Patients with familial partial lipodystrophy of the Dunnigan type due to a LMNA R482W mutation show muscular and cardiac abnormalities.

Diseases due to mutations in the lamin A/C gene (LMNA) are highly heterogeneous, including neuromuscular and cardiac dystrophies, lipodystrophies, and premature ageing syndromes. In this study we characterized the neuromuscular and cardiac phenotypes of patients bearing the heterozygous LMNA R482W mutation, which is the most frequent genotype associated with the familial partial lipodystrophy of the Dunnigan type (FPLD). Fourteen patients from two unrelated families, including 10 affected subjects, were studied. The two probands had been referred for lipoatrophy and/or diabetes. Lipodystrophy, exclusively observed in LMNA-mutated patients, was of variable severity and limited to postpubertal subjects. Lipodystrophy and metabolic disturbances were more severe in women, even if an enlarged neck was a constant finding. The severity of hypertriglyceridemia and hirsutism in females was related to that of insulin resistance. Clinical muscular alterations were only present in LMNA-mutated patients. Clinical and histological examination showed an invalidating, progressive limb-girdle muscular dystrophy in a 42-yr-old woman that had been present since childhood, associated with a typical postpubertal FPLD phenotype. Six of eight adults presented the association of calf hypertrophy, perihumeral muscular atrophy, and a rolling gait due to proximal lower limb weakness. Muscular histology was compatible with muscular dystrophy in one of them and/or showed a nonspecific excess of lipid droplets (in three cases). Immunostaining of lamin A/C was normal in the six muscular biopsies. Surprisingly, calpain 3 expression was undetectable in the patient with the severe limb-girdle muscular dystrophy, although the gene did not reveal any molecular alterations. At the cardiac level, cardiac septal hypertrophy and atherosclerosis were frequent in FPLD patients. In addition, a 24-yr-old FPLD patient had a symptomatic second degree atrioventricular block. In conclusion, we showed that most lipodystrophic patients affected by the FPLD-linked LMNA R482W mutation show muscular and cardiac abnormalities. The occurrence and severity of the myopathic and lipoatrophic phenotypes varied and were not related. The muscular phenotype was evocative of limb girdle muscular dystrophy. Cardiac hypertrophy and advanced atherosclerosis were frequent. FPLD patients should receive careful neuromuscular and cardiac examination whatever the underlying LMNA mutation.

Effects of bisoprolol in patients with stable congestive heart failure.

AIM OF THE STUDY: To analyze the effect of bisoprolol in patients with stable congestive heart failure and who tolerated beta-blockers. MATERIAL AND METHODS: Two hundred and one patients performed before and 3 months after maximal tolerated doses of bisoprolol have been reached, a clinical evaluation, an echocardiography, a radionuclide angiography, a cardiopulmonary exercise test and hormonal determinations. RESULTS: Mean dose of bisoprolol was 8.8 +/- 2.4 mg/d. Patients had a significant improvement in NYHA classification. Heart rate at rest decreased from 87 +/- 17 to 66 +/- 12 beats/min (P < 0.0001) without any effect on electrocardiographic parameters. Left ventricular ejection fraction improved from 31 +/- 11 to 41 +/- 13% (P < 0.0001), with a significant decrease in end-diastolic and end-systolic left ventricle diameters and volumes. Mitral profile improved. Peak VO2 increased from 16.1 +/- 5 to 16.8 +/- 5.5 ml/min/kg (P = 0.001) with a significant increase in O2 pulse (from 8.52 +/- 2.7 to 11.2 +/- 3.5 ml/min/beats, P < 0.0001). Plasma levels of A-type and of B-type natriuretic peptides and of norepinephrine significantly decreased after bisoprolol. CONCLUSIONS: Bisoprolol significantly improved left ventricle ejection fraction with a reverse remodeling of the left ventricle, a decrease in hormonal activation and a modest improvement in exercise capacity.

Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations.

AIMS: Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms. METHODS: We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified. RESULTS: A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H). CONCLUSION: For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations.

[Bilateral phrenic nerve paralysis, dysautonomia and restrictive cardiomyopathy in a case of POEMS syndrome]. / Paralysie phrénique bilatérale, dysautonomie et cardiomyopathie restrictive dans un cas de syndrome POEMS.

We report a case of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M protein and Skin changes) with unusual clinical features. A 62-year-old woman presented a severe polyneuropathy with dysphonia and vegetative symptoms, including bradycardia and sphincterial disorders. The clinical examination showed facial hyperpigmentation, cachexia, anasarca and splenomegaly. She also presented restrictive cardiomyopathy and endocrine disturbances. Nerve conduction studies revealed a severe demyelinating sensorimotor neuropathy. Cerebrospinal fluid analysis showed an elevated protein level. We detected a biclonal gammapathy (Ig G and Ig A with lambda light chain) and lytic pelvic bone lesions. Later, she developed a severe ventilatory failure due to a bilateral phrenic nerve paralysis leading to a mechanical ventilation. Steroids followed by localized radiotherapy partially improved the respiratory status and stabilized the neuropathy. Phrenic nerve paralysis, restrictive cardiomyopathy, vegetative symptoms and cranial nerve palsy are exceptional in POEMS syndrome. Moreover, this case emphasizes the importance of radiological investigations since the discover of plasmocytoma may improve the prognosis of POEMS syndrome.

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.

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.

[Aspirin, angiotensin converting enzyme inhibitors and cardiac insufficiency]. / Aspirine, inhibiteur de l'enzyme de conversion de l'angiotensine et insuffisance cardiaque.

The possible negative therapeutic interaction between aspirin and angiotensin converting enzyme inhibitors arose from the conclusions of several experimental studies and retrospective analysis of large scale mortality trials with converting enzyme inhibitors. Some experimental results show inhibition of the vasodilatation of converting enzyme inhibitors, increase in pulmonary pressures, vascular resistances and blood pressure, and degradation of renal function and exercise capacity. However, other studies did not confirm these results. In large scale therapeutic trials, some retrospective analyses, but not all of them, have shown less benefit on morbi-mortality of converting enzyme inhibitors in patients on aspirin. The differences between the doses of aspirin, the type and dosage of the converting enzyme inhibitors and neuro-hormonal activation of the patients could explain the discordant results. The results of randomised trials are awaited but, in the meantime, it is logical to propose small doses of aspirin (< or = 100 mg/day) for patients with cardiac failure and atherosclerosis and to avoid the association in all the other patients.

Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study.

OBJECTIVES: The study investigated the potential role of eight candidate genes in the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several genetic loci have been identified in rare monogenic forms of the disease. These findings led to the hypothesis that genetic factors might also be involved in sporadic forms of the disease. In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate gene approach is a strategy widely used to identify susceptibility genes. All genes coding for proteins involved in biochemical or physiological abnormalities of cardiac function are potential candidates for IDC. METHODS: We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were significantly associated with the risk or the severity of the disease. CONCLUSIONS: We did not find evidence for an involvement of any of the 10 investigated polymorphisms in the susceptibility to IDC.

Pericardoscopy for primary management of pericardial effusion in cancer patients.

OBJECTIVE: To assess the usefulness of pericardoscopy via the subxyphoid route for the diagnosis and treatment of pericardial effusion in patients with a history of cancer. METHODS: All patients with a recent or remote history of cancer and a pericardial effusion of unknown origin requiring drainage for diagnostic and therapeutic purposes were included in the study. They underwent complete exploration and cleansing of the pericardial cavity. Abnormal structures or deposits were biopsied under direct visual control, with a 24 cm long rigid pericardoscope. RESULTS: Between 1985 and 1998, pericardoscopy was completed in 112 of the 114 patients included (feasibility 98%), resulting in the immediate relief of symptoms in all the cases. Peri-operative mortality was 3.5%, and post-operative morbidity, 6.1%. After pericardioscopy pericardial effusions were considered malignant in 43 cases. One more case (2.3%) due to a false negative result of pericardioscopy was diagnosed during follow-up. Overall, 44 of the 114 patients (38.6%) had a malignant effusion, and 70 (61.4%), a non-malignant effusion according the follow up. In 10 of the 44 patients with a malignant pericardial effusion (22.7%), pericardoscopy corrected the results of cytological pericardial fluid studies and pericardial window biopsy, both false negatives. The sensitivities of cytological studies of the pericardial fluid, pathological examinations of pericardial window biopsy and pericardioscopy were 75, 65 and 97%, respectively. One patient with a malignant effusion had a non-symptomatic recurrence 1 month after pericardioscopy (2.3%). CONCLUSION: We recommend pericardioscopy to ascertain the malignant nature of the effusion and to diminish the recurrence rate, this avoiding repeat procedures in patients with a short life expectancy.

Identification of a genetic risk factor for idiopathic dilated cardiomyopathy. Involvement of a polymorphism in the endothelin receptor type A gene. CARDIGENE group.

BACKGROUND: Idiopathic dilated cardiomyopathy is a frequent cause of heart failure, a major concern of public health. Although idiopathic dilated cardiomyopathy may be familial, most cases are sporadic and the disease is considered to be multifactorial, for which genetic factors may account for a significant part. METHODS AND RESULTS: We hypothesized that genetic abnormalities of the endothelin pathway may be involved in idiopathic dilated cardiomyopathy pathophysiology and therefore examined the possible association between idiopathic dilated cardiomyopathy and polymorphisms in genes encoding endothelin 1, endothelin type A and type B receptors, in a case-control study (433 patients and 400 age- and sex-matched control subjects). Analysis of the Exon 8 C/T polymorphism in the endothelin receptor type A gene indicated that individuals who are homozygote for the T allele were at significantly increased risk for the disease (odds ratio: 1.9; 95% confidence interval: 1.2 to 3. 01;P<0.006). Analysis of the other polymorphisms indicated that no significant difference was observed in genotype or allele frequencies between cases and controls. CONCLUSIONS: The variant in the Exon 8 of the endothelin receptor type A gene appears as a genetic risk factor for idiopathic forms of heart failure. These results provide a new approach to the pathophysiology of idiopathic dilated cardiomyopathy.

[Effect of resection of the anterior chordae on cardiac function after surgical correction of mitral valve insufficiency]. / Effet de la résection des cordages antérieurs sur la fonction cardiaque après correction chirurgicale d'une insuffisance mitrale.

The preservation of cardiac function in surgical correction of mitral regurgitation implies partially or totally preserving the subvalvular apparatus. However, the conservation of the whole subvalvular apparatus during mitral valve replacement is technically difficult as the anatomical conditions are not always favourable. In order to determine the consequences of isolated resection of the anterior chordae, the authors studied global and segmental cardiac function by isotopic angiocardiography after mitral valve repair (n = 23) or replacement with conservation of the posterior chordae (n = 16) in 39 patients with isolated, non-ischaemic mitral regurgitation. The left ventricular ejection fraction decreased after valve replacement (64.1 +/- 8.5% to 57.4 +/- 10%, p = 0.01) but not after mitral valve repair (65 +/- 11.3% to 62.1 +/- 12.2%, p = NS). The ejection fractions of segments 4 and 5, corresponding to the zones of insertion of the anterior papillary muscle, decreased after valve replacement compared with repair (segment 4: -9 +/- 13.7 versus +2 +/- 11.3, p = 0.01) (segment 5: -15 +/- 13.2 versus 2 +/- 11.7, p = 0.003). The right ventricular ejection fraction improved after valve repair (40.9 +/- 9.1% to 46.4 +/- 10.1%, p = 0.03), whereas it remained unchanged after valve replacement (42.9 +/- 10.3% to 42.8 +/- 8.6%, p = NS). These results indicate a deleterious effect of isolated resection of the anterior chordae on cardiac function during mitral valve replacement with localised abnormalities of left ventricular function. This study supports the rationale of mitral valve repair or conservation of the anterior and posterior chordae during valve replacement for isolated mitral regurgitation.

[Diastolic cardiac failure: therapeutic modalities]. / Insuffisance cardiaque diastolique. Modalités thérapeutiques.

The management of cardiac failure due to diastolic dysfunction is not well codified and is often empirical. It has three objectives: improving the physiopathological components of ventricular filling, treating the associated aggravating pathological conditions, and treating the basic cause of the dysfunction. Symptomatic treatment aims to reduce venous congestion (by diuretics or nitrate derivatives), to prolong the diastolic period by slowing the heart rate (by betablockers, bradycardising calcium antagonists or digitalis in cases of irreducible atrial fibrillation), to improve passive ventricular distensibility by an effect on remodelling (by angiotensin converting enzyme inhibitors or anti-aldosterone diuretics). The treatment of associated pathological conditions is particularly important. It is essential to maintain or reestablish an effective atrial systole by cardioversion and anti-arrhythmic drugs in atrial fibrillation, by dual chamber pacing in cases of atrioventricular asynchrony due to atrioventricular block. Treatment of the underlying cause aims to induce regression of ventricular hypertrophy of hypertensive origin by using antihypertensive drugs with this property. In coronary artery disease, the choice is determined by the clinical context because nearly all anti-anginal or interventional treatments may improve ischaemic diastolic dysfunction. The same applies in hypertrophic cardiomyopathy because most types of treatment (betablockers, verapamil, cardiac pacing, surgery) may improve diastolic function. Finally, in valvular aortic stenosis, aortic valve replacement restores normal diastolic function.

Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease in which one of the most frequently implicated gene is the gene encoding the beta-myosin heavy chain. To date, more than 40 distinct mutations have been found within this gene. In order to progress on the determination of genotype-phenotype relationship, we have screened the beta-myosin heavy chain gene for mutations in 18 probands from unrelated families. We identified the mutation implicated in the disease in four families. Two of them, the Glu930 codon deletion and the Ile263Thr mutation, are reported here for the first time. The two other mutations are the Arg723Cys mutation, that was previously described in a proband as a de novo mutation, and the Arg719Trp mutation. A poor prognosis was associated with the Glu930codon deletion (mean maximal wall thickness (MWT) = 19.5 mm +/- 5) and the Arg719Trp mutation (mean MWT = 15.3 mm +/- 7), whereas a good prognosis was associated with the Arg723Cys mutation (mean MWT = 20.1 mm +/- 7). The combination of clinical and genetic characteristics of each family member suggests that prognosis is related neither to the degree of left ventricular wall thickness nor to a change in the net electrical charge of the protein. Additional family studies are needed to confirm these findings and to contribute to stratify the prognosis according to the mutation involved.

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.

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.

Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population.

BACKGROUND: The diagnostic value of ECG and echocardiography for familial hypertrophic cardiomyopathy (FHC) has not been reassessed since the development of molecular genetics. The aim of the study was to evaluate it in adults, with the genetic status used as the criterion of reference. METHODS AND RESULTS: Ten families with previously identified mutations were studied (9 mutations in 3 genes). ECG and echocardiography were analyzed in 155 adults, of whom 77 were genetically affected and 78 unaffected. The major diagnostic criteria were, for echocardiography, a left ventricular wall thickness > 13 mm and, for ECG, abnormal Q waves, left ventricular hypertrophy, and marked ST-T changes. Minor ECG and echographic abnormalities were also analyzed. (1) Sensitivity and specificity of major criteria were 61% and 97% for ECG and 62% and 100% for echocardiography. (2) Sensitivity but not specificity was age related (from 50% at < 30 years to 94% at > 50 years old, P < .01) and sex related (83% in men versus 57% in women, P = .01). (3) Sensitivity was improved by the addition of minor criteria and by the association of ECG and echocardiography. The negative predictive value was therefore very good (95%) at > 30 years of age. (4) Healthy carriers without any ECG or echocardiographic abnormality represented 17% of genetically affected adults. CONCLUSIONS: ECG and echocardiography have similar diagnostic values for FHC in adults, with an excellent specificity and a lower sensitivity. The association of the two techniques allows a better evaluation of the risk of being genetically affected in families with hypertrophic cardiomyopathy.

Incidence and prognosis of embolic events and metastatic infections in infective endocarditis.

AIMS: In infective endocarditis, the true incidence of embolic events and metastatic infections remains unknown probably because a large number of events are asymptomatic. The consequences of the prognosis of such events have never been evaluated by a prospective follow-up. This study aimed to assess the incidence of symptomatic or asymptomatic embolic events and metastatic infections in definite infective endocarditis and to determine whether these events carry a risk of mortality. METHODS AND RESULTS: From January 1991 to December 1993, 102 patients with suspected or known infective endocarditis were referred to our institution. Among them, we selected 68 patients (50 males, 18 females, mean age = 52.7 years) exhibiting definite infective endocarditis according to the Duke University criteria. Blood cultures were positive in 49 cases (72%). Echocardiography revealed valvular vegetations in 55 cases (81%). Irrespective of the clinical presentation, patients were examined radiologically by cerebral computed tomography scanning (n = 60), magnetic resonance imaging (n = 3), abdominal computed tomography scanning (n = 32) or abdominal echocardiography (n = 20). Depending on the symptoms, thoracic computed tomography scanning (n = 22), pulmonary angiography (n = 2), ventilation-perfusion scintigraphy (n = 4), or gallium citrate radionuclide scanning (n = 7) were also performed. All patients were prospectively followed-up for a mean period of 21.4 +/- 17.5 months. In 35 patients (51%), 51 embolic or metastatic events were revealed, involving the central nervous system (n = 23), spleen (n = 7), kidney (n = 5), lung (n = 5), liver (n = 4), bone and joint (n = 4), iliac (n = 2) or mesenteric (n = 1) arteries. During the hospital stay, the mortality rate was higher in patients exhibiting embolic or metastatic events (20 vs 12%), but the difference did not reach statistical significance. Kaplan-Meier analysis demonstrated no difference in long-term follow-up. CONCLUSION: Our data suggest that embolic or metastatic events had a high incidence (51%) during infective endocarditis, but were not associated with significant attributable mortality.

Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease. In some families, the disease is linked to the CMH2 locus on chromosome 1q3, in which the cardiac troponin T gene (TNNT2) has been identified as the disease gene. The mutations found in this gene appear to be associated with incomplete penetrance and poor prognosis. Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy. METHODS AND RESULTS: Family members were genotyped with microsatellite markers to detect linkage to the four known disease loci. In family 715, analyses showed linkage to CMH2 only. To accurately position potential mutations on TNNT2, its partial genomic organization was established. Screening for mutations was performed by single-strand conformation polymorphism analysis and sequencing. A new missense mutation, Arg102Leu, was identified in affected members of family 715 because of a G-->T transversion located in the 10th exon of the gene. Penetrance of this new mutation is complete; echocardiographic data show a wide range of hypertrophy; and there was no sudden cardiac death in this family. CONCLUSIONS: The codon 102 of the TNNT2 gene is a putative mutational hot spot in familial hypertrophic cardiomyopathy and is associated with phenotypic variability. Analysis of more pedigrees carrying mutations in this codon is necessary to better characterize the clinical and prognostic implications of TNNT2 mutations.

Pericardioscopy in the etiologic diagnosis of pericardial effusion in 141 consecutive patients.

BACKGROUND: Although previous small series have documented the utility of pericardioscopy for accurate etiologic diagnosis of pericardial effusion, this technique remains underused. The aim of our study was to assess the benefits and risks of surgical pericardioscopy in a large prospective series. METHODS AND RESULTS: One hundred forty-one consecutive patients with unexplained pericardial effusion underwent 142 pericardioscopies with a rigid mediastinoscope. For each patient, the etiologic data obtained by pericardioscopy (visualization of pericardium, guided biopsies, subxiphoid window biopsy, and fluid analysis) were compared with the results that would have been obtained with only conventional surgical drainage and biopsy (subxiphoid window biopsy and fluid analysis). After complete workup, a specific cause was found in 69 cases (48.6%); the other 73 cases were considered idiopathic effusions (51.4%). Procedural and in-hospital mortality was 8 of 141 patients (5.6%). No death was directly attributable to pericardioscopy. During long-term follow-up (median duration, 24 months; range, 6 to 96), a previously unrecognized cause was discovered in 6 patients (4%). By comparing the areas under the receiver-operating characteristic curves, the diagnostic advantage of pericardioscopy was significant for the whole series (pericardioscopy, 0.98 +/- 0.011; conventional surgical drainage, 0.89 +/- 0.029; P < .001). The increase in sensitivity was more marked for some types such as neoplastic (21%), radiation-induced (100%), or purulent (83%) effusions. CONCLUSIONS: Our data demonstrate that pericardioscopy increases the diagnostic sensitivity of surgical pericardial drainage and biopsy without specific risk.

Prevalence and clinical significance of antiphospholipid antibodies in heart valve disease: a case-control study.

The purposes of this study were (1) to assess the prevalence of antiphospholipid (aPL) antibodies in patients with non-specific heart valve disease referred for valve replacement and (2) to determine whether the presence of aPL antibodies carries a risk for thrombotic events during a postoperative follow-up in a prospective cohort. The sera of 89 consecutive patients and 80 matched control subjects were tested for antibodies to cardiolipin (immunoglobulin G and immunoglobulin M) and for lupus anticoagulant. The prevalence of aPL antibodies was significantly higher in patients (19 [21%] of 89) than in control subjects (7 [9%] of 80) (p < 0.05). Patients were divided into two subgroups according to the presence (subgroup A) or the absence (subgroup B) of aPL antibodies. No significant difference in age or sex ratio was observed between the two subgroups. A history of arterial thrombosis was more frequent in subgroup A (8 [42%] of 19) than in subgroup B (8 [11%] of 70) (p < 0.01). No significant difference with respect to the occurrence of thrombotic events was observed during a median follow-up period of 8.7 months. Thus a high prevalence of aPL antibodies was found in patients referred for heart valve replacement compared with matched control subjects. No increased risk has been demonstrated in the patients with aPL antibodies.