Brain natriuretic peptide (BNP) and N-terminal-pro BNP in chronic haemodialysed renal failure

Brain natiuretic peptide (BNP) and N-Terminal-pro BNP (NT-proBNP) are biological markers of left ventricular dysfunction. An increase of one of these peptides is commonly observed in patients with chronic renal failure (CRF) undergoing haemodialysis, in the absence of cardiac failure or acute myocardial ischaemia. The interpretation and clinical implications of this finding are not known. This is a problem because cardiovascular disease is the main cause of morbidity and mortality in patients undergoing haemodialysis. In these patients, left ventricular hypertrophy and left ventricular dysfunction were associated with increased mortality. A biological marker of left ventricular dysfunction enabling early identification of high risk patients would be very useful in this population. Chronic renal failure and haemodialysis do not explain increased levels of BNP and NT-proBNP. Expansion of extra-cellular volume causing myocardial stretching and increased left ventricular pressures is the principal cause of increased BNP and NT-proBNP in haemodialysis patients. The left ventricular hypertrophy and endothelial dysfunction in severe chronic renal failure, systolic and diastolic left ventricular dysfunction, the associated cardiac disease (usually ischaemic) also contribute to this increase. In view of the relationship with left ventricular hypertrophy, left ventricular dysfunction, ischaemic heart disease, BNP and NT-proBNP are predictive factors of total and/or cardiovascular mortality in asymptomatic haemodialysed patients. The BNP/NT-proBNP value should allow identification of high risk asymptomatic haemodialysed patients who would benefit from aggressive evaluation of left ventricular hypertrophy and dysfunction and appropriate, targeted therapeutic intervention.     

The clinical implications of aldosterone escape in congestive heart failure

Angiotensin converting enzyme (ACE) inhibitor therapy does not reliably suppress aldosterone production, and 'aldosterone escape' occurs in up to 40% of patients with congestive heart failure (CHF). Aldosterone levels correlate with the risk of cardiovascular events. Aldosterone adversely affects the risk of cardiovascular events via mineralocorticoid receptors in the heart, blood vessels and other sites. Notably, aldosterone contributes to endothelial dysfunction and attenuates endothelium-dependent vasodilatation, at least partly by reducing nitric oxide bioavailability. Aldosterone also promotes myocardial fibrosis and cardiac remodelling by enhancing collagen synthesis, resulting in increased myocardial stiffness and increased left ventricular mass. These mechanisms mediated by aldosterone contribute to increased risk of ventricular arrhythmias and sudden cardiac death. Two major prospective trials, including one in which patients routinely received ACE inhibitor and beta blocker therapy, have shown that the use of an aldosterone blocker significantly reduces all-cause mortality, sudden cardiovascular death and hospitalisation in patients with acute or chronic left ventricular dysfunction or CHF. Inhibition of aldosterone's effect on mineralocorticoid receptors should now be considered standard therapy in these patient populations.     

Coxsackie viral myocarditis: a clinical and echocardiographic study

Thirty two patients with acute onset of cardiac symptoms following an episode suggestive of viral infection, were studied. 11 patients had Coxsackie viral myocarditis. All had 4 fold rise of neutralising Coxsackie viral antibody titres on paired sera tested. Coxsackie B virus types 2 and 4 were commonly detected. Among the eleven patients, 8 presented with congestive heart failure, 2 with ventricular arrhythmias and one with chest pain and S3 gallop. All had ECG changes. Echocardiographic examination showed global left ventricular dysfunction in 7, regional wall motion abnormalities in 2 and normal left ventricular function in one. Serial echocardiographic examination showed progressive myocardial dysfunction in 3 and improvement in myocardial function in two patients. Two patients died during the follow up period. Echocardiography helped in assessing the course of patients with viral myocarditis.     

Circulating interleukin-6 significantly correlates to thyroid hormone in acute myocardial infarction but not in chronic heart failure

To investigate relationships between thyroid states and the cardiac endocrine system, we analyzed thyrotropin (TSH), thyroid hormone, plasma levels of interleukin-6 (IL-6) and brain natriuretic peptide (BNP) in 50 patients with chronic heart failure (CHF), in 30 patients with heart failure from acute myocardial infarction (AMI), and in 15 controls. Plasma levels of IL-6 and BNP in both CHF and AMI were significantly elevated, while free triiodothyronine (FT3) was significantly decreased compared to controls. FT3/free thyroxine (FT4) ratio was significantly decreased in CHF but not in AMI compared to controls. In CHF, diuretic treatment diminished circulating BNP but not IL-6, while diuretic treatment increased FT3/FT4 ratio. In AMI, FT3/FT4 ratio was significantly decreased 72 h compared to 12 h after the onset of AMI, while BNP and IL-6 were significantly increased 72 h compared to 12 h after the onset of AMI. In both CHF and AMI, BNP significantly correlated with FT4. On the other hand, significant correlations between IL-6 and FT3, and between IL-6 and FT3/FT4 ratio were detected in AMI but not in CHF. This preliminary study suggests that IL-6, BNP and thyroid hormone reflect ventricular dysfunction in both acute and chronic heart failure, and that IL-6 significantly relates to circulating thyroid hormone in AMI but not in CHF.     

Myocardial carnitine in end-stage congestive heart failure

To test the hypothesis that carnitine is decreased in the myocardial tissue of patients with end-stage congestive heart failure (CHF), left ventricular myocardial carnitine was measured in 51 patients undergoing orthotopic cardiac transplantation. The study group included patients with idiopathic dilated cardiomyopathy, coronary artery disease, myocarditis and rheumatic heart disease. Myocardial carnitine varied in different cardiac chambers. In normal control hearts, the left and right ventricular total carnitine was similar, but the ventricles had higher levels than the atria (p less than 0.005); in 30 hearts in CHF, the left ventricular total carnitine was higher than in the right ventricle (p less than 0.001) and both ventricles had higher total carnitine than the atria (p less than 0.005). Only 7 of 51 patients with CHF had low myocardial carnitine, whereas plasma carnitine was elevated in all diagnostic groups of end-stage CHF studied.     

Diastolic dysfunction in exercise and its role for exercise capacity

Diastolic dysfunction is frequent in elderly subjects and in patients with left ventricular hypertrophy, vascular disease and diabetes mellitus. Patients with diastolic dysfunction demonstrate a reduced exercise capacity and might suffer from congestive heart failure (CHF). Presence of symptoms of CHF in the setting of a normal systolic function is referred to as heart failure with normal ejection fraction (HFNEF) or, if evidence of an impaired diastolic function is observed, as diastolic heart failure (DHF). Reduced exercise capacity in diastolic dysfunction results from a number of pathophysiological alterations such as slowed myocardial relaxation, reduced myocardial distensibility, elevated filling pressures, and reduced ventricular suction forces. These alterations limit the increase of ventricular diastolic filling and cardiac output during exercise and lead to pulmonary congestion. In healthy subjects, exercise training can enhance diastolic function and exercise capacity and prevent deterioration of diastolic function in the course of aging. In patients with diastolic dysfunction, exercise capacity can be enhanced by exercise training and pharmacological treatment, whereas improvement of diastolic function can only be observed in few patients.     

Evaluation of the patient with congestive heart failure and ventricular arrhythmias

Although vasodilators and new inotropic agents have been shown to improve ventricular function and reduce symptoms, their effect on mortality is uncertain. In view of our failure to reduce mortality in patients with congestive heart failure (CHF), the identification and amelioration of potentially reversible factors that might alter survival are crucial before initiating therapy. The first step is to establish the diagnosis of CHF and the presence or absence of dilated congestive cardiomyopathy. The extent of myocardial dysfunction, both right and left, must also be evaluated. In post-myocardial infarction patients, left ventricular ejection fraction is an important indicator of prognosis during the first 1 to 2 years. However, in patients with chronic CHF and dilated cardiomyopathy, right ventricular ejection fraction may be a more effective predictor of survival. The presence, frequency and complexity of ventricular arrhythmias must be determined, because these arrhythmias may independently increase the risk of sudden cardiac death in patients with ischemic cardiomyopathy. Their role in patients with idiopathic cardiomyopathy is less certain. In addition, myocardial ischemia, left ventricular dyskinesis or aneurysm, occult myocarditis and neurothrombosis formation must be ruled out. Detection and correction of serum electrolyte and neurohumeral abnormalities are essential. Our failure to reduce mortality in patients with CHF may not entirely lie in the lack of effective therapeutic agents but rather in our failure to apply properly the diagnostic and therapeutic approaches now available.     

Myocardial Remodeling in Viral Heart Disease: Possible Interactions Between Inflammatory Mediators and MMP-TIMP System

Matrix metalloproteinases (MMP), a family of proteases, are involved in the degradation of extracellular matrix proteins and hence in the determination of interstitial architecture. In the heart, MMPs have been found to play a significant role in the development of myocardial remodeling and congestive heart failure. Tissue inhibitors of matrix metalloproteinases (TIMPs) represent a family of proteins which are known to regulate the expression and activity of MMPs. TIMPs are endogenous physiological inhibitors of MMPs and their concomitant downregulation in heart failure suggests the existence of a critical balance between MMPs and TIMPs in the normal maintenance of myocardial interstitial homeostasis. In addition, cytokines regulate expression of both MMPs and TIMPs besides eliciting a direct effect on myocardial cell function. Therefore, myocardial inflammation may also contribute to the development of cardiac remodeling along with other stimuli like mechanical stress and humoral factors. Viral myocarditis, a predisposing factor for dilated cardiomyopathy, is a condition in which extent of intramyocardial inflammation is thought to determine the progression of disease. Inflammatory events in the heart following viral infection are speculated to be responsible for the transition of myocarditis to dilated cardiomyopathy. In viral myocarditis and other inflammatory heart diseases, the inflammatory cells and their battery of cytokines may also alter the myocardial MMP-TIMP system and eventually lead to dilation of the heart and ventricular dysfunction. The objective of this review is to present an overall picture of the inflammatory phase in viral myocarditis and discuss the possible interactions between inflammation and myocardial MMP profiles which may lead to the evolution of dilated cardiomyopathy.     

Aminoguanidine inhibits mitogen-activated protein kinase and improves cardiac performance and cardiovascular remodeling in failing hearts of salt-sensitive hypertensive rats

OBJECTIVES: Congestive heart failure (CHF) is associated with inducible nitric oxide synthase (iNOS) expression in the failing human heart, and recently we have also demonstrated that iNOS expression was upregulated in Dahl salt-sensitive hypertensive (DS) rats with cardiac dysfunction and vascular remodeling. Thus, we evaluated whether aminoguanidine (AG), a selective iNOS inhibitor, protects against cardiac dysfunction and vascular remodeling in DS rats receiving a high-salt diet. METHODS: AG (DSHF-AG, 150 mg/kg per day) or vehicle (DSHF-V) were given from left ventricular hypertrophy stage (11 weeks) to CHF stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship (contractility: E(es)) was measured by conductance catheter. RESULTS: Decreased E(es) in DSHF-V was significantly ameliorated by AG treatment. The iNOS mRNA and protein expression and phospho-p42/p44 extracellular signal-regulated kinase (ERK) activities in the left ventricle were significantly upregulated in DSHF-V compared with control rats, and significantly suppressed in DSHF-AG compared with DSHF-V. DSHF-V showed a significant increase of perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by AG treatment. CONCLUSIONS: We demonstrated that the selective iNOS inhibitor, AG, may be at least a potential therapeutic strategy for treating CHF and cardiovascular remodeling.     

Pulmonary endothelium as a site of synthesis and storage of interleukin-6 in experimental congestive heart failure

BACKGROUND: Pulmonary endothelium is an early upstream hemodynamic target of left ventricular dysfunction. Interleukin 6 (IL-6) is a pro-inflammatory cytokine reported to increase in congestive heart failure (CHF) patients. AIMS: We sought to determine the origin of IL-6, IL-6 receptor (IL-6R) and gp130 in experimental CHF. METHODS: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure. Lung and aorta samples were analysed by RT-PCR, ELISA and immunohistochemistry for IL-6 and its receptors. RESULTS: IL-6 mRNA expression increased in the lung of rats with decompensated heart failure and was positively correlated with infarct severity whereas IL-6R mRNA decreased in the lung of myocardial infarction rats and gp130 mRNA remained unchanged. In contrast, there were no changes in IL-6 mRNA expression in the aorta and left ventricular myocardium. IL-6 peptide content as determined by ELISA and Western Blot in lung tissue was 2-fold higher in decompensated heart failure as compared to control rats. These data were confirmed by immunohistochemistry showing a preferential endothelial localization of IL-6 in the CHF lung. IL-6 peptide was also present in the pleural effusion of decompensated heart failure and was positively correlated with IL-6 mRNA expression in the lungs of decompensated HF rats. Pulmonary IL-6 overexpression was associated with nuclear translocation of NF-kappaB and cytosolic degradation of IkappaB. CONCLUSION: Dysfunctional pulmonary endothelium is a source of synthesis and storage of IL-6 in an experimental model of CHF.