[Diagnostic value of a two-dimensional echocardiographic score for left ventricular hypertrophy validated by the Imatron CT scan in familial hypertrophic cardiomyopathy]. / Valeur diagnostique d'un score echocardiographique bidimensionnel d'hypertrophie du ventricule gauche validé par scanner Imatron dans la cardiomyopathie hypertrophique familiale.

The aim of this study was to validate a two-dimensional echocardiographic score for left ventricular hypertrophy in familial hypertrophic cardiomyopathy (HCM) by fast CT scan and to study the diagnostic value by an indexed threshold value in affected and genotyped families in comparison with the classical diagnostic method of maximal wall thickness (E max). The study was performed successively in two patient groups with HCM. The echo/CT scan population comprised 26 patients. They underwent echocardiography and Imatron CT scanning. The E max and 2D echo score (sum of the thickness of 4 segments) were measured by echocardiography and compared to the left ventricular mass obtained by the CT method. The 2D echo score was closely correlated to the CT left ventricular mass (r = 0.85) with a higher correlation coefficient than the E max (r = 0.78). The echo/generic population comprised 109 genotyped adults with an identified mutation. The E max and 2D echo score were measured. The genotype was the reference for diagnosis. A theoretical value of the 2D echo score was determined in healthy individuals by a multiple linear regression model of ages, sex and body surface area. A threshold value for abnormality was established after analysis of the ROC. The sensitivity and specificity were 63% and 100% respectively for E max and 73% and 96% respectively for the indexed 2D echo score. The improvement in sensitivity was marked in young adults (< 50 years) with 69% for the indexed 2D echo score versus 54% for E max, p < 0.04. The authors conclude that the indexed 2D score has been validated as an index of hypertrophy by the Imatron CT and has a better diagnostic value than E max, especially in young adults. This echocardiographic criterion could be proposed as an alternative diagnostic sign for screening families.

Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.

Thrombolysis or heparin therapy in massive pulmonary embolism with right ventricular dilation: results from a 128-patient monocenter registry.

STUDY OBJECTIVES: To assess the potential benefit of thrombolysis in patients with massive pulmonary embolism (PE) with stable hemodynamics and right ventricular dysfunction. DESIGN: Retrospective, cohort study. SETTING: University-based, tertiary referral medical center. PATIENTS: One hundred fifty-three consecutive patients with massive PE from January 1992 to December 1997 treated with heparin or thrombolysis. MEASUREMENTS AND RESULTS: Massive PE was confirmed by perfusion lung scan or pulmonary angiography. Right ventricular dysfunction was assessed by echocardiography (right ventricular/left ventricular [RV/LV] diastolic diameter ratio > 0.6) in all patients. In order to study a homogeneous population, 64 patients treated with thrombolysis (group 1) were matched on baseline RV/LV diameter ratio to 64 patients treated with heparin (group 2). Perfusion lung scan was repeated at day 7 to day 10. Mean relative improvement in perfusion lung scans was higher in group 1 than group 2 (54% vs 42%, respectively). PE recurrences were the same in both groups (4.7%; n = 3). There were no bleeding complications and no deaths in group 2. Conversely, in group 1, 15.6% (n = 10) of patients suffered from bleeding (4.7%; n = 3 with intracranial bleeding) and 6.25% (n = 4) of them died. CONCLUSIONS: The results of this monocenter registry do not support the indication for thrombolysis in patients suffering from massive PE with stable hemodynamics and right ventricular dysfunction. Appropriate therapy in such patients still remains unknown. Further prospective randomized trials should be performed.

Influence of carvedilol on the benefits of physical training in patients with moderate chronic heart failure.

AIMS: To evaluate prospectively the impact of carvedilol on a short-term physical training program in stable patients with moderate chronic heart failure (CHF), and to analyze parameters predictive of improvement after training. METHODS AND RESULTS: Thirty-eight patients with CHF were referred for cardiac rehabilitation. Etiology was ischemic in 26 patients, dilated in 12 patients and left ventricular ejection fraction was <35%. Patients were classified into three groups: group 1 (n=14)=ACE inhibitors, diuretics and digitalis; group 2 (n=11)=idem group 1+cardioselective beta-blocker; group 3 (n=13)=idem group 1+carvedilol. Exercise tests with VO2 measurement were performed before and after a 4-week exercise training program. Patients with carvedilol experienced a 16.6% increase in peak VO2 which was similar to the 13.9% increase in the group with cardioselective beta-blocker and to the 18.5% in the group without beta-blocker. Moreover non-ischemic etiology of CHF was the only parameter predictive of improvement after training (P=0.02). CONCLUSION: Addition of carvedilol did not alter benefits of a short-term physical training program in patients with moderate CHF. No baseline characteristic except for etiology of CHF was predictive of a response to training.

Accuracy of European diagnostic criteria for familial hypertrophic cardiomyopathy in a genotyped population.

BACKGROUND: Since the sensitivity of conventional diagnostic criteria for familial hypertrophic cardiomyopathy (HCM) is low, new diagnostic criteria were proposed by a European collaboration. However, their diagnostic value remains unknown. The aim of the study was to evaluate the accuracy of these new criteria, using the genetic status as the criterion of reference. METHODS: We studied 109 genotyped adults (54 genetically affected, 55 unaffected) from 7 families (mutations in 3 genes). Major European echographic criteria were a maximal wall thickness >or=13 mm or >or=15 mm according to the segment involved, or the presence of SAM. Major European ECG criteria were abnormal Q waves, left ventricular hypertrophy, or marked ST-T changes. Combined major/minor European criteria were also evaluated. RESULTS: Sensitivity and specificity of major European criteria (72 and 92%, respectively) were similar to those of major conventional criteria (70 and 94%) and were not improved by combined major/minor European criteria (72 and 90%). When all the minor European criteria were considered, sensitivity increased to 87% but specificity dramatically decreased to 51%. However, one of these minor ECG criteria, deep S V2, was of interest and when added to major European criteria, sensitivity increased to 76% and specificity remained good (90%). CONCLUSIONS: The diagnostic value of new European criteria for HCM was evaluated for the first time. We found that it was not different from that of conventional criteria, with a good specificity but a low sensitivity. Additional criteria should be studied to improve the early identification of HCM.

[Diagnostic value of stress echocardiography under dobutamine and myocardial scintigraphy for restenosis at 6 months after angioplasty of the left anterior descending artery]. / Valeur diagnostique de l'échocardiographie de stress sous dobutamine et de la scintigraphie myocardique d'effort dans le dépistage de la resténose à 6 mois d'une angioplastie de l'interventriculaire antérieure.

This study compared prospectively the diagnostic value of dobutamine echocardiography and exercise myocardial scintigraphy for restenosis at 6 months after angioplasty of the left anterior descending artery. Forty-one patients aged 58 +/- 10 years, admitted to hospital for myocardium infarction (N = 22) or unstable angina (N = 19), with single vessel disease, were treated by angioplasty of one lesion of the left anterior descending artery after initial evaluation of the left ventricular ejection fraction by echocardiography. At 6 months, left ventricular function was reassessed by echocardiography, dobutamine echocardiography and exercise myocardial scintigraphy (Thallium 201) performed without treatment. Coronary angiography was performed at the same time and showed 8 restenosis (19.5%). Overall, in this series, dobutamine echo and scintigraphy had respectively a sensitivity of 37.5% and 75%, and a specificity of 97% and 70% (p < 0.02). Nine patients had left ventricular dysfunction unchanged compared with the initial measurement without viability in the territory of the left anterior descending artery with low dose dobutamine (group 1); thirty-two patients had improved or normal left ventricular ejection fraction with myocardial viability (group 2). In group 1, no cases of restenosis were detected by dobutamine echocardiography but_of them had myocardial scintigraphic evidence of ischaemia. In group 2, the sensitivity of the two techniques was comparable but dobutamine echo was more specific than scintigraphy (96 versus 75%, p = 0.03). In conclusion, dobutamine echocardiography may be indicated in the diagnosis of restenosis of the left anterior descending artery and in cases of viability in its territory. In its absence, myocardial scintigraphy seems to be preferable.

[Incidental discovery of a giant myxoma]. / A propos d'un volumineux myxome de découverte fortuite.

The authors report a case of very large myxoma of the left atrium, original in terms of its mode of discovery, its very calcified appearance, in a totally asymptomatic elderly patient. A complete ultrasound assessment, catheterization, and coronary angiography allowed assessment of the morphology, topography, blood supply and cardiac repercussions of this tumour. Myxoma of the left auricle is the commonest cardiac tumour, with multiple clinical features and presentations. This benign tumour arises from embryonic vestigial remains, usually in the fossa ovale. The present case is original by its unusual mode of discovery in a totally asymptomatic patient.

[Ventricular late potentials in myocardial infarction: comparison of thrombolysis, primary angioplasty, and conventional treatment]. / Etude des potentiels tardifs ventriculaires dans l'infarctus du myocarde: comparaison entre thrombolyse, angioplastie primaire et traitement conventionnel.

OBJECTIVES: The aim of this study was to compare the prevalence of ventricular late potentials (VLP) during the acute phase of myocardial infarction (MI) depending on the treatment used. METHODS AND RESULTS: This retrospective study was carried out over the period January 1992 to December 1997, and involved 238 patients admitted for primary MI and treated less than six hours after the onset of symptoms by intravenous thrombolysis (rt-PA, n = 83) or primary angioplasty (ATCI, n = 82) and in those cases treated over six hours after the onset of symptoms by standard treatment (heparin, n = 73). Rt-PA perfusion was considered to be effective when the three following criteria were simultaneously present: i) pain sedation; ii) regression of the ST dysfunction > 50%; iii) creatine phosphokinase (CPK) peak before the 16th hour. Treatment success for angioplasty (ATCI+) was confirmed by a TIMI 3 (Thrombolysis in Myocardial Infarction) score for MI arterial perfusion, with residual stenosis of the MI artery of < 50%. Ventricular late potentials (VLP) were investigated between day six and 14, and considered to be present when two of the following criteria were met: total duration of filtered QRS, i.e., QRSd > 114 ms; signal amplitude in the 49 last ms of filtered QRS, i.e., RMS40 < 20 mV, duration of the terminal part of filtered QRS that was below 40 mV, i.e., LAS40 > 38 ms (40 Hz). VLP prevalence was as follows: 25% (rt-PA group), 345 (ATCI group), and 33% (standard treatment) respectively (P = NS). In the thrombolysis with reperfusion subgroup (n = 54/83, 65%), VLP incidence was 18.5% (n = 10/54) versus 35.5% (n = 27/76) in the subgroup ACTI+ (n = 76/82, 93%) (P = 0.03). CONCLUSIONS: The prevalence of VLP appears to be significantly decreased in the the case of thrombolysis with reperfusion compared to that observed in the ATCI+ group. One of the possible explanations for this abnormally high prevalence in the angioplasty group could be a dysfunction involving reocclusion after initially successful myocardial reperfusion therapy.

First description of germline mosaicism in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disease caused by mutations in seven sarcomeric protein genes. It is known to be transmitted as an autosomal dominant trait with rare de novo mutations.A French family in which two members are affected by hypertrophic cardiomyopathy was clinically screened with electrocardiography and echocardiography. Genetic analyses were performed on leucocyte DNA by haplotype analysis with microsatellite markers at the MYH7 locus and mutation screening by single strand conformation polymorphism analysis. Two subjects exhibited severe hypertrophic cardiomyopathy. A mutation in the MYH7 gene was found in exon 14 (Arg453Cys). The two affected patients were carriers of the mutation, which was not found in the circulating lymphocytes of their parents. Haplotype analysis at the MYH7 locus with two intragenic microsatellite markers (MYOI and MYOII) and the absence of the mutation in the father's sperm DNA suggested that the mutation had been inherited from the mother. However, it was not found in either her fibroblasts or hair. This is the first description of germline mosaicism shown by molecular genetic analysis in an autosomal dominant disorder and more especially in hypertrophic cardiomyopathy. This mosaicism had been inherited from the mother but did not affect her somatic cells. Such a phenomenon might account for some de novo mutations in familial hypertrophic cardiomyopathy.

Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene.

Troponin T (TnT) is a component of the troponin complex which regulates muscle contraction in response to alterations in intracellular calcium ion concentration. In human heart, multiple isoforms of cardiac TnT have been described on the basis of antibody studies and molecular cloning of corresponding cDNAs. These isoforms are all derived from the transcription of a single gene, TNNT2, located on chromosome 1q32, and generated by alternative splicing. We show here that isoform diversity is achieved by the use of both alternative exons and alternative acceptor sites and present the organisation of the human TNNT2 gene, which is composed of 17 exons spread over 17 kb. A potential structure of the promoter region is also presented. Several polymorphisms in both the exonic and intronic regions were identified, some of which may act as modulators of the expression of this gene.

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.