atrial-natriuretic-factor and Cardiomyopathy--Hypertrophic

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Biomarkers; Calcium Channel Blockers; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Humans; Natriuretic Peptide, Brain

Topics: Actins; Animals; Atrial Natriuretic Factor; beta-Adrenergic Receptor Kinases; Calcium-Binding Proteins; Cardiomyopathy, Hypertrophic; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Heart Failure; Humans; Myosin Heavy Chains; Receptors, Adrenergic, beta-2; Signal Transduction

Topics: Animals; Atrial Natriuretic Factor; Biopsy; Cardiomyopathy, Hypertrophic; Cricetinae; Endocardium; Gene Expression; Humans; Immunohistochemistry; Mesocricetus; Microscopy, Electron; Myocardium; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Rats; Rats, Inbred SHR; RNA, Messenger; Swine

Topics: Adult; Aging; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Child; Heart Failure; Humans; Myocardial Infarction; Natriuretic Peptide, Brain; Nerve Tissue Proteins

Cibenzoline is able to improve left ventricular (LV) diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM), but the exact mechanism remains to be determined.. The present study was designed to elucidate the effect of intravenous administration of 1.4 mg/kg of cibenzoline on aortic and LV pressures, and transmitral Doppler flow pattern in 7 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 9 patients with hypertrophic nonobstructive cardiomyopathy (HNCM). Before and at the end of the administration, aortic and LV pressures, LV pressure gradient (LVPG) and transmitral Doppler velocity profiles were examined. After the administration of cibenzoline, LV minimal and end-diastolic pressures decreased from 9+/-4 mmHg to 1+/-5 mmHg (p=0.0049) and from 22+/-7 mmHg to 14+/-5 mmHg (p=0.0106) in patients with HOCM, and from 9+/-5 mmHg to 5+/-3 mmHg (p=0.0036) and from 20+/-6 mmHg to 14+/-3 mmHg (p=0.0033) in patients with HNCM. LVPG decreased in all patients with HOCM. E-wave velocity increased, A-wave velocity decreased, and thus the E/A ratio increased from 0.77+/-0.29 to 1.20+/-0.48 (p=0.0004).. Reduction of LV diastolic pressures by intravenous administration of cibenzoline may be related to an improvement in the E/A ratio in patients with HCM.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Hypertrophic; Catecholamines; Female; Humans; Imidazoles; Infusions, Intravenous; Laser-Doppler Flowmetry; Male; Middle Aged; Ventricular Dysfunction, Left

The aim of this study was to investigate what factor determines tachycardia-induced secretion of atrial and brain natriuretic peptides (ANP and BNP, respectively) in patients with hypertrophic cardiomyopathy (HCM). HCM patients with normal left ventricular (LV) systolic function and intact coronary artery (n = 22) underwent rapid atrial pacing test. The cardiac secretion of ANP and BNP and the lactate extraction ratio (LER) were evaluated by using blood samples from the coronary sinus and aorta. LV end-diastolic pressure (LVEDP) and the time constant of LV relaxation of tau were measured by a catheter-tip transducer. These parameters were compared with normal controls (n = 8). HCM patients were divided into obstructive (HOCM) and nonobstructive (HNCM) groups. The cardiac secretion of ANP was significantly increased by rapid pacing in HOCM from 384 +/- 101 to 1,268 +/- 334 pg/ml (P < 0.05); however, it was not significant in control and HNCM groups. In contrast, the cardiac secretion of BNP was fairly constant and rather significantly decreased in HCM (P < 0.01). The cardiac ANP secretion was significantly correlated with changes in LER (r = -0.57, P < 0.01) and tau (r = 0.73, P < 0.001) in HCM patients. Tachycardia potentiates the cardiac secretion of ANP, not BNP, in patients with HCM, particularly when it induces myocardial ischemia and LV diastolic dysfunction.

Topics: Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cardiomyopathy, Hypertrophic; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Tachycardia; Ventricular Dysfunction, Left

We investigated the relation between left ventricular structure and the secretion patterns of A- and B-type natriuretic peptides (ANP and BNP) by comparing their plasma levels in patients with hypertrophic cardiomyopathy (HC) and patients with idiopathic dilated cardiomyopathy (IDC). The secretion of ANP and BNP was much higher in patients with HC than in those with IDC; this shows that left ventricular cavity size is a key factor that regulates the secretion of ANP and BNP.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Female; Humans; Linear Models; Male; Middle Aged; Natriuretic Peptide, Brain; Probability; Prognosis; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Stroke Volume

N-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM.. We prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion.. Of 357 patients enrolled, the median age was 52 (IQR: 36-65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p<10. MR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Hypertrophic; Cause of Death; Disease Progression; Europe; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Reproducibility of Results; Risk Factors; Time Factors

In cardiac myocytes activation of an exchange factor activated by cAMP (Epac) leads to activation of phospholipase Cε (PLCε)-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) in the Golgi apparatus a process critical for development of cardiac hypertrophy. Here we show that β-adrenergic receptor (βAR) stimulation does not stimulate this pathway in the presence of the broad spectrum phosphodiesterase (PDE) inhibitor IBMX, but selective PDE3 inhibition revealed βAR-dependent PI4P depletion. On the other hand, selective inhibition of PDE2 or PDE9A blocked endothelin-1 (ET-1) and cAMP-dependent PI4P hydrolysis by PLCε. Direct activation of protein kinase A (PKA), protein kinase G (PKG), or the atrial natriuretic factor (ANF) receptor abolished PI4P hydrolysis in response to multiple upstream stimuli. These results reveal distinct pools of cyclic nucleotides that either inhibit PLCε at the Golgi through PKA/PKG, or activate PLCε at the Golgi through Epac. These data together reveal a new mechanism by which ANF and selective PDE inhibitors can protect against cardiac hypertrophy.

Topics: 1-Methyl-3-isobutylxanthine; A Kinase Anchor Proteins; Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathy, Hypertrophic; Cell Compartmentation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Golgi Apparatus; Humans; Myocytes, Cardiac; Nucleotides; Phosphatidylinositol Phosphates; Phosphoinositide Phospholipase C; Phosphoric Diester Hydrolases; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Signal Transduction

BACKGROUND Dracocephalum heterophyllum Benth flavonoid (DHBF) is a Tibetan and Uighur traditional medicine used to treat various disorders such as hypertension, lung heat, cough, and bronchitis; it has good antioxidant activity. Previous studies have shown that DHBF can reduce blood pressure in renovascular hypertensive rats, improve left ventricular systolic and diastolic function, and improve myocardial contractility. Therefore, we aimed to study the effect of DHBF on cardiomyocyte hypertrophy in cultured cells. MATERIAL AND METHODS Neonatal rat cardiomyocytes were cultured, and hypertrophy was induced by angiotensin II (Ang II), with or without varying concentrations of the DHBF extract. Cell Counting Kit-8 assay was used to assess cell viability, RT-qPCR was used to determine mRNA levels, confocal laser scanning microscopy was used to measure cell surface area and intracellular Ca2+ concentrations ([Ca2+]i), and colorimetric assays were used to assess nitric oxide (NO) levels and nitric oxide synthase (NOS) activity. RESULTS Ang II treatment of cardiomyocytes reduced cell viability to ~75% that of controls. Ang II treatment also increased cell surface area; increased mRNA expression of c-jun, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC); increased [Ca2+]i; and reduced NOS activity and NO production. DHBF treatment could reverse these effects in a concentration-dependent manner. CONCLUSIONS These results showed that DHBF can ameliorate cardiomyocyte hypertrophy induced by Ang II, as indicated by the downregulation of cardiac hypertrophy genes (ANP, BNP, and β-MHC) and reduction in cell surface area. The mechanism may be related to NO release and [Ca2+]I regulation.

Topics: Angiotensin II; Animals; Animals, Newborn; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathy, Hypertrophic; Cells, Cultured; China; Flavonoids; Heart Ventricles; Medicine, Tibetan Traditional; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Signal Transduction

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Remodeling; Biomarkers; Blood Pressure; Cardiomyopathy, Hypertrophic; Case-Control Studies; Catheter Ablation; Female; Heart Atria; Heart Diseases; Humans; Hypertension; Imaging, Three-Dimensional; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Veins; Tomography, X-Ray Computed; Troponin T; Vascular Remodeling

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.

Topics: Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Cell Differentiation; Cells, Cultured; Humans; Induced Pluripotent Stem Cells; Mutation; Myocardial Contraction; Myocytes, Cardiac; Proto-Oncogene Proteins B-raf; Tissue Engineering

The aim of this study was to determine if atrial natriuretic peptide can be used as an early screening tool for hypertrophic cardiomyopathy in Maine coon cats.. The study was performed in 43 Maine coon cats of both sexes, aged 11 to 92 months. Clinical and echocardiographic examinations were done and proANP serum concentrations were measured every three months over a period of one year (each cat had a total of five examinations). Cats were divided into 3 groups based on echocardiographic results: group 1 - healthy cats, group 2 - cats with unequivocal hypertrophic cardiomyopathy results, group 3 - cats with HCM. The study showed that the concentration of atrial natriuretic peptide correlates with the severity of HCM. A significant increase in serum concentration of this peptide was observed in cats from group 3, but it did not differ significantly between cats from group 2 and the healthy animals (p>0.05). A correlation was also found between proANP and age of the cats (p<0.01, r=0.5578) as well as between the ejection fraction (p=0.0285, r=0.5305) and end-systolic left ventricular diameter (p=0.05, r=0.48) in the affected animals. Atrial natriuretic peptide may be used to help in the diagnosis of advanced stages of HCM in Maine coon cats. Cats with high levels of proANP should be assigned to echocardiographic studies to confirm the disease.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Hypertrophic; Cat Diseases; Cats; Genetic Predisposition to Disease

Several mutations in αB-crystallin (CryAB), a heat shock protein with chaperone-like activities, are causally linked to skeletal and cardiac myopathies in humans. To better understand the underlying pathogenic mechanisms, we had previously generated transgenic (TG) mice expressing R120GCryAB, which recapitulated distinguishing features of the myopathic disorder (e.g., protein aggregates, hypertrophic cardiomyopathy). To determine whether induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a new experimental approach for human disease modeling, would be relevant to aggregation-prone disorders, we decided to exploit the existing transgenic mouse model to derive iPSCs from tail tip fibroblasts. Several iPSC lines were generated from TG and non-TG mice and validated for pluripotency. TG iPSC-derived cardiomyocytes contained perinuclear aggregates positive for CryAB staining, whereas CryAB protein accumulated in both detergent-soluble and insoluble fractions. iPSC-derived cardiomyocytes identified by cardiac troponin T staining were significantly larger when expressing R120GCryAB at a high level in comparison with TG low expressor or non-TG cells. Expression of fetal genes such as atrial natriuretic factor, B-type natriuretic peptide, and α-skeletal α-actin, assessed by quantitative reverse transcription-polymerase chain reaction, were increased in TG cardiomyocytes compared with non-TG, indicating the activation of the hypertrophic genetic program in vitro. Our study demonstrates for the first time that differentiation of R120G iPSCs into cardiomyocytes causes protein aggregation and cellular hypertrophy, recapitulating in vitro key pathognomonic hallmarks found in both animal models and patients. Our findings pave the way for further studies exploiting this cell model system for mechanistic and therapeutic investigations.

Topics: Actins; alpha-Crystallins; Animals; Atrial Natriuretic Factor; beta-Crystallins; Cardiomyopathy, Hypertrophic; Cell Differentiation; Cell Line; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; Mice; Mice, Transgenic; Myocytes, Cardiac; Natriuretic Peptide, Brain; Protein Multimerization; Reverse Transcriptase Polymerase Chain Reaction; Troponin T

Doxorubicin [(DOX) Adriamycin] is an effective anticancer agent whose major limiting side effect is cardiotoxicity. This cardiotoxicity is predicted only by the cumulative dose of DOX where the clinical situation involves chronic drug administration. Therefore, we investigate the effect of chronic DOX cardiotoxicity on expression of the cardiac cytochrome P450 (P450) enzymes and arachidonic acid (AA) metabolism in male Sprague-Dawley (SD) rats. The chronic toxicity was induced by multiple intraperitoneal injections for a cumulative dose of 15 mg/kg divided into six injections within 2 weeks. After 14 days of the last injection, the heart, liver, and kidney were harvested, and the expression of different genes was determined by real-time polymerase chain reaction. In addition, microsomal protein from the heart was prepared and incubated with AA. Thereafter, different AA metabolites were analyzed by liquid chromatography-electrospray ionization-mass spectrometry. The chronic DOX cardiotoxicity significantly induced gene expression of hypertrophic markers, apoptotic markers, CYP2E1, CYP4A3, CYP4F1, CYP4F5, and soluble epoxide hydrolase (sEH) enzyme, which was accompanied by an increase in the activity of P450 ω-hydroxylases and sEH. In addition, both the sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid, and the ω-hydroxylase inhibitor, N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), significantly prevented the DOX-mediated induction of the hypertrophic markers in the cardiac-derived H9c2 cells, which further confirms the role of these enzymes in DOX cardiotoxicity. Furthermore, gene expression of P450 and sEH was altered in an organ-specific manner. As a result, the chronic DOX administration leads to an imbalance between P450-mediated cardiotoxic and cardioprotective pathways. Therefore, P450 ω-hydroxylases and sEH might be considered as novel targets to prevent and/or treat DOX cardiotoxicity.

Topics: Animals; Apoptosis; Arachidonic Acid; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Hypertrophic; Cells, Cultured; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Doxorubicin; Epoxide Hydrolases; Gene Expression; Heart; Inflammation; Kidney; Liver; Male; Microsomes; Myocardium; Natriuretic Peptide, Brain; Rats; Rats, Sprague-Dawley; RNA, Messenger

Interventricular septum myocardium was studied in 40 patients with obstructive hypertrophic cardiomyopathy. Immunohistochemical assay revealed c-kit-positive resident cardiac stem cells in 82.5% patients. The content of the connective tissue and myofibrillar disarray zones and the degree of cardiomyocyte hypertrophy and myolysis were determined. In 30% cases, cardiomyocytes containing atrial natriuretic peptide were detected in the interventricular septum myocardium. The data were compared with clinical and functional parameters of patients. It was found that cardiac stem cells are present in patients, whose myocardium was characterized by increased density of the connective tissue, hypertrophy of mature cardiomyocytes, medium degree of myolysis in them, and accumulation of natriuretic peptide, a cardiac failure marker, in cardiomyocytes.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Echocardiography; Humans; Immunohistochemistry; Middle Aged; Myocardium; Myocytes, Cardiac; Proto-Oncogene Proteins c-kit; Statistics, Nonparametric; Stem Cells; Ventricular Septum

We aimed to determine the diagnostic performance of biomarkers in predicting myocardial fibrosis assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) in patients with hypertrophic cardiomyopathy (HCM). LGE CMR was performed in 40 consecutive patients with HCM. Left and right ventricular parameters, as well as the extent of LGE were determined and correlated to the plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), carboxy-terminal pro-vasopressin (CT-proAVP), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8). Myocardial fibrosis was assumed positive, if CMR indicated LGE. LGE was present in 26 of 40 patients with HCM (65%) with variable extent (mean: 14%, range: 1.3-42%). The extent of LGE was positively associated with MR-proANP (r = 0.4; P = 0.01). No correlations were found between LGE and MR-proADM (r = 0.1; P = 0.5), CT-proET-1 (r = 0.07; P = 0.66), CT-proAVP (r = 0.16; P = 0.3), MMP-9 (r = 0.01; P = 0.9), TIMP-1 (r = 0.02; P = 0.85), and IL-8 (r = 0.02; P = 0.89). After adjustment for confounding factors, MR-proANP was the only independent predictor associated with the presence of LGE (P = 0.007) in multivariate analysis. The area under the ROC curve (AUC) indicated good predictive performance (AUC = 0.882) of MR-proANP with respect to LGE. The odds ratio was 1.268 (95% confidence interval 1.066-1.508). The sensitivity of MR-proANP at a cut-off value of 207 pmol/L was 69%, the specificity 94%, the positive predictive value 90% and the negative predictive value 80%. The results imply that MR-proANP serves as a novel marker of myocardial fibrosis assessed by LGE CMR in patients with HCM.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Hypertrophic; Contrast Media; Endothelin-1; Female; Fibrosis; Gadolinium DTPA; Germany; Glycopeptides; Humans; Interleukin-8; Logistic Models; Magnetic Resonance Imaging, Cine; Male; Matrix Metalloproteinase 9; Middle Aged; Myocardium; Odds Ratio; Predictive Value of Tests; Protein Precursors; ROC Curve; Stroke Volume; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left

Angiotensin II (Ang II) is released by stretch of cardiac myocytes and has paracrine and autocrine effects on cardiac myocytes and fibroblasts. However, the direct effect of Ang II on the secretion of atrial natriuretic peptide (ANP) is unclear. The aim of the present study is to test whether Ang II affects stretch-induced ANP secretion. The isolated perfused beating atria were used from control and two-kidney one-clip hypertensive (2K1C) rats. The volume load was achieved by elevating the height of outflow catheter connected with isolated atria from 5cmH(2)O to 7.5cmH(2)O. Atrial stretch by volume load caused increases in atrial contractility by 60% and in ANP secretion by 100%. Ang II suppressed stretch-induced ANP secretion and tended to increase atrial contractility whereas losartan stimulated stretch-induced ANP secretion. Neither PD123319 nor A779 had direct effect on stretch-induced ANP secretion. The suppressive effect of Ang II on stretch-induced ANP secretion was blocked by the pretreatment of losartan but not by the pretreatment of PD123319 or A779. In hypertrophied atria from 2K1C rats, stretch-induced ANP concentration attenuated and atrial contractility augmented. The response of stretch-induced ANP secretion to Ang II and losartan augmented. The expression of AT1 receptor protein and mRNA increased but AT2 and Mas receptor mRNA did not change in 2K1C rat atria. Therefore, we suggest that Ang II generated endogenously by atrial stretch suppresses stretch-induced ANP secretion through the AT1 receptor and alteration of Ang II effect in 2K1C rat may be due to upregulation of AT1 receptor.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Hypertrophic; Extracellular Fluid; Gene Expression; Heart Atria; Hypertension, Renal; Imidazoles; Losartan; Male; Myocardial Contraction; Peptide Fragments; Perfusion; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Reflex, Stretch

In the clinical setting, natriuretic peptides (NPs) have proven to be reliable noninvasive markers for diagnostic, prognostic, and therapeutic monitoring of heart failure. Given their proven utility in humans, NPs are potential candidates for translational biomarkers during drug development to detect drug-induced hemodynamic stress resulting in cardiac hypertrophy in preclinical species. We evaluated the intra- and interassay precision and the stability of serum N-terminal-proatrial natriuretic peptide (NT-proANP) using a commercially available enzyme-linked immunoassay (EIA). We then measured NT-proANP concentrations in 532 serum samples from 337 male Crl:CD(SD) rats with or without pressure-induced cardiac hypertrophy. Additionally, we established a reference range using samples from control animals across multiple studies. The data demonstrate that the NT-proANP EIA is a robust and reproducible assay for the measurement of NT-proANP. The noninvasive translational utility, minimal sample volume requirement, and the lack of existing hypertrophic biomarkers in the male rat make NT-proANP an excellent candidate for further interrogation as a biomarker of cardiac hypertrophy in preclinical toxicology investigations.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Protein Precursors; Protein Stability; Rats; Rats, Sprague-Dawley; Time Factors

The overexpression of the transcription factor, E2F1, induces hypertrophy and apoptosis with cell cycle re-entry in cardiomyocytes in vitro and in vivo, suggesting that targeting E2F1 may have therapeutic potential. Accordingly, we tested the hypothesis that blocking the E2F1-mediated signal transduction pathway prevents cardiac hypertrophy by treating E2F1 knockout mice (E2F1-/-) with either isoproterenol (ISO) or Angiotensin II (ANG). Echocardi-ography was used to measure left ventricular mass index and myocardial performance index, a measure of combined systolic and diastolic left ventricular function. In control mice (E2F1+/+) both ISO and ANG treatments induced cardiac hypertrophy, and impaired ventricular function in ANG treated mice. In contrast to previously published work, E2F1-/- mice also demonstrated a similar pattern of cardiac hypertrophy and function after either treatment. Atrial natriuretic peptide, a molecular marker of hypertrophy and necropsy-determined body weight-normalized left ventricle mass were similarly increased in ISO and ANG treated E2F1+/+ and E2F-/- mice, supporting the echocardiographic data. These data indicate that E2F1 is not necessary for the development of cardiac hypertrophy although studies using an overexpression approach suggest a causal role of E2F1. The reason for this discrepancy is unclear, although it is possible that other E2F-family members (e.g., E2F2) may play a compensatory role. In conclusion, our data demonstrate that cardiac hypertrophy can be induced in an E2F1-independent fashion and suggest that in contrast to previous reports, targeting E2F1 may not be a good therapeutic approach.

Topics: Angiotensin II; Animals; Apoptosis; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cell Cycle; E2F1 Transcription Factor; Gene Expression Regulation; Humans; Isoproterenol; Male; Mice; Mice, Knockout; Mice, Transgenic; Myocytes, Cardiac; RNA, Messenger; Signal Transduction; Vasoconstrictor Agents

Hypertrophic cardiomyopathy (HCM) is a primary autosomal dominant inheritant myocardial disease with heterogeneity in clinical manifestations, natural history and prognosis. Even carrying an identical gene mutation among family members, a variety of clinical phenotypes have been found in patients with HCM. Modifier genes may contribute to the diversity. The plasma levels of atrial natriuretic peptides (ANP) were found previously to be elevated in HCM. Our studies suggested that ANP gene promoter polymorphism is associated with left ventricular hypertrophy in hypertension. The present study aimed to determine whether the two SNPs in the ANP gene are associated with HCM.. We determined the relationships between the ANP gene polymorphism and HCM in 262 HCM patients and 614 age- and sex-matched healthy individuals. All of the subjects were genotyped for -A2843G and A188G polymorphisms.. The genotype frequency in the -A2843G and A188G polymorphisms of the ANP gene was not significantly different between the HCM patients and controls. The -A2843G and A188G polymorphisms were also not associated with clinical phenotype in cardiomyopathy patients.. The polymorphisms of the ANP gene are not associated with increasing risk of HCM or clinical phenotypes. The variations of the ANP gene may not serve as a genetic modifier for the development of HCM.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Case-Control Studies; Echocardiography; Female; Genotype; Humans; Linkage Disequilibrium; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Young Adult

Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.

Topics: Actins; Animals; Atrial Natriuretic Factor; Calcium-Binding Proteins; Cardiomyopathy, Hypertrophic; Crosses, Genetic; Dietary Proteins; Disease Models, Animal; Female; Fibrosis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart Ventricles; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Myocardial Contraction; Myosin Heavy Chains; Phosphorylation; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sex Factors; Time Factors; Ventricular Remodeling

Left ventricular hypertrophy is considered an independent risk factor for cardiac morbidity and mortality, and many studies have shown that women have a lower incidence of left ventricular hypertrophy even after correcting for numerous risk factors. This cardio-protective effect seen in women has been attributed to estrogen, which likely modulates specific growth-promoting systems such as the renin-angiotensin system, and in turn may lead to the prevention of left ventricular hypertrophy. Furthermore, the underlying mechanisms responsible are poorly understood. The aim of the present study was to examine the effect of estrogen in relation to its impact on the development of left ventricular hypertrophy through its interaction with the renin-angiotensin system by using the proANP heterozygous (ANP +/-) mouse as a model of salt-sensitive cardiac hypertrophy. Male, female ANP +/- mice and also ovariectomized female ANP +/- mice treated with oil or estrogen, were fed either a normal or high-salt diet. All four groups exhibited a general suppression of the renin-angiotensin system under the high salt challenge. However, after the 5-week treatment period, marked left ventricular hypertrophy was noted only in the male and oil-injected ovariectomized female ANP +/- mice treated with high salt. Collectively, we provide direct evidence that the differences in cardiac hypertrophy between genders in ANP +/- mice is attributed to estrogen. Furthermore, estrogen may play a key role in slowing down the progression of salt-induced left ventricular hypertrophy in ANP +/- mice, in part, independent of the classical systemic renin-angiotensin system and possibly through other pathways.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Cardiomyopathy, Hypertrophic; Electrophoresis, Polyacrylamide Gel; Estrogens; Female; Male; Mice; Mice, Knockout; Ovariectomy; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA Probes; RNA, Messenger; Sodium Chloride, Dietary

To study interrelation of main clinico-hemodynamic parameters and levels of natriuretic peptides (NUP) in patients with hypertrophic cardiomyopathy (HCMP).. We measured concentrations of N-terminal fragments of precursors of plasma brain and atrial natriuretic peptides (NT-proBNP and NT-proANP) and conducted complex echocardiographical examination in 94 patients (mean age 42.3 +/- 133.8 years) with obstructive (n=43) and nonobstructive (n=51) HCMP.. Content of NUP did not depend on patients age, contractile function and dimensions of the left ventricle (LV), moderate and significant correlation between content of NT-proBNP, NT-proANP and type of ventricular filling (r=0.45 and 0.46, respectively), heart failure functional class (r=0.41 and 0.44, respectively), severity of LV hypertrophy (r=0.42 and 0.34, respectively), left atrial dimension (r=0.26 and 0.35, respectively), magnitude of pressure gradient in LV outflow tract (r=0.35 and 0.26, respectively). Degree of mitral regurgitation correlated significantly only with NT -proBNP level (r=0.34). The patients who eventually died (n=6) were characterized by higher plasma content of NUP.. In patients with HCMP elevated plasma content of N-terminal precursors of brain and atrial natriuretic peptides are associated with severity of LV diastolic dysfunction and hypertrophy of LV as well as of hemodynamic and functional disturbances.

Topics: Adult; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Female; Humans; Hypertrophy, Left Ventricular; Male

We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children.. In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations.. All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children.. Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children.. In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

Topics: Adolescent; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Carrier Proteins; Child; Child, Preschool; Diastole; Echocardiography, Doppler; Electrocardiography; Female; Humans; Hypertrophy, Left Ventricular; Imaging, Three-Dimensional; Infant; Male; Tropomyosin; Ventricular Myosins

For several years, the severe side effects associated with the use of high doses of the aldosterone antagonist, spironolactone, limited its clinical use. Studies have recently shown efficacy and minimal side effects of low-dose spironolactone combined with standard therapy in the treatment of heart failure and hypertensive patients. The authors evaluated the effects of low-dose spironolactone alone or in combination with angiotensin-converting enzyme (ACE) inhibitors on the progression of left ventricular dysfunction and remodeling in a congenic rat model of hypertrophic cardiomyopathy. The congenic SS-16/Mcwi rats developed severe cardiac hypertrophy despite being normotensive even on high-salt diet. SS-16/Mcwi and SS/Mcwi rats were fed a low-salt (0.4% NaCl) diet and were treated with vehicle (CON), spironolactone (20 mg/kg/d subcutaneously), captopril (100 mg/kg/d drinking water), or both spironolactone and captopril for 4 weeks. Blood pressure, plasma peptides, cardiac fibrosis, and echocardiography measurements were evaluated. Spironolactone at a low dose had no effect on blood pressure, cardiac hypertrophy, and fibrosis in either strain. However, in combination with captopril, spironolactone decreased the cardiac hypertrophy more than captopril treatment alone. In the SS-16/Mcwi rats, the combined therapy significantly preserved the cardiac index when compared with control. These data indicate that the addition of low-dose spironolactone to captopril treatment was more effective in preventing the progression of heart hypertrophy and ventricular dysfunction in the SS-16/Mcwi than captopril alone. This study suggests that combined spironolactone and captopril therapy may be useful in the treatment of hypertrophic cardiomyopathy.

Topics: Administration, Oral; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Congenic; Atrial Natriuretic Factor; Blood Pressure; Captopril; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echocardiography; Injections, Subcutaneous; Myocardium; Organ Size; Random Allocation; Rats; Rats, Inbred Strains; Spironolactone; Ventricular Function, Left; Weight Loss

We examined the plasma levels of soluble Fas (sFas) or Fas ligand (sFas-L), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in patients with idiopathic nonobstructive (HNCM) and dilated-phase (DHCM) hypertrophic cardiomyopathy. Patients with idiopathic hypertrophic cardiomyopathy (HCM) may deteriorate to DHCM and the pathogenesis is unknown. The levels of these plasma cytokines were measured by ELISA and echocardiography was performed in 38 HNCM and 11 DHCM patients, and 10 normal subjects. The follow-up period was three years. In HNCM, TNF-alpha (43.3 +/- 45.2 versus 16.9 +/- 4.3 pg/mL) and IL-6 (65.1 +/- 86.4 versus 4.0 +/- 2.1 pg/mL) were slightly higher compared to normal subjects and sFas (3.7 +/- 1.2 versus 2.1 +/- 0.7 ng/mL) increased significantly. sFas (3.9 +/- 1.8), TNF-alpha (79.3 +/- 72.4), and IL-6 (234.1 +/- 135.2) in DHCM were significantly increased and only IL-6 was significantly different from HNCM. sFas-L (0.18 +/- 0.08 versus 0.25 +/- 0.05 ng/mL) in HNCM was significantly decreased, and the decrease was marked in DHCM (0.05 +/- 0.02). In HNCM, TNF-alpha was negatively correlated with fractional shortening (r = -0.432, P = 0.0062) or positively with IL-6 (r = 0.665, P < 0.0001), while sFas-L was negatively correlated with IL-6 (r = -0.580, P < 0.0001). DHCM with high sFas had significantly higher cumulative incidences of worsening heart failure. The Fas/Fas-L system and proinflammatory cytokines may play an important role in the status of HCM and its progression to DHCM.

Topics: Aged; Apoptosis; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Cytokines; Disease Progression; Echocardiography; Fas Ligand Protein; fas Receptor; Female; Humans; Interleukin-6; Male; Membrane Glycoproteins; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Tumor Necrosis Factor-alpha

Patients with hypertrophic cardiomyopathy (HCM) or hypertensive heart disease (HHD) have increased concentrations of various neurohumoral factors. Thus, the aim of the present study was to evaluate the differences in the neurohumoral profiles of HCM and HHD.. Plasma concentrations of epinephrine, norepinephrine, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II and endothelin-1 were measured in 40 patients with HCM, 35 with HHD, and 15 controls. Additionally, the concentrations of these neurohumoral factors in the coronary sinus and aortic root were measured in 12 HCM patients and 10 controls. Plasma concentrations of norepinephrine, ANP and BNP were significantly higher in HCM than HHD and controls. In HCM, there was no significant correlation between the left ventricular mass index and any neurohumoral factor. The plasma BNP concentration significantly correlated with left intraventricular pressure gradient in HCM. There were significant differences in the plasma concentrations of ANP and BNP between HCM with and without left ventricular diastolic dysfunction. Transcardiac production of BNP was significantly higher in patients with obstructive HCM than in those with non-obstructive HCM.. The significant neurohumoral differences between HCM and HHD were the plasma concentrations of norepinephrine, ANP and BNP. In HCM patients, the plasma BNP concentration may reflect the intraventricular pressure gradient and left ventricular diastolic dysfunction whereas the plasma ANP concentration reflects only the left ventricular diastolic dysfunction.

Topics: Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Coronary Vessels; Echocardiography; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Pressure; Ventricular Dysfunction, Left; Ventricular Function

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones involved in electrolyte and fluid homeostasis. Our laboratory has investigated the use of ANP and BNP as diagnostic markers of cardiac disease in cats. We hypothesize that the cardiac distribution of ANP and BNP increases in cats with hypertrophic cardiomyopathy (HCM). Accordingly, we evaluated the immunohistochemical distribution of ANP and BNP in hearts of four cats with naturally occurring HCM relative to five healthy controls. Indirect immunoperoxidase was performed with polyclonal immunoglobulin G against feline ANP (1-28) and proBNP (43-56). In control cats, ANP and BNP immunoreactivity was restricted to the atria. Staining for both peptides was most intense adjacent to the endocardial surface. Auricles stained more diffusely than atria for both peptides. The interstitial capillaries and nerve fibers within the heart were positive only for BNP. Atrial immunoreactivity for ANP and BNP was more diffuse and had a less distinctly layered pattern in HCM than in control cats. Ventricular cardiomyocytes of HCM cats were negative for ANP but stained lightly and diffusely for BNP. The capillaries and nerve fibers remained positive for BNP. We conclude that in cats with HCM, the cardiac distribution of ANP and BNP is more diffuse in the atria and that novel expression of BNP in the ventricular cardiomyocytes occurs.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Cat Diseases; Cats; Heart Atria; Heart Ventricles; Immunohistochemistry; Natriuretic Peptide, Brain

The precise function of angiotensin II type 2 receptor (AT2-R) in the mammalian heart in vivo is unknown. Here, we investigated the role of AT2-R in cardiac pressure overload.. Rats were infused with vehicle, angiotensin II (Ang II), PD123319 (an AT2-R antagonist), or the combination of Ang II and PD123319 via subcutaneously implanted osmotic minipumps for 12 or 72 hours. Ang II-induced increases in mean arterial pressure, left ventricular weight/body weight ratio, and elevation of skeletal alpha-actin and beta-myosin heavy chain mRNA levels were not altered by PD123319. In contrast, AT2-R blockade resulted in a marked increase in the gene expression of c-fos, endothelin-1, and insulin-like growth factor-1 in Ang II-induced hypertension. In parallel, Ang II-stimulated mRNA and protein expression of atrial natriuretic peptide were significantly augmented by AT2-R blockade. Moreover, PD123319 markedly increased the synthesis of B-type natriuretic peptide. Furthermore, the expression of vascular endothelial growth factor and fibroblast growth factor-1 was downregulated by Ang II only in the presence of AT2-R blockade.. Our results provide evidence that AT2-R plays a functional role in the cardiac hypertrophic process in vivo by selectively regulating the expression of growth-promoting and growth-inhibiting factors.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathy, Hypertrophic; Fibroblast Growth Factor 1; Gene Expression Regulation; Genes, fos; Heart Rate; Hypertension; Imidazoles; Infusion Pumps, Implantable; Losartan; Male; Natriuretic Peptide, Brain; Proto-Oncogene Proteins c-fos; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; RNA, Messenger; Vascular Endothelial Growth Factor A

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/ deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3-7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.

Topics: Aged; Atrial Fibrillation; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptidyl-Dipeptidase A; Risk Factors

Members of the protein kinase C (PKC) isozyme family are important signal transducers in virtually every mammalian cell type. Within the heart, PKC isozymes are thought to participate in a signaling network that programs developmental and pathological cardiomyocyte hypertrophic growth. To investigate the function of PKC signaling in regulating cardiomyocyte growth, adenoviral-mediated gene transfer of wild-type and dominant negative mutants of PKC alpha, beta II, delta, and epsilon (only wild-type zeta) was performed in cultured neonatal rat cardiomyocytes. Overexpression of wild-type PKC alpha, beta II, delta, and epsilon revealed distinct subcellular localizations upon activation suggesting unique functions of each isozyme in cardiomyocytes. Indeed, overexpression of wild-type PKC alpha, but not betaI I, delta, epsilon, or zeta induced hypertrophic growth of cardiomyocytes characterized by increased cell surface area, increased [(3)H]-leucine incorporation, and increased expression of the hypertrophic marker gene atrial natriuretic factor. In contrast, expression of dominant negative PKC alpha, beta II, delta, and epsilon revealed a necessary role for PKC alpha as a mediator of agonist-induced cardiomyocyte hypertrophy, whereas dominant negative PKC epsilon reduced cellular viability. A mechanism whereby PKC alpha might regulate hypertrophy was suggested by the observations that wild-type PKC alpha induced extracellular signal-regulated kinase1/2 (ERK1/2), that dominant negative PKC alpha inhibited PMA-induced ERK1/2 activation, and that dominant negative MEK1 (up-stream of ERK1/2) inhibited wild-type PKC alpha-induced hypertrophic growth. These results implicate PKC alpha as a necessary mediator of cardiomyocyte hypertrophic growth, in part, through a ERK1/2-dependent signaling pathway.

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Cell Compartmentation; Cell Differentiation; Cell Membrane; Cytosol; Heart; Immunohistochemistry; Isoenzymes; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Myocardium; Protein Kinase C; Protein Kinase C-alpha; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; Tubulin

Plasma level of B-type natriuretic peptide is a sensitive marker of left ventricular dysfunction and the level is markedly elevated in patients with hypertrophic obstructive cardiomyopathy. Percutaneous transluminal septal myocardial ablation, a catheter-based treatment of hypertrophic obstructive cardiomyopathy, has been widely used as a new therapeutic option for the disease. This study was designed to evaluate clinical implications of natriuretic peptides after the new treatment.. Seven consecutive patients with hypertrophic obstructive cardiomyopathy unresponsive to usual medical treatments (age: 57.9+/-22.0 years) were enrolled in the study. Serial changes in atrial and B-type natriuretic peptide in plasma were examined after percutaneous transluminal septal myocardial ablation.. Atrial and B-type natriuretic peptides levels (pg/ml, mean+/-S.D.) at baseline were higher in hypertrophic obstructive cardiomyopathy than in control (80.0+/-43.0 vs. 12.8+/-5.2, P<0.0001; 858.0+/-458.4 vs. 12.4+/-7.0, P<0.0001; respectively). Left ventricular outflow-tract pressure gradient (mmHg) immediately decreased from 115.3+/-23.3 to 30.6+/-12.4 (P<0.0001) after the treatment and concomitantly B-type natriuretic peptide level decreased (858.0+/-458.4 to 264.1+/-137.7, P=0.0084). The level re-increased and peaked at the 2nd day (634.4+/-429.6) and gradually decreased again until 4 weeks. Reduction rate of left ventricular outflow-tract pressure gradient between before and 4 weeks after percutaneous transluminal septal myocardial ablation positively correlated with that of B-type natriuretic peptide (r(2)=0.817, P=0.0053). Changes in atrial natriuretic peptide were not significant in contrast to those of B-type natriuretic peptide.. Plasma B-type natriuretic peptide level could be useful to predict the effects of percutaneous transluminal septal myocardial ablation in patients with hypertrophic obstructive cardiomyopathy.

Topics: Adolescent; Aged; Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Calcium-Calmodulin-Dependent Protein Kinases; Cardiomyopathy, Hypertrophic; Catheter Ablation; Creatine Kinase; Creatine Kinase, MB Form; Female; Humans; Isoenzymes; Linear Models; Male; Middle Aged; Postoperative Period; Probability; Prognosis; Prospective Studies; Sensitivity and Specificity

We measured plasma atrial/brain natriuretic peptide (ANP/BNP) levels at rest and during exercise and correlated the results with various clinical findings, particularly with myocardial ischemia, in asymptomatic hypertrophic cardiomyopathy (HCM).. In patients with HCM, ANP and BNP levels are elevated and exercise-induced myocardial ischemia is common. However, it has not yet been elucidated how these levels at rest and their change with dynamic exercise are related to ischemia.. Levels of ANP and BNP were measured at rest and at peak exercise during (99m)Tc-tetrofosmin scintigraphy in 31 asymptomatic patients with non-obstructive HCM and in 10 control subjects.. Levels of ANP and BNP at rest and the change of ANP and BNP levels (PG/ML) from rest to exercise were significantly greater in HCM than in control subjects (ANP: rest, 53.2 +/- 31.8 vs. 11.6 +/- 6.1; exercise, 114.5 +/- 74.8 vs. 28.3 +/- 23.4. BNP: rest, 156.7 +/- 104.1 vs. 9.8 +/- 9.6; exercise, 201.6 +/- 131.5 vs. 13.2 +/- 14.5). Septal perforator compression (SPC) and exercise-induced ischemia were observed, respectively, in 20 (64.5%) and in 19 (61.3%) patients with HCM. The increment of ANP during exercise was similar between HCM subgroups with or without inducible ischemia. However, BNP levels at rest and BNP increments during exercise were significantly greater in the HCM subgroup with inducible ischemia than in the subgroup without (rest, 190.5 +/- 116.2 vs. 103.1 +/- 48.3; exercise, 250.5 +/- 142.2 vs. 124.2 +/- 58.6). Multiple logistic regression analysis revealed that SPC and BNP levels at rest were independently associated with exercise-induced ischemia.. Measurement of plasma BNP levels at rest may be useful in predicting silent myocardial ischemia in HCM.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Predictive Value of Tests; Reference Values

Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Topics: Actins; Alleles; Animals; Atrial Natriuretic Factor; Blotting, Northern; Cardiomyopathy, Hypertrophic; Carrier Proteins; Disease Models, Animal; Echocardiography; Electrophysiology; Family Health; Male; Mice; Mutation; Mutation, Missense; Myocardium; RNA Splicing; RNA, Messenger; Sarcomeres; Time Factors; Transgenes; Ventricular Dysfunction, Left

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

Topics: Actins; Animals; Atrial Natriuretic Factor; beta-Adrenergic Receptor Kinases; Biomarkers; Calcium; Calcium Signaling; Calcium-Binding Proteins; Cardiomyopathy, Hypertrophic; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Disease Progression; Female; Gene Expression; Heart Failure; Male; Mice; Mice, Transgenic; Motor Activity; Myocardium; Myosin Heavy Chains; Receptors, Adrenergic, beta-2

Topics: Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Hemodynamics; Humans; Natriuretic Peptide, Brain; Ventricular Function, Left

Atrial and brain natriuretic peptide levels closely reflect impaired left ventricular function in patients with heart failure. In the present study we assessed the determinants and the clinical significance of atrial and brain natriuretic peptide plasma levels in hypertrophic cardiomyopathy.. In 44 patients with hypertrophic cardiomyopathy (40+/-15 years) we evaluated: (a) atrial and brain natriuretic peptide plasma levels; (b) left ventricular hypertrophy; (c) left ventricular ejection fraction; (d) transmitral and pulmonary venous flow velocity patterns, and left atrial fractional shortening; (e) left ventricular outflow tract gradient; (f) maximal oxygen consumption. Left ventricular hypertrophy influenced only brain natriuretic peptide levels (r=0.32;P<0.05). Atrial and brain natriuretic peptide plasma levels did not correlate with left ventricular ejection fraction, but correlated with left ventricular outflow tract gradient (r=0.35;P<0.05; and r=0.40, P=0.022, respectively) and left atrial fractional shortening (r=-0.57;P<0.001, and r=-0.35;P<0.05, respectively). Atrial but not brain natriuretic peptide plasma levels were inversely related to maximal oxygen consumption (r=-0.35;P<0.05). By stepwise multiple regression analysis, left atrial fractional shortening and left ventricular outflow tract gradient were the only predictors of atrial and brain natriuretic peptide plasma levels, respectively.. In hypertrophic cardiomyopathy, atrial natriuretic peptide plasma levels are mainly determined by diastolic function: this explains the relationship with exercise tolerance. In contrast, brain natriuretic peptide plasma levels are mainly determined by left ventricular outflow tract gradient.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Echocardiography, Doppler; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Contraction; Natriuretic Peptide, Brain; Regression Analysis; Stroke Volume; Ventricular Function, Left

We examined whether measurement of the plasma BNP concentrations might be useful for the early diagnosis of the existence and severity of disease in patients with heart disease in daily clinical practice.. The plasma BNP and ANP concentrations in 415 patients with heart disease and hypertension and 65 control subjects were measured. Patients with heart disease had higher plasma BNP and ANP concentrations than did those with hypertension or control subjects. Among the etiology of cardiac diseases, specifically dilated cardiomyopathy and hypertrophic cardiomyopathy, was associated with the highest plasma BNP concentrations, whereas dilated cardiomyopathy was associated with the highest plasma ANP concentrations. Plasma BNP concentrations showed an increase as the severity of the heart disease, as graded according to the NYHA classification of cardiac function, increased. In both patients with heart disease and hypertension, the plasma BNP values were higher in those who had abnormalities in their echocardiogram and electrocardiogram as compared to those without any abnormalities. The plasma BNP levels also showed a significant correlation with left ventricular wall thickness and left ventricular mass. On the other hand, the plasma ANP levels showed significant correlations with left ventricular dimension. Receiver operative characteristic analysis revealed that plasma BNP levels showed substantially high sensitivity and specificity to detect the existence of heart diseases.. Measurements of the plasma BNP concentrations is useful to detect the existence of the diseases, and abnormalities of left ventricular function and hypertrophy in patients with heart disease in daily clinical practice.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Heart Diseases; Humans; Hypertension; Natriuretic Peptide, Brain; ROC Curve; Sensitivity and Specificity

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, we created transgenic mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q) allele analogous to one found in FHC. Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type. In striking contrast to truncation mice, however, the R92Q hearts demonstrate significant induction of atrial natriuretic factor and beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice have increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data are consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of FHC. The distinct phenotypes of mice with different TnT alleles suggest that the clinical heterogeneity of FHC is at least partially due to allele-specific mechanisms.

Topics: Alleles; Animals; Atrial Natriuretic Factor; Base Sequence; Cardiomyopathy, Hypertrophic; Cell Size; Disease Models, Animal; DNA Primers; Heart Ventricles; Humans; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Microscopy, Electron; Mutation, Missense; Myocardial Contraction; Myosin Heavy Chains; Phenotype; Sarcomeres; Troponin T

1. The aim of this study was to elucidate the pathophysiological role of adrenomedullin and the relation between adrenomedullin and other hormones in patients with hypertrophic cardiomyopathy. 2. Fourteen patients with hypertrophic obstructive cardiomyopathy (HOCM), 26 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) and 14 normal control subjects participated in this study. Radioimmunoassay for plasma adrenomedullin concentration was performed with adrenomedullin-M antibody. Plasma levels of endothelin-1, atrial and brain natriuretic peptides and noradrenaline were also measured. 3. Plasma levels of adrenomedullin were higher in patients with hypertrophic cardiomyopathy (8.43 +/- 3.73 pmol/l) than in normal controls (5.24 +/- 0.44 pmol/l, P < 0.005). There was no significant difference between HOCM and HNCM patients. There was a weak correlation between plasma levels of adrenomedullin and total 12-lead QRS voltage in patients with hypertrophic cardiomyopathy (r = 0.323, P < 0.05). 4. Plasma levels of endothelin-1, atrial and brain natriuretic peptides were higher in hypertrophic cardiomyopathy than in normal controls. Endothelin-1 showed no significant difference between HOCM and HNCM patients, but atrial and brain natriuretic peptides were higher in HOCM than in HNCM patients. There was a positive correlation between plasma levels of adrenomedullin and endothelin-1 (r = 0.575, P < 0.0001), but no correlation between plasma levels of adrenomedullin and atrial natriuretic peptide, brain natriuretic peptide and noradrenaline. 5. Our results indicate that adrenomedullin may play an important role to maintain haemodynamics in patients with hypertrophic cardiomyopathy, and its action may be related to endothelin-1 but independent of atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Endothelin-1; Humans; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Norepinephrine; Peptides; Vasodilator Agents

This study examined the acute and long-term effects of DDD pacing on ergospirometric parameters and neurohormonal activity in patients with hypertrophic obstructive cardiomyopathy (HOCM). We studied eight patients (five males), aged 56 +/- 7 years, with HOCM refractory to drugs. In all patients a DDD pacemaker was implanted and programmed with an atrioventricular (AV) delay that insured full ventricular activation. The patients underwent echocardiographic examination and exercise stress testing before and 3 days, 3 months, and 12 months after pacemaker implantation. Oxygen consumption was measured at the anaerobic threshold (VO2AT) and peak exercise (pVO2). Atrial natriuretic peptide (ANP) and cyclic adenosine monophosphate (c-AMP) levels were measured concomitantly. Left ventricular outflow tract (LVOT) pressure gradient decreased significantly from 70 +/- 18 to 25 +/- 12 mmHg (P < 0.05) 3 days after pacing and remained unchanged at 3 and 12 months. pVO2 and VO2AT increased significantly, from 20.1 +/- 3 to 23.4 +/- 3 mL/kg/min and from 16 +/- 3 to 17.8 +/- 2 mL/kg/min, respectively (P < 0.05). This improvement continued up to 3 months, and then remained stable until the end of the 12-month follow-up period. ANP levels decreased at 3 days from 85.4 +/- 5.7 to 75.4 +/- 7.3 fmol/mL (P < 0.05), and remained unchanged over the 12 months. c-AMP levels did not change significantly after the onset of pacing. DDD pacing in patients with HOCM not only reduces the LVOT pressure gradient but also causes a significant early and long-term improvement in exercise capacity and neurohormonal profile.

Topics: Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cardiomyopathy, Hypertrophic; Cyclic AMP; Exercise Test; Exercise Tolerance; Female; Follow-Up Studies; Hemodynamics; Humans; Male; Middle Aged; Oxygen Consumption; Pacemaker, Artificial; Time Factors

This study investigated whether atrial natriuretic peptide (ANP) secretion from the left ventricle occurs and correlated any secretion with the hemodynamic or echocardiographic parameters in patients with hypertrophic non-obstructive cardiomyopathy (HNCM). Volume overload was induced by intravenous injection of low-molecular weight dextran in 19 patients with HNCM and seven normal subjects (control group). Simultaneous measurements of plasma ANP concentrations in the aortic root, anterior interventricular vein and coronary sinus, and hemodynamic parameters were performed before and after volume overload. Echocardiographic parameters were measured under the basal conditions in the HNCM group. There was no difference in ANP concentrations between the aorta and anterior interventricular vein either before or after volume overload in the control group, whereas they were significantly higher in the anterior interventricular vein than in the aorta both before and after volume overload in the HNCM group, suggesting increased ANP secretion from the left ventricle. Moreover, the difference in ANP concentrations between these locations was enhanced by volume overload. In the HNCM group, the differences in ANP concentrations between these locations were positively correlated with the pulmonary capillary wedge pressure and left ventricular end-diastolic pressure before and after volume overload, but not with left ventricular thickness or left atrial dimension. These results suggest that enhanced ANP secretion from the left ventricle in both basal and volume overloaded states occurs in HNCM, and this ANP secretion from the left ventricle is closely related to left ventricular end-diastolic pressure but not to wall thickness and mass index of left ventricle.

Topics: Aorta; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Dextrans; Echocardiography; Female; Heart; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Pulmonary Wedge Pressure

Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure.. To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation.. Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap.. In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Calcium-Transporting ATPases; Captopril; Cardiomyopathy, Hypertrophic; Diastole; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertension; Mice; Mice, Transgenic; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sarcoplasmic Reticulum; Tetrazoles

To determine if plasma levels of atrial natriuretic peptide are elevated in patients with hypertrophic cardiomyopathy and to determine the relationship of atrial natriuretic peptide to symptoms and echocardiographic indices of left ventricular structure and diastolic function in these patients.. A prospective study in which atrial natriuretic peptide was measured in peripheral venous plasma in 14 patients (age 44 +/- 14 years) with hypertrophic cardiomyopathy and 17 healthy controls. Echocardiography was performed in all cases and 30 controls to examine indices of left heart structure and function. All patients underwent clinical evaluation.. The concentration of atrial natriuretic peptide was significantly higher in patients with hypertrophic cardiomyopathy than controls, (17.86 +/- 8.72 vs. 6.22 +/- 3.26 pmol/l, P = 0.0001). Diastolic dysfunction was observed in 11 of 14 patients with hypertrophic cardiomyopathy. No correlation was demonstrated between atrial natriuretic peptide levels and the degree of diastolic dysfunction, septal or free wall thickness, left atrial size, degree of mitral regurgitation or New York Heart Association functional class.. Plasma levels of atrial natriuretic peptide are elevated in patients with hypertrophic cardiomyopathy but do not correlate with symptoms or echocardiographically-derived indices of left ventricular structure or diastolic function.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Case-Control Studies; Echocardiography; Female; Humans; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Ventricular Dysfunction, Left

We examined whether plasma brain natriuretic peptide levels are abnormally elevated in hypertrophic obstructive cardiomyopathy compared with other cardiac diseases.. We previously reported that plasma brain and atrial natriuretic peptide levels were elevated in hypertrophic cardiomyopathy.. We compared plasma concentrations of brain and atrial natriuretic peptide and hemodynamic and echocardiographic data in 50 patients with hypertrophic obstructive cardiomyopathy (n = 15, mean [+/-SD] intraventricular pressure gradient 37 +/- 16 mm Hg), hypertrophic nonobstructive cardiomyopathy (n = 15), aortic stenosis (n = 10, mean pressure gradient 41 +/- 18 mm Hg) and hypertensive heart disease (n = 10, mean systolic/diastolic blood pressure 203 +/- 16/108 +/- 11 mm Hg, respectively) and 10 normal subjects.. Plasma brain natriuretic peptide levels were higher in the hypertrophic obstructive cardiomyopathy group (397.1 +/- 167.8 pg/ml*) than in the hypertrophic nonobstructive cardiomyopathy (60.0 +/- 48.1 pg/ml*), hypertensive heart disease (53.9 +/- 31.4 pg/ml*), aortic stenosis (75.4 +/- 54.3 pg/ml*) and normal groups (9.8 +/- 6.4 pg/ml [*p < 0.05 vs. normal group, p < 0.05 vs. hypertrophic obstructive cardiomyopathy group]). Although plasma atrial natriuretic peptide levels were higher in the hypertrophic obstructive cardiomyopathy group than the other patient groups, the brain/atrial natriuretic peptide ratio in the hypertrophic obstructive cardiomyopathy group was higher (4.5 +/- 2.3) than those in the other three patient groups (1.1 to 1.4) and the normal group (0.7 +/- 0.5). Left ventricular end-diastolic pressure and left ventricular end-diastolic volume index were similar among the four patient groups. The interventricular septal thickness and the ratio of interventricular septal thickness to left ventricular posterior wall thickness were similar between the hypertrophic obstructive and nonobstructive cardiomyopathy groups.. Abnormal elevations of plasma brain natriuretic peptide levels are difficult to explain on the basis of hemodynamic and echocardiographic data and are a special feature of hypertrophic obstructive cardiomyopathy.

Topics: Adult; Aged; Aortic Valve Stenosis; Atrial Natriuretic Factor; Brain-Derived Neurotrophic Factor; Cardiomyopathy, Hypertrophic; Echocardiography; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Osmolar Concentration

We investigated the redistribution of myocardial isoenzymes of creatine kinase (CK) and lactate dehydrogenase (LD) in rats with right heart failure induced by monocrotaline and assessed the effect of enalapril, an angiotensin converting enzyme inhibitor. Wistar rats were divided into four groups: (1) control (n = 20), (2) control + enalapril (25 mg/kg/day) (n = 22), (3) monocrotaline (50 mg/kg) (n = 45), (4) monocrotaline (50 mg/kg) + enalapril (25 mg/kg/day) (n = 32). After 4 weeks, the monocrotaline group developed severe pulmonary hypertension and right ventricular hypertrophy with marked decrease in myocardial norepinephrine and increase in both plasma atrial natriuretic peptide and mortality rate (33.3%). The marked decrease in both MM and mitochondrial CK ('creatine shuttle') and the relatively constant BB and MB CK caused the net depression of total CK. The depression of LD1 (aerobic LD) was remarkable compared with the relatively constant total LD. In the monocrotaline+enalapril group, mortality rate (9.4%), cardiac hypertrophy and plasma atrial natriuretic peptide were all significantly reduced and myocardial norepinephrine recovered although pulmonary hypertension was not improved at all. However, myocardial total, MM and mitochondrial CK and LD1 activities were all recovered completely or partially in this group. Thus, enalapril reduced cardiac hypertrophy and failure and improved the prognosis in this model of pulmonary hypertension. This beneficial effect of enalapril was not associated with pulmonary vasodepression but with the inhibition of myocardial isoenzyme redistribution of CK and LD, i.e. the preservation of 'creatine shuttle' and aerobic LD.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Creatine Kinase; Enalapril; Heart; Hypertension, Pulmonary; Isoenzymes; L-Lactate Dehydrogenase; Male; Monocrotaline; Myocardium; Norepinephrine; Rats; Rats, Wistar

Topics: Analysis of Variance; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Humans; Natriuretic Peptide, Brain; Nerve Tissue Proteins

Brain natriuretic peptide (BNP), as a cardiac hormone, is expressed together with atrial natriuretic peptide (ANP) in the ventricles in congestive heart failure. However, the ventricular expression of BNP in hypertrophic cardiomyopathy (HCM) with normal systolic function is still unclear.. The study population consisted of 39 HCM patients with asymmetric septal hypertrophy and 10 control subjects without any specific cardiac disease. Eleven cases of HCM were obstructive (HOCM), and the other 28 cases were nonobstructive (HNCM). All of these patients had a normal ejection fraction. Immunohistochemical analysis of endomyocardial biopsy specimens with specific monoclonal antibodies showed BNP immunoreactivity in the HOCM group (5/10, 50%) but not in the HNCM group (0/22) or in control subjects (0/5). In HOCM, left ventricular end-diastolic pressure was significantly higher in the BNP-positive patients than the BNP-negative patients. Histological changes such as myocardial fiber disarray, hypertrophy of myocytes, and fibrosis were greater in BNP-positive patients than BNP-negative patients in HCM. However, the expression had no significant relation with other clinical parameters. The elevation of the BNP plasma level versus control subjects was marked in both HOCM (85-fold) and HNCM (23-fold). By contrast, the elevation of the ANP plasma level versus control subjects was mild in HOCM (5.7-fold) and HNCM (4.2-fold). The ratio of BNP level to ANP level was higher in HOCM (4.16) than in HNCM (1.46) and control subjects (0.28), and it was higher than the ratio previously reported for severe congestive heart failure (1.72).. These findings suggest that BNP is expressed in the ventricular myocytes of HCM with normal systolic function. In HOCM, ventricular expression of BNP may be augmented in response to both obstruction and diastolic dysfunction.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Female; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Radioimmunoassay

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Child; Echocardiography; Electrocardiography; Female; Heart Atria; Humans; Male; Middle Aged; Mitral Valve Insufficiency

To investigate the ventricular expression of atrial natriuretic peptide (ANP) in human hypertrophic hearts, we conducted an immunohistochemical study of 130 endomyocardial biopsy specimens obtained from the right side of the ventricular septum (RVB), left ventricular free wall (LVB), or both from a total of 80 patients: 44 patients with hypertrophic cardiomyopathy (HCM), 14 with apical hypertrophic cardiomyopathy (APH), 13 with hypertensive hearts (HHD), and nine without hypertrophy (controls). No patients had apparent congestive heart failure. ANP was not seen in ventricular myocytes in controls but was identified in biopsy specimens of hypertrophic hearts, and its distribution was characteristic in each hypertrophic group: 15 RVB (37%) and two LVB (7%) of the HCM group, one RVB (7%) and two LVB (18%) of the APH group, and zero RVB (0%) and five LVB (46%) of the HHD group. Clinical data (including echocardiographic, hemodynamic, and angiographic data) were not directly related to ventricular ANP expression in HCM, APH, or HHD with one exception. In HHD patients, LVB specimens with ANP showed greater ventricular wall thickness than LVB specimens without ANP. According to histological data, however, the ANP-present RVB specimens of HCM or ANP-present LVB specimens of HHD had greater myocyte size than did the ANP-absent specimens. In addition, in HCM patients, the ANP-present RVB specimens showed more severe fibrosis and myofiber disarray than did the ANP-absent specimens. We conclude that a failing state and hemodynamic overload are not likely to be indispensable for ANP expression in human hypertrophic ventricles and that ventricular ANP expression occurs as a response to disease-specific changes: hemodynamic overload in HHD and histological changes such as myocardial fiber disarray, hypertrophy of myocytes, and fibrosis in HCM, which may reflect the characteristic distribution of intraventricular ANP.

Topics: Adult; Atrial Natriuretic Factor; Biopsy; Cardiomegaly; Cardiomyopathy, Hypertrophic; Female; Heart Ventricles; Humans; Hypertension; Immunoenzyme Techniques; Male; Myocardium

To investigate the ventricular expression of atrial natriuretic polypeptide (ANP) in human hypertrophic heart, we conducted an immunohistochemical study using endomyocardial biopsy specimens obtained from the right side of the interventricular septum (RVB), left ventricular free wall (LVB), or both of 39 patients with hypertrophic cardiomyopathy (HCM), and 9 control subjects without hypertrophy. No HCM patients had apparent congestive heart failure. ANP was not present in control subjects' RVB or LVB specimens, but was found in HCM patients', showing its characteristic distribution patterns (RVB > LVB, p < 0.05); it was present in 15 of 36 RVB (42%) and 2 of 25 LVB (8%). No clinical data, including echocardiographic, hemodynamic and angiographic data, were directly related to ventricular ANP expression in HCM. According to histological data, however, ANP-present RVB specimens of HCM had larger myocytes, severer fibrosis and myofiber disarray than the specimens without ANP. This indicates that a failing state may not be a prerequisite for ANP expression in human hypertrophic ventricles, but that ventricular ANP expression may occur concomitantly with myocyte hypertrophy as an adaptive response to focal stress due to "histological overloads" such as disarray and fibrosis in HCM, which may be reflected in the characteristic distribution patterns of intraventricular ANP.

Topics: Atrial Natriuretic Factor; Biopsy; Cardiomyopathy, Hypertrophic; Endocardium; Female; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Myocardium

The correlation between the plasma atrial natriuretic peptide (ANP) levels and echocardiographically measured atrial and ventricular dimensions was studied in various cardiovascular diseases. A total of 107 patients (valvular heart disease 27, cardiomyopathy 11, ischemic heart disease 17, hypertension 42, congenital heart disease 2, and normal 8) were studied. None of the patients had overt signs of heart failure, though 22 of them had atrial fibrillation. Left ventricular end-diastolic and end-systolic diameters, ejection rate and end-diastolic posterior wall thickness were measured by M-mode echocardiography. Maximal left and right atrial diameters and right ventricular end-diastolic diameter were measured by the apical four-chamber view. Following echocardiographic evaluation and blood pressure measurement, blood sampling was performed via the antecubital vein into a tube containing aprotinin and the samples were analyzed by radioimmunoassay. There was no significant correlation between ANP level and heart rate, systemic blood pressure, left ventricular end-diastolic and end-systolic diameters, ejection fraction, posterior wall thickness or right ventricular end-diastolic diameter. The most probable reason for the insignificant relationships was that the correlation varied according to the underlying cardiovascular diseases; e.g., correlation between ANP level and left ventricular diameter was significantly positive in mitral regurgitation, while it was significantly negative in hypertrophic cardiomyopathy. There was a significant correlation between ANP level and the maximal right (r = 0.40, p less than 0.001) or left atrial diameter (r = 0.57, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Cardiovascular Diseases; Echocardiography; Humans; Middle Aged; Mitral Valve Insufficiency; Myocardium

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathy, Hypertrophic; Cricetinae; Genetic Markers; Humans