Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients.

OBJECTIVES: To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc). METHODS: Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities. RESULTS: At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation. CONCLUSIONS: This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.

Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis.

OBJECTIVES: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. METHODS: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. RESULTS: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. CONCLUSIONS: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey.

BACKGROUND: Recent registries have shown that recommended drugs for the treatment of chronic heart failure (CHF) are under-prescribed in daily practice. AIMS: To determine prescription rates of CHF drugs, and to assess predictive factors for drug prescription using data from a large panel of French cardiologists. METHODS AND RESULTS: We included 1919 outpatients, with NYHA class II-IV heart failure and a left ventricular ejection fraction <40%. The most frequently prescribed drugs were diuretics (83%), angiotensin converting enzyme inhibitors (ACE-I) (71%), beta-blockers (65%), spironolactone (35%) and angiotensin receptor blockers (ARB) (21%); 61% of patients received a combination of a beta-blocker and an ACE-I or ARB. Target doses were reached in 49% of the patients for ACE-I, but in only 18% for beta-blockers and in 9% for ARBs. Multivariate analyses showed that age >75 years was an independent factor associated with under-prescription of ACE-I-ARBs, beta-blockers or spironolactone. Renal failure was associated with a lower prescription of ACE-I-ARB and spironolactone, and asthma was a predictor of under-prescription of beta-blockers. CONCLUSIONS: In this contemporary survey, prescription rates of CHF drugs were higher than previously reported. However, dosages were lower than those recommended in guidelines. Age remained an independent predictor of under-prescription of CHF drugs.

[Treating heart failure with carvedilol in private practice (initiating treatment and follow-up at one year. The KEOPS study]. / Traitement par carvedilol dans l'insuffisance cardiaque en pratique libérale (initiation du traitement et suivi à un an). Etude KEOPS.

AIMS: This study aimed at describing usual conditions of carvedilol use in heart failure (HF) patients. METHODS: KEOPS was a one-year, multi-centre, prospective pharmaco-epidemiological study in carvedilol treated HF patients recruited by private cardiologists. RESULTS: Two thousand nine patients (mean age: 68) with heart failure were included by 401 cardiologists. 64% of patients were in class II of NYHA and 27% in class III, 87% of patients presented stable heart failure for at least four weeks. Contraindication to beta blocking was observed in 24% of patients, mean left ventricular fraction of ejection was 39% and only 39% of patients had mean left ventricular fraction of ejection<35%. Co-medications included a diuretic agent, ACE inhibitor or ARB in 68% of cases. Eighty three percent of patients had a titration of carvedilol (median duration=1 20 days). Thirty percent reached the recommended maximal dose. The dose of carvedilol at the titration's visit for all the patients (patient in stop included) was on average 30.5 +/- 22.1 mg/day with a median on 25 [confidence interval: 23-27] During the year of follow-up, 10% of patients have stopped the treatment (3% of patients having reached the maximum recommended dose of carvedilol versus 13% for the others), for cardiovascular reasons in 50% of patients (aggravation of heart failure: 28%, symptomatic arterial hypotension: 9%, symptomatic bradycardia: 5%). Finally, symptomatology of patients has improved during the study (59% of patients in class mild to severe at inclusion, versus 36% at the end of the observation), especially for the 30% of patients followed at one year and having reached the maximum recommended dose of carvedilol. Only in univariate analysis, patients with an inclusion high weight (>85 kg) were likely less to reach recommended maximal dose (37.2 versus 8.7%, p-value<0.0001), the patients with systolic heart failure had more chance than the patients with diastolic heart failure to reach the recommended maximal dose (31 versus 17.4%, p-value=0.006), in the same way, the lack of auricular supported more the reach of recommended maximal dose (31.2 versus 24.1%, p-value=0.018) CONCLUSION: KEOPS study suggests an improvement of usual conditions of carvedilol compared to the last investigation but the persistence of prescription outside medical authorization and less dosage of this product compared with clinical studies.

[Assessment of plasma endothelin level measurement in systemic sclerosis]. / Intérêt du dosage plasmatique de l'endothéline au cours de la sclérodermie systémique.

PURPOSE: According to current knowledge, endothelin (ET)-1 plays an important role in the pathogenesis of systemic sclerosis (SSc). We assessed ET plasma levels in SSc patients according to the clinical presentation and the presence of complications such as pulmonary arterial hypertension (PAH). METHODS: Sixty-three consecutive patients with SSc were included. The control group included 17 healthy patients. ET plasma level was determined for all patients. Pulmonary function test and pulmonary high resolution computed tomography were performed in 44 patients and echocardiography in 51 patients, to screen for PAH, always confirmed by a right heart catheterization. RESULTS: ET plasmatic levels were higher in SSc patients than in healthy group subjects but the difference was not significant (3.72+/-1.13 vs 3.40+/-0.71 pmol/l, p=0.27). ET plasmatic levels were significantly higher in patients with PAH than in patients without PAH (4.28+/-0.65 vs 3.62+/-1.07 pmol/l, p=0.04) and in patients with anticentromere antibodies (3.96+/-1.11 vs 3.19+/-1.12 pmol/l, p=0.03). There was a positive linear correlation between ET plasmatic levels and systolic pulmonary arterial pressure (r=0.34, p=0.013). The best cut-off value for ET plasmatic level to discriminate patients affected by PAH was determined by ROC curve method: 4.1 pmol/l (sensibility 85.7%, specificity 66%). CONCLUSION: ET plasmatic levels were higher in SSc patients affected by PAH and patients with anticentromere antibodies. There was a positive linear correlation between ET plasmatic levels and systolic pulmonary arterial pressure. Assessment of ET plasmatic levels for detection and monitoring of pulmonary hypertension during SSc is warranted in larger prospective studies.

[Protein-losing enteropathy revealing an idiopathic constrictive pericarditis]. / Entéropathie exsudative révélant une péricardite chronique constrictive idiopathique.

INTRODUCTION: The cause of protein-losing enteropathy is sometimes difficult to establish. It can be rarely due to a constrictive pericarditis. EXEGESIS: We report a patient presenting a protein-losing enteropathy revealing a constrictive pericarditis. CONCLUSION: Chronic pericarditis should be evoked in case of unexplained protein-losing enteropathy. Echocardiography can sometimes be normal. Therefore, chest computed tomography scan or cardiac MRI followed by confirmation right heart catheterization should be performed in case of persistent unexplained protein-losing enteropathy.

[Tolerance of bevacizumab therapy in systemic sclerosis-associated pulmonary arterial hypertension: A case report]. / Tolérance du bévacizumab au cours de l'hypertension artérielle pulmonaire associée à la sclérodermie systémique : à propos d'une observation.

INTRODUCTION: No data is available regarding the safety of bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, in patients with pulmonary arterial hypertension (PAH), a condition in which VEGF seems to play a significant and probably protective role. CASE REPORT: We report a patient with a history of systemic sclerosis-associated PAH, stable under bosentan therapy. She was diagnosed with metastatic cervical epidermoid carcinoma and treated by two successive cytotoxic chemotherapy regimens. As these treatments failed to control disease progression, she was started on anti-angiogenic therapy: 3 infusions of bevacizumab 15 mg/kg were administered. Over the course of this treatment, no change in the clinical status or echocardiography parameters was noted. CONCLUSION: This observation suggests that, under careful clinical and echocardiographic follow-up, bevacizumab therapy can be well tolerated in case of stable and moderate PAH. Decision of treatment should be taken cautiously, as the possibility of PAH worsening is not excluded.

Management of heart failure in the elderly: recommendations from the French Society of Cardiology (SFC) and the French Society of Gerontology and Geriatrics (SFGG).

Heart failure, a frequent disease in the elderly, has a pejorative prognosis. Clinical diagnosis is complicated by atypical or difficult-to-interpret symptoms and by the concomitant presence of other diseases, particularly cognitive impairment, neurological disorders and diseases of the musculoskeletal system. Among the additional investigations, echocardiography remains underused. Impairment of diastolic left ventricular function is frequent. The usual laboratory tests must include calculation of the creatinine clearance, which is indispensable for dosage adjustment of certain drugs (ACE inhibitors, digoxin, spironolactone). The value of plasma natriuretic peptide assays as diagnostic tools has not been determined in elderly or very elderly populations and the plasma B-type natriuretic peptide increases with age. Comprehensive geriatric assessment is essential in order to screen for concomitant diseases and determine the patient's degree of dependence. The general objectives of treatment remain applicable to the elderly subject: improvement in the quality of life, reduction of mortality and the number and duration of hospitalisations, and slowing disease progression. In the frail elderly subject, symptom alleviation is to be the primary objective. In the absence of specific studies on elderly or very elderly subjects, most of the recommendations have been extrapolated from the data based on the evidence generated in younger populations. The dietary rules are to be more flexible than those used for younger subjects, particularly in order to prevent the risk of denutrition induced by strict salt-free diets. Special precautions for the use of heart failure drugs are due to comorbidities and the pharmacokinetic and pharmacodynamic changes related to aging. Drugs dosage increase is to be cautious and carefully monitored for adverse reactions. The therapeutic programmes in which multidisciplinary teams are involved reduce the number and duration of hospitalisations and the costs generated by the disease.

[Hyponatraemia, antagonists of the antidiuretic hormone and cardiac failure]. / Hyponatrémie, antagonistes de l'hormone antidiurétique et insuffisance cardiaque.

Hyponatraemia is a common clinical finding in cardiac failure, complicating the management of these patients. Vasopressin plays a fundamental role in the physiopathology of the hyponatraemia of cardiac failure and binds to two distinct specific receptors, receptor V1a and V2. The V2 receptors, situated in the renal collecting duct, control the resorbtion of free water. The V1a receptors, present everywhere, are responsible for the vasoconstrictive effect of vasopressin. Specific antagonists of vasopressin receptors are being evaluated in pathologies associated with hyponatraemia. The preliminary results in patients with cardiac failure are encouraging and mortality studies are underway.

Heart failure with preserved systolic function: a diagnostic algorithm for a pragmatic definition.

Heart failure is a major health problem which often concerns the elderly. Prevalence of heart failure with preserved systolic function is increasing and varies from 40 to 50%. In the literature, and in the large epidemiological studies, it is commonly designed with the term of "diastolic heart failure", even if a precise analysis of diastolic function is not performed. A diagnostic algorithm is proposed in order to better define the concept of heart failure with preserved systolic function. It consists of seven steps from symptoms and clinical signs to the echocardiographic analysis of diastolic function, in order to confirm the definition of heart failure with preserved systolic function.

Functional mitral regurgitation and chronic heart failure.

Functional mitral regurgitation (MR) frequently develops during the progression of chronic heart failure and predicts poor outcome. Impaired left ventricular (LV) function, LV remodeling associated with papillary muscle apical displacement and annular enlargement result in decreased mitral closing forces and tenting of the mitral valve at closure. Reduced closing forces and tenting both promote MR. Active myocardial ischemia, myocardial asynchronism and excessive loading conditions worsen MR at rest and during exercise. The therapeutic target in functional MR is the left ventricle and not the valve.

Anterior chordal transection impairs not only regional left ventricular function but also regional right ventricular function in mitral regurgitation.

BACKGROUND: Preservation of annuloventricular continuity through the chordae tendinae aims to maintain left ventricular (LV) function and thus improve postoperative prognosis. This study was designed to prospectively investigate the effect of anterior chordal transection on global and regional LV and right ventricular (RV) function in mitral regurgitation (MR). METHODS AND RESULTS: Sixty-five patients with severe MR underwent radionuclide angiography before and after either mitral valve (MV) repair (42 patients) or replacement with anterior chordal transection (23 patients). LV and RV ejection fractions (EF) were determined at rest. Both ventricles were divided into 9 regions to analyze regional EF and the effect of anteromedial translation related to surgery. After surgery there was a significant decrease in LVEF (P=0.038) and an increase in RVEF (P=0.036). However, LVEF did not change after MV repair (63.8+/-9.9% to 62.6+/-10.3%), whereas RVEF improved (40.7+/-10.1% to 44.5+/-8.1%, P=0.027). In contrast, LVEF decreased after MV replacement (61.7+/-10.1% to 57.2+/-9.9%, P=0.03), and RVEF was unchanged (40.9+/-10.9% to 41.3+/-9.1%). LVEF 4 and 5, in the area of anterior papillary muscle insertion, were impaired after MV replacement compared with MV repair (region 4, 77.6+/-16.7% versus 87.7+/-10.8%, P=0.005, and region 5, 73.9+/-19.3% versus 89.9+/-13.1%, P<0.001). Moreover, anterior chordal transection led to a significant impairment in the apicoseptal region of the RV (RVEF 4, 50.3+/-15.6% versus 59.3+/-13.8%, P=0.02). CONCLUSIONS: Anterior chordal transection during MV replacement for MR impairs not only regional LV function but also regional RV function.

Kinetics of oxygen consumption during and after exercise in patients with dilated cardiomyopathy. New markers of exercise intolerance with clinical implications.

OBJECTIVES: This study analyzed the kinetics of oxygen consumption during and after a maximal cardiopulmonary exercise test in patients with dilated cardiomyopathy. The prognostic information derived from indexes of recovery was also studied. BACKGROUND: Previous studies have examined the kinetics of oxygen consumption during a short recovery period in a limited number of patients. To our knowledge, no study has examined the prognostic information derived from indexes of recovery. METHODS: We studied 153 patients and 55 control subjects. We calculated the ratio between total oxygen consumption during exercise and recovery, the half-recovery time of peak oxygen consumption, the time constant of recovery, the recovery time and the ratio between duration of exercise and recovery time. RESULTS: Recovery of oxygen consumption was significantly delayed in patients, and this delay was related to the degree of exercise intolerance. After a median follow-up period of 439 days, for the total study group, percent of predicted peak oxygen consumption (p = 0.003) and ejection fraction (p = 0.03) were independent predictors of survival. In a subgroup of patients with moderate exercise intolerance (percent peak oxygen consumption > 40%), the ratio between total oxygen consumption during exercise and recovery (p = 0.013) and the ejection fraction (p = 0.013) were independent predictors of survival. CONCLUSIONS: The kinetics of oxygen consumption during recovery was delayed in patients with dilated cardiomyopathy. Although indexes of recovery were not prognostic markers in the total study group, the ratio between total oxygen consumption during exercise and recovery was an independent prognostic marker in patients with moderate exercise intolerance.

Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure.

OBJECTIVES: We sought to study the relationship between survival and right ventricular ejection fraction (RVEF) in a subgroup of patients with moderate congestive heart failure (CHF). BACKGROUND: It has been demonstrated that RVEF is an independent predictor of survival in patients with advanced CHF. METHODS: Cardiopulmonary exercise testing and radionuclide angiography (to determine right and left ventricular ejection fraction) were prospectively performed in 205 consecutive patients with moderate CHF (140 patients in New York Heart Association [NYHA] class II, 65 in class III). RESULTS: Left ventricular ejection fraction was 29.3%+/-10.1%, RVEF was 37.5%+/-14.6% and peak oxygen consumption (VO2) was 16.2+/-5.4 ml/min/kg (60.2%+/-19% of maximal predicted VO2). After a median follow-up period of 755 days, there were 44 cardiac-related deaths, 3 deaths from noncardiac causes and 15 transplantations of whom 2 were urgent; 1 patient was lost to follow-up. Multivariate analysis showed that three variables-NYHA classification, percent of maximal predicted VO2 and RVEF-were independent predictors of both survival and event-free cardiac survival. Left ventricular ejection fraction and peak VO2 normalized to body weight had no predictive value. The event-free survival rates from cardiovascular mortality and urgent transplantation at 1 year were 80%, 90% and 95% in patients with an RVEF <25%, with a RVEF > or =25% and <35% and with a RVEF > or =35%, respectively. At 2 years, survival rates were 59%, 77% and 93% in the same subgroups, respectively. CONCLUSIONS: In addition to the NYHA classification and to the percent of maximal predicted VO2, RVEF is an independent predictor of survival in patients with moderate CHF.

Effect of mitral valve surgery on exercise capacity, ventricular ejection fraction and neurohormonal activation in patients with severe mitral regurgitation.

OBJECTIVES: The purpose of this study was to prospectively investigate the effects of surgical correction of mitral regurgitation (MR) on exercise performance, cardiac function and neurohormonal activation. BACKGROUND: Little is known about the effect of surgical correction of MR on functional status or on neurohormonal activation. METHODS: Cardiopulmonary exercise test, radionuclide angiography and blood samples for assessment of neurohormonal status were obtained in 40 patients with nonischemic MR before and within one year (216+/-80 days) after surgery. Twenty-four patients underwent mitral valve repair (MVr), and 16 underwent valve replacement (VR) with anterior chordal transection. RESULTS: Despite an improvement in New York Heart Association functional class, exercise performance did not change (peak oxygen consumption: 19.3+/-6.1 to 18.5+/-5.6 ml/kg/min, percentage of maximal predicted oxygen consumption: 79.5+/-18.2% to 76.8+/-16.9%). After surgery, left ventricular (LV) ejection fraction (EF) decreased (64.2+/-10.3% to 59.9+/-11.4%, p = 0.003) while right ventricular (RV) EF increased (41.4+/-9.6% to 44.7+/-9.5%, p = 0.03). Left ventricular EF did not change after MVr (64.3+/-11.5% to 61.5+/-12.2%), but RVEF improved (40.4+/-9.2% to 46.0+/-10.0%, p = 0.02). In contrast, VR was associated with an impairment of LV function in the apicolateral area and a decrease in LVEF (64.1+/-8.5% to 57.4+/-10.0%, p = 0.01), whereas RVEF did not change (42.9+/-10.3% to 42.8+/-8.6%). Moreover, there was only a slight decrease in neurohormonal activation after surgery. CONCLUSIONS: Despite an improvement in symptomatic status, exercise performance was not improved seven months after either MVr or VR for MR, and neurohormonal activation persisted. Compared with MVr, VR resulted in a significant impairment of cardiac function in this study.

A novel RIPK4-IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes.

Receptor-interacting protein kinase 4 (RIPK4)-deficient mice have epidermal defects and fusion of all external orifices. These are similar to Bartsocas-Papas syndrome and popliteal pterygium syndrome (PPS) in humans, for which causative mutations have been documented in the RIPK4 and IRF6 (interferon regulatory factor 6) gene, respectively. Although genetically distinct, these syndromes share the anomalies of marked pterygia, syndactyly, clefting and hypoplastic genitalia. Despite the strong resemblance of these two syndromes, no molecular connection between the transcription factor IRF6 and the kinase RIPK4 was known and the mechanism underlying the phenotype was unclear. Here we describe that RIPK4 deficiency in mice causes epithelial fusions associated with abnormal periderm development and aberrant ectopic localization of E-cadherin on the apical membrane of the outer peridermal cell layers. In Xenopus, RIPK4 depletion causes the absence of ectodermal epiboly and concomitant gastrulation defects that phenocopy ectopic expression of dominant-negative IRF6. We found that IRF6 controls RIPK4 expression and that wild-type, but not kinase-dead, RIPK4 can complement the gastrulation defect in Xenopus caused by IRF6 malfunctioning. In contrast to the mouse, we observed only minor effects on cadherin membrane expression in Xenopus RIPK4 morphants. However, gastrulation defects were associated with a virtual absence of cortical actin in the ectodermal cells that face the blastocoel cavity and this was phenocopied in embryos expressing dominant-negative IRF6. A role for RIPK4 in actin cytoskeleton organization was also revealed in mouse epidermis and in human epithelial HaCaT cells. In conclusion, we showed that in mice RIPK4 is implicated in cortical actin organization and in E-cadherin localization or function, which can explain the characteristic epithelial fusions observed in PPSs. In addition, we provide a novel molecular link between IRF6 and RIPK4 that unifies the different PPSs to a common molecular pathway.

Association between anticardiolipin antibodies and mortality in patients with peripheral arterial disease.

PURPOSE: Anticardiolipin antibodies may be associated with recurrent thromboembolic events in patients with myocardial infarction or stroke. We sought to determine the prevalence of anticardiolipin antibodies in patients with peripheral arterial disease and their association with subsequent thromboembolic events and mortality. METHODS: We ascertained anticardiolipin antibodies using a standardized enzyme-linked immunosorbent assay (immunoglobulin G [IgG] anticardiolipin > or =15 GPL units or IgM anticardiolipin > or =15 MPL units) in 232 patients with peripheral arterial disease and 100 control subjects. Patients were observed to determine overall and cardiovascular mortality, and incident thromboembolic events. RESULTS: IgG anticardiolipin antibodies were significantly more common in the patients with peripheral arterial disease (36 of 232 [16%]) than in the controls (7 of 100 [7%], P = 0.03). During a median follow-up of 3.5 years, 3 of the 232 patients were lost to follow-up and 56 (24%) died. Overall mortality was significantly greater in the IgG anticardiolipin-positive patients (16 of 35 [46%]) compared with those who were IgG anticardiolipin-negative (40 of 194 [21%], P = 0.0003), largely due to an increase in cardiovascular mortality among the IgG anticardiolipin-positive patients. In a multivariate proportional hazards analysis, IgG anticardiolipin antibodies were an independent risk factor for overall mortality (hazard ratio [HR] = 2.1, 95% confidence interval [CI]: 1.2 to 4.0) and cardiovascular mortality (HR = 4.4, 95% CI: 1.6 to 12). CONCLUSIONS: IgG anticardiolipin antibodies are common in patients with peripheral arterial disease and are associated with an increased risk of overall and cardiovascular mortality.

Plasma levels of atrial natriuretic peptide at peak exercise: a prognostic marker of cardiovascular-related death and heart transplantation in patients with moderate congestive heart failure.

BACKGROUND: Conflicting data have been published concerning exercise performance and hormonal activation. Previous studies have demonstrated the prognostic information of plasma levels of neurohormones at rest in patients with congestive heart failure. No study has examined the prognostic information of plasma levels of hormones at peak exercise. METHODS: Fifty-five consecutive ambulatory patients with stable moderate congestive heart failure (New York Heart Association class II to III) performed a maximal symptom limited cardiopulmonary exercise test with the determination of peak oxygen consumption. Blood samples were drawn at rest and at peak exercise for the determination of plasma levels of atrial natriuretic peptide, aldosterone, and plasma renin activity. RESULTS: Hormonal activation was present at rest, and exercise significantly increased hormonal values. There was no correlation between exercise parameters and hormonal values either at rest or at peak exercise. After a median follow-up period of 724 days, in univariate and multivariate Cox analysis, the most significant independent prognostic marker was the plasma level of atrial natriuretic peptide at peak exercise. Patients with a plasma level of atrial natriuretic peptide > 38 pmol/L had an event rate of 48% compared with an event rate of 14.8% in the other subgroup (p < 0.01). CONCLUSIONS: In patients with stable moderate congestive heart failure, exercise increased hormonal values, but there was no relationship between hormonal activation and exercise performance. Plasma level of atrial natriuretic peptide at peak exercise was the most significant independent marker of cardiovascular-related death and of cardiovascular-related death and heart transplantation.

Folding of the mouse hepatitis virus spike protein and its association with the membrane protein.

Coronaviruses are assembled by budding into pre-Golgi membranes. Using different approaches we have demonstrated that the spike (S) protein and the membrane (M) protein of mouse hepatitis virus (MHV) associate to form large complexes. Newly synthesized M was found in these complexes almost immediately after its synthesis, whereas the S protein started to appear in heterocomplexes after 10-20 min. This is consistent with the slow rate of folding of S and with the observation that folding of S preceeds its association with M. While the folding of S involves the formation of multiple disulfide bonds, folding of M is disulfide-independent. This contrast was reflected by the differential sensitivity of the two proteins to reduction with dithiothreitol (DTT). Addition of DTT to the culture medium of MHV-infected cells drastically impaired the folding of S, but not of M. Consequently, the S protein was unable to interact with M. Under these conditions, S stayed in the ER while M was transported efficiently beyond the site of budding to the Golgi complex. We conclude that the association of S with M is an essential step in the formation of the viral envelope and in the accumulation of both proteins at the site of virus assembly.

Plasma levels of endothelin-1 at rest and after exercise in patients with moderate congestive heart failure.

Plasma levels of endothelin-1 are increased in patients with severe congestive heart failure related to various etiologies. However, conflicting data have been published in patients with moderate congestive heart failure. Moreover, the effect of exercise on plasma levels of endothelin-1 is not precisely known. We determined the plasma levels of endothelin-1 in a homogenous group of patients with idiopathic dilated cardiomyopathy in stage II of the New York Heart Association functional classification at rest and at peak exercise. In this group of patients, plasma levels of endothelin-1 were increased compared to a control group (2.9 +/- 0.27 vs. 1.96 +/- 0.24 pmol/l, P < 0.01, mean +/- S.E.M.), as were plasma levels of atrial natriuretic peptide (26.3 +/- 6.3 vs. 2.95 +/- 0.7 pmol/l, P < 0.001), plasma renin activity (12.6 +/- 2.98 vs. 1.75 +/- 0.23 ng/ml per h, P < 0.001) and plasma levels of aldosterone (217 +/- 29.3 vs. 154 +/- 18.8 pg/ml, P < 0.05). In contrast to the other hormones, exercise did not increase plasma levels of endothelin-1. There was no correlation between plasma levels of endothelin-1 and plasma levels of atrial natriuretic peptide, and no correlation between left ventricular ejection fraction, peak oxygen consumption and hormonal values. In conclusion, plasma levels of endothelin-1 are increased in a homogeneous group of patients with idiopathic dilated cardiomyopathy and moderate congestive heart failure. Endothelin-1 could participate in the progression of heart failure. Exercise did not increase the plasma levels of endothelin-1 in contrast to the other hormones.