atrial-natriuretic-factor and Cardiomyopathies

Heart failure (HF) is a fatal complication in many muscular dystrophy cases and has become the most common cause of death in Duchenne muscular dystrophy (DMD) since 2001. HF deaths in DMD occur in young patients and increase, along with respiratory failure, in older patients. Managing HF, therefore, is the most important component of DMD treatment. Management of HF is necessary in DMD patients of all ages because myocardial damage progresses regardless of age and disability. Electrocardiography, echocardiography, myocardial single-photon emission computed tomography (SPECT), and natriuretic peptides are used for the diagnosis of myocardial damage and chronic HF. Tissue Doppler echocardiography is in particularly useful for early detection of minute myocardial damage and dysfunction in DMD. The first-line drugs for chronic HF are angiotensin-converting enzyme inhibitors, and the prognosis of DMD patients has been improved using these drugs and beta-blockers. Diuretics are added in the presence of pulmonary congestion. Digoxin is most effective at a blood level of 0.5-0.8 ng/mL because of its pharmacokinetics in DMD. Surgical treatment may be necessary in cases of intractable HF. Cardiac resynchronization therapy (biventricular pacing), a treatment with an artificial pacemaker, is indicated for cases that meet specific criteria, including HF with ventricular dyssynchrony. Applications of partial left ventriculectomy (Batista procedure) and left ventricular assist devices in muscular dystrophy are likely in the near future.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiac Resynchronization Therapy; Cardiomyopathies; Chronic Disease; Diagnostic Imaging; Heart Failure; Humans; Muscular Dystrophy, Duchenne; Natriuretic Peptide, Brain

This review focuses on recent studies investigating the genetic regulatory mechanisms leading to formation of morphologically, functionally, and molecularly distinct cardiac chambers. The regulation of four representative chamber-specific genes that have been studied in detail is reviewed. These genes include the atrial-specific genes, myosin light chain-2a (MLC2a), slow myosin heavy chain-3 (slow MyHC3), and atrial natriuretic factor (ANF) and the ventricular specific gene, myosin light chain-2v (MLC2v). Comparison of these promoters reveals some generalizations about the regulatory mechanisms involved in chamber-specific gene expression but, equally, indicates the large gaps in the knowledge concerning this intriguing genetic program.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Female; Gene Expression Regulation, Developmental; Heart; Humans; Male; Molecular Biology; Myosin Heavy Chains; Myosin Light Chains; Sensitivity and Specificity

The authors give a brief summary about the process and significance of cardiotoxicity produced by chemotherapy and irradiation used for malignancy. After the introduction, those invasive and noninvasive processes are put into focus and explained in detail, which are applied in the research of the effects of cardiotoxic chemotherapy. The clinical importance of this research is the life prolongation effect of the treatment, which allows the late-appearing toxic cardiomyopathy, resulting in congestive heart failure and increasing mortality. Summarizing the last decade's progress in research, it is evident that even in the planning of chemotherapy, the cardiovascular risks have to be taken into account, because they can greatly influence the cardiac side effect of the treatment.

Topics: Antineoplastic Agents; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Diastole; Electrocardiography; Heart Failure; Heart Rate; Humans; Magnetic Resonance Imaging; Natriuretic Peptide, Brain; Radionuclide Ventriculography; Systole; Ventricular Function, Left

During the past two decades, the heart has been known to undergo endocrine action, harbouring peptides with hormonal activities. These, termed "atrial natriuretic peptide (ANP)," "brain natriuretic peptide (BNP)," and "C-type natriuretic peptide (CNP)," are polypeptides mainly produced in the cardiac myocardium, where they are released into the circulation, producing profound hypotensive effects due to their diuretic, natriuretic, and vascular dilatory properties. It is, furthermore, well established that cardiac disorders such as congestive heart failure and different forms of cardiomyopathy are combined with increased expression of ANP and BNP, leading to elevated levels of these peptides in the plasma. Besides the occurrence of natriuretic peptides (NPs) in the ordinary myocardium, the presence of ANP in the cardiac conduction system has been described. There is also evidence of ANP gene expression in nervous tissue such as the nodose ganglion and the superior cervical ganglion of the rat, ganglia known to be involved in the neuronal regulation of the heart. Furthermore, in the mammalian heart, ANP appears to affect the cardiac autonomic nervous system by sympathoinhibitory and vagoexcitatory actions. This article provides an overview of the relationship between the cardiac conduction system, the cardiac innervation and NPs in the mammalian heart and provides data for the concept that ANP is also involved in neuronal cardiac regulation.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Heart; Heart Conduction System; Heart Failure; Humans; Immunohistochemistry; Mammals; Myocardium; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nodose Ganglion; Receptors, Atrial Natriuretic Factor; Superior Cervical Ganglion

Guanylyl cyclases (GC) exist as soluble and particulate, membrane-associated enzymes which catalyse the conversion of GTP to cGMP, an intracellular signalling molecule. Several membrane forms of the enzyme have been identified up to now. Some of them serve as receptors for the natriuretic peptides, a family of peptides which includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), three peptides known to play important roles in renal and cardiovascular physiology. These are transmembrane proteins composed of a single transmembrane domain, a variable extracellular natriuretic peptide-binding domain, and a more conserved intracellular kinase homology domain (KHD) and catalytic domain. GC-A, the receptor for ANP and BNP, also named natriuretic peptide receptor-A or -1 (NPR-A or NPR- 1), has been studied widely. Its mode of activation by peptide ligands and mechanisms of regulation serve as prototypes for understanding the function of other particulate GC. Activation of this enzyme by its ligand is a complex process requiring oligomerization, ligand binding, KHD phosphorylation and ATP binding. Gene knockout and genetic segregation studies have provided strong evidence for the importance of GC-A in the regulation of blood pressure and heart and renal functions. GC-B is the main receptor for CNP, the latter having a more paracrine role at the vascular and venous levels. The structure and regulation of GC-B is similar to that of GC-A. This chapter reviews the structure and roles of GC-A and GC-B in blood pressure regulation and cardiac and renal pathophysiology.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cardiomyopathies; Down-Regulation; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Isoenzymes; Natriuretic Peptide, Brain; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Structure-Activity Relationship

Several anticancer drugs have been associated with cardiac toxicity, especially the anthracyclines and trastuzumab. The pathogenesis of anthracycline-associated toxicity has been well described, whereas the mechanism of trastuzumab-associated toxicity is unknown. Although routine cardiac imaging studies (e.g. echocardiogram or multiple gated acquisition scans) may identify subclinical evidence of myocardial dysfunction, available data do not support their routine use for monitoring asymptomatic patients undergoing cancer therapy. Other modalities such as nuclear medicine scintigraphy with indium-111-antimyosin antibody and endomyocardial biopsy have been shown to be useful in identifying early cardiac damage, but their routine use is limited by practical considerations such as feasibility and cost. Consequently, there is significant interest in developing simple and reproducible methods for identifying patients at risk for treatment-induced myocardial damage. Available data suggest that circulating markers such as troponins and natriuretic peptides could potentially be useful for this purpose. Measurement of plasma troponin levels are commonly used in clinical practice in order to provide diagnostic and prognostic information in patients with myocardial ischaemia. Elevated levels may likewise correlate with anthracycline-induced cardiac damage, although plasma levels are only minimally elevated (well below that associated with ischaemia), and elevations may persist for weeks or months after anthracycline exposure. Clinical trials are currently evaluating the role of these markers in predicting both early and late, clinical and subclinical damage associated with anthracyclines and trastuzumab.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Humans; Natriuretic Peptide, Brain; Neoplasms; Trastuzumab; Troponin T

The purpose of this study was to evaluate whether or not cardiac sympathetic nerve activity, using (123)I-meta-iodobenzylguanidine ((123)I-MIBG) imaging, and cardiac natriuretic peptides (atrial and brain, ANP and BNP) were independent predictors of cardiac events, and, if so, which was the stronger predictor. Planar (123)I-MIBG images were obtained from 62 patients with heart disease. Plasma ANP and BNP levels, left ventricular ejection fraction (LVEF) by echocardiography, serum total cholesterol and triglyceride were measured. (123)I-MIBG was assessed as the heart-to-mediastinum (H/M) ratio of the delayed image and the washout rate (WoR) from the early to the delayed image. Patients were followed up for an average of 16.2 months, and 12 of 62 patients had cardiac events. Patients with events had significantly lower LVEF and H/M ratio compared with those without events. They had significantly higher WoR, ANP and BNP. By multivariate Cox proportional hazard analysis, (123)I-MIBG (H/M or WoR), ANP and BNP were independent predictors for cardiac events. Event-free survival using a Kaplan-Meier model, with a threshold value of 2.0 for H/M and 45% for WoR, showed that patients with H/M<2.0 and/or WoR>45% had a significantly poorer prognosis. These results suggest that (123)I-MIBG imaging and cardiac natriuretic peptides are useful tools for the evaluation of patients with heart disease, and that cardiac sympathetic nerve activity is a stronger predictor of cardiac events.

Topics: 3-Iodobenzylguanidine; Angina Pectoris; Atrial Natriuretic Factor; Cardiomyopathies; Chronic Disease; Female; Follow-Up Studies; Heart Diseases; Heart Valve Diseases; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Radionuclide Imaging; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Statistics as Topic

This study assessed the prognostic value of Iodine-123-metaiodobenzylguanidine (MIBG) imaging and of the plasma level of cardiac natriuretic peptides in patients with left ventricular dysfunction resulting from cardiomyopathy. Predictors of cardiac death or hospitalization related to progressive heart failure were examined in 171 patients with chronic heart failure (96 patients with idiopathic cardiomyopathy and 75 patients with ischemic cardiomyopathy). All patients underwent MIBG imaging at rest and other hemodynamic studies. During a mean (+/-SD) follow-up period of 27+/-11 months, 11 patients died from heart failure and 16 required hospitalization. High MIBG washout was an independent predictor of cardiac death (relative risk [RR] = 1.158, p<0.0001) whereas the plasma level of brain natriuretic peptide (BNP: relative risk [RR] = 1.005, p<0.0001) and high MIBG washout (relative risk [RR] = 1.094, p<0.0001) were predictors of progressive heart failure (ie, combined cardiac death and hospitalization). Accelerated myocardial adrenergic nerve activity as assessed by MIBG imaging and the plasma levels of BNP are powerful predictors of the patient's prognosis.

Topics: 3-Iodobenzylguanidine; Aged; Atrial Natriuretic Factor; Cardiomyopathies; Death; Disease-Free Survival; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Radionuclide Imaging; Radiopharmaceuticals; Regression Analysis; Treatment Outcome; Ventricular Dysfunction, Left

Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings.. The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure.. In all, 98 patients [65 men and 33 women, aged 58.2 +/- 11.0 years, mean +/- standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 +/- 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification.. Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one-fifth to one-seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration.. Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiac Catheterization; Cardiomyopathies; Epinephrine; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peptides; Prognosis; Proteins; Radioimmunoassay; Vasodilator Agents

The atrial natriuretic factor (ANF) plays an important role in the pathogenesis of congestive heart failure (CHF), by influencing electrolyte and water balance and by modifying peripheral vascular resistance, thus affecting left ventricular performance. Anthracycline derivatives are glycoside antibiotics, active against a wide spectrum of tumours. It is well known that acute and severe dose-related delayed cardiotoxicity constitutes the major limitation to their optimal use. A total of 26 female patients (mean age 53 years) undergoing monochemotherapy for advanced breast cancer, were studied. 4'-Epidoxorubicin (Epidx) 120 mg/m2 intravenously was administered every three weeks for a total of a mean of 6.6 therapeutic cycles (3 to 10). Left ventricular ejection fraction (LVEF) determined by radionuclide ventriculography and circulating ANF were measured periodically in all patients. Epidx administration was limited at a cumulative dose ranging between 840 and 1200 mg/m2 because of a 25% decrease in LVEF and due to a progressive rising in ANF plasma levels. Furthermore, two patients who presented clinical symptoms of CHF had also significantly increased ANF levels (56 and 49% respectively). The current evidence suggests an important pathophysiological role of ANF in anthracyclinic related CHF. Hopefully measurement of plasma ANF will provide a simple non-invasive method of assessing ventricular dysfunction related to anthracycline cardiac toxicity and might represent an additional objective indicator of the severity of haemodynamic compromise in patients with impaired cardiac function.

Topics: Adult; Aged; Atrial Natriuretic Factor; Breast Neoplasms; Cardiomyopathies; Dose-Response Relationship, Drug; Epirubicin; Female; Humans; Middle Aged; Stroke Volume

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Natriuretic Factor; Cardiomyopathies; Fibrosis; Heart Atria; Humans; Hypertension; Natriuretic Peptide, Brain; Serine Endopeptidases; Siblings

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathies; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Fibrosis; Hyperglycemia; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinase 10; Natriuretic Peptide, Brain; Receptors, Leptin; RNA, Messenger; Signal Transduction; Sirtuin 1

Electroconvulsive therapy (ECT) is a remarkably safe procedure. However, there might exist a subgroup of patients with an increased risk for cardiovascular events. The cardiac-specific enzymes high-sensitive cardiac troponin I (hscTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured before and after ECT in 23 patients. No relevant increase of hscTnI after ECT was found. Mean NT-proBNP levels were higher after ECT and in three patients a new NT-proBNP elevation after ECT was identified. In conclusion, our small study did not find any evidence for myocardial damage due to ECT by measuring hsTnI, but an increase of NT-proBNP, whose clinical relevance could only be speculated, yet.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiomyopathies; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Protein Precursors; Troponin I

To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging.. One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone.. Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.

Topics: Aged; Aged, 80 and over; Aortic Valve Stenosis; Atrial Natriuretic Factor; Biopsy; Cardiomyopathies; Female; Gadolinium; Heart Valve Prosthesis Implantation; Heart Ventricles; Humans; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Prospective Studies; Protein Precursors; Troponin T

Plasma atrial natriuretic peptide (ANP) levels have been reported to be elevated in cats with cardiomyopathy. We investigated the diagnostic accuracy of plasma ANP concentration as an indicator of the severity of cardiomyopathies.. This study included 78 control cats and 83 cats with various types of cardiomyopathy.. This was a prospective multicentre study. Control cats were determined to have a normal heart, and diseased cats were diagnosed by echocardiography. Diseased cats were divided into asymptomatic cats without left atrial dilation (LAD), asymptomatic cats with LAD, and cats with heart failure. Plasma C-terminal ANP concentrations were measured using chemiluminescence.. The median plasma ANP concentration in controls was 43.3 (interquartile range, 33.0-56.3) pg/mL. Plasma ANP values were significantly higher in the cardiomyopathic cats with LAD and heart failure, but the values in cats without LAD were comparable to those in control cats. To distinguish cats with cardiomyopathy from controls, a plasma ANP concentration >77.5 pg/mL afforded sensitivity of 66.3% and specificity of 84.6%. Use of plasma ANP concentration >110.9 pg/mL to identify cats with LAD had a sensitivity of 73.6% and specificity of 93.5%. The areas under the receiver-operating characteristic curve were 0.80 and 0.86.. Plasma ANP concentrations were higher in cats with more advanced cardiomyopathy. Although assaying the ANP concentration alone may not help to diagnose cardiac disease, measuring provides additional information that is useful for assessing the severity of cardiomyopathies.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cat Diseases; Cats; Echocardiography; Female; Heart Atria; Heart Failure; Male; Prospective Studies; Sensitivity and Specificity

To examine the role of LY294002 in cardiac function and myocardial structure in dilated cardiomyopathy (DCM) rats.
 Methods: Fifty-two male SD rats were randomly assigned to a control group (n=16) and a DCM group (n=36). The DCM rats were induced by intraperitoneal injection of adriamycin, and the control rats were given normal saline. After observation for 2 weeks, 6 rats from each group were killed randomly. In the end of the 8th week, the 24 DCM rats were randomly assigned to a DCM group (n=12) and a LY294002 group (n=12), which were given normal saline and LY294002, respectively. In the end of the 8th week and 16th week, the cardiac function was analyzed by ultrasonic cardiogram (UCG) and the plasma was collected to test the level of N-terminal pro-brain natriuretic peptide (NT-pro BNP). HE and Van Gieson (VG) staining were performed to calculate the collagen volume fraction (CVF).
 Results: Compared with the control group, the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and NT-proBNP level of in the DCM rats were increased obviously, while the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS) in the DCM rats were decreased obviously (P<0.01). These changes were consistent with DCM characteristics. Compared with the DCM group, the LVEDD, LVESD and NT-proBNP levels in the LY294002 group were decreased, while the LVEF and LVFS were increased (P<0.05). Histopathology showed that the myocardium in the DCM rats was fibrotic and the CVF was increased compared with the control rats (P<0.01). The myocardial structure was improved in the LY294002 group compared to the DCM group.
 Conclusion: LY294002 can reduce the myocardial fibrosis in the DCM rats and improve the cardiac function.. 目的：探讨PI3K抑制剂LY294002对腹腔注射阿霉素诱导的扩张型心肌病(dilated cardiomyopathy，DCM)大鼠模型心肌结构及心功能的影响。方法：将52只雄性SD大鼠随机分为对照组(n=16)和模型组(n=36)，模型组前6周通过腹腔注射阿霉素建立DCM大鼠模型，对照组同期腹腔注射等量的生理盐水。观察2周后(8周末)每组随机处死6只存活大鼠；9~16周将建模成功的24只模型大鼠随机分为DCM组(n=12)和LY294002组(n=12)，分别予以生理盐水和LY294002，16周末处死所有存活大鼠。8周末及16周末，所有存活大鼠行血浆氨基末端脑钠肽前体(NT-proBNP)浓度检测及超声心动图检查，并取8周末及16周末处死大鼠的心肌组织行HE及Van Gieson(VG)染色，计算心肌胶原容积分数(CVF)。结果：与对照组比较，8周末模型组大鼠左室收缩末期内径(LVEDD)，左室舒张末期内径(LVESD)，NT-proBNP均明显增大，左室射血分数(LVEF)及左室短轴缩短率(LVFS)均明显下降(均P<0.01)，符合DCM的特征；与DCM组比较，LY294002组LVEDD，LVESD，NT-proBNP均减低，LVEF及LVFS均增高(P<0.05)；组织病理学检查示：与对照组比较，模型组心肌间质明显纤维化且CVF明显增加(P<0.01)，与DCM组比较，LY294002组心肌间质纤维化改善且CVF下降(P<0.01)。结论：LY294002可减轻DCM大鼠模型心肌纤维化，改善其心功能。.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cardiomyopathy, Dilated; Collagen; Fibrosis; Heart; Male; Myocardium; Protein Precursors; Random Allocation; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

The fibroblast growth factor (FGF) 16 gene is preferentially expressed by cardiomyocytes after birth with levels increasing into adulthood. Null mice and isolated heart studies suggest a role for FGF-16 in cardiac maintenance and survival, including increased resistance to doxorubicin (DOX)-induced injury. A single treatment with DOX was also shown to rapidly deplete endogenous rat FGF-16 mRNA at 6 h in both adult heart and neonatal cardiomyocytes. However, the effect of DOX on rat cardiac function at the time of decreased FGF-16 gene expression and the effect of FGF-16 availability on cardiomyocyte survival, including in the context of acute DOX cytotoxicity, have not been reported. The objective was to assess the effect of acute (6 and 24 h) DOX treatment on cardiac function and the effects of FGF-16 small interfering RNA "knockdown," as well as adenoviral overexpression, in the context of acute DOX cytotoxicity, including cardiomyocyte survival and DOX efflux transport. A significant decrease in heart systolic function was detected by echocardiography in adult rats treated with 15 mg DOX/kg at 6 h; however, unlike FGF-16, there was no change in atrial natriuretic peptide transcript levels. Both systolic and diastolic dysfunctions were observed at 24 h. In addition, specific FGF-16 "knockdown" in neonatal rat cardiomyocytes results in a significant increase in cell death. Conversely, adenoviral FGF-16 overexpression was associated with a significant decrease in cardiomyocyte injury as a result of 1 μM DOX treatment. A specific increase in efflux transporter gene expression and DOX efflux was also seen, which is consistent with a reduction in DOX cytotoxicity. Finally, the increased efflux and decreased DOX-induced damage with FGF-16 overexpression were blunted by inhibition of FGF receptor signaling. These observations are consistent with FGF-16 serving as an endogenous cardiomyocyte survival factor, which may involve a positive effect on regulating efflux transport to reduce cardiotoxicity.

Topics: Adenoviridae; Animals; Animals, Newborn; Apoptosis; Atrial Natriuretic Factor; Biological Transport; Cardiomyopathies; Cell Survival; Cytotoxins; Doxorubicin; Echocardiography; Fibroblast Growth Factors; Gene Expression Regulation; Genetic Vectors; Heart Function Tests; Injections, Intraperitoneal; Myocardium; Myocytes, Cardiac; Primary Cell Culture; Pyrroles; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; RNA, Small Interfering; Signal Transduction

Noncompaction cardiomyopathy is characterized by the presence of extensive trabeculations, which could lead to heart failure and malignant arrhythmias. How trabeculations resolve to form compact myocardium is poorly understood. Elucidation of this process is critical to understanding the pathophysiology of noncompaction disease. Here we use genetic lineage tracing to mark the Nppa

Topics: Animals; Animals, Newborn; Atrial Natriuretic Factor; Basic Helix-Loop-Helix Transcription Factors; Cardiomyopathies; Cell Lineage; Heart; Heart Defects, Congenital; Heart Ventricles; Mice; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Organogenesis; Protein Precursors; Repressor Proteins

Probiotics and antioxidants have a definite improving effect in cardiovascular diseases. This study aims at mitigating doxorubicin toxicity on cardiac function through consuming a functional food. Five groups of adult male Sprague-Dawley rats were used along 22 weeks. Group I received 30 g/kg/day food enriched with yogurt, green tea extract, and carrots (80, 0.84, and 100 g/kg diet, respectively) from the first week, group II received carvedilol 30 mg/kg/day orally from week 17, group III received both carvedilol and tested food, and groups IV and V were +ve and -ve control groups, respectively. In week 17, cardiomyopathy was induced by i.p. injection of 2.5 mg/kg doxorubicin every 48 h for 2 weeks. Histopathological and electrophysiological examinations and biochemical analysis were done. Lipid peroxidation, antioxidant effect, heart failure compensatory mediators, and proinflammatory cytokines were assessed. Tested food normalized time between the start of Q wave and the end of T wave on electrocardiogram (QT interval) and heart rate compared to the doxorubicin group (P<.05). It also improved hypertrophy indicated by a significant (P<.05) decrease in heart/body weight ratio, angiotensin-II (Ang-II), and atrial natriuretic peptide (ANP) serum levels. Histopathological examination of cardiac sections from the tested food group revealed less marked vacuolization and low perivascular fibrosis percentage (0.7803 ± 0.04). A significant (P<.001) decrease in serum creatine kinase-membrane bound, lactate dehydrogenase, triglycerides, cholesterol, low-density lipoprotein cholesterol, and tissue malondialdehyde (MDA) levels was observed in addition to an increase in serum Na(+)/K(+) ATP1A1 and cardiac reduced glutathione (GSH) levels. Tested food also lowered the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) serum levels significantly (P<.01). Probiotic food containing Lactobacillus acidophilus, green tea, and carrots can improve membrane integrity and cardiac contractility in doxorubicin-induced cardiomyopathy by decreasing TNF-α, IL-6, MDA, increasing GSH, and modulating compensatory mediators such as Ang-II and ANP.

Topics: Angiotensin II; Animals; Antioxidants; Atrial Natriuretic Factor; Camellia sinensis; Carbazoles; Cardiomyopathies; Cardiotonic Agents; Carvedilol; Cholesterol; Cytokines; Daucus carota; Doxorubicin; Functional Food; Heart; Lactobacillus acidophilus; Lipid Peroxidation; Male; Malondialdehyde; Myocardium; Oxidative Stress; Probiotics; Propanolamines; Rats, Sprague-Dawley; Yogurt

Anthracycline-containing chemotherapy can cause irreversible and progressive left ventricular dysfunction. Epirubicin, which is widely used for breast cancer chemotherapy, is an anthracycline that has less cardiac toxicity than doxorubicin. The present report describes the case of a 70-year-old woman with breast cancer who developed severe congestive heart failure and severe cardiac dysfunction at 6 weeks from epirubicin final administration. Left ventricular function gradually improved after intensive treatment for heart failure and recovered completely within 2 months. To the best of our knowledge, this is the first report to describe epirubicin-induced subacute reversible cardiotoxicity.

Topics: Aged; Antibiotics, Antineoplastic; Atrial Natriuretic Factor; Breast Neoplasms; Cardiomyopathies; Cardiotonic Agents; Diuretics; Dobutamine; Echocardiography; Electrocardiography; Epirubicin; Female; Heart Failure; Heart Ventricles; Humans; Magnetic Resonance Imaging, Cine; Respiration, Artificial; Severity of Illness Index; Treatment Outcome

Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in N(ω)-nitro-l-arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, heme-arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, heme-arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of heme-arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of heme-arginate, exacerbating inflammatory injury and oxidative insults. We conclude that heme-arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.

Topics: Adiponectin; Aldosterone; Animals; Antioxidants; Arginine; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiomyopathies; Cardiotonic Agents; Chemokine CCL2; Chemokine CCL3; Cyclic GMP; Dinoprost; Endothelin-1; Enzyme Induction; Extracellular Matrix Proteins; Heart Failure; Heme; Heme Oxygenase (Decyclizing); Hypertension; Interleukin-1beta; Interleukin-6; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Tyrosine

Topics: Atrial Natriuretic Factor; Cardiomyopathies; Cardiomyopathy, Dilated; Female; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Male

: Caveolin-1-deficient (cav1) mice display a severely diseased cardiac phenotype with systolic and diastolic heart failure. Accumulating evidence supports a causative role of uncoupled endothelial nitric oxide synthase in the development of these abnormalities. Interestingly, a similar molecular mechanism was proposed for anthracycline-induced cardiomyopathy. Currently, dexrazoxane is approved for the prevention of anthracycline-induced cardiomyopathy. Given the molecular similarities between the anthracycline-induced cardiomyopathy and the cardiomyopathy in cav1 mice, we questioned whether dexrazoxane may also prevent the evolution of the cardiac pathologies in cav1 mice. We evaluated dexrazoxane treatment for 6 weeks in cav1 mice and wild-type controls. This study provides the first evidence for a reduced reactive oxygen species formation in the vessels of dexrazoxane-treated cav1 mice. This reduced oxidative stress resulted in a markedly reduced rate of apoptosis, which finally was translated into a significantly improved heart function in dexrazoxane-treated cav1 mice. These hemodynamic improvements were accompanied by significantly lowered proatrial natriuretic peptide levels. Notably, these protective properties of dexrazoxane were not evident in wild-type animals. Taken together, these novel findings indicate that dexrazoxane significantly reduces vascular reactive oxygen species formation cav1. Because this is paralleled by an improved cardiac performance in cav1 mice, our data suggest dexrazoxane as a novel therapeutic strategy in this specific cardiomyopathy.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Cardiomyopathies; Cardiovascular Agents; Caveolin 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase; Phenotype; Razoxane; Reactive Oxygen Species; Treatment Outcome; Ventricular Function, Left

Left ventricular hypertrophy (LVH), a common complication in chronic kidney disease (CKD), is associated with high cardiovascular mortality. The aim of this experimental study was to analyze the effect of different vitamin D receptor activators (VDRAs) on both LVH and myocardial fibrosis in chronic renal failure (CRF).. Male Wistar rats with CRF, carried out by 7/8 nephrectomy, were treated intraperitoneally with equivalent doses of VDRAs (calcitriol, paricalcitol and alfacalcidol, 5 days per week) during 4 weeks. A placebo group (CRF + vehicle) and a Sham group with normal renal function served as controls. Biochemical, morphological, functional and molecular parameters associated with LVH were evaluated, as well as cardiac fibrosis, collagen I, transforming growth factor β1 (TGFβ1) and matrix metalloproteinase-1 (MMP1) expression.. All VDRAs treatment prevented LVH, with values of cardiomyocyte size, LV wall and septum thickness and heart-body weight ratio similar to those observed in the Sham group. At molecular levels, all VDRAs attenuated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression compared with CRF + vehicle. The phosphorylation of ERK1/2, a signal for activating growth, was stimulated in the CRF + vehicle group; VDRAs use prevented this activation. Paricalcitol was the only VDRA used that maintained in the normal range all parameters associated with myocardial fibrosis (total collagen, collagen I, TGFβ1 and MMP1).. Our findings demonstrated that the three VDRAs used induced similar changes in bone metabolic parameters and LVH. In addition, paricalcitol was the only VDRA which showed a relevant beneficial effect in the reduction of myocardial fibrosis, a key factor in the myocardial dysfunction in CKD patients.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Bone Density Conservation Agents; Calcitriol; Cardiomyopathies; Ergocalciferols; Fibrosis; Humans; Hydroxycholecalciferols; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; MAP Kinase Signaling System; Natriuretic Peptide, Brain; Phosphorylation; Rats; Rats, Wistar; Receptors, Calcitriol

Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy.. We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A, we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide.. Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

Topics: Adult; Atrial Natriuretic Factor; Base Sequence; Cardiomyopathies; Cardiomyopathy, Dilated; Cohort Studies; Female; Follow-Up Studies; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Italy; Male; Middle Aged; Molecular Sequence Data; Mutation; Pedigree; Phenotype

There are few experimental models of heart failure (HF) in large animals, despite structural and functional similarities to human myocardium. We have developed a porcine model of chronic tachycardia-induced cardiomyopathy.. Homogenous siblings of White Large breed swine (n=6) underwent continuous right ventricular (RV) pacing at 170 bpm; 2 subjects served as controls. In the course of RV pacing, animals developed a clinical picture of HF and were presented for euthanasia at subsequent stages: mild, moderate and end-stage HF. Left ventricle (LV) sections were analyzed histologically and relative ANP, BNP, phospholamban and sarcoplasmic reticulum calcium ATPase 2a transcript levels in LV were quantified by real time RT-PCR.. In the course of RV pacing, animals demonstrated reduced exercise capacity (time of running until being dyspnoeic: 6.6 ± 0.5 vs. 2.4 ± 1.4 min), LV dilatation (LVEDD: 4.9 ± 0.4 vs. 6.7 ± 0.4 cm), impaired LV systolic function (LVEF: 69 ± 8 vs. 32 ± 7 %), (all baseline vs. before euthanasia, all p<0.001). LV tissues from animals with moderate and end-stage HF demonstrated local foci of interstitial fibrosis, congestion, cardiomyocyte hypertrophy and atrophy, which was not detected in controls and mild HF animals. The up-regulation of ANP and BNP and a reduction in a ratio of sarcoplasmic reticulum calcium ATPase 2a and phospholamban in failing myocardium were observed as compared to controls.. In pigs, chronic RV pacing at relatively low rate can be used as an experimental model of HF, as it results in a gradual deterioration of exercise tolerance accompanied by myocardial remodeling confirmed at subcellular level.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cardiomyopathies; Chronic Disease; Disease Models, Animal; Exercise Test; Female; Natriuretic Peptide, Brain; Random Allocation; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Swine; Tachycardia

Spontaneously hypertensive heart failure rats (SHHFs) take longer to develop compensated heart failure (HF) and congestive decompensation than common surgical models of HF. Isoproterenol (ISO) infusion can accelerate cardiomyopathy in young SHHFs, while dietary salt loading in hypertensive rats induces cardiac fibrosis, hypertrophy, and--in a minority-congestive HF. By combining ISO with dietary salt loading in young SHHFs, the authors sought a nonsurgical model that is more time--and resource-efficient than any of these factors alone. The authors hypothesized that salt loading would enhance ISO-accelerated cardiomyopathy, promoting fibrosis, hypertrophy, and biochemical characteristics of HF. SHHFs (lean male, 90d) were infused for 4 wk with ISO (2.5 mg/kg/day) or saline. After 2 wk of infusion, a 6-wk high-salt diet (4%, 6%, or 8% NaCl) was initiated. Eight percent salt increased heart weight, HF markers (plasma B-type natriuretic peptide, IL-6), lung lymphocytes, and indicators of lung injury and edema (albumin and protein) relative to control diet, while increasing urine pro-atrial natriuretic peptide relative to ISO-only. High salt also exacerbated ISO-cardiomyopathy and fibrosis. Thus, combining ISO infusion with dietary salt loading in SHHFs holds promise for a new rat HF model that may help researchers to elucidate HF mechanisms and unearth effective treatments.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Bronchoalveolar Lavage Fluid; Cardiomyopathies; Fibrosis; Heart; Heart Failure; Interleukin-6; Isoproterenol; Male; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary

Doxorubicin is an effective antineoplastic drug; however, its clinical benefit is limited by its cardiotoxicity. The inhibition of mitochondrial biogenesis is responsible for the pathogenesis of doxorubicin-induced cardiomyopathy. Endothelin-1 is a vasoconstrictive peptide produced from big endothelin-1 by endothelin-converting enzyme-1 (ECE-1) and a multifunctional peptide. Although plasma endothelin-1 levels are elevated in patients treated with doxorubicin, the effect of ECE-1 inhibition on doxorubicin-induced cardiomyopathy is not understood. Cardiomyopathy was induced by a single IP injection of doxorubicin (15 mg/kg). Five days after treatment, cardiac function, histological change, and mitochondrial biogenesis were assessed. Echocardiography revealed that cardiac systolic function was significantly deteriorated in doxorubicin-treated wild-type (ECE-1(+/+)) mice compared with ECE-1 heterozygous knockout (ECE-1(+/-)) mice. In histological analysis, cardiomyocyte size in ECE-1(+/-) mice was larger, and cardiomyocyte damage was less. In ECE-1(+/+) mice, tissue adenosine triphosphate content and mitochondrial superoxide dismutase were decreased, and reactive oxygen species generation was increased compared with ECE-1(+/-) mice. Cardiac mitochondrial deoxyribonucleic acid copy number and expressions of key regulators for mitochondrial biogenesis were decreased in ECE-1(+/+) mice. Cardiac cGMP content and serum atrial natriuretic peptide concentration were increased in ECE-1(+/-) mice. In conclusion, the inhibition of ECE-1 attenuated doxorubicin-induced cardiomyopathy by inhibiting the impairment of cardiac mitochondrial biogenesis. This was mainly induced by decreased endothelin-1 levels and an enhanced atrial natriuretic peptide-cGMP pathway. Thus, the inhibition of ECE-1 may be a new therapeutic strategy for doxorubicin-induced cardiomyopathy.

Topics: Animals; Antibiotics, Antineoplastic; Antihypertensive Agents; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathies; Cyclic GMP; Disease Models, Animal; Doxorubicin; Echocardiography; Endothelin-1; Endothelin-Converting Enzymes; Heart Rate; Male; Metalloendopeptidases; Mice; Mice, Knockout; Mitochondria; Myocardium; Peptides, Cyclic

Topics: Adult; Atrial Natriuretic Factor; Biopsy, Needle; Cardiomyopathies; Drug Therapy, Combination; Echocardiography, Doppler; Electrocardiography; Female; Follow-Up Studies; Furosemide; Growth Disorders; Growth Hormone; Humans; Immunohistochemistry; Prader-Willi Syndrome; Radiography, Thoracic

To determine whether plasma N-terminal proatrial natriuretic peptide (NT-proANP) concentration could predict the outcome (survival duration) of cats with cardiomyopathy (CM).. Case-control study.. 51 cats with CM (25 with and 26 without congestive heart failure [CHF]) and 17 healthy cats.. Cats were thoroughly examined and assigned to 1 of 3 groups (control, CM with CHF, and CM alone). Plasma NT-proANP concentrations were measured by use of a human proANP(1-98) ELISA. Survival durations were compared between CM groups.. Plasma NT-proANP concentrations differed significantly among the 3 groups, and survival durations differed significantly between the 2 CM groups. Median (range) NT-proANP concentration was 413 fmol/mL (52 to 940 fmol/mL) in the control group, 1,254 fmol/mL (167 to 2,818 fmol/mL) in the CM alone group, and 3,208 fmol/mL (1,189 to 15,462 fmol/mL) in the CM with CHF group. At a cutoff of 517 fmol/mL, NT-proANP concentration had a sensitivity of 90% and specificity of 82% for detecting CM. Multivariate analysis revealed that only the variable left atrium-to-aortic diameter ratio was a significant predictor of survival duration.. Plasma NT-proANP concentration may have potential as a testing marker for distinguishing healthy cats from cats with CM. It may also be useful for distinguishing CM cats with CHF from those without CHF The value of NT-proANP concentration as a predictor of survival duration was not supported in this study and requires further evaluation.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Case-Control Studies; Cat Diseases; Cats; Female; Heart Failure; Male; Protein Precursors

The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels.. We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1(-/-)) to define its functional role in the vasculature and in age- and hypertension-associated myocardial remodeling.. Cardiac structure and vasculature were analyzed by light and electron microscopy. Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1(-/-) mice.. Col XV is necessary for ECM organization in the heart, and for the structure and functions of microvessels. Col XV deficiency leads to a complex cardiac phenotype and predisposes the subject to pathological responses under cardiac stress.

Topics: Age Factors; Aging; Angiotensin II; Animals; Atrial Natriuretic Factor; Cardiomyopathies; Collagen; Coronary Circulation; Disease Models, Animal; Echocardiography; Elasticity; Enzyme Inhibitors; Extracellular Matrix; Female; Gene Expression Profiling; Gene Expression Regulation; Genotype; Heart Ventricles; Hemodynamics; Hypertension; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Microscopy, Electron; Microscopy, Video; Myocardium; Natriuretic Peptide, Brain; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Phenotype; Polymerase Chain Reaction; RNA, Messenger; Telemetry; Ventricular Remodeling

The human heart can be frequently affected by an organ-limited amyloidosis called isolated atrial amyloidosis (IAA). IAA is a frequent histopathological finding in patients with long-standing atrial fibrillation (AF). The aim of this paper was to investigate the ultrastructure of cardiomyocytes and telocytes in patients with AF and IAA. Human atrial biopsies were obtained from 37 patients undergoing cardiac surgery, 23 having AF (62%). Small fragments were harvested from the left and right atrial appendages and from the atrial sleeves of pulmonary veins and processed for electron microscopy (EM). Additional fragments were paraffin embedded for Congo-red staining. The EM examination certified that 17 patients had IAA and 82% of them had AF. EM showed that amyloid deposits, composed of characteristic 10-nm-thick filaments were strictly extra-cellular. Although, under light microscope some amyloid deposits seemed to be located within the cardiomyocyte cytoplasm, EM showed that these deposits are actually located in interstitial recesses. Moreover, EM revealed that telopodes, the long and slender processes of telocytes, usually surround the amyloid deposits limiting their spreading into the interstitium. Our results come to endorse the presumptive association of AF and IAA, and show the exclusive, extracellular localization of amyloid fibrils. The particular connection of telopodes with amyloid deposits suggests their involvement in isolated atrial amyloidosis and AF pathogenesis.

Topics: Adult; Aged; Amyloid; Amyloidosis; Atrial Appendage; Atrial Fibrillation; Atrial Natriuretic Factor; Cardiomyopathies; Cells, Cultured; Female; Heart Atria; Humans; Interstitial Cells of Cajal; Male; Microscopy, Electron; Middle Aged; Myocytes, Cardiac; Plaque, Amyloid; Stromal Cells

To determine whether plasma N-terminal proatrial natriuretic peptide (Nt-proANP) concentrations in cats with cardiomyopathy (CM) differ from values in healthy cats and evaluate whether plasma Nt-proANP concentrations can be used to discriminate cats with CM and congestive heart failure (CHF) from CM-affected cats without CHF.. 16 cats that had CM without CHF, 16 cats that had CM with CHF, and 11 healthy control cats.. All cats underwent a physical examination, assessment of clinicopathologic variables (including plasma thyroxine concentration), thoracic radiography, and echocardiography. On the basis of findings, cats were assigned to 1 of 3 groups (control cats, cats with CM and CHF, and cats with CM without CHF). Venous blood samples were obtained from all 43 cats, and plasma Nt-proANP concentrations were measured by use of a human proANP(1-98) ELISA.. Plasma Nt-proANP concentrations differed significantly among the 3 groups. Median Nt-proANP concentration was 381 fmol/mL (range, 52 to 450 fmol/mL), 763 fmol/mL (range, 167 to 2,386 fmol/mL), and 2,443 fmol/mL (range, 1,189 to 15,462 fmol/mL) in the control group, in cats with CM without CHF, and in cats with CM and CHF, respectively.. Measurement of plasma Nt-proANP concentration could be of benefit in the assessment of cats with naturally occurring CM and might have potential as a screening marker for the disease. Furthermore, measurement of plasma NtproANP concentration may be useful for distinguishing cats with CM and CHF from those with CM and no CHF.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cat Diseases; Cats; Echocardiography; Enzyme-Linked Immunosorbent Assay; Heart Failure; Protein Precursors; Radiography, Thoracic

Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.

Topics: Angiotensinogen; Animals; Animals, Newborn; Atrial Natriuretic Factor; Blotting, Western; Cardiomyopathies; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Glucose; Male; MEF2 Transcription Factors; Myocytes, Cardiac; Myogenic Regulatory Factors; Natriuretic Peptide, Brain; p300-CBP Transcription Factors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic

We recently demonstrated early metabolic alterations in the dystrophin-deficient mdx heart that precede overt cardiomyopathy and may represent an early "subclinical" signature of a defective nitric oxide (NO)/cGMP pathway. In this study, we used genetic and pharmacological approaches to test the hypothesis that enhancing cGMP, downstream of NO formation, improves the contractile function, energy metabolism, and sarcolemmal integrity of the mdx heart. We first generated mdx mice overexpressing, in a cardiomyocyte-specific manner, guanylyl cyclase (GC) (mdx/GC(+/0)). When perfused ex vivo in the working mode, 12- and 20-week-old hearts maintained their contractile performance, as opposed to the severe deterioration observed in age-matched mdx hearts, which also displayed two to three times more lactate dehydrogenase release than mdx/GC(+/0). At the metabolic level, mdx/GC(+/0) displayed a pattern of substrate selection for energy production that was similar to that of their mdx counterparts, but levels of citric acid cycle intermediates were significantly higher (36 +/- 8%), suggesting improved mitochondrial function. Finally, the ability of dystrophin-deficient hearts to resist sarcolemmal damage induced in vivo by increasing the cardiac workload acutely with isoproterenol was enhanced by the presence of the transgene and even more so by inhibiting cGMP breakdown using the phosphodiesterase inhibitor sildenafil (44.4 +/- 1.0% reduction in cardiomyocyte damage). Overall, these findings demonstrate that enhancing cGMP signaling, specifically downstream and independent of NO formation, in the dystrophin-deficient heart improves contractile performance, myocardial metabolic status, and sarcolemmal integrity and thus constitutes a potential clinical avenue for the treatment of the dystrophin-related cardiomyopathies.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cyclic GMP; Dystrophin; Enzyme Activation; Gene Expression Regulation; Guanylate Cyclase; Heart Rate; In Vitro Techniques; Mice; Mice, Transgenic; Mitochondria; Myocardial Contraction; Myocytes, Cardiac; Organ Specificity; Piperazines; Purines; Sarcolemma; Signal Transduction; Sildenafil Citrate; Sulfones

To evaluate the use of measuring plasma concentrations of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and cardiac troponin-I (cTnI) to detect dogs with occult dilated cardiomyopathy (DCM).. 118 client-owned dogs.. Dogs were prospectively examined by use of ECG; echocardiography; and evaluation of concentrations of ANP, BNP, and cTnI. Occult DCM was diagnosed by evaluation of echocardiographic left ventricular dimensions and detection of ventricular arrhythmias on ECG. Sensitivity and specificity of assays for measurement of plasma concentrations of ANP, BNP, and cTnI to detect dogs with occult DCM were determined.. Occult DCM was diagnosed in 21 dogs. A concentration of > 6.21 pg/mL for BNP had a sensitivity of 95.2% and specificity of 61.9% for identifying dogs with occult DCM. In contrast, concentrations of ANP and cTnI had relatively low predictive values.. Blood-based screening for occult DCM in dogs can be accomplished by use of a BNP assay. Additional studies should be performed to optimize this method of screening dogs to detect occult DCM.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Dog Diseases; Dogs; Echocardiography, Doppler; Electrocardiography; Female; Male; Natriuretic Peptide, Brain; Predictive Value of Tests; Prospective Studies; ROC Curve; Sensitivity and Specificity; Troponin I

To assess the effect of short-term treatment with GH on left ventricular contractility and remodeling, after the development of heart failure in cardiomyopathic hamsters (CMH).. Two groups of 200-day-old UM-X7.1 CMH received daily subcutaneous injections of recombinant bovine (rb) GH (1mg/kg/day) or 0.9% NaCl for 40 days. Golden Syrian hamsters (GSH) were used as controls. At 240-day-old, the hamsters were randomly subjected to (i) assessment of left ventricular systolic function in a Langendorff perfused mode followed by the determination of the passive diastolic pressure-volume relationship and morphometric measurements; (ii) assessment of left ventricular mRNA expression of genes belonging to the fetal gene program including atrial (ANP) and brain (BNP) natriuretic peptides and cardiac myosin heavy chain isoforms and of the circulating levels of the natriuretic peptides.. Hearts from CMH were hypertrophied and dilated (p<0.05) compared to hearts from GSH, along with a approximately 10-fold increase in the circulating ANP and BNP levels. Left ventricular BNP and ANP mRNAs were elevated by 2- and 3-fold, respectively, compared to GSH. rbGH reduced both ANP mRNA and ANP circulating levels by 34% (p<0.01) but did not significantly modulate BNP levels. This effect was associated with a preserved systolic function and reverse remodeling as assessed by a leftward shift of the passive diastolic pressure-volume relationship indicating reduced ventricular dilatation.. The data show that a short-term administration of GH in the terminal phase of the disease confers cardioprotection by attenuating systolic dysfunction and by inducing beneficial reverse remodeling.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cardiotonic Agents; Cattle; Cricetinae; Growth Hormone; Heart Failure; Heart Ventricles; Insulin-Like Growth Factor I; Mesocricetus; Myocardial Contraction; Myosin Heavy Chains; Natriuretic Peptides; Protein Isoforms; Ventricular Function, Left

It has been reported that high intramyocardial peroxisome proliferator-activated receptor alpha (PPARalpha) stimulation or overexpression altered cardiac contractile function in mouse models of cardiac hypertrophy and heart failure. Nevertheless, it has never been demonstrated that clinically relevant doses of drugs stimulating PPARalpha activity such as fenofibrate increase the risk to develop heart failure in humans. To determine if fenofibrate accelerates the development of heart failure in large mammals, we have tested its effects on the progression of left ventricular dysfunction in pacing-induced heart failure in pigs. Fenofibrate treatment blunted reduction in left ventricular ejection fraction, reduced cardiac hypertrophy, and attenuated clinical signs of heart failure. Fenofibrate impeded the increase in atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 plasma levels. The expression of PPARalpha, fatty acyl-CoA-oxidase, and carnitine palmitoyltransferase-Ibeta was reduced at mRNA levels in the left ventricle from untreated heart failure pigs but maintained near normal values with fenofibrate. Fenofibrate prevented heart failure-induced overexpression of TNFalpha mRNA and enhanced catalase activity in left ventricle compared to placebo. These data suggest that a clinically relevant dose of fenofibrate does not accelerate but slows down heart failure development in the model of pacing-induced heart failure in large mammals.

Topics: Acyl-CoA Oxidase; Animals; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Cardiomyopathies; Carnitine O-Palmitoyltransferase; Endothelin-1; Female; Fenofibrate; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; PPAR alpha; RNA, Messenger; Swine; Tachycardia; Thiobarbituric Acid Reactive Substances; Ventricular Dysfunction, Left

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Topics: Adenosine Triphosphate; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiomyopathies; Carnitine; Constriction; Echocardiography; Genetic Predisposition to Disease; Heterozygote; Hypertension; Lung; Male; Mice; Mice, Mutant Strains; Mutation; Myocardium; Organ Size; Organic Cation Transport Proteins; Phosphocreatine; RNA, Messenger; Solute Carrier Family 22 Member 5

Heat shock protein (HSP) 60 is a mitochondrial and cytosolic protein. Previously, we reported that HSP60 doubled in end-stage heart failure, even though levels of the protective HSP72 were unchanged. Furthermore, we observed that acute injury in adult cardiac myocytes resulted in movement of HSP60 to the plasma membrane. We hypothesized that the inflammatory state of heart failure would cause translocation of HSP60 to the plasma membrane and that this would provide a pathway for cardiac injury. Two models were used to test this hypothesis: 1) a rat model of heart failure and 2) human explanted failing hearts. We found that HSP60 localized to the plasma membrane and was also found in the plasma early in heart failure. Plasma membrane HSP60 localized to lipid rafts and was detectable on the cell surface with the use of both flow cytometry and confocal microscopy. Localization of HSP60 to the cell surface correlated with increased apoptosis. In heart failure, HSP60 is in the plasma membrane fraction, on the cell surface, and in the plasma. Membrane HSP60 correlated with increased apoptosis. Release of HSP60 may activate the innate immune system, promoting a proinflammatory state, including an increase in TNF-alpha. Thus abnormal trafficking of HSP60 to the cell surface may be an early trigger for myocyte loss and the progression of heart failure.

Topics: Aged; Animals; Apoptosis; Atrial Natriuretic Factor; Cardiomyopathies; Chaperonin 60; Cytosol; Disease Models, Animal; Disease Progression; Female; Heart Failure; Heart Ventricles; Humans; Male; Membrane Microdomains; Middle Aged; Mitochondria, Heart; Myocardial Contraction; Myocytes, Cardiac; Natriuretic Peptide, Brain; Protein Transport; Rats; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

Biomarkers are not established for cardiovascular phenotyping in mice. We compared the use of echocardiography with the determination of N-terminal propeptide of the atrial natriuretic peptide (Nt-proANP) and osteopontin (Opn). We measured plasma Nt-proANP and Opn levels in (1) the inbred strains C57BL/6, BALB/c, C3H/He, DBA/2, FVB/N, 129S1/Sv; (2) a surgical model of nonischemic myocardial infarction; and (3) delta-sarcoglycan (Sgcd) and calsarcin 1 [also known as myozenin 2 (Myoz2)] knockout models of cardiomyopathy. Left ventricular function was assessed as fractional shortening (FS) by echocardiography in conscious mice. Plasma Nt-proANP exhibited marked variability and ranged from 0.31 +/- 0.19 (C57BL/6 male mice) to 1.34 +/- 0.43 nmol/l (DBA/2 female mice), depending on sex, age, and genetic background. Opn was less variable than Nt-proANP and was decreased significantly in C3H/He and DBA/2 throughout the 16 wk of study. Nt-proANP increased temporarily in mice with myocardial injury. In contrast, Opn increased in both operated and sham-treated mice. Nt-proANP was inversely correlated with FS and distinguished controls from Sgcd and Myoz2 mutants with 100% sensitivity and 71% specificity. Opn was increased in Sgcd mutants, which exhibited only mildly reduced FS but marked myocardial degeneration and fibrosis. Both of these histologic features were absent in Myoz2 mutants. Nt-proANP is an early marker of cardiac disease and is suitable for age- and sex-matched comparisons between groups of transgenic and matched control mice. Opn is useful to detect inflammatory and degenerative myocardial disorders that may be missed by echocardiography.

Topics: Aging; Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Carrier Proteins; Disease Models, Animal; Female; Heart Diseases; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Microfilament Proteins; Muscle Proteins; Osteopontin; Phenotype; Sarcoglycans; Species Specificity; Ventricular Remodeling

Measurement of natriuretic peptides, particularly brain natriuretic peptide (BNP) is an established method for the diagnosis of cardiovascular disorders, chiefly left ventricular (LV) dysfunction. The influence of renal function on the diagnostic utility of natriuretic peptides is unclear.. We performed a cross-sectional study of 296 patients with renal disease but no history of cardiac disease using echocardiography to assess LV mass and function. Circulating levels of atrial natriuretic peptide (ANP) and BNP were also measured.. The incidence of LV hypertrophy increased with progressive renal dysfunction; from 39% in patients with near-normal renal function, to 80% in renal transplant patients. There was a negative correlation between both ANP and BNP, and glomerular filtration rate (GFR) (ANP: r = -0.28, P<0.001; BNP: r = -0.40, P<0.001). Serum ANP and BNP had sensitivity and specificity for LV hypertrophy of 39.9%, 87.4% (ANP) and 61.4%, 67.6% (BNP) respectively. Sensitivity and specificity for LV dysfunction was 77.2%, 32.4% (ANP) and 71.8%, 40.0% (BNP). Significant confounders in determining serum ANP were haemoglobin, beta blockade and albumin, while serum BNP levels were significantly confounded by GFR, albumin, haemoglobin, beta blockade and age.. Across a spectrum of renal dysfunction, GFR is a more important determinant of serum BNP than ventricular function, and several factors are predictors of natriuretic peptide levels. In chronic kidney disease, the use of natriuretic peptides to diagnose LV hypertrophy must be interpreted in light of these other factors. The use of these peptides in renal dysfunction to diagnose LV dysfunction may be of limited value.

Topics: Adult; Atrial Natriuretic Factor; Cardiomyopathies; Chronic Disease; Cross-Sectional Studies; Female; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Middle Aged; Natriuretic Peptide, Brain

Topics: Animals; Antiviral Agents; Atrial Natriuretic Factor; Cardiomyopathies; Gene Expression Regulation, Viral; Heart; Heart Failure; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; HLA-D Antigens; Humans; Interferons; Mice; Mice, Transgenic; Myocarditis; Myocardium; Natriuretic Peptide, Brain; NF-kappa B; Paraffin Embedding; Phenotype; Prevalence; RNA, Viral; Species Specificity; Transcription Factor AP-1; Viral Core Proteins

Although increased levels of circulating interleukin (IL)-18 have been demonstrated in patients with cardiovascular diseases, the functional consequences of chronically increased circulating IL-18 with respect to myocardial function have not been defined. Thus we aimed to examine the effects of chronic IL-18 exposure on left ventricular (LV) function in healthy mice. Moreover, to clarify whether IL-18 has direct effects on the cardiomyocyte, we examined effects of IL-18 on cardiomyocytes in vitro. After 7 days of daily intraperitoneal injections of 0.5 microg IL-18 in healthy mice, a 40% (P < 0.05) reduction in the LV maximal positive derivative, a 25% (P < 0.05) reduction in the LV maximal rate of pressure decay, and a 2.8-fold (P < 0.001) increase in the LV end-diastolic pressure were measured, consistent with myocardial dysfunction. Furthermore, we measured a 75% (P < 0.05) reduction in beta-adrenergic responsiveness to isoproterenol. IL-18 induced myocardial hypertrophy, and there was a 2.9-fold increase (P < 0.05) in atrial natriuretic peptide mRNA expression in the LV myocardium. In vitro examinations of isolated adult rat cardiomyocytes being stimulated with IL-18 (0.1 microg/ml) exhibited an increase in peak Ca2+ transients (P < 0.05) and in diastolic Ca2+ concentrations (P < 0.05). In conclusion, this study shows that daily administration of IL-18 in healthy mice causes LV myocardial dysfunction and blunted beta-adrenergic responsiveness to isoproterenol. A direct effect of IL-18 on the cardiomyocyte in vitro was demonstrated, suggesting that IL-18 reduces the responsiveness of the myofilaments to Ca2+. Finally, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.

Topics: Adrenergic beta-Agonists; Animals; Atrial Natriuretic Factor; Calcium; Calcium-Binding Proteins; Calcium-Transporting ATPases; Cardiomegaly; Cardiomyopathies; Drug Administration Schedule; In Vitro Techniques; Intercellular Adhesion Molecule-1; Interleukin-18; Isoproterenol; Male; Mice; Mice, Inbred BALB C; Myocardium; Myocytes, Cardiac; Rats; Receptors, Adrenergic, beta; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tumor Necrosis Factor-alpha; Ventricular Function, Left

It is not known whether cardiac markers and cyclic variations of integrated backscatter can be used to detect cardiac sarcoidosis.. We studied 62 patients with sarcoidosis affecting the lung, eyes, skin, or heart (27 patients with cardiac involvement and 35 patients without). The cyclic variation of integrated backscatter and wall thickening was evaluated in the left ventricular anterior septum and posterior wall. Plasma A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) concentrations and serum cardiac troponin T were also determined.. Plasma natriuretic peptide concentrations were higher in the cardiac involvement group (ANP: 15.5 [interquartile range (IQR) 2.5-34.0] vs. 12.0 [10.0-16.5] pg/ml, P=0.25; BNP: 28.6 [5.9-141] vs. 10.1 [4.8-15.4] pg/ml, P=0.049). However, cardiac troponin T concentration was <0.01 ng/ml in all patients. Receiver-operator characteristic (ROC) analysis showed that both ANP and BNP could identify patients with high-degree atrioventricular block, ventricular tachyarrhythmias, or symptomatic heart failure (the areas under the ROC curve were 0.94 and 0.97, respectively). The cardiac involvement group could be distinguished from the noninvolvement group by combining cutoff values for the magnitude of integrated backscatter cyclic variation (5.5 dB) and wall thickening (30%), albeit only for the posterior wall.. Both ANP and BNP are useful markers for identifying patients with sarcoidosis and cardiac complication(s). Moreover, evaluation of integrated backscatter cyclic variation combined with wall thickening may be of help in detecting cardiac involvement in the posterior wall.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Echocardiography; Female; Follow-Up Studies; Gated Blood-Pool Imaging; Heart Ventricles; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Retrospective Studies; ROC Curve; Sarcoidosis; Severity of Illness Index; Troponin T

Clinical methods for the early detection of doxorubicine (adriamycin; ADR) -induced cardiotoxicity have not been established. This study prospectively investigated whether atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and cardiac troponin T (TnT) are predictors for ADR-induced cardiotoxicity, and examined the correlations between the serum concentrations of these biomarkers and the functional alternations associated with ADR-induced myocardial damage.. Male Wistar rats were injected weekly with 2 mg/kg of ADR via the tail vein for 8 weeks to induce cardiotoxicity. Echocardiograms of each ether anesthetized rat were taken at 6, 8, 10 and 12 weeks after the first administration of ADR, and blood samples collected from the tail vein were used to quantify plasma ANP and BNP, and serum TnT after echocardiography. Plasma BNP and serum TnT significantly increased from 6 to 12 weeks (81.5 to 173.3 pg/ml (p<0.001), <0.01 to 1.09 ng/ml (p<0.05), respectively) with deterioration of left ventricular % fractional shortening (%FS) (58.6% to 36.8%). The %FS significantly correlated with TnT (r=-0.51, p<0.001) and BNP (r=-0.75, p<0.0001); however, the increase of TnT was antecedent to the increase of BNP and the deterioration of %FS.. Plasma BNP and serum TnT concentrations, especially TnT, measured by this highly sensitive method are useful predictors for ADR-induced cardiomyopathy.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Disease Progression; Doxorubicin; Male; Natriuretic Peptide, Brain; Predictive Value of Tests; Rats; Rats, Wistar; Troponin T; Ventricular Dysfunction, Left

We evaluated the analytical performance of a fully-automated electrochemiluminescence "sandwich" immunoassay method for the N-terminal fragment of the pro-peptide of brain natriuretic peptide (BNP). We then compared the diagnostic accuracy of this method in discriminating between normal subjects and patients with cardiomyopathy with that found with two previously described immunoradiometric assay methods for the assay of atrial natriuretic peptide (ANP) and BNP. We studied 193 consecutive patients (mean age 64.4 +/- 12.3 years, range 20-89 years, including 56 women and 137 men) with chronic cardiomyopathy and a group of 85 healthy subjects (mean age 52.3 +/- 12.0 years, 42 women and 43 men, range 20-79 years). N-terminal fragment of proBNP1-76 (NT-proBNP) was measured with a fully-automated "sandwich" electrochemiluminescence method using an Elecsys 2010 analyzer, while ANP and BNP were measured with immunoradiometric assay methods. The low detection limit of the NT-proBNP assay was 4.2 pg/ml (0.50 pmol/l), while the functional sensitivity was 22 pg/ml (2.60 pmol/l) with a working range (imprecision profile < or = 10% coefficient of variation) extended up to about 30 000 pg/ml (3540 pmol/l). Healthy women (64.3 +/- 41.6 pg/ml, 7.59 +/- 4.91 pmol/l) showed significantly higher values than men (46.9 +/- 30.9 pg/ml, 5.53 +/- 3.64 pmol/l, p = 0.0118). Moreover, age and sex were significantly and independently related to the NT-proBNP values in healthy subjects, as assessed by a multiple linear regression analysis (R = 0.389, F-value = 7.316, P-value = 0.0012). As expected, the NT-proBNP values of patients with cardiomyopathy were significantly higher than those of normal subjects and progressively increased with the severity of heart failure. The respective diagnostic accuracy of the ANP, BNP and NT-proBNP assays in discriminating between the group of normal subjects and that of patients with cardiomyopathy was tested by the response operating characteristic curve analysis. Our data indicated that the NT-proBNP assay is significantly better than either of the ANP or BNP immunoradiometric assays in discriminating affected patients from healthy subjects, especially when only patients with mild disease severity (New York Heart Association class I and II) are considered.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Automation; Cardiomyopathies; Female; Humans; Immunoassay; Immunoradiometric Assay; Linear Models; Luminescent Measurements; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protein Precursors; Reference Standards; Reproducibility of Results; Sensitivity and Specificity

To study whether natriuretic peptide types B (BNP) and A (ANP) reflect clinical signs of heart failure (CSHF) in children with congenital heart defects or cardiomyopathy resulting in different types of haemodynamic situations, such as pressure overload in coarctation of the aorta (CoA), volume overload in ventricular septal defect (VSD) or systolic dysfunction in dilated cardiomyopathy (DCM).. Blood samples for plasma P-BNP and P-ANP were taken before procedures during regular investigation from 26 children (9 CoA, 11 VSD and 6 DCM). The ordinary paediatric cardiologist performed the cardiac evaluation and the data were retrieved from medical charts. CSHF was considered positive if two of the following criteria were fulfilled: reduced physical capacity, feeding disorders, dyspnoea, tachypnoea, hepatomegaly and oedema. The statistical methods were non-parametric.. 0/9 children with CoA, 5/11 with VSD and 6/6 with DCM had CSHF. In children with CSHF, P-BNP and P-ANP were higher, 263 ng l(-1) (range 47.5-1300) and 303 ng l(-1) (range 168-466), than in those without CSHF, 12.3 ng l(-1) (range 4.8-30.8) and 42.9 ng l(-1) (range 13.7-189), respectively (p < 0.001, Mann-Whitney U-test), irrespective of the diagnosis. The same relationship was also found in the group of children with VSD.. Plasma levels of ANP and BNP increase in children with CSHF. This increase is seen irrespective of whether it is due to systolic dysfunction, as in children with DCM, or to a volume overload with a normal systolic function, as in children with VSD.

Topics: Adolescent; Aortic Coarctation; Atrial Natriuretic Factor; Cardiomyopathies; Child; Child, Preschool; Female; Heart Defects, Congenital; Hemodynamics; Humans; Infant; Male; Natriuretic Peptide, Brain

It has been reported previously that granulocyte colony-stimulating factor (GCSF) injection improves infarcted heart function, but the mechanism remains unclear. In this study we sought to determine whether GCSF-mobilized bone marrow cells could regenerate neo-myocardium and repair doxorubicin-induced cardiomyopathy.. C57BL/6 mice were irradiated and bone marrow cells (BMC; 1 x 10(6)) from green fluorescent protein (GFP) mice (GFP-BMC) were transplanted intravenously, followed by splenectomy. Doxorubicin (2.5 mg/kg, 6 times for 2 weeks) was administered intraperitoneally 2 weeks later. GCSF (50 microg/kg/day for 8 days) was administered sub-cutaneously after doxorubicin injection (Group I, n = 11) and 3 weeks later (Group II, n = 8), and saline was injected in Group III animals (n = 8). Eight weeks after doxorubicin injection, the excised hearts were studied immunologically and electron microscopically.. Survival rates were 81.8% in Group I, 50.0% in Group II and 62.5% in Group III. The number of GFP-BMC in Group I (15.4 +/- 7.4 per high-power field) was highest (p < 0.05). In all groups, cardiac troponin I-positive cells derived from GFP-BMC were observed in the hearts. GFP-BMC in hearts stained positively against cardiac troponin I (4.3 +/- 2.5%), myosin heavy chain (5.0 +/- 4.3%), atrial natriuretic peptide (ANP; 3.9 +/- 2.4%) and connexin 43 (11.9 +/- 7.3%) in Group I. Myofibrils, mitochondria and fundamental architecture were almost all preserved in Group I, whereas hearts were severely damaged in Groups II and III.. Bone marrow was shown to be one of the sources of regenerated cardiomyocytes in the doxorubicin-induced cardiomyopathic heart. Early administration of GCSF enhanced the migration of bone marrow cells into the heart, and attenuated the cardiotoxicity of doxorubicin.

Topics: Animals; Atrial Natriuretic Factor; Bone Marrow Cells; Bone Marrow Transplantation; Cardiomyopathies; Cell Movement; Doxorubicin; Granulocyte Colony-Stimulating Factor; Mice; Mice, Inbred C57BL; Mitochondria; Myofibrils; Myosin Heavy Chains; Regeneration; Troponin I

Topics: Amyloid; Amyloidosis; Atrial Fibrillation; Atrial Function; Atrial Natriuretic Factor; Cardiomyopathies; Echocardiography; Heart Atria; Heart Valve Diseases; Humans

The transcription factor serum response factor (SRF) plays an important role in the regulation of a variety of cardiac genes during development and during adult aging. A novel SRF cofactor, herein called p49/STRAP, for SRF-dependent transcription regulation-associated protein, was recently identified in our laboratory. This protein interacted mainly with the transcriptional activation domain of the SRF protein and was found to bind to SRF or to the complex of SRF and another cofactor, such as myocardin or Nkx2.5. The expression of p49/STRAP affected the promoter activity of SRF target genes in a non-uniform manner. For example, p49 activated MLC2v and cardiac actin promoters when it was co-transfected with SRF, but it repressed atrial natriuretic factor promoter activity, which was strongly induced by myocardin. The p49/STRAP mRNA was observed to be highly expressed in fetal, adult, and senescent human hearts, and also in hearts of young adult and old mice, suggesting that p49/STRAP may be an important SRF cofactor in the transcriptional regulation of mammalian cardiac muscle genes throughout the life span.

Topics: Actins; Aging; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blotting, Northern; Blotting, Western; Cardiomyopathies; DNA, Complementary; Gene Expression Regulation; Glutathione Transferase; Homeobox Protein Nkx-2.5; Homeodomain Proteins; Humans; Immunoprecipitation; Mice; Microscopy, Fluorescence; Models, Biological; Molecular Sequence Data; Myocardium; NIH 3T3 Cells; Nuclear Proteins; Plasmids; Promoter Regions, Genetic; Protein Binding; RNA, Messenger; Sequence Homology, Amino Acid; Serum Response Factor; Time Factors; Tissue Distribution; Trans-Activators; Transcription Factors; Transcriptional Activation; Two-Hybrid System Techniques

We investigated whether plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) reflect impaired diastolic relaxation or its improvement after ACE inhibition.. 7 long-term Type 1 diabetic patients with normal systolic but impaired diastolic function and with sympathetic myocardial dysinnervation and 10 controls were included. Exercise tolerance and maximal O 2 uptake were evaluated by bicycle exercise prior to the study. ANP, BNP and norepinephrine/epinephrine (NE/E) were determined at baseline and at 80 % .VO2 max workload and after recovery, before and following 12 weeks of treatment with fosinopril (10 mg/d).. Isovolumetric relaxation time (IVRT) and A/E wave ratio were increased by 26.7 +/- 11.5 % and 54.4 +/- 26.1 % in diabetic patients as compared to controls, respectively (p < 0.02). After 12 weeks of fosinopril treatment, no differences in IVRT or A/E wave ratio were detectable between groups. ANP was enhanced in Type 1 diabetes as compared to controls (baseline: 9.2 +/- 3.0 vs. 4.5 +/- 1.1; exercise: 22.4 +/- 7.7 vs. 7.9 +/- 1.2; recovery: 20.3. +/- 4.6 vs. 9.5 +/- 2.0 fmol/ml, p < 0.02). Fosinopril treatment abolished any differences between groups. BNP plasma levels did not differ between groups and no exercise dependent changes were observed. NE- and E-increase was greater at 80 % .VO2 max work load in Type 1 diabetes than in controls (p < 0.05). Again, fosinopril abolished differences between groups.. In Type 1 diabetes, impaired diastolic function is associated with elevated ANP and catecholamine plasma levels that are normalized after ACE inhibition. Thus, ANP but not BNP appears to be a sensitive biochemical marker for early diastolic dysfunction in Type 1 diabetes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Cardiomyopathies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diastole; Female; Fosinopril; Glycated Hemoglobin; Heart; Hemodynamics; Humans; Male; Natriuretic Peptide, Brain

Cardiac expression of a transgene is a common approach for determining the role of gene products in the processes underlying cardiomyopathy and heart failure (HF). We have generated transgenic mice that express the 'harmless' yeast transcription factor Gal4 in the heart under control of the alpha-myosin heavy chain promoter and found that expression of this gene causes cardiomyopathy and HF, the severity of which correlated with the number of copies of the transgene integrated into the genome and with the expression level. A line with a single copy of the transgene targeted to the hprt locus correctly expressed the transgene but did not develop cardiomyopathy. Our results indicate that expression of a transgene in the heart may non-specifically cause HF in a dose-dependent manner.

Topics: Animals; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Cardiac Myosins; Cardiomyopathies; Cardiomyopathy, Dilated; Connexin 43; DNA-Binding Proteins; Down-Regulation; Gene Dosage; Gene Expression; Gene Expression Regulation, Developmental; Genetic Vectors; Heart Atria; Heart Failure; In Situ Hybridization; Mice; Mice, Transgenic; Myocardium; Myosin Heavy Chains; Myosin Light Chains; Organ Size; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Saccharomyces cerevisiae Proteins; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sex Factors; Transcription Factors; Up-Regulation; Ventricular Myosins

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathies; Embryo, Mammalian; Female; Fibrosis; Guanylate Cyclase; Heart Ventricles; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Receptors, Atrial Natriuretic Factor; Reference Values; RNA, Messenger

Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy. Our laboratory previously developed a transgenic mouse model with targeted overexpression of the antioxidant protein metallothionein (MT) in the heart. In this study we used MT-transgenic mice to test whether an antioxidant protein can reduce cardiomyopathy in the OVE26 transgenic model of diabetes. OVE26 diabetic mice exhibited cardiomyopathy characterized by significantly altered mRNA expression, clear morphological abnormalities, and reduced contractility under ischemic conditions. Diabetic hearts appeared to be under oxidative stress because they had significantly elevated oxidized glutathione (GSSG). Diabetic mice with elevated cardiac MT (called OVE26MT mice) were obtained by crossing OVE26 transgenic mice with MT transgenic mice. Hyperglycemia in OVE26MT mice was indistinguishable from hyperglycemia in OVE26 mice. Despite this, the MT transgene significantly reduced cardiomyopathy in diabetic mice: OVE26MT hearts showed more normal levels of mRNA and GSSG. Typically, OVE26MT hearts were found to be morphologically normal, and elevated MT improved the impaired ischemic contractility seen in diabetic hearts. These results demonstrate that cardiomyocyte-specific expression of an antioxidant protein reduces damage to the diabetic heart.

Topics: Actins; Animals; Antioxidants; Atrial Natriuretic Factor; Base Sequence; Blood Glucose; Blotting, Northern; Cardiomyopathies; Diabetic Angiopathies; Disease Models, Animal; Gene Expression Regulation; Glutathione Disulfide; Insulin; Metallothionein; Mice; Mice, Transgenic; Molecular Sequence Data; Myocardial Contraction; Oligonucleotide Probes; RNA, Messenger; Transcription, Genetic; Triglycerides

The contractile force of the cardiomyocyte is transmitted through the adherens junction, a component of the intercalated disc, enabling the myocardium to function as a syncytium. The cadherin family of cell adhesion receptors, located in the adherens junction, interact homophilically to mediate strong cell-cell adhesion. Ectopic expression of cadherins is associated with changes in tumor cell behavior and pathology. To examine the effect of cadherin specificity on cardiac structure and function, we expressed either the epithelial cadherin, E-cadherin, or N-cadherin in the heart of transgenic mice. E-cadherin was localized to the intercalated disc structure in these animals similar to endogenous N-cadherin. Both N- and E-cadherin transgenic animals developed dilated cardiomyopathy. However, misexpression of E-cadherin led to earlier onset and increased mortality compared with N-cadherin mice. A dramatic decrease in connexin 43 was associated with the hypertrophic response in E-cadherin transgenic mice. Myofibril organization appeared normal although, vinculin, which normally localizes to the intercalated disc, was redistributed to the cytoplasm in the E-cadherin transgenic mice. Furthermore, E-cadherin induced cyclin D1, nuclear reduplication, and karyokinesis in the absence of cytokinesis, resulting in myocytes with two closely opposed nuclei. By contrast, N-cadherin overexpressing transgenic mice did not exhibit an increase in cyclin D1, suggesting that E-cadherin may provide a specific growth signal to the myocyte. This study demonstrates that modulation of cadherin-mediated adhesion can lead to dilated cardiomyopathy and that E-cadherin can stimulate DNA replication in myocytes normally withdrawn from the cell cycle.

Topics: Animals; Atrial Natriuretic Factor; Cadherins; Cardiomyopathies; Cell Adhesion; Connexin 43; Female; Humans; Hypertrophy; Intercellular Junctions; Mice; Mice, Transgenic; Myocardium; Myosin Heavy Chains; Vinculin

Cardiac effects of human immunodeficiency virus (HIV) transactivator (Tat) are unclear, but Tat decreases liver glutathione (an important mitochondrial antioxidant) when ubiquitously expressed in transgenic mice (TG). With an alpha-myosin heavy chain promoter, Tat was selectively targeted to murine cardiac myocytes. One high-expression hemizygous ((+/-)Tat(high); 12 copies) and two low-expression ((+/-)Tat(lowA,B); 2-5 copies) TG lines were created. Cardiomyopathy was documented with increased left ventricle (LV) mass, ventricular expression of atrial natriuretic factor (ANF) mRNA, mitochondrial ultrastructural defects, and myocardial depletion of glutathione. In (+/-)Tat(high) TGs, normalized LV mass (determined echocardiographically) increased 46% (90 days), 134% (240 days), and 96% (365 days) compared with wild-type littermates (WT). LV fractional shortening was decreased to 28% (90 days), 27% (240 days), and 19% (365 days). (+/-)Tat(low) LV mass was unchanged (or=210 days); however, profound mitochondrial destruction occurred in homozygous (+/+)Tat(high) hearts (10 days) and the pups died (14 days). Tat caused cardiac dysfunction in this TG and may impact on cardiomyopathy in acquired immunodeficiency syndrome.

Topics: Animals; Antioxidants; Ascorbic Acid; Atrial Natriuretic Factor; Blotting, Western; Cardiomyopathies; Echocardiography; Electrocardiography; Gene Expression; Gene Products, tat; Gene Targeting; Glutathione; Heart Ventricles; Mice; Mice, Transgenic; Microscopy, Electron; Mitochondria, Heart; Muscle, Skeletal; Myocardial Contraction; Myocardium; Organ Specificity; RNA, Messenger

The caveolin gene family consists of caveolins 1, 2, and 3. Caveolins 1 and 2 are co-expressed in many cell types, such as endothelial cells, fibroblasts, smooth muscle cells and adipocytes, where they form a heteroligomeric complex. In contrast, the expression of caveolin-3 is muscle-specific. Thus, the expression of caveolin-1 is required for caveolae formation in non-muscle cells, while the expression of caveolin-3 drives caveolae formation in striated muscle cell types (cardiac and skeletal). To create a truly caveolae-deficient mouse, we interbred Cav-1 null mice and Cav-3 null mice to generate Cav-1/Cav-3 double-knockout (Cav-1/3 dKO) mice. Here, we report that Cav-1/3 dKO mice are viable and fertile, despite the fact that they lack morphologically identifiable caveolae in endothelia, adipocytes, smooth muscle cells, skeletal muscle fibers, and cardiac myocytes. We also show that these mice are deficient in all three caveolin gene products, as caveolin-2 is unstable in the absence of caveolin-1. Interestingly, Cav-1/3 dKO mice develop a severe cardiomyopathy. At 2 months of age, analysis of Cav-1/3 dKO hearts via gated magnetic resonance imaging reveals a dramatic increase in left ventricular wall thickness, as compared with Cav-1-KO, Cav-3 KO, and wild-type mice. Further functional analysis of Cav-1/3 dKO hearts via transthoracic echocardiography demonstrates hypertrophy and dilation of the left ventricle, with a significant decrease in fractional shortening. As predicted, Northern analysis of RNA derived from the left ventricle of Cav-1/3 dKO mice shows a dramatic up-regulation of the atrial natriuretic factor message, a well-established biochemical marker of cardiac hypertrophy. Finally, histological analysis of Cav-1/3 dKO hearts reveals hypertrophy, disorganization, and degeneration of the cardiac myocytes, as well as chronic interstitial fibrosis and inflammation. Thus, dual ablation of both Cav-1 and Cav-3 genes in mice leads to a pleiotropic defect in caveolae formation and severe cardiomyopathy.

Topics: Adipocytes; Animals; Atrial Natriuretic Factor; Cardiomyopathies; Caveolae; Caveolin 1; Caveolin 3; Caveolins; Echocardiography; Endothelium; Magnetic Resonance Imaging; Mice; Mice, Knockout; Muscles; Myocardium; Phenotype; Up-Regulation

To assess the value of alpha-atrial natriuretic peptide (alpha-ANP), second messenger cyclic guanosine monophosphate (cGMP,) and endothelin as markers of myocardial depression in septic shock.. Prospective observational study.. Medical intensive care unit (ICU) of a university hospital.. Fourteen consecutive patients with septic shock and arterial and pulmonary artery catheters in place.. Hemodynamic variables and plasma levels of alpha-ANP, cGMP, and endothelin were measured every 6 hrs for 3 days after admission. Eight patients died from shock in the ICU. The nadir left ventricular stroke work index (LVSWI) was below 35 g/m2 in all patients, and the median peak circulating alpha-ANP (n < 68 pg/mL) was 276 pg/mL (range, 79-1056), the median peak cGMP (n < 2.1 ng/mL) was 8.1 ng/mL (range, 3.2-29.7), and the median peak endothelin (n < 5.3 pg/mL) was 15.5 pg/mL (range, 8.5-33.9), supranormal in all patients. Outcome groups differed in the course of cardiac index and LVSWI, which were lower in nonsurvivors despite similar filling pressures and more intensive inotropic treatment (p < .01). The course of alpha-ANP, cGMP, and endothelin plasma levels also differed between groups, with higher levels in nonsurvivors (p < .05). As for pooled data, the mean daily or nadir LVSWI inversely related to mean daily or peak alpha-ANP, cGMP, and endothelin levels, respectively (p < .05). The area under the receiver operating characteristic curve for myocardial depression (LVSWI < 35 g/m2) was for alpha-ANP and endothelin 0.77, and for cGMP 0.85 (p < .01). The optimum cutoff values for alpha-ANP, cGMP, and endothelin were 172 pg/mL, 4.5 ng/mL, and 10.0 pg/mL, respectively. The sensitivity for myocardial depression of alpha-ANP, cGMP, and endothelin was 68%, 77%, and 72%, and the specificity was 82%, 93%, and 69%, respectively.. Circulating alpha-ANP, endothelin, and, particularly, cGMP may be markers of the myocardial depression of human septic shock, which is associated with mortality.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Cyclic GMP; Endothelins; Female; Hemodynamics; Humans; Male; Middle Aged; Netherlands; Prognosis; Prospective Studies; Respiratory Mechanics; Sensitivity and Specificity; Shock, Septic; Statistics, Nonparametric; Survival Rate; Ventricular Function

To define the role of Irx4, a member of the Iroquois family of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designated Irx4(Delta ex2/Delta ex2)) was normal during embryogenesis and in early postnatal life. Adult Irx4(Delta ex2/Delta ex2) mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy, Irx4(Delta ex2/Delta ex2) hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increased Irx2 expression, and ventricular induction of an atrial chamber-specific transgene. In neonatal hearts, ventricular expression of atrial natriuretic factor and alpha-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and beta-myosin heavy chain accompanied adult-onset cardiac hypertrophy. Cardiac expression of Irx1, Irx2, and Irx5 may partially compensate for loss of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program. In the absence of genes under the control of Irx4, ventricular function deteriorates and cardiomyopathy ensues.

Topics: Actins; Alleles; Animals; Atrial Natriuretic Factor; Basic Helix-Loop-Helix Transcription Factors; Blotting, Northern; Cardiomyopathies; Cytokines; DNA-Binding Proteins; DNA, Complementary; Down-Regulation; Echocardiography; Gene Expression Regulation, Developmental; Heterozygote; Homeodomain Proteins; Homozygote; Mice; Mice, Transgenic; Models, Genetic; Mutagenesis; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transcription Factors; Transgenes; Up-Regulation

Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac alpha-actin, skeletal alpha-actin, alpha-myosin heavy chain (alpha-MHC), and beta-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.

Topics: Actins; Aging; Animals; Atrial Natriuretic Factor; Blotting, Northern; Cardiomyopathies; DNA-Binding Proteins; Dystrophin; Echocardiography; Gene Expression Regulation, Developmental; Genes, fos; Genes, jun; Heart; Humans; Mice; Mice, Transgenic; Myocardium; Myosin Heavy Chains; Nuclear Proteins; Protein Isoforms; Serum Response Factor; Transcription Factors; Ventricular Function, Left

To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients.. Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction.. No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV.. Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

Topics: Adult; Antibiotics, Antineoplastic; Atrial Natriuretic Factor; Breast Neoplasms; Cardiomyopathies; Chemotherapy, Adjuvant; Electrocardiography; Epirubicin; Female; Humans; Middle Aged; Prospective Studies; Ultrasonography; Ventriculography, First-Pass

The natriuretic hormones ANP and BNP are expressed differently in the myocardium. Both hormones have compensatory diuretic activity during heart failure. Mechanical stretch of the myocardial walls induces the expression of these hormones. In failing human myocardium, both ANP and BNP are transcribed in the ventricular myocardium in high amounts. We measured the plasma concentrations of ANP and BNP in patients supported by various ventricular assist devices (VADs) at various times. We analyzed the time courses of ANP and BNP to determine (1) the time scale of their down-regulation as a marker of putative myocardial recovery, (2) their steady-state levels under VAD support and (3) differences caused by various VAD devices.. We analyzed ANP and BNP using commercially available radioimmune assays. We analyzed the time courses of patients supported by Thoratec (THO) LVAD (n = 8), TCI Heartmate (TCI) (n = 6), Novacor (NOV) (n = 7), and Lionheart (LIO) (n = 3).. Patients supported with NOV and some patients with TCI showed down-regulation of BNP to a steady-state level at 30 to 50 days, following a single exponential decay. In contrast, patients supported by THO or LIO did not reveal a determined time course of the natriuretic hormones. Only a few patients reached normal plasma values during VAD support.. The time courses of ANP and BNP differ among VAD types because of construction and/or driving mode, which might be important when considering patients for weaning from VAD without heart transplant.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Heart Transplantation; Heart-Assist Devices; Humans; Middle Aged; Myocardium; Natriuretic Agents; Natriuretic Peptide, Brain; Predictive Value of Tests; Time Factors

The left ventricular assist system (LVAS) has been used increasingly for patients with end-stage heart failure who are awaiting transplantation. Sympathetic nerve activity is known to correlate with cardiac function in chronic heart failure patients, but little is known about sympathetic nerve activity during LVAS support. In this study, we examined the status of sympathetic nerve activity in relation to mechanical support.. In this study, we included 10 consecutive patients with end-stage cardiomyopathy who were on LVAS support for at least 2 months (duration, 222 +/- 59 days). None of these patients achieved enough functional recovery to be taken off LVAS. In these patients, we used iodine-125-metaiodobenzylguanidine (125I-MIBG) scintigraphy to examine the change of sympathetic nerve activity after LVAS implantation, and compared the results with the change of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as well as with histologic optional findings. Samples for ANP and BNP measurement were obtained before and 30 days after LVAS implantation. Specimens for histologic analysis were obtained at the time of LVAS implantation and at the time of cardiac transplantation or autopsy.. We observed marked decrease in serum levels of ANP and BNP 1 month after LVAS implantation. But myocardial sympathetic nerve function, which was evaluated with 125I-MIBG scintigraphy and expressed as the heart-to-mediastinum activity ratio, remained below normal even 2 months after the LVAS implantation (1.57 +/- 0.19; normal, 2.34 +/- 0.36). Serial histologic analysis in these 10 patients showed continuous increase in percentage of fibrosis and cell diameter despite ventricular unloading by the LVAS.. Sympathetic nerve function, which was evaluated on 125I-MIBG scintigraphy, did not improve during left ventricular support. Because none of the patients included in our study showed improvement in cardiac function or histologic findings, the recovery of myocardial sympathetic nerve function may be an important factor in myocardial recovery for cardiomyopathy patients on LVAS support.

Topics: 3-Iodobenzylguanidine; Adult; Atrial Natriuretic Factor; Cardiomyopathies; Echocardiography; Female; Heart Failure; Heart-Assist Devices; Humans; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Radionuclide Imaging; Radiopharmaceuticals; Sympathetic Nervous System

Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4-3Delta gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass increased 160% by echocardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mM). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atrial Natriuretic Factor; Calcium-Transporting ATPases; Cardiomyopathies; Drug Therapy, Combination; Echocardiography; Gene Expression; HIV Protease Inhibitors; Indinavir; Lactic Acid; Lamivudine; Mice; Mice, Transgenic; Microscopy, Electron; Myocardium; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Zidovudine

Subtle cardiac abnormalities have been described in patients with cirrhosis. Natriuretic peptide hormones have been reported to be sensitive markers of early cardiac disease. We postulate that plasma levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide could be used as markers of cardiac dysfunction in cirrhosis. The aim of the study was to evaluate the levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide and their relationship with cardiac structure and function in patients with cirrhosis. The study population comprised 36 patients with cirrhosis of mixed aetiologies, but with no cardiac symptoms; 19 of the patients had ascites and 17 did not. The subjects underwent (i) trans-thoracic two-dimensional echocardiography, and (ii) radionuclide angiography for measurements of cardiac structural parameters, diastolic and systolic function. Levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide were also measured. The results were compared with those from eight age- and sex-matched healthy volunteers. Compared with the controls, the baseline mean ejection fraction was increased significantly in both patient groups (P=0.02), together with prolonged deceleration times (P=0.03), left atrial enlargement (P=0.03) and interventricular septal thickening (P=0.02), findings that are compatible with diastolic dysfunction. Levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide were significantly higher in all patients with cirrhosis with ascites (P=0.01 and P=0.05 respectively), but in only some of the pre-ascitic cirrhotic patients, compared with controls. All high levels of brain natriuretic peptide were correlated significantly with septal thickness (P<0.01), left ventricular diameter at the end of diastole (P=0.02) and deceleration time (P<0.01). We conclude that elevated levels of brain natriuretic peptide are related to interventricular septal thickness and the impairment of diastolic function in asymptomatic patients with cirrhosis. Levels of brain natriuretic peptide may prove to be useful as a marker for screening patients with cirrhosis for the presence of cirrhotic cardiomyopathy, and thereby identifying such patients for further investigations.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Diastole; Female; Heart Septum; Humans; Liver Cirrhosis; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Protein Precursors; Systole

The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase families and plays a pivotal role in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (STAT3-TG) were generated. STAT3-TG manifested myocardial hypertrophy at 12 wk of age with increased expression of the atrial natriuretic factor (ANF), beta-myosin heavy chain (MHC), and cardiotrophin (CT)-1 genes. The animals were injected i.p. with 15 mg/kg doxorubicin (Dox), an antineoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (5/20) for control littermates (WT), but 80% (16/20) for STAT3-TG (P < 0.01). WT showed increased expression of beta-MHC and ANF mRNAs in the hearts 1 day after Dox treatment; this expression peaked at 3 days, suggesting that the WT suffered from congestive heart failure. Although the expression of these mRNAs was elevated in STAT3-TG hearts before Dox treatment, no additional increase was observed after the treatment. Dox administration significantly reduced the expression of the cardiac alpha-actin and Stat3 genes in WT hearts but not in STAT3-TG. These results provide direct evidence that STAT3 transduces not only a hypertrophic signal but also a protective signal against Dox-induced cardiomyopathy by inhibiting reduction of cardiac contractile genes and inducing cardiac protective factors.

Topics: Actins; Animals; Antineoplastic Agents; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathies; Cytokines; DNA-Binding Proteins; Doxorubicin; Gene Expression Regulation; Mice; Mice, Transgenic; Myocardium; Myosin Heavy Chains; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators

The present study was designed to study the progression of heart failure in rabbits with catecholamine-induced cardiomyopathy.. We investigated the effects of three repetitive applications (at 16-day intervals) of high-dose epinephrine (first infusion, 5 micrograms/kg/min for 60 minutes; second and third infusions, 4 micrograms/kg/min for 60 minutes) on hemodynamics, echocardiographic parameters, and plasma hormone levels in eight conscious rabbits chronically instrumented with a Doppler flow probe around the proximal abdominal aorta and a catheter in the right atrium. Mean arterial pressure and blood flow velocity, as well as the acceleration of blood flow velocity (df/dt) in the proximal abdominal aorta were progressively reduced, and right atrial pressure was significantly elevated. On echocardiography, progressive left ventricular (LV) dilatation with depressed LV systolic function and an increase in LV mass were observed. Plasma atrial natriuretic peptide level was enhanced approximately fourfold after each epinephrine infusion, with a tendency to return to baseline values. Plasma renin activity (PRA) was increased after the first epinephrine application (3.0 +/- 0.5 to 6.4 +/- 0.9 ng angiotensin I (AI)/mL/h; P < .05), followed by a return to control levels. After the second epinephrine infusion, a significant decrease to 1.0 +/- 0.3 ng AI/mL/h (P < .05) was observed. After the third catecholamine treatment, PRA levels insignificantly increased. Plasma vasopressin level significantly increased from 0.5 +/- 0.2 to 1.1 +/- 0.5 pg/mL (P < .05) after the second epinephrine infusion.. Repetitive infusions of high doses of epinephrine induce a cardiomyopathy with progressive hemodynamic deterioration, LV dilatation and hypertrophy, depressed systolic function, and different stages of neurohumoral compensation. This model appears to be suitable to study the progression of chronic heart failure by serial measurements in a small animal preparation.

Topics: Adrenergic alpha-Antagonists; Animals; Atrial Natriuretic Factor; Cardiomyopathies; Consciousness; Disease Models, Animal; Disease Progression; Echocardiography, Doppler; Epinephrine; Heart Failure; Hemodynamics; Male; Rabbits; Radioimmunoassay; Renin; Statistics, Nonparametric; Ventricular Dysfunction, Left

Few experimental studies are available on aging, because of the lack of suitable experimental models to test specific pathophysiologic mechanisms. In the present study, the cardiomyopathic Syrian hamster is proposed as experimental model of the aging myocardium. In fact, the hamster myocardium develops an early alpha to beta myosin isoform shifting in ventricles that is independent of hemodynamic overload and repeats the phenomenon physiologically occurring in healthy hamsters during the entire lifespan. At the same time, in atria there is a progressive decline of ANF production that is independent of intracavitary pressure. Conversely, ANF production in ventricles is enhanced before the onset of hemodynamic overload, but parallel to the increase in the fibrotic proportion of the ventricular wall. These characteristics mimic the modifications occurring in otherwise healthy aged mammals and candidate the cardiomyopathic hamster as a model of early myocardial aging.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Disease Models, Animal; Heart; Mesocricetus; Mice; Myocardium; Myosin Heavy Chains

Growth hormone (GH) improves cardiac function in the rat with myocardial infarction, but its effects in a model of primary dilated cardiomyopathy have not been reported. GH effects were examined at early (4 months) and late (10 months) phases of disease in the cardiomyopathic (CM) hamster, and the combination of GH with chronic ACE inhibition was assessed in late-phase heart failure.. CM hamsters (CHF 147 line) at 4 months showed severe systolic left ventricular (LV) dysfunction with normal LV filling pressure, and at 10 months there was more severe systolic as well as diastolic dysfunction with increasing myocardial fibrosis. Recombinant human GH alone for 3 weeks at age 4 months increased LV wall thickness and reduced systolic wall stress without altering diastolic wall stress, whereas at 10 months, wall stress and fractional shortening did not improve. The LV dP/dt(max) was enhanced at both ages by GH, which at 4 months reflected increased contractility, but at 10 months was most likely caused by elevation of the LV filling pressure. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by GH. In other CM hamsters, high-dose ACE inhibition alone (quinapril), started at 8 months and continued for 11 weeks, improved LV function and inhibited unfavorable remodeling, but the addition of GH for 3 weeks at age 10 months produced increased wall thickness with little additional functional benefit and increased the LV filling pressure and diastolic wall stress.. GH treatment alone improved LV dysfunction at 4 months of age in CM hamsters by increasing contractility and reducing wall stress but had few beneficial effects at 10 months in severe LV failure. After chronic ACE inhibition, addition of GH at 10 months had no additional beneficial effects and further increased LV diastolic pressure. These differing effects of GH may relate to the progressive increase of LV fibrosis in the CM hamster.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathies; Collagen; Cricetinae; Echocardiography; Fibrosis; Gene Expression Regulation; Heart; Heart Rate; Hemodynamics; Human Growth Hormone; Humans; Isoquinolines; Male; Mesocricetus; Myocardium; Quinapril; Rats; Recombinant Proteins; RNA, Messenger; Tetrahydroisoquinolines; Transcription, Genetic; Ventricular Function, Left

We investigated the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and their genes in the hearts of patients with cardiac amyloidosis and those with isolated atrial amyloidosis.. The expression of ANP and BNP is augmented in the ventricles of failing or hypertrophied hearts, or both. The expression of ANP and BNP in the ventricles of hearts with cardiac amyloidosis, which is hemodynamically similar to restrictive cardiomyopathy, is not yet known. ANP is the precursor protein of isolated atrial amyloid.. We analyzed the immunohistocytochemical localizations of ANP and BNP as well as the expression of their mRNAs by in situ hybridization in the myocardium and measured the plasma levels of ANP and BNP in patients with cardiac amyloidosis.. Four of the five right and all six left ventricular endomyocardial biopsy specimens obtained from six patients with cardiac amyloidosis were immunohistochemically positive for both ANP and BNP; none of the biopsy specimens from eight normal subjects were positive for ANP or BNP. All four of the right atria obtained at operation showed positive immunoreactions for both peptides. Electron microscopy identified specific secretory granules in ventricular myocytes of the patients with cardiac amyloidosis, but not in ventricular myocytes from the normal control subjects. Double immunocytochemical analysis revealed the co-localization of ANP and BNP in the same granules and that isolated atrial amyloid fibrils were immunoreactive for ANP and BNP, whereas ventricular amyloid fibrils were negative for both peptides. Both ANP mRNA and BNP mRNA were expressed in the ventricles of the patients with cardiac amyloidosis but not in the normal ventricles. The autopsy study of four patients with cardiac amyloidosis revealed an almost transmural distribution of ANP and BNP, with predominance in the endocardial side. Plasma BNP levels in the patients were markedly elevated ([mean +/- SD] 1,165.1+/-561.2 pg/ml) compared with those in the control subjects (8.9+/-6.0 pg/ml, p < 0.05).. Expression of ANP and BNP and their genes was augmented in the ventricular myocytes of the patients with cardiac amyloidosis. Both regional mechanical stress by amyloid deposits and hemodynamic stress by diastolic dysfunction may be responsible for the expression of the peptides in patients with cardiac amyloidosis.

Topics: Aged; Amyloidosis; Atrial Natriuretic Factor; Cardiomyopathies; Cytoplasmic Granules; Endocardium; Female; Gene Expression; Heart Ventricles; Humans; Immunohistochemistry; In Situ Hybridization; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; RNA, Messenger

The mechanisms responsible for abnormal fluid retention in congestive heart failure (CHF) are unclear. Studies were conducted to elucidate how endothelin (ET) may contribute to salt and water retention. Cardiomyopathic (CM) hamsters with moderate heart failure were employed for in vivo and in vitro trials. Clearance methods were used to compare the level of renal function in CM hamsters and control animals. Radioligand binding studies were also performed to determine ET receptor distribution in the inner medullary collecting ducts. CM hamsters exhibited an attenuated response to ANF infusion (FENa: 2.7 +/- 0.5 vs. 5.9 +/- 0.8%, p < 0.01; FEH2O: 1.7 +/- 0.3 vs. 3.2 +/- 0.4%, p < 0.01; UcGMP: 11.2 +/- 2.3 vs. 16.6 +/- 2.0 pmol/min, p < 0.05) and a decrease in total ET receptor density (532 +/- 77 vs. 959 +/- 154 fmol/mg protein, p < 0.005). Particularly ETB receptors were significantly reduced (214 +/- 26 vs. 483 +/- 88 fmol/mg protein, p < 0.003). Enalapril therapy simultaneously restored the natriuretic and diuretic effects of ANF and ET receptor density in the diseased animals. These studies suggest that the renin-angiotensin-aldosterone system and ET hormonal system act together, via ETB receptor downregulation, to promote the abnormal fluid retention observed in CHF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Water; Cardiomyopathies; Cricetinae; Down-Regulation; Enalapril; Glomerular Filtration Rate; Hematocrit; Kidney Medulla; Organ Size; Radioligand Assay; Receptor, Endothelin B; Receptors, Endothelin; Urodynamics

The influence of the atrial natriuretic factor (ANF) on heart-cell communication was investigated in cell pairs isolated from the ventricle of cardiomyopathic hamsters (BIO TO-2; 11 months old), and the results were compared with controls (F1B) of same age. The results indicated that ANF (10(-8) M) added to the bath caused a decline in junctional conductance (gj) of 48 +/- 2% (n = 15) within 90 s. The effect of ANF was suppressed by HS-142-1, a specific antagonist of guanylyl cyclase ANF receptor. Moreover, the decline in gj elicited by ANF was related to the synthesis of cyclic guanosine monophosphate (cGMP). Indeed, dibutyryl-cGMP (10(-4) M) decreased gj by 80 +/- 3.5% (n = 15) within 90 s, and zaprinast, a selective inhibitor of cGMP phosphodiesterase, enhanced the effect of ANF on gj. The possible relationship between ischemia, ANF release, and impairment of cell coupling is discussed.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Bucladesine; Cardiomyopathies; Cell Communication; Cricetinae; Cyclic GMP; Electrophysiology; Gap Junctions; Heart Failure; Heart Ventricles; Male; Mesocricetus; Phosphodiesterase Inhibitors; Purinones; Receptors, Atrial Natriuretic Factor

We evaluated 30 consecutive patients and 48 age- and sex-matched controls to explore the possibility of a pathogenic contribution by plasma endothelin-1 in the cardiac expression of systemic sclerosis. Venous plasma endothelin-1 was measured by radio-immunoassay and left ventricular function by echocardiography. The patient group had elevated plasma endothelin-1 (2.6 +/- 0.2 vs. 1.8 +/- 0.1 pmol/1, P < 0.001), but endothelin-1 was not related to age, heart rate, blood pressure, total peripheral resistance, disease duration or systemic sclerosis score. Endothelin-1 was related to left ventricular hypertrophy in terms of septal thickness (r = 0.33, P < 0.01) and left ventricular mass index (r = 0.32, P < 0.01). Plasma endothelin-1 was further related to measures indicating reduced left ventricular filling; left atrial emptying index (r = -0.50, P < 0.0005), the first third filling fraction (r = -0.31, P < 0.05) and the time velocity integral of Doppler early/late filling velocity (r = -0.40, P < 0.001). Furthermore, circulating endothelin-1 was related to impaired left ventricular contractility as estimated by pre-ejection period/left ventricular ejection time (r = 0.32, P < 0.01) and end-systolic wall stress/volume index (r = -0.30, P < 0.05). We conclude that plasma endothelin-1 is elevated in relation to the degree of left ventricular hypertrophy, diastolic dysfunction and impaired contractility in systemic sclerosis. It may be of pathogenic importance to the cardiac involvement in systemic sclerosis which is not mediated via an increase in systemic blood pressure. It is not yet clear whether our findings are exclusive to systemic sclerosis patients or represent a generalized phenomenon in patients with impaired left ventricular function.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cardiomyopathies; Case-Control Studies; Echocardiography; Endothelin-1; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Multivariate Analysis; Scleroderma, Systemic; Ventricular Dysfunction, Left

The level of plasma brain natriuretic peptide (BNP) was elevated in 8 of 15 female gene carriers of Duchenne muscular dystrophy (DMD), and the level correlated with indices of cardiac function. In one of these carriers, whose clinical course was followed for one year, the plasma BNP level was elevated before the development of cardiac symptoms, further increased with the evolution of cardiac symptoms, and then decreased after treatment for cardiac failure. These results suggest that the plasma BNP level may be useful for the early detection of cardiac dysfunction and for evaluating the efficacy of cardiac treatment in female DMD carriers.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Cardiomyopathies; Female; Heterozygote; Humans; Middle Aged; Muscular Dystrophies; Natriuretic Peptide, Brain; Nerve Tissue Proteins

Various alterations in the natriuretic peptide system have been observed in heart and plasma in humans and animals with heart failure. However, there is limited information about these hormones in hamster lung especially in those with genetic cardiomyopathy, a model of human congestive heart failure. Therefore, the aim of the present study was to investigate the content of the three natriuretic peptides (atrial natriuretic peptide (ANP); brain natriuretic peptide (BNP); C-type natriuretic peptide (CNP) and their gene expression in lungs of normal and cardiomyopathic hamsters. The presence of mRNA coding for ANP and BNP in lungs and heart was investigated by Northern blot and confirmed by reverse transcription polymerase chain reaction (RT-PCR). The peptide contents and plasma concentrations were determined by specific radioimmunoassays. Plasma ANP increased in hamsters with moderate to severe cardiomyopathy (aged 230 days) from control levels of 71.8+/-15.8 to 243.1+/-44.0 pg/ml (P < 0.01). Plasma BNP also increased from 79.7+/-23.5 to 227.9+/-51.6 pg/ml (P < 0.01). The levels of the three peptides in lungs of 30- and 120-day-old cardiomyopathic (CMO) hamsters were not different from their corresponding age-matched controls. However, lung ANP increased in 230-day-old CMO from 589+/-63 to 1624+/-219 pg/mg protein (P < 0.01). Lung BNP and CNP also increased from 332+/-35 to 531+/-55 pg/mg protein (P < 0.01) and from 118+/-21 to 224+/-29 pg/mg protein (P < 0.01), respectively. Lung ANP mRNA and BNP mRNA were significantly (P < 0.05) higher in 230-day-old hamsters than those detected in age-matched normal controls. Our data demonstrate that the hamster lungs produce ANP, BNP and CNP, and that this production is enhanced in moderate to severe cardiomyopathy. These findings imply that the lung natriuretic peptide system may participate in pulmonary function especially during cardiac dysfunction.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Lung; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Polymerase Chain Reaction; Proteins; RNA, Messenger

Cocaine abuse induces severe cardiomyopathy. To investigate the molecular effects of acute and prolonged administration of cocaine, mRNAs encoding markers of either mechanical overload, as atrial natriuretic factor (ANF) and alpha- and beta-myosin heavy chains, or fibrosis as type I and III procollagens, were quantitated in the left ventricle of rats 4 h after one injection of cocaine (40 mg/kg, n = 7), or 14 (n = 15) and 28 days (n = 10) after chronic infusion of cocaine (40 mg/kg per day). Plasma cocaine and benzylecgonine concentrations were both significantly augmented during the infusion while plasma levels of triiodothyronine and thyroxine were lowered. Acute injection of cocaine induced ANF gene expression. Cocaine treatment during 28 days resulted in left ventricular hypertrophy (+ 20% after 24 days, P < 0.05) with normal blood pressure, associated with an accumulation of mRNAs encoding ANF and type I and III collagens (+66% and +55%, P < 0.05). Such a chronic treatment also induced a shift from the alpha- to the beta-myosin heavy chain gene expression (-40% and +50%, P < 0.05). In conclusion, cocaine activates markers of both hemodynamic overload and fibrosis. Such an activation may result from direct and/or indirect effects of the drug such as myocardial ischemia, mechanical overload and/or hypothyroidism.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Cardiomyopathies; Cocaine; Collagen; Hemodynamics; Hormones; Male; Myocardium; Myosin Heavy Chains; Narcotics; Rats; Rats, Sprague-Dawley; RNA, Messenger

Patients with heart failure generally show improvement in their clinical condition after enoximone infusion over the period of treatment; this effect cannot be ascribed only to the known hemodynamic action of this drug. Thirty-six patients (age range 44-82 years) with heart failure (NYHA class II-IV) underwent 48-hour enoximone infusion to study whether this prolonged improvement might depend on changes in systemic or renal hemodynamics or in neurohormonal balance. All patients underwent Swan-Ganz hemodynamic monitoring; renal plasma flow, glomerular filtration rate, plasma atrial natriuretic factor (ANF), and plasma renin activity (PRA) were all measured at baseline, at the peak of the enoximone action, and 48 hours after drug discontinuation. The main hemodynamic parameters were significantly improved during enoximone infusion and after drug discontinuation. The cardiac index basal value of 2.2 +/- 0.1 l/min/m2 increased to 3.1 +/- 0.1 l/min/m2 after 24-hour therapy (p < 0.01); similarly, pulmonary wedge pressure, mean pulmonary arterial pressure, and right atrial pressure decreased markedly (p < 0.01). Beneficial effects were also observed in renal hemodynamics; indeed, renal plasma flow (basal value 485 +/- 39 ml/min) increased significantly after 24-hour enoximone infusion (575 +/- 35 ml/min; p < 0.01), and this tendency was also observed 48 hours after drug discontinuation. No significant modifications were observed in plasma hormone data; however, the PRA plasma level had a tendency to decrease. We conclude that in patients with heart failure, enoximone infusion has a less marked effect on renal hemodynamics, but this is more lasting than systemic hemodynamic effects. The tendency of PRA to decrease (although not statistically significant), still detectable 2 days after treatment in the presence of steady high plasma ANF concentrations, may also contribute to the paradoxical longlasting benefit despite the short-lived improvement in systemic hemodynamics after brief cycles of enoximone infusion.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Atrial Natriuretic Factor; Cardiomyopathies; Cardiotonic Agents; Enoximone; Female; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Kidney Function Tests; Male; Middle Aged; Renal Circulation; Renin

Atrial natriuretic factor (ANF) and ANF receptor C (ANF.RC) expression have been investigated in healthy and cardiomyopathic hamsters (CMPH) with widespread necrosis of the diaphragm and myocardium leading to respiratory and heart failure. ANF- and ANF.RC-producing cells were localized in different structures of the respiratory system, and the regulation of their expression by the individual and/or combined action of hypoxia and hemodynamic overload was analyzed. The study was performed in 20-, 90-, and 150-day-old animals using immunohistochemistry, in situ hybridization, Northern blot, and RIA analyses. ANF was shown to be expressed in the tracheo-bronchial epithelium and muscle and, to a lesser extent, in the alveolar wall and muscular media of the pulmonary arteries and extraparenchymal pulmonary veins in both healthy hamsters and CMPH. In 150-day-old CMPH, hypoxia (PaO2 < 50 mm Hg) induced a 10-fold increase in ANF messenger RNA accumulation and a 6-fold increase in the immunoreactive ANF (IR-ANF) concentration in lungs, as quantitated by RIA. As plasma IR-ANF concentrations were elevated in all CMPH age groups, it was most likely produced by the myocardium. ANF.RC messenger RNA was homogeneously distributed throughout the entire respiratory system and was increased 2-fold in hypoxic 150-day-old CMPH only. These results suggest that ANF originating in the respiratory system exerts only paracrine effects on different structures of the respiratory system in addition to the action of circulating ANF. Hemodynamic overload (left ventricular end-diastolic pressure, 17.20 +/- 3.80 mm Hg) might contribute to enhanced ANF gene expression only in extraparenchymal pulmonary vein walls of 150-day-old CMPH. We also propose that ANF.RC overexpression might be a protective mechanism operated via either ANF clearance or inhibition of adenylate cyclase activity to counteract exaggerated smooth muscle relaxation.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Gases; Gene Expression; Hemodynamics; Hydrogen-Ion Concentration; Hypoxia; Immunohistochemistry; In Situ Hybridization; Mesocricetus; Receptors, Atrial Natriuretic Factor; Respiratory System; RNA, Messenger; Tissue Distribution

This study was designed to characterize left ventricular (LV) function and mass in a modified cardiomyopathy model in the dog in which right ventricular pacing rates are gradually increased throughout 38 days. On the last day of the pacing protocol, ejection fraction was reduced (25 +/- 3 vs. 60 +/- 1%) and LV end-diastolic diameter index (a ratio of LV end-diastolic diameter to body weight, 2.09 +/- 0.02 vs. 1.79 +/- 0.08 mm/kg) and LV mass index (a ratio of LV mass to body weight, 5.2 +/- 0.3 vs. 4.3 +/- 0.2 g/kg) were greater than in the normal dogs (P < 0.05, respectively). Cardiac filling pressures increased, and LV diastolic function and coronary blood flow were impaired. After 4 wk of recovery from the progressive pacing protocol, LV end-diastolic diameter index (2.12 +/- 0.06 mm/kg) and LV mass index (5.6 +/- 0.2 g/kg) remained increased. Ejection fraction was improved (38 +/- 4%) but still depressed. LV diastolic function, coronary blood flow, and cardiac filling pressures returned to levels seen in the normal dogs. This modified cardiomyopathy model associated with LV hypertrophy complements the conventional tachycardia-induced cardiomyopathy model without LV hypertrophy.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cardiomyopathies; Dogs; Hemodynamics; Immunohistochemistry; Myocardium; Radioimmunoassay; Tachycardia; Ventricular Function

Atrial natriuretic peptide (ANP) kinetics was studied in 12 patients with idiopathic dilated cardiomyopathy at different sodium excretion (30-175 mmol/day) and variable degrees of hemodynamic dysfunction [New York Heart Association (NYHA) class range I-III] to investigate whether differences in renewal and distribution of this hormone (as compared with those of a control group) play a role in pathogenesis and evolution of heart failure. [125I]Labeled ANP was injected as a bolus, and a high-performance liquid chromatography (HPLC) procedure was used to purify the labeled hormone in venous plasma samples collected for < or = 50 min after injection; the main ANP kinetic parameters were then derived from the disappearance curve of the labeled hormone. As in controls, a positive linear regression between ANP metabolic clearance rate (MCR, ml/min/m2) values and daily urinary excretion of sodium (NaUE, mmol/day) was noted in patients. The different linear regression coefficients between normal subjects (MCR = 365 +/- 8.08 NaUE, r = 0.986, p < 0.0001) and patients (MCR = 497 + 18.5 NaUE, r = 0.867, p = 0.001) indicate that in patients a higher peptide clearance rate is needed to obtain the same biologic effect (sodium excretion) and suggest that resistance to biologic effects of the hormone exists in patients at an early stage of disease (NYHA class I). When the efficiency of the ANP system in excreting sodium was expressed as the ratio of NaUE to ANP production rate (PR = MCR x ANP plasma concentration, microgram/day/m2) patients showed significantly lower values (p = 0.0126) than normal volunteers, thus confirming resistance to the hormone effects. Significantly lower values for ANP total distribution volume (16.5 +/- 8.4 L/m2), mean residence time in the sampling space (4.04 +/- 1.14 min), mean residence time in the body (7.25 +/- 2.13 min), and fewer recycles through the initial (sampling) space (0.27 +/- 0.16) were noted in patients, indicating an altered mechanism regulating distribution of the hormone. The positive correlations between ANP MCR (L/min/m2) values and cardiac index (CI, L/min/m2) (MCR = -1.24 + 1.17 CI, r = 0.689, p = 0.0092) and between initial distribution volume (IDV, L/m2) and CI (IDV = -11.2 + 6.85 CI, r = 0.730, p = 0.0046) in all patients indicate that hemodynamic factors contribute to the progressive reduction in MCR and IDV values throughout the progression of myocardial involvement.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Cardiomyopathies; Cardiomyopathy, Dilated; Chromatography, High Pressure Liquid; Hemodynamics; Humans; Male; Metabolic Clearance Rate; Middle Aged; Radioimmunoassay; Radionuclide Angiography; Renin; Sodium

Myocardiopathy in rats with monocrotaline (MCT)-induced pulmonary hypertension was investigated morphologically and immunohistochemically. A single subcutaneous injection of MCT (60 mg/kg body weight) to SD rats produced progressive cardiac lesions. Histologically, the lesions were characterized by myocardial hypertrophy and myocardial degeneration followed by mononuclear cell infiltration and fibroblast proliferation in the right atrium and ventricle. Such histological changes began to be seen 3 weeks after injection and thereafter progressively developed in rats killed 4 and 5 weeks after injection. These findings indicate progressive hypertrophic myocardiopathy, due probably to pulmonary hypertension induced by MCT. Immunohistochemically, atrial natriuretic peptide (ANP)-positive myocardial cells were frequently observed in the left and right ventricle in MCT-treated rats killed 4 and 5 weeks after injection. The intensive immunopositive reaction was observed mainly in hypertrophic myocardial cells in the subendocardium of the right ventricle and also present in hypertrophic myocardial cells around injured areas consisting of degenerated myocardial cells, mononuclear cell infiltration and fibrosis. These findings suggest a close relationship between the ANP expression and cardiac hypertrophy in MCT-treated rats.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Hypertension, Pulmonary; Immunohistochemistry; Male; Monocrotaline; Rats; Time Factors

Brain and atrial natriuretic peptides (BNP and ANP) are cardiac hormones with diuretic, natriuretic, and vasodilatory activities. Cardiomyopathic hamsters are widely used animal models of heart failure. Due to the structural divergence of BNP among species, examination on pathophysiological roles of BNP using cardiomyopathic hamsters is so far impossible. We therefore isolated hamster BNP and ANP cDNAs, and investigated synthesis and secretion of these peptides in normal and cardiomyopathic hamsters. The COOH-terminal 32-residue peptide of cloned hamster preproBNP with 122 amino acids, preceded by a single arginine residue, supposedly represents hamster BNP showing < 50% homology to rat BNP. Alpha-hamster ANP, 28-residue peptide, is identical to alpha-rat ANP. In hamsters, BNP and ANP occur mainly in the ventricle and the atrium, respectively. The 32-wk-old hypertrophic cardiomyopathic BIO14.6 strain exhibited ventricular hypertrophy. The 32-wk-old dilated cardiomyopathic BIO53.58 strain remained at the stage without apparent heart failure. In BIO14.6 and BIO53.58 strains at this age, ventricular BNP and ANP gene expressions are augmented, and the plasma BNP concentration is elevated to 136 and 108 fmol/ml, respectively, three times greater than the elevated plasma ANP concentration, which well mimics changes of the plasma BNP and ANP concentrations in human heart failure. Cardiomyopathic hamsters, therefore, are useful models to investigate the implication of BNP in human cardiovascular diseases.

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Base Sequence; Blotting, Northern; Cardiomyopathies; Cloning, Molecular; Conserved Sequence; Cricetinae; DNA Primers; DNA Probes; DNA, Complementary; Gene Expression; Heart Atria; Heart Ventricles; Humans; Mesocricetus; Mice; Molecular Sequence Data; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Polymerase Chain Reaction; Rats; Restriction Mapping; RNA, Messenger; Sequence Homology, Amino Acid

Topics: Adult; Atrial Fibrillation; Atrial Natriuretic Factor; Biopsy; Cardiomyopathies; Chronic Disease; Female; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Tachycardia

Ventricular cardiomyocytes represent the most important source of atrial natriuretic factor (ANF) in pathological conditions such as congestive heart failure (CHF). It has been suggested that in cardiomyopathic Syrian hamster ventricles the ANF gene can be reactivated during the hypertrophic stage occurring before heart failure. The present study was undertaken to investigate ANF gene expression during early stages of myocardial damage and its distribution throughout atrial and ventricular myocardium in UM-X7.1 cardiomyopathic Syrian hamsters (CMPH) before hypertrophy and cardiac failure occur. Atria, right and left ventricles, and interventricular septum of hearts of 20-23 days old (young) and 90-95 days old (adult) CMPH were studied. The absence of hypertrophy and cardiac failure was preliminarly ascertained by microscopic and hemodynamic evaluation. ANF-mRNA as well as tissue and plasma immunoreactive ANF were assayed. Moreover, ANF secretion pattern was evaluated by immunocytochemical techniques. Young and adult CMPH hearts were in the necrotic stage of myocardial disease, as demonstrated by histopathological evaluation and by decreased wet weights (mg/g body weight) of different heart regions. Hemodynamic assessment showed no significant changes of left ventricular end-diastolic pressure (LVEDP) and a decrease of the left ventricular peak systolic pressure (LVSP) and +dP/dt. Plasma immunoreactive ANF (IR-ANF) levels were higher in young (3-fold) and adult (6-fold) CMPH than in age-matched normal hamsters. A reduced IR-ANF concentration (per milligram protein) was observed in both young and adult cardiomyopathic atria in respect to healthy controls, whereas a higher IR-ANF concentration was present in ventricles. A 3-fold, 6-fold and 20-fold increase of IR-ANF concentration was found in right ventricular free-wall (RV), left ventricular free-wall (LV) and interventricular septum (IVS), respectively. Northern-blot analysis confirmed that IVS was the major site of ventricular ANF-mRNA transcription in both young and adult CMPH. ANF-mRNA was increased also in atria where a faster peptide secretion can be hypothesized to lower tissue IR-ANF concentration. ANF secretion in ventricular myocardium was achieved via constitutive pathway as demonstrated by immunocytochemistry. Different patterns of ANF gene reactivation occur in CMPH myocardium before intraventricular pressure increases and structural hypertrophic modifications are detectable. The extent of ANF

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Gene Expression; Heart Ventricles; Hemodynamics; Immunohistochemistry; Mesocricetus; Myocardium; Random Allocation; Reference Values; RNA, Messenger; Time Factors

Topics: Amyloidosis; Atrial Natriuretic Factor; Cardiomyopathies; Female; Heart Atria; Heart Failure; Humans; Middle Aged; Systole

Studies were done in male cardiomyopathic and normal hamsters to examine the effect of heart failure on atrial natriuretic factor (ANF) secretion. Five groups of animals were studied. The hamsters were 70, 150, 200, 250 and 300 days old. The degree of heart failure became more severe with age. This was associated with a marked increase in left and right atrial weight. Plasma ANF rose in the cardiomyopathic hamsters with age, and no significant change was seen in the normal animals. ANF levels in the atrial tissue declined as the animals developed heart failure, suggesting that ANF release increased in heart failure. To examine these directly, the right and left atria of these animals were isolated and superfused in a modified Langendorff apparatus. The effluents from these experiments were collected and analyzed for ANF levels. Analysis showed that ANF secretion (expressed as pg/min/mg of tissue) declined in heart failure. Since there were significant atrial hypertrophy, the results were also expressed as picogram per minute per atrium. When the data were shown as picogram per minute per atrium, there was a marked increase in ANF secretion. The present data show that one of the factors causing an increase in circulating ANF in heart failure is augmented secretion.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Heart Atria; Heart Failure; Male; Mesocricetus

In order to determine the involvement of the atrial natriuretic factor (ANF) in a model of drug-induced cardiomyopathy, the effects of a single or repeated doses of doxorubicin on plasma ANF levels were examined. Female Wistar rats were treated with doxorubicin at two different schedules: a single 10 mg/kg iv dose or multiple 3 mg/kg iv doses once a week for 3 weeks; control groups were given vehicle (isotonic saline, 0.9% NaCl) intravenously. ANF was assayed in plasma by a specific and sensitive radioimmunoassay method and cardiac function was evaluated by monitoring of ECG and hemodynamic parameters. In the doxorubicin single-dose study plasma ANF values were measured during a period of 6 hours after dosing and were found to be significantly decreased at the 180th (12.5 +/- 2.9 pg/ml) and 360th minute (19.4 +/- 1.2 pg/ml) after dosing, compared to vehicle-treated animals (35.1 +/- 5.7 and 37.9 +/- 4.1 pg/ml, 180 and 360th minute, respectively). Rats treated with multiple doses of doxorubicin showed a significant increase in plasma ANF levels at the 21st (88.3 +/- 7.7 pg/ml) and 31st day (61.0 +/- 14.3 pg/ml) of the study compared to vehicle-treated animals at the same time points (41.8 +/- 8.0 and 26.5 +/- 7.2 pg/ml, respectively). At the 42nd day plasma ANF concentration in doxorubicin-treated rats was not significantly different from vehicle-treated rats. In both studies ANF level changes occurred in the setting of acute or chronic doxorubicin-induced cardiac damage, as evidenced by alterations of hemodynamic and ECG parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Disease Models, Animal; Doxorubicin; Rats; Rats, Inbred Strains

In patients with congestive heart failure, the release of atrial natriuretic peptide (ANP) is decreased. This study sought to determine the extent of ANP, sympathetic and haemodynamic responses to acutely increased atrial pressure in patients with cardiomyopathies undergoing orthotopic cardiac transplantation. Haemodynamic variables, plasma ANP, norepinephrine, and epinephrine concentrations were measured in 17 patients at five times before and after induction of anaesthesia using either ketamine 1.5 micrograms.kg-1 or sufentanil 3.6 +/- 0.3 micrograms.kg-1. Preinduction values in the ketamine and sufentanil groups were not significantly different. Compared with preinduction values, increases in mean arterial pressure (26%), pulmonary capillary wedge pressure (90%), right atrial pressure (107%), and heart rate (24%) occurred in the ketamine group while cardiac index decreased by 19% (P less than 0.05). Haemodynamic variables in the sufentanil group did not change at any of the times studied. Plasma concentrations of atrial natriuretic peptide were not different within or between treatment groups. Following tracheal intubation plasma norepinephrine levels increased by 116% in the ketamine group (P less than 0.05), but did not change in the sufentanil group. Plasma norepinephrine concentrations differed significantly between the ketamine and sufentanil groups. There were no differences in epinephrine concentrations in either group. Despite the anticipated haemodynamic and catecholamine differences found between the ketamine and sufentanil groups, the levels of plasma ANP were similar. Based upon these results, it is concluded that ANP exerts little influence in the control of fluid volume or blood pressure in patients with refractory cardiomyopathy.

Topics: Adult; Anesthesia, Intravenous; Anesthetics; Atrial Function, Right; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiomyopathies; Epinephrine; Female; Fentanyl; Heart Rate; Heart Transplantation; Humans; Ketamine; Male; Middle Aged; Narcotics; Norepinephrine; Pulmonary Wedge Pressure; Stroke Volume; Sufentanil; Vascular Resistance

Atrial amyloid deposits are common in the ageing human heart and contain alpha-atrial natriuretic peptide (proANP99-126) immunoreactivity. However, atrial myocytes secrete both amino and carboxy terminal fragments of the ANP prohormone (proANP1-126) and also express an homologous, but separate brain natriuretic peptide (BNP). Characteristic amyloid deposits were identified in the atria of 9/22 patients (26-63 years of age) with end-stage heart failure. Amyloid fibrils displayed immunoreactivity for both amino and carboxy terminal fragments of proANP1-126 and for the distinct BNP sequence. As in other endocrine organs, both mature and precursor peptide sequences appear to be constituents of amyloid fibrils. Whilst immunoreactivity for cardiac peptide hormones is co-localized in atrial amyloid deposits, it is uncertain whether the increase in natriuretic peptide expression which accompanies cardiac failure contributes to the incidence of isolated atrial amyloidosis.

Topics: Adolescent; Adult; Amyloid; Amyloidosis; Atrial Natriuretic Factor; Cardiomyopathies; Coronary Disease; Female; Heart Atria; Heart Diseases; Heart Valve Diseases; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Muscle Proteins; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protein Precursors

An elevated plasma concentration of atrial natriuretic peptide (ANP) is characteristic of congestive heart failure (CHF) in both humans and animals. One strategy for facilitating the biological actions of this circulating hormone is to inhibit its metabolism. Neutral endopeptidase 24.11, an enzyme known to degrade ANP, has been implicated in the metabolic clearance of this hormone. Inhibition of endopeptidase 24.11 may produce increases in the local concentrations of ANP in organs rich in the enzyme, such as the kidney, thereby enhancing local actions, e.g. natriuresis. Exogenous administration of ANP to CHF patients produces limited natriuresis, perhaps because of the associated fall in arterial pressure. This approach of blocking endopeptidase 24.11 activity in CHF could offset the general effects of exogenous administration of ANP and result in enhanced natriuresis. We therefore undertook studies to determine if thiorphan, an endopeptidase 24.11 inhibitor, would increase circulating ANP levels and enhance natriuresis in conscious cardiomyopathic hamsters with CHF. Cardiomyopathic hamsters had significantly lower (P less than .05) basal mean arterial pressures in comparison to normal hamsters (90 +/- 2 vs. 135 +/- 3 mm Hg). Treatment with thiorphan (10 mg/kg i.v. bolus followed by 10 mg/kg/hr i.v. infusion) did not change arterial pressure in either group and produced a 3-fold increase in urinary sodium excretion in the cardiomyopathic group but not in the normal hamsters. This natriuretic response in the cardiomyopathic hamsters was associated with a doubling of the plasma concentration of ANP. These results indicate that inhibition of endopeptidase 24.11 increases natriuresis and circulating ANP concentrations in this model of CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Heart Failure; Male; Neprilysin; Sodium; Thiorphan

The present study reports about novel findings concerning the interrelationship between release of human atrial natriuretic factor (hANP) and the clinical situation of patients suffering from congestive heart failure. Estimations of plasma hANP were done by specific and sensitive extraction-based RIA. The normal range was 5 to 80 ng/l, mean +/- SEM = 30 +/- 15 ng/l, n = 106. Influence of response to therapy on hANP-release was studied in altogether 14 patients. 12 of these patients had elevated plasma hANP at admittance, surprisingly peptide levels were normal in 2 patients throughout the study. 9 out of the 14 patients responded well to therapy (shift from NYHA IV/III to NYHA II within about 10 days), hANP-levels decreased to normal values: 235 +/- 104 ng/l vs. 65 +/- 13 ng/l; p less than 0.001. The 5 residual patients responded to therapy only partially (shift from HYHA IV to NYHA III within an observation interval of about 2 weeks). Plasma hANP values decreased from 225 +/- 94 ng/l to 137 +/- 22 ng/l (p less than 0.02), but were still supranormal. Atrial fibrillation, which persisted in 8 out of the 14 patients after therapy did not influence hANP levels: hANP levels paralleled clinical signs of improvement, irrespective of atrial fibrillation. Right heart catheterization revealed very high mean right atrial pressures in those 2 patients mentioned above, who had normal pretherapeutic hANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Fibrillation; Atrial Flutter; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiomyopathies; Cardiotonic Agents; Diuretics; Female; Heart Failure; Heart Valve Diseases; Humans; Longitudinal Studies; Male

The regulation of water and electrolyte homeostasis is multifactorial and includes the heart and kidneys as important regulatory centers. Within the heart, a recently discovered hormone, atrial natriuretic factor (ANF), has been implicated in the maintenance of water and salt balance. Primarily found in mammalian atria, ANF has been detected in low amounts in several tissues, including lungs. A disorder of the ANF system has been demonstrated in genetically cardiomyopathic hamsters, a model for human congestive cardiomyopathy. Atrial ANF gene expression and storage are decreased during development of this disease, while paradoxically, circulating levels of ANF are increased. We have hypothesized that an extracardiac source may contribute to ANF production in these pathological conditions. In this paper we provide evidence that ANF synthesis is stimulated in the lungs of hamsters during development of cardiomyopathy as revealed by increased ANF mRNA and peptide levels. Furthermore, we show that ANF synthesized in lungs is secreted and has identical chromatographic and biological properties to circulating ANF. The increased production of ANF in lungs may be physiologically important in preventing pulmonary edema. Alternatively, during cardiac dysfunction, lungs may play a compensatory role by increasing their contribution to plasma ANF levels.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Heart Atria; Heart Failure; Lung; Peptide Biosynthesis; Perfusion; RNA, Messenger

The aim of the present study was to correlate in cardiomyopathic hamsters with congestive heart failure the levels of atrial and ventricular atrial natriuretic factor (ANF) messenger RNA (mRNA) with immunoreactive ANF (IR-ANF) plasma levels and the relative amount of IR-ANF released by the whole heart versus isolated ventricles in the Langendorff preparation. High-performance liquid chromatography analysis of the forms of ANF present in plasma and in the Langendorff effluent of whole heart versus isolated ventricles was also performed. As previously found for cardiac IR-ANF, the levels of ANF mRNA decreased gradually in atria and increased in an analogous fashion in ventricles with the severity of congestive heart failure. Plasma IR-ANF levels (C-terminal) were more elevated in moderate than in severe congestive heart failure, as were the IR-ANF levels in the Langendorff effluent of the whole heart. On the contrary, the effluent of isolated ventricles from animals in severe heart failure yielded more IR-ANF than that from hamsters in moderate heart failure. Thus, while the isolated ventricles from controls contributed 35.8% of IR-ANF released by the whole heart, ventricles from hamsters in moderate heart failure contributed 17.5%, and those from hamsters in severe heart failure contributed 73.9%. These results indicate that atrial cardiocytes contribute more IR-ANF than their ventricular counterpart in moderate heart failure and that ventricles are a major source of plasma IR-ANF in severe heart failure. Analysis of IR-ANF from plasma and the Langendorff effluent from whole hearts and isolated ventricles revealed that the ventricles are the major source of the propeptide (and of its cleaved products) found in the circulation of cardiomyopathic hamsters. These results suggest that ANF synthesis and secretion do not increase conjointly in atria but do increase in ventricles during congestive heart failure.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Northern; Cardiomyopathies; Chromatography, High Pressure Liquid; Cricetinae; Heart Failure; Heart Ventricles; Immunohistochemistry; Mesocricetus; Myocardium; Plasma; Reference Values; RNA, Messenger

1. A biventricular, low-output congestive cardiomyopathy was induced in 19 rabbits by administering adriamycin (16 mg/kg). The effects of alpha-rat atrial natriuretic peptide (ANP) infused at 0.1, 0.2 and 0.4 micrograms/kg per min, were then examined in terms of (i) central haemodynamics (ii) regional blood flow (iii) renal function and (iv) plasma norepinephrine and plasma renin. 2. In this dose range, ANP produced progressive and significant falls in stroke volume, cardiac output and mean arterial pressure, owing to a fall in venous return. The heart rate response to this was blunted. 3. Using radiolabelled microspheres, significant falls in the perfusion of cutaneous, gastrointestinal and musculoskeletal tissues were observed, due to reduced vascular conductances in these beds. These changes were accompanied by activation of the sympathetic nervous system as evidenced by a progressive rise in plasma norepinephrine. A significant increase in plasma renin was only observed with the highest infusion of ANP. 4. Renal blood flow was maintained in the face of a falling mean arterial pressure and cardiac output, but diuretic and natriuretic effects were absent. 5. It was concluded that the dominant influence of ANP infusion in this model of heart failure appeared to be a reduction in cardiac preload with detrimental overall haemodynamic consequences.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Body Fluids; Cardiac Output; Cardiomyopathies; Doxorubicin; Heart Failure; Infusions, Intravenous; Injections, Intraventricular; Kidney; Kidney Function Tests; Male; Norepinephrine; Rabbits; Renin

To determine a possible basis for the decreased action of atrial natriuretic factors (ANF) in congestive heart failure, we compared the cardiomyopathic hamster (CMH) in frank congestive failure, and the age-matched, normal, F1B strain of Golden Syrian Hamsters. Scatchard analysis of competitive binding studies revealed two classes of glomerular receptors. The CMH exhibited decreased binding overall and a markedly decreased number of high affinity receptors but comparable receptor affinity compared to the F1B. In contrast, the low affinity receptor population in the CMH had a much greater affinity compared to the F1B while receptor number was similar. Plasma ANF levels were substantially elevated in the CMH compared to the F1B and in-vitro generation of cGMP was significantly lower in the CMH. Such abnormalities could contribute to the resistance to ANF in this disease.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Cricetinae; Cyclic GMP; Heart Failure; Kidney Glomerulus; Kinetics; Mesocricetus; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Second Messenger Systems

A quantitative in vitro autoradiographic study was performed on the aorta, renal glomeruli, and adrenal cortex of cardiomyopathic hamsters in various stages of heart failure and correlated, in some instances, with in vivo autoradiography. The results indicate virtually no correlation between the degree of congestive heart failure and the density of 125I-labeled atrial natriuretic factor [(Ser99, Tyr126)ANF] binding sites (Bmax) in the tissues examined. Whereas the Bmax was increased in the thoracic aorta in moderate and severe heart failure, there were no significant changes in the zona glomerulosa. The renal glomeruli Bmax was lower in mild and moderate heart failure compared with control and severe heart failure. The proportion of ANF B- and C-receptors was also evaluated in sections of the aorta, adrenal, and kidney of control and cardiomyopathic hamsters with severe heart failure. (Arg102, Cys121)ANF [des-(Gln113, Ser114, Gly115, Leu116, Gly117) NH2] (C-ANF) at 10(-6) M displaced approximately 505 of (Ser99, Tyr126)125I-ANF bound in the aorta and renal glomeruli and approximately 20% in the adrenal zona glomerulosa in both series of animals. These results suggest that ANF may exert a buffering effect on the vasoconstriction of heart failure and to a certain extent may inhibit aldosterone secretion. The impairment of renal sodium excretion does not appear to be related to glomerular ANF binding sites at any stage of the disease.

Topics: Adrenal Glands; Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Autoradiography; Cardiomyopathies; Computer Simulation; Cricetinae; Disease Models, Animal; Heart Failure; Iodine Radioisotopes; Kidney; Kidney Cortex; Kidney Glomerulus; Kidney Medulla; Kinetics; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Reference Values

Since previous investigations have suggested a relationship between atrial natriuretic factor (ANF) and dopamine-beta-hydroxylation, cardiomyopathic hamsters were studied for atrial and ventricular catecholamine (CA) and dopamine-beta-hydroxylase (D beta H) content as correlates to a parallel finding of markedly decreased atrial but increased ventricular ANF concentrations in these animals. It was noted that, with progressive cardiomyopathy, the reduced tissue norepinephrine (NE) content paralleled the declining D beta H activity in the atria. In the ventricles, however, the progressively-decreasing NE content was associated with an increase of D beta H. These data indicate that the NE depletion is mediated by different mechanisms in the ventricles and atria. They do not support a simple relationship between NE depletion and tissue D beta H activity or between the latter and tissue ANF concentrations.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathies; Catecholamines; Cricetinae; Dopamine; Dopamine beta-Hydroxylase; Heart Atria; Heart Ventricles; Mesocricetus; Norepinephrine

Chronic infusion of atrial natriuretic factor (ANF) decreased blood pressure in two-kidney, one clip (2-K, 1C), spontaneously hypertensive rat (SHR) and one-kidney, one clip (1-K, 1C) models of experimental hypertension in the rat, but produced increased sodium excretion only in the 1-K, 1C model. In ANF-infused 2-K, 1C animals plasma renin activity did not differ from normotensive controls. Atrial content of immunoreactive (ir) ANF was significantly lower in SHR and 1-K, 1C animals. At 40-50 days old, cardiomyopathic hamsters had a higher concentration of plasma irANF and a lower ANF content in the left but not in the right atrium, although the difference in plasma ANF was more obvious once heart failure was well established. At 110-130 and 200-300 days old, the hamster atrial ANF content was not only lower in the left but also in the right atrium. No differences were observed in plasma irANF between normal subjects and either untreated or treated essential hypertensive patients. However, a significantly higher plasma ANF was observed in two groups with secondary hypertension, primary hyperaldosteronism and renovascular hypertension. Bolus injection of ANF into healthy subjects produced a dose-related decrease in blood pressure and an increase in the heart rate and natriuresis.

Topics: Adult; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathies; Cricetinae; Humans; Hypertension; Hypertension, Renovascular; Male; Mesocricetus; Natriuresis; Peptide Fragments; Rats; Rats, Inbred Strains; Rats, Inbred WKY; Renin

Immunoreactive atrial natriuretic factor (IR-ANF) was measured in plasma and atrial extracts from normal and cardiomyopathic Syrian golden hamsters. Plasma IR-ANF was increased from 84.8 +/- 9.8 pg/ml (n = 17) to 234 +/- 23 (n = 25; P less than .0001) in hamsters with moderate failure, and to 1085 +/- 321 pg/ml (n = 10; P less than .02) in animals with severe failure. Plasma IR-ANF increased with increased atrial hypertrophy. Atrial IR-ANF content was essentially the same in normal animals and in those with moderate heart failure (3.06 +/- 0.28 vs. 3.17 +/- 0.19 microgram/100 g body wt.) and lower in the majority of those with severe failure (1.82 micrograms/100 g body wt., P less than .001). The elevations of IR-ANF in plasma are similar to those seen in patients with congestive heart failure. Our studies do not support bioassay results showing a deficiency of atrial ANF content as being important in the congestive heart failure associated with cardiomyopathy in the hamster.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomyopathies; Cricetinae; Heart Atria; Heart Failure; Male; Mesocricetus; Organ Size; Radioimmunoassay

Plasma concentrations of the atrial natriuretic peptide (ANP) were measured during cardiac catheterization in 289 patients with heart disease. It was elevated in all types of cardiac disease investigated, irrespective of the nature and duration of the disease. Close relationships were observed between the elevated ANP concentrations and the increased right and/or left atrial pressure. Further increments in ANP concentration were measured during exercise in direct response to the rise in mean pulmonary artery pressure. Thus, ANP concentrations may be regarded as a non-invasive marker of the haemodynamic burden in cardiac disease.

Topics: Atrial Natriuretic Factor; Cardiomyopathies; Cardiomyopathy, Dilated; Chronic Disease; Heart Diseases; Heart Valve Diseases; Hemodynamics; Humans; Osmolar Concentration; Physical Exertion; Rest

Constriction of the thoracic inferior vena cava to decrease venous return and atrial filling markedly elevates plasma renin activity (PRA) and plasma aldosterone concentration (PAC) and produces chronic sodium retention and ascites in the dog. Infusion of a synthetic atrial natriuretic factor into conscious dogs with caval constriction and ascites at doses of 175 and 350 ng X kg-1 X min-1 for 30 min each produced striking increases (P less than 0.05) in creatinine clearance, diuresis, and kaliuresis but failed to increase urinary sodium excretion. Infusions of atrial natriuretic factor at these doses into conscious normal dogs, however, produced a striking increase in sodium excretion from 41 +/- 14 and 55 +/- 19 mu eq/min to 150 +/- 58 and 181 +/- 49 mu eq/min (P less than 0.05 for both values). Creatinine clearance and urine flow also increased in these normal dogs, but potassium excretion remained unchanged during the infusion periods. Atrial natriuretic factor produced parallel suppression (P less than 0.05) of the elevated levels of PRA and PAC in the caval dogs but failed to significantly decrease either PRA or PAC in the normal animals. Arterial pressure, heart rate, and PAH clearance were unchanged in both groups of dogs during infusion of atrial natriuretic factor. These results suggest that the pattern of renal electrolyte excretion elicited in response to the acute infusion of atrial natriuretic factor is dependent, at least partially, on the preexisting status of the renal tubules to facilitate sodium reabsorption and potassium excretion. The results also are consistent with the concept that atrial natriuretic factor might function to tonically inhibit the renin-angiotensin-aldosterone system.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiomyopathies; Consciousness; Constriction, Pathologic; Creatine; Dogs; Female; Heart Rate; Kidney; Muscle Proteins; p-Aminohippuric Acid; Potassium; Renin; Sodium; Vena Cava, Inferior