Comparison of clinical and morphologic cardiac findings in patients having cardiac transplantation for ischemic cardiomyopathy, idiopathic dilated cardiomyopathy, and dilated hypertrophic cardiomyopathy

This article compares intergroup and intragroup clinical and morphologic findings in patients with ischemic cardiomyopathy (IC), idiopathic dilated cardiomyopathy (IDC), and dilated hypertrophic cardiomyopathy (HC) undergoing cardiac transplantation (CT). Few previous publications have described findings in native hearts explanted at the time of CT. The explanted heart in 92 patients having CT was examined in uniform manner with particular attention to the sizes of the ventricular cavities and the presence of and extent of ventricular scarring. Of the 92 hearts examined, 47 had IC, 35 had IDC, and 10 had dilated HC. Although considerable degrees of intragroup variation occurred, the mean degree of left ventricular dilatation was similar among the patients with IC, IDC, and dilated HC. All patients with IC had left ventricular free wall scarring more extensive than that involving the ventricular septum, but the intragroup variation in the amounts of scarring was considerable. Nine of the 10 patients with dilated HC also had ventricular wall scarring, but it was more extensive in the ventricular septum than in the left ventricular free wall and involvement of the right ventricular wall also was present. Eight (23%) of the 35 IDC patients also had grossly visible ventricular scars but they were small and only 1 of the 8 had coronary narrowing and that was not in the distribution of the scarring. Narrowing of 1 or more epicardial coronary arteries >75% in cross-sectional area by plaque was present in all 47 IC patients, in 8 of the 35 IDC patients (7 had no ventricular scars), and in none of the 10 dilated HC patients. Coronary angiography was the major clinical tool allowing separation of the IC, IDC, and HC patients. Coronary angiography did not detect narrowing in any of the 8 patients with IDC who were found to have coronary narrowing on anatomic study. Thus, among patients with IC, IDC, and dilated HC having CT, distinctive anatomic features allow separation of patients with IC, IDC, and dilated HC, but within each group considerable variation in left ventricular cavity size and extent of ventricular scarring occurs.     

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.     

An investigation into the interaction between drug efficacy and drug price of praziquantel in determining the cost-effectiveness of school-targeted treatment for Schistosoma mansoni using a population dynamic model

The data from animal and human in-vivo studies suggest that cardiac function is dependent in part on the normal function of the GH/IGF-1 axis (growth hormone/insulin-like growth factor-1). The syndrome of heart failure appears to be associated with a perturbation of the GH/IGF-1 axis. So far encouraging results from phase II clinical trials evaluating the effects of long-term growth hormone treatment in patients with moderate to severe chronic congestive heart failure due to dilated cardiomyopathy have been published. In these studies growth hormone (i.e., DNA-derived recombinant human growth hormone) was not used alone but in addition to standard optimal therapy for chronic heart failure. The following rationale is the basis of this new approach for the treatment of chronic congestive heart failure due to dilated cardiomyopathy. According to Laplace's Law, cardiac wall stress(i.e., the force acting per unit of cross-sectional area of the ventricular wall) is directly related to intraventricular pressure and ventricular radius and inversely related to ventricular wall thickness. Cardiac (ventricular) wall stress if increased in dilated cardiomyopathy (mainly because of the dilatation of the ventricles and to a minor extent because of the relative reduction in ventricular thickness). Growth hormone seems to be capable of increasing ventricular wall thickness in dilated cardiomyopathy, thus, reducing cardiac wall stress which in turn leads to an improvement in systolic cardiac performance. Recombinant human growth hormone as a pharmacologic treatment is not only an expensive but also risky therapeutic modality (e.g., potential risk of inducing colonic carcinoma, de-novo leukemias, relapses of leukemias and central nervous system tumors). Given these prerequisites and a receptivity for cost effectiveness and risk-benefit analyses, it seems as if subcutaneous recombinant human growth hormone-as an additional therapeutic substance in conjunction with one of the widely accepted drugs for end-stage chronic congestive heart failure due to dilated cardiomyopathy-e.g., angiotensin converting-enzyme inhibitors, diuretics, nitrates, digoxin, and beta-adrenergic receptor blockers (Carvedilol) could either become a bridge to transplantation (i.e., supporting patients awaiting transplantation) or an alternative to the very expensive cardiac transplantation. There are three reasons for this hypothesis. First, the fact that end-state dilated cardiomyopathy along with ischemic heart disease are the main indications for heart transplantation in adults; second, the worldwide small supply of human donor organs for heart transplantation; and, third, the urgent need to find alternative cost-effective and risk-beneficial therapeutic modalities.     

Bilateral adrenal ganglioneuroblastomas in a teenage boy

We report perioperative management of two patients with severe dilated cardiomyopathy belonging to the group IV of classification of Inoh (ejection fraction 18% and 30%). In the preoperative period, they developed severe congestive heart failure. Dopamine, dobutamine, and furosemide were given to improve cardiac function. Anesthesia was performed safely under continuous cardiac output and mixed venous saturation monitoring. We consider that preoperative evaluation and management are very important to prevent intraoperative and postoperative complications in patients with severe dilated cardiomyopathy.     

Incidence of primary malignancies other than breast cancer among women treated with radiation therapy for benign breast disease

In addition to left ventricular pump failure and low cardiac output, structural and metabolic alterations of skeletal muscle are thought to contribute to exercise intolerance seen in patients with CHF. Studies using cardiac myocytes have implicated nitric oxide elaborated by inducible nitric oxide synthase (iNOS) as a potential agent associated with the genesis of dilated cardiomyopathy. The present study was designed to locate iNOS in the working skeletal muscle of patients with congestive heart failure. Specific antibodies were used to detect iNOS by immunohistochemistry in skeletal muscle biopsies (m. vastus lateralis) of 37 patients with left ventricular pump failure and 8 normal controls. The expression was restricted to skeletal muscle myocytes and was increased five- to ninefold in patients with chronic heart failure. There was no statistically significant difference in iNOS expression between patients with dilated cardiomyopathy and those with ischemic cardiomyopathy. The finding of a locally increased expression of iNOS and the experimental evidence that NO attenuates the contractile performance of the skeletal muscle suggest that the expression of iNOS may be responsible for the exercise intolerance seen in patients with chronic heart failure.     

Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23

Inherited cardiomyopathies may arise from mutations in genes that are normally expressed in both heart and skeletal muscle and therefore may be accompanied by skeletal muscle weakness. Phenotypically, patients with familial dilated cardiomyopathy (FDC) show enlargement of all four chambers of the heart and develop symptoms of congestive heart failure. Inherited cardiomyopathies may also be accompanied by cardiac conduction-system defects that affect the atrioventricular node, resulting in bradycardia. Several different chromosomal regions have been linked with the development of autosomal dominant FDC, but the gene defects in these disorders remain unknown. We now characterize an autosomal dominant disorder involving dilated cardiomyopathy, cardiac conduction-system disease, and adult-onset limb-girdle muscular dystrophy (FDC, conduction disease, and myopathy [FDC-CDM]). Genetic linkage was used to exclude regions of the genome known to be linked to dilated cardiomyopathy and muscular dystrophy phenotypes and to confirm genetic heterogeneity of these disorders. A genomewide scan identified a region on the long arm of chromosome 6 that is significantly associated with the presence of myopathy (D6S262; maximum LOD score [Z(max)] 4.99 at maximum recombination fraction [theta(max)] .00), identifying FDC-CDM as a genetically distinct disease. Haplotype analysis refined the interval containing the genetic defect, to a 3-cM interval between D6S1705 and D6S1656. This haplotype analysis excludes a number of striated muscle-expressed genes present in this region, including laminin alpha2, laminin alpha4, triadin, and phospholamban.     

Molecular and cellular changes in vein grafts: influence of pulsatile stretch

Sudden cardiac death is frequent in patients with dilated cardiomyopathy. To assess the risk of an arrhythmic event is still difficult. Here the analysis of the heart rate variability offers new possibilities. METHOD: 25 patients (18 males, 7 females, age 53 +/- 9 yrs) with dilated cardiomyopathy were included in the study. Analysis of heart rate variability assessed by time- and frequency-domain measures was determined from Holter recording. The mean follow-up was 18 +/- 5 months. RESULTS: 6 patients died (5 of sudden cardiac death, 1 of heart failure), 1 patient with an implanted defibrillator received an adequate shock. Parameters influenced by low- and mid-frequent oscillations of the heart rate were significantly lower in patients who died suddenly or had adequate shocks. The best predictive parameter was the s.d.RR: all patients with an s.d.RR < 50 ms had lethal arrhythmias whereas the s.d.RR of the surviving patients was > or = 50 ms. No significant difference was found or high frequency parameters, which are mainly influenced by parasympathetic activity. CONCLUSION: The analysis of heart rate variability is of prognostic relevance in patients with dilated cardiomyopathy. Especially the s.d.RR is able to identify patients with a high risk of a sudden cardiac death.     

Barriers to cardiac transplantation in idiopathic dilated cardiomyopathy: the Washington, DC, Dilated Cardiomyopathy Study

Although cardiac transplantation offers prolonged survival and improved quality of life to patients with end-stage heart failure, many patients with idiopathic dilated cardiomyopathy do not undergo this procedure. Possible barriers to cardiac transplantation were examined among 138 patients with idiopathic dilated cardiomyopathy from five hospitals in Washington, DC. Patients underwent follow-up for approximately 5 years. The patients or a close family member were interviewed at baseline about socioeconomic factors and medical history. The patients or their next-of-kin were recontacted at 1-year intervals to determine patients' vital status and to obtain information about cardiac transplantation. Overall, the cumulative survival at 12 and 60 months was 75.8% and 37.3%, respectively. Only 3.6% (5 of 138) of the patients underwent cardiac transplantation, and 19 (13.8%) patients had been placed on a waiting list for a heart transplant. Black race and nonmarried status were inversely associated with cardiac transplantation. Factors associated with not having been placed on a waiting list included older age, lower income, and lack of private health insurance. Black race was found to be significantly, but inversely associated with cardiac transplantation while older age was inversely associated with having been placed on a waiting list after adjusting for sex, race, education, and private insurance. These findings suggest that black patients with idiopathic dilated cardiomyopathy are less likely to undergo cardiac transplantation.     

An analytical comparison of cobalt cardiomyopathy and idiopathic dilated cardiomyopathy

Toxic cardiomyopathy (TC) has a rapid clinical course and morphologically resembles idiopathic dilated cardiomyopathy (IDC). To further characterize TC, we used light microscopy to compare lesions caused by cobalt (Co) to those of IDC. Cobalt levels were also measured as a chemical marker to differentiate TC from IDC. We reviewed cases with TC and IDC and excluded all cases with chemotherapy-induced myopathy and catecholamine toxicity as well as cases with possible infectious, ischemic, or hypersensitivity-induced myopathies. We compared the light microscopic findings of 12 TC cases of 12 cases of IDC, and measured trace Co levels on digested heart tissue samples. The TC cases had prominent myofibrillar loss and atrophy; no cases had neutrophil infiltration or frank myocyte necrosis. In contrast, IDC had minimal myofibril loss and atrophy. Cobalt levels in the range of 0.6 to 5.45 micrograms/g of dry tissue were obtained for the TC cases, while IDC demonstrated Co levels of 0.01-0.2 micrograms/g. Distinction between TC and IDC is predominantly a function of myocyte change, with TC showing myofibrillar loss and atrophy in the absence of inflammatory infiltrates and fibrosis; IDC is predominantly associated with myocyte hypertrophy, atrophy, and fibrosis.     

Reversal of Borrelia burgdorferi associated dilated cardiomyopathy by antibiotic treatment?

It is suggested that Borrelia burgdorferi infection could be associated with dilated cardiomyopathy (IDC). Stanek et al. were able to cultivate Borrelia burgdorferi from myocardial biopsy tissue of a patient with longstanding dilated cardiomyopathy. Here we present a study in which we examined the effect of standard antibiotic treatment on the left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy associated with Borrelia burgdorferi infection. In this study we assessed the serum (IgG, IgM Elisa) and history of 46 IDC patients with specific regard to Borrelia burgdorferi infection (mean LVEF 30.4 +/- 1.3%, measured by cardiac catheterization and echocardiography with the length-area-volume method). All 46 patients received standard treatment for dilated cardiomyopathy: ACE inhibitors, digitalis, and diuretics. Eleven (24%) patients showed positive serology and a history of Borrelia burgdorferi infection; nine of these also had a typical history of tick bite and erythema chronicum migrans (ECM) and/or other organ involvement, and two had no recollection of tick bite or ECM but showed other Borrelia burgdorferi-associated disorders (neuropathy, oligoarthritis). These 11 patients with Borrelia burgdorferi infection received standard antibiotic treatment with intravenous ceftriaxone 2 g bid for 14 days. Six (55%) recovered completely and showed a normal LVEF after 6 months, three (27%) improved their LVEF, and two (18%) did not improve at all. This amounts to nine (82%) patients with recovery/improvement in the Borrelia burgdorferi group. The 35 patients who did not show positive serology or a history of Borrelia burgdorferi infection did not receive antibiotic treatment. In this group without Borrelia burgdorferi infection 12 (26%), showed recovery/improvement following the standard treatment of dilated cardiomyopathy (see earlier). Our results indicate that Borrelia burgdorferi infection could play a decisive role in the development of dilated cardiomyopathy, especially in a geographical region such as Graz, where Borrelia burgdorferi is endemic. While we are aware of the small number of Borrelia burgdorferi patients in this study, we nevertheless conclude that in a remarkable number of patients with signs of Borrelia burgdorferi infection, dilated cardiomyopathy could be reversed and LVEF improved.     

In situ detection of DNA fragmentation and expression of bcl-2 in human neuroblastoma: relation to apoptosis and spontaneous regression

In patients with alcoholic cardiomyopathy there is evidence that mild heart failure is reversible if patients abstain from alcohol, but there is no consensus whether the disease is progressive once structural myocardial dilation has evolved. The aim of the present study was to compare the long-term course of congestive heart failure due to alcoholic and idiopathic dilated cardiomyopathy. Of 75 patients with overt congestive heart failure, 23 had alcoholic cardiomyopathy and were compared to 52 patients with idiopathic cardiomyopathy. The mean age was 48 +/- 12 years. Despite medical therapy, heart failure class New York Heart Association III-IV was present in 52% of patients with alcoholic and 47% of patients with idiopathic cardiomyopathy (not significant). Their mean left ventricular ejection fraction was 30 +/- 12% vs 28 +/- 12% and left ventricular end-diastolic volumes were 264 +/- 125 ml and 254 +/- 100 ml respectively (not significant). Overall survival at 1, 5 and 10 years was 100%, 81% and 81% for the group with alcoholic dilated cardiomyopathy and 89%, 48% and 30% for the group with idiopathic cardiomyopathy, respectively (P = 0.041), and the difference was even greater for transplant-free survival P = 0.005). Clinical and invasive signs of left and right heart failure as well as left ventricular dimensions were predictive of a fatal outcome; however, symptom duration and left ventricular volumes were only predictive in patients with idiopathic cardiomyopathy, suggesting that in the two patient groups different mechanisms may lead to death. Mortality in patients with severe congestive heart failure and left ventricular dilatation due to alcoholic cardiomyopathy is significantly lower than that in patients with idiopathic cardiomyopathy and similar degrees of heart failure. Thus, despite structural changes inherent in marked left ventricular dilatation, disease progression in alcoholic dilated cardiomyopathy is different from that in idiopathic cardiomyopathy and thus may have implications for the choice of therapy.     

Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy

Numerous studies have implicated Coxsackievirus in acute and chronic heart failure. Although enteroviral nucleic acids have been detected in selected patients with dilated cardiomyopathy, the significance of such persistent nucleic acids is unknown. To investigate the mechanisms by which restricted viral replication with low level expression of Coxsackieviral proteins may be able to induce cardiomyopathy, we generated transgenic mice which express a replication-restricted full-length Coxsackievirus B3 (CVB3) cDNA mutant (CVB3DeltaVP0) in the heart driven by the cardiac myocyte-specific myosin light chain-2v (MLC-2v) promoter. CVB3DeltaVP0 was generated by mutating infectious CVB3 cDNA at the VP4/VP2 autocatalytic cleavage site from Asn-Ser to Lys-Ala. Cardiac-specific expression of this cDNA leads to synthesis of positive- and negative-strand viral RNA in the heart without formation of infectious viral progeny. Histopathologic analysis of transgenic hearts revealed typical morphologic features of myocardial interstitial fibrosis and in some cases degeneration of myocytes, thus resembling dilated cardiomyopathy in humans. There was also an increase in ventricular atrial natriuretic factor mRNA levels, demonstrating activation of the embryonic program of gene expression typical of ventricular hypertrophy and failure. Echocardiographic analysis demonstrated the presence of left ventricular dilation and decreased systolic function in the transgenic mice compared with wild-type littermates, evidenced by increased ventricular end-diastolic and end-systolic dimensions and decreased fractional shortening. Analysis of isolated myocytes from transgenic mice demonstrate that there is defective excitation-contraction coupling and a decrease in the magnitude of isolated cell shortening. These data demonstrate that restricted replication of enteroviral genomes in the heart can induce dilated cardiomyopathy with excitation-contraction coupling abnormalities similar to pressure overload models of dilated cardiomyopathy.     

Symptomatic cardiomyopathy as a presentation in Whipple's disease

A patient presenting with congestive cardiac failure and anaemia underwent investigation which led to the diagnosis of Whipple's disease, associated with dilated cardiomyopathy. Conventional antibiotic therapy for Whipple's disease resulted in resolution of the traditional features of Whipple's disease and a marked improvement in the patient's heart failure.     

Heart transplantation in children and young adults: early and intermediate-term results

The purpose of this article is to report our short- and intermediate-term follow-up of cardiac transplantation for congenital heart disease and cardiomyopathy in children (age greater than 6 months), adolescents, and young adults. Thirty patients (ages 8 months to 24 years) with end-stage heart failure have undergone cardiac transplantation in our program: 12 (40%) for postoperative end-stage heart failure, 9 (30%) as primary treatment for congenital heart disease, 5 (17%) for dilated cardiomyopathy, and 4 (13%) for restrictive/hypertrophic cardiomyopathy. Nineteen patients (63%) had undergone prior operations; 4 patients received transplants for failed Fontan procedures. Induction therapy with antithymocyte therapy was used routinely, and long-term immunosuppression was by cyclosporine and azathioprine alone. Rejection surveillance/diagnosis was based on echocardiographic criteria. Posttransplantation follow-up ranges from 3 to 78 months. Operative mortality was 3.3% (1/30). No patients have been diagnosed with either accelerated allograft atherosclerosis or posttransplantation lymphoproliferative disease. We conclude that cardiac transplantation may be performed with excellent early and intermediate-term results.     

Absence of linkage between idiopathic dilated cardiomyopathy and candidate genes involved in the immune function in a large Italian pedigree

Idiopathic dilated cardiomyopathy (IDC) is a heart disease of unknown aetiology characterised by impaired ventricular function usually associated with dilatation of the cardiac chambers. In order to test the hypothesis of an immunological cause for the disease at the genetic level, we performed linkage analysis between the putative disease locus and some of the potential candidate genes involved in the immune response or coding for the targets for autoantibodies in a large multigeneration family (63 members) from southern Italy with autosomal dominant transmission of the disease. Twenty-nine polymorphic markers on 18 different chromosomal locations were investigated, including markers linked to the genes coding for the HLA antigens, the immunoglobulin heavy and light chains, the receptors for the immunoglobulin Fc fragments, the subunits of the T cell receptor and the associated CD3, CD4, CD8, and CD45 antigens, interleukins 1, 3, 4, 5, 6, 9, and 11, the interleukin 1 and 2 receptors, and the genes coding for the beta 1 adrenoreceptor, the adenine nucleotide translocator-1, and the cardiac alpha and beta myosin heavy chains. No evidence for genetic linkage to IDC was found at any of these candidate loci. These results indicate that the still unidentified IDC gene maps outside several loci involved in the regulation of immune reactivity.     

Effects of exercise on plasma level of brain natriuretic peptide in congestive heart failure with and without left ventricular dysfunction

This study was designed to determine whether plasma brain natriuretic peptide (BNP) increases in response to exercise in patients with congestive heart failure and to show what kind of hemodynamic abnormalities induce increased secretion of BNP during exercise. Plasma levels of atrial natriuretic peptide (ANP) and BNP and hemodynamic parameters were measured during upright bicycle exercise tests in seven patients with dilated cardiomyopathy and nine with mitral stenosis. At rest, there were no intergroup differences in cardiac output or pulmonary capillary wedge pressure; however, the group with dilated cardiomyopathy had higher left ventricular end-diastolic pressures and lower left ventricular ejection fractions than did the group with mitral stenosis. Plasma ANP levels were comparable between the dilated cardiomyopathy group (170 +/- 77 [SE] pg/ml) and the mitral stenosis group (106 +/- 33 pg/ml) (p, not significant), whereas BNP was significantly higher in the dilated cardiomyopathy group (221 +/- 80 pg/ml) than in the other group (37 +/- 10 pg/ml) (p < 0.05). The plasma concentration of BNP but not of ANP significantly correlated with left ventricular end-diastolic pressure and volume. Exercise increased plasma ANP and BNP in the two groups. The dilated cardiomyopathy group had a larger increment in BNP (+157 +/- 79 pg/ml) than did the mitral stenosis group (+17 +/- 5 pg/ml) (p < 0.05), although the increase in pulmonary capillary wedge pressure was greater in the mitral stenosis group. Thus exercise increases plasma levels of BNP, and impaired left ventricular function may be a main factor in the greater increment in BNP during exercise in patients with congestive heart failure.     

Ventricular late potentials and ventricular arrhythmias in noncoronarogenic myocardial diseases

Hemodynamic parameters and survival were studied in 48 patients with noncoronarogenic myocardial diseases (NCMD). The examination included high-resolution electrocardiography and Holter monitoring of cardiac rhythm. Deterioration of pump capacity of the heart was associated with high-grade arrhythmias (4B and higher) while ventricular late potentials were more characteristic for patients with severe hemodynamic disorders and, in particular, with dilated cardiomyopathy. The prognosis in NCMD is based on clinical evidence on functional class of the heart failure, parameters of central and intrapulmonary hemodynamics.     

Relation between atherosclerotic risk factors and abdominal wall fat thickness

Dilated cardiomyopathy is a common cause of heart failure with systolic dysfunction. Medications used to treat this condition are usually for symptomatic relief. We studied the effect of atenolol in heart failure caused by dilated cardiomyopathy in a double blinded randomized fashion. There were 17 males and 5 females. All patients underwent right and left heart catheterization, coronary angiography, endomyocardial biopsy, exercise testing and doppler echocardiography. By 3 months, atenolol significantly reduced resting and exercise heart rate and pulmonary capillary wedge pressure. There was no difference in exercise capacity. We conclude from this study that atenolol improve hemodynamic condition in patients with dilated cardiomyopathy without improving exercise capacity during this short observation period.     

Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure

Nitric oxide (NO) plays a role in controlling vascular tone and regulates the contractile properties of cardiac myocytes. Patients with heart failure exhibit high plasma levels of nitrite/nitrate (NOx), a stable metabolite of NO, and of cytokines such as tumor necrosis factor-alpha, a potent inducer of NO synthase. An increase in inducible NO synthase activity has been found in cardiac tissue from patients with dilated cardiomyopathy. These findings raise the possibility that local or systemic overproduction of NO induced by cytokines exerts a chronic negative inotropic effect on the myocardium and may have detrimental effects on systemic hemodynamics in patients with heart failure. Plasma levels of NG,NG-dimethylarginine (asymmetric dimethylarginine; ADMA), a circulating endogenous NO synthase inhibitor, were measured in control subjects and patients with valvular, hypertensive, or ischemic heart diseases or idiopathic cardiomyopathy. The plasma levels of NOx and ADMA were assessed by high performance liquid chromatography. The plasma levels of NOx and ADMA were significantly elevated in patients with heart failure. Both NOx and ADMA were positively correlated with New York Heart Association functional class. There was a significant inverse correlation between plasma NOx and ejection fraction, as estimated by echocardiography. A significant relationship between plasma NOx and ADMA was found only in patients with moderate to severe heart failure (r=0.41, p=0.01). Findings suggest a compensatory role of a circulating endogenous NO synthase inhibitor against induced NO synthase activity in patients with heart failure.