang I/ml) plus Ao (110 pmol Ang I generated by renin by exhaustion) decreased the cell volume concurrently with the activation of the sodium pump; b) intracellular losartan (10(-)8 M) or extracellular ouabain (10(-8) M) abolished the effect of renin plus Ao on cell volume; c) intracellular Ang II (10(-8) M), by itself, reduced cell volume and increased the pump current density; d) extracellular administration of renin plus Ao, at the same concentration used intracellularly, increased cell volume and inhibited the sodium pump. This increase of cell volume elicited by extracellular renin plus Ao was related to the activation of the Na-K-2Cl cotransporter; e) intracellular Ang II (10(-8) M) reversed cell swelling induced by hypotonic solutions.. Intracellular and extracellular renin plus Ao have opposite effects on sodium pump and cell volume regulation in the failing heart. Both effects of renin plus Ao are dependent upon the formation of Ang II. Since intracellular Ang II counteracted the cell swelling induced by hypotonic solution, it is reasonable to think that the activation of the intracrine renin-angiotensin system might play a protective role during myocardial ischaemia by reducing cell volume.

Topics: Angiotensin II; Angiotensinogen; Animals; Bumetanide; Cardiomyopathy, Dilated; Cardiotonic Agents; Cell Separation; Cell Size; Cricetinae; Diuretics; Extracellular Space; Hypotonic Solutions; Myocardial Ischemia; Myocytes, Cardiac; Ouabain; Patch-Clamp Techniques; Renin; Serine Proteinase Inhibitors; Sodium-Potassium-Exchanging ATPase

Evidence is available that activation of the renin-angiotensin system is involved in cardiac remodeling. It is unknown whether renin can change the inward calcium current (ICa) in the failing heart. This problem was investigated in the present study.. Cardiomyocytes were isolated from the ventricle of 4-month-old cardiomyopathic hamsters and measurements of the L-type ICa were performed using the patch-clamp technique in a whole-cell configuration.. Extracellular renin (128 pmol Ang I/ml per min) plus angiotensinogen (110 pmol angiotensin I generated by renin to exhaustion) incremented the peak ICa density significantly, an effect suppressed by enalapril maleate (10 mol/l) or by losartan (10 mol/l) added to the bath, indicating that the effect of renin plus angiotensinogen was related to the formation of angiotensin I and its conversion to angiotensin II at the surface cell membrane. Renin internalization seems to increment the ICa because intracellular dialysis of renin (128 pmol Ang I/ml per min) plus angiotensinogen (110 pmol angiotensin I generated by renin to exhaustion) also increased the peak ICa density significantly, an effect suppressed by intracellular losartan (10 mol/l) but not by extracellular losartan (10 mol/l).. Extracellular renin plus angiotensinogen increases the ICa in isolated myocytes from the failing heart of cardiomyopathic hamsters through the formation of angiotensin II and the activation of angiotensin type 1 receptors at the surface cell membrane. A similar increment of ICa was found with intracellular administration of renin plus angiotensinogen. This finding might indicate that renin internalization is involved in control of inward calcium current in the failing heart.

Topics: Angiotensin II; Angiotensinogen; Animals; Calcium; Cardiomyopathy, Dilated; Cricetinae; Extracellular Fluid; In Vitro Techniques; Intracellular Fluid; Mesocricetus; Myocytes, Cardiac; Renin

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II-mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (approximately 45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.

Topics: Aging; Angiotensin II; Angiotensinogen; Animals; Calcium; Calcium-Transporting ATPases; Cardiac Output, Low; Cardiomegaly; Cardiomyopathy, Dilated; Male; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Phenotype; Promoter Regions, Genetic; Rats; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Remodeling

To explore the role of angiotensin II, we assessed hemodynamics and cardiac function in angiotensinogen-deficient mice in comparison to wild-type animals. Left ventricular end-diastolic diameter and wall thickness were evaluated by echocardiography and systolic and diastolic left ventricular function by pressure-volume relations using a micro-conductance catheter. Compared to wild-type animals, the angiotensinogen-deficient mice were hypotensive and showed impaired systolic function. The hearts were dilated, demonstrated by echocardiography and by a right-ward shift of the pressure-volume loops, but end-diastolic pressure, isovolumic relaxation (tau) and diastolic stiffness were unchanged. Afterload, however, was reduced leading to maintained cardiac output. Although a blockade of the renin-angiotensin system via angiotensin converting enzyme inhibitors or angiotensin AT1 receptor antagonist is beneficial after cardiac failure, the absence of angiotensin peptides during the ontogenesis leads to dilated cardiomyopathy.

Topics: Angiotensin II; Angiotensinogen; Animals; Cardiomyopathy, Dilated; Disease Models, Animal; Echocardiography; Hemodynamics; Hypotension; Male; Mice; Mice, Knockout; Netherlands; Receptors, Angiotensin; Stroke Volume; Ventricular Function, Left

To assess whether renin-angiotensin-aldosterone (RAA) system gene polymorphisms shown to be associated with alterations in the activity of the system, may predict cardiac function changes subsequent to initiating medical therapy in heart failure.. The impact of RAA system genotypes on left ventricular ejection fraction (LVEF) following therapy to patients with idiopathic dilated cardiomyopathy (IDC) and class II-III heart failure was assessed. In 107 patients LVEF and LV dimensions were determined using radionuclide ventriculography and echocardiography prior to and subsequent to receiving furosemide, digoxin and angiotensin-converting enzyme (ACE) inhibitor therapy. Patients and controls were genotyped for variants of the ACE (insertion-deletion polymorphism), angiotensinogen (AGT; M235T polymorphism) and the aldosterone synthase (CYP11B2, C-344T polymorphism) genes.. RAA system genotypes were not significantly associated with LVEF prior to initiating medical therapy. However, the CYP11B2 gene variant (P=0.0064 on covariate analysis [adjusted for multiple genotyping] with a 1-2% chance of false positive data), but neither the ACE, nor the AGT variants, predicted improvement in LV ejection fraction in patients on medical therapy.. A CYP11B2 gene variant predicts the variable improvement in LV ejection fraction that occurs subsequent to initiating medical therapy in IDC. These data suggest a role for the aldosterone synthase locus in regulating the progression of heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cardiomyopathy, Dilated; Case-Control Studies; Cytochrome P-450 CYP11B2; Digoxin; Diuretics; Echocardiography; Enzyme Inhibitors; Female; Furosemide; Heart Ventricles; Humans; Logistic Models; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Radionuclide Ventriculography; Stroke Volume

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensinogen; Cardiomyopathy, Dilated; Cardiovascular Diseases; Chymases; Endothelin-1; Gene Expression; Gene Expression Regulation; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Iodine Radioisotopes; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Platelet-Derived Growth Factor; Protein Precursors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Serine Endopeptidases; Ventricular Function, Left

A local renin-angiotensin system in the heart is often invoked to explain the beneficial effects of ACE inhibitors in heart failure. The heart, however, produces little or no renin under normal conditions.. We compared the cardiac tissue levels of renin-angiotensin system components in 10 potential heart donors who died of noncardiac disorders and 10 subjects with dilated cardiomyopathy (DCM) who underwent cardiac transplantation. Cardiac levels of renin and prorenin in DCM patients were higher than in the donors. The cardiac and plasma levels of renin in DCM were positively correlated, and extrapolation of the regression line to normal plasma levels yielded a tissue level close to that measured in the donor hearts. The cardiac tissue-to-plasma concentration (T/P) ratios for renin and prorenin were threefold the ratio for albumin, which indicates that the tissue levels were too high to be accounted for by admixture with blood and diffusion into the interstitial fluid. Cell membranes from porcine cardiac tissue bound porcine renin with high affinity. The T/P ratio for ACE, which is membrane bound, was fivefold the ratio for albumin. Cardiac angiotensinogen was lower in DCM patients than in the donors, and its T/P ratio was half that for albumin, which is compatible with substrate consumption by cardiac renin.. These data in patients with heart failure support the concept of local angiotensin production in the heart by renin that is taken up from the circulation. Membrane binding may be part of the uptake process.

Topics: Adolescent; Adult; Angiotensinogen; Cardiomyopathy, Dilated; Child; Child, Preschool; Enzyme Precursors; Female; Heart Ventricles; Humans; In Vitro Techniques; Male; Middle Aged; Myocardium; Peptidyl-Dipeptidase A; Reference Values; Renin