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A causal relationship between treatment with tricyclic antidepressant (TCA) at therapeutic doses and cases of dilated cardiomyopathy has been suspected, but not definitely evidenced. We present a case of a dilated cardiomyopathy, which seemed idiopathic, but occurred during treatment with imipramine and recovered after its withdrawal. For the first recorded time, the cardiomyopathy recurred 9 years later, after a 2-year period of treatment with amitriptyline and lithium, and recovered again 1 year after both psychotropic drugs withdrawal. New arguments for the existence of TCA-induced dilated cardiomyopathy are brought.

Aims: To study the diagnostic value of a new 2D left ventricle hypertrophy (2D LVH) score in families with hypertrophic cardiomyopathy (HCM) in comparison with the conventional maximal wall thickness (MWT) measurement (>13 mm in adults), which is limited by a low sensitivity in relatives., Methods and Results: The study was performed in 237 adults from genotyped families with HCM. Population A (derivation sample) comprised 109 adults and population B (validation sample) comprised 128 adults. MWT and 2D LVH scores (sum of thicknesses of four segments) were determined by echocardiography. Genotyping was the gold standard for diagnosis. In population A, a theoretical value for LVH score was determined in the healthy population by a multiple linear regression model including age, sex, and body surface area. An abnormal cut-off value was defined as an LVH score above a maximum theoretical value according to receiver operating characteristic analysis. Sensitivity and specificity were, respectively, 73 and 96% for 2D LVH score and 62.5 and 100% for MWT. Improvement of sensitivity was particularly important in adults <50 years of age (69 vs. 54%, respectively, P<0.04). These results were validated in population B: sensitivity and specificity of LVH score were, respectively, 75 and 96% in this sample and 67 and 97%, in the subgroup <50 years. In the latter, sensitivity of LVH score increased when compared with that of MWT (67 vs. 53%, P<0.03)., Conclusions: The LVH score has a higher diagnostic value for HCM than the conventional criterion of MWT, particularly in young adults. This echographic parameter may be proposed as an alternative diagnostic criterion for familial screening.

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.

Aims: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and the organisation of the procedure. The aim of this work was (1) to discuss the different questions related to genetic testing in HCM, and propose guidelines for the different situations, (2) to report our preliminary experience with a specific procedure., Methods and Results: The main questions asked by patients and relatives concern presymptomatic diagnosis and prenatal counselling/diagnosis, while clinicians sometimes discuss diagnostic and prognostic testing. To take into account the complex medical and psychological implications of this new approach, we developed a specific, multidisciplinary, and multiple step procedure, including a cardiologist, a geneticist, and a psychologist. Seventy subjects were examined, including (1) 29 adults for presymptomatic diagnosis (of whom 10 left the procedure after the first visit and 19 continued, among whom six had a mutation and two experienced negative psychological impact, observed during follow up), (2) nine couples of parents for presymptomatic diagnosis in their children (the procedure was stopped after the first visit in eight and continued in one), (3) 22 couples for prenatal counselling (no prenatal genetic testing was asked for after the first visit), and (4) 10 subjects for diagnostic testing. We decided to perform no prognostic testing., Conclusion: Our preliminary experience confirms the complexity of the situation and suggests the necessity for a specific procedure to ensure good practice in genetic testing of HCM.

Background: QT abnormalities have been reported in left ventricular hypertrophy and hypertrophic cardiomyopathy., Objective: To determine the relation between left ventricular hypertrophy and increased QT interval in familial hypertrophic cardiomyopathy., Methods: The QT interval was measured in 206 genotyped adult subjects with familial hypertrophic cardiomyopathy from 15 unrelated families carrying mutations in the beta myosin heavy chain (beta-MHC) gene (five families, n = 68) or the cardiac myosin binding protein C (MyBPC) gene (10 families, n = 138). Subjects were classified as genetically unaffected (controls, n = 112), affected with left ventricular hypertrophy (penetrants, n = 58), or affected without left ventricular hypertrophy (non-penetrants, n = 36)., Results: There was a significant increase in QTmax and QTmin from controls to non-penetrants and penetrants for both the MyBPC group (p < or = 0.001 and p < or = 0.001, respectively) and the beta-MHC group (p < or = 0.001 and p < or = 0.001, respectively). In the MyBPC group, the increase in the QT interval could be explained by increased left ventricular hypertrophy. In the beta-MHC group, non-penetrants had a significantly longer QTmax than controls despite the absence of left ventricular hypertrophy, and a similar QT interval to penetrants despite a lesser degree of left ventricular hypertrophy., Conclusions: In familial hypertrophic cardiomyopathy, genetically affected subjects without left ventricular hypertrophy may have a prolonged QT duration, which depends not only on the degree of left ventricular hypertrophy, when present, but also on the causative mutation.

Cardiac transplant remains the treatment of reference for end-stage cardiac insufficiency. The very great disparity between the number of grafts available and the number of patients eligible to be included on the transplant list drives some of them to contemplate a surgical alternative in order to improve their clinical condition and to delay as much as possible the date of transplant. The objective is to treat surgically one or several of the lesions causing the cardiac insufficiency. It could be valvular surgery, coronary surgery or a combination of both, ventricular remodelling or cardiomyoplasty. It is coronary revascularisation surgery which gives the most spectacular results on condition that it is aimed at the myocardial zones for which viability has been demonstrated by stress echocardiography or a PET scan.

Hypertrophic cardiomyopathy (HCM) is a rare, often familial condition, which may be complicated by syncope, atrial or ventricular arrhythmias and episodes of cardiac failure. This genetic disease affects young people and may be observed in women wishing for a pregnancy. The duration and outcome of such pregnancies has not been extensively studied. The authors undertook a retrospective study by questionnaire to compare the pregnancies of 41 women with HCM, a total of 150 pregnancies, with those of 39 unaffected women from the same families: a total of 132 pregnancies. None of the women died, there were no hospital admission for cardiac causes and there was no aggravation of functional status (31% of women with HCM had symptoms before pregnancy compared with 27% during pregnancy). The foetal prognosis was good with no increase in prematurity or neonatal crises. Only the women with symptoms before pregnancy had an increased risk of foetal prematurity compared with healthy women (18% versus 5%). These results indicate the good tolerance of pregnancy of women with HCM and should lead to a revision of systematic medical contra-indication of pregnancy in these patients.

Prevalence of symptomatic heart failure estimates range from 0.4 to 2@1000 with the mean age being 74 years in the european population. This chronic pathology will increase in the next decade. We have to optimize the management of heart failure and try to decrease the number of expensive hospital readmissions, especially the ones that can be avoid. In the future we must respect the practical recommendations, evaluate the new drugs, develop primary cardiovascular prevention, institute a real information and education for heart failure patients and coordinate the management programs within the community. There are the stakes to overcome for reducing the number of heart failure patients and improve their prognosis.

The authors report the case of a 31 year old woman, admitted as an emergency for acute myopericarditis, in cardiogenic shock. Echocardiography showed severe left ventricular dysfunction associated with concentric biventricular hypertrophy with increased echogenicity of the myocardial walls. Poor response to treatment with intravenous inotropic drugs led to referral for biventricular circulatory assistance with a Biomedicus pump, which was withdrawn on the 9th day after recovery of normal left ventricular function. Myocardial biopsies showed massive interstitial inflammation with a predominance of eosinophilic cells suggesting a hypersensitivity reaction. Steroid therapy was prescribed when the results of biopsy were known and stopped after 6 months. This case emphasises the value of echocardiography and myocardial biopsy in diagnosis and treatment of acute myocarditis with cardiogenic shock.

This retrospective study was undertaken to assess the long-term clinical outcome of hypertrophic cardiomyopathy (HCM) in a regional cohort of 243 patients aged 40.4 years on average at the time of diagnosis and followed up for 12.3 +/- 8.1 years. Forty-one deaths were recorded during the follow-up period directly related to HCM (including 20 sudden deaths and 17 deaths due to cardiac failure), an annual cardiac mortality rate of 1.37%. In multivariate analysis, two factors were associated with extra mortality: occurrence of the first symptoms before the age of 20 (RR x 2.35) (p = 0.006) and NYHA functional classes III: IV at the latest clinical assessment (p = 0.005). The risk of sudden death increased significantly with septal wall thickness: RR x 2.34 (p = 0.05), RR x 3.27 (p = 0.007) and RR x 3.67 (p = 0.02) respectively, for septal thickness equal to or greater than 25, 30 and 35 mm. Eighty-three patients (34%) had major cardiovascular events (sudden death, congestive cardiac failure, cerebrovascular accident) during follow-up. However, at the latest clinical assessment, 79% were relatively unaffected by their disease, without treatment (12%) or with drug therapy alone (60%). In a minority of patients (28%) a more aggressive therapeutic approach was necessary: cardiac pacing (N = 48), implantable cardiac defibrillators (N = 2) myomectomy (N = 27) or cardiac transplantation (N = 6). The authors conclude that HCM is a complex disease, less serious than initially thought in the majority of patients, but the cause of major cardiovascular events and premature deaths which still remain difficult to prevent.

Unlabelled: Management of ambulatory heart failure was assessed in a group of 600 patients, mean age 73, 64% males, NYHA I: 9%; II: 52%; III: 33%; IV: 6%; followed up by a representative sample of private cardiologists. Fifty-two percent of patients had been previously hospitalised for worsening heart failure with a mean duration of stay of 13.1 days, for those hospitalised in the year preceding the survey (26%). First diagnosis of heart failure had been performed by a cardiologist (57%), a general practitioner (37%) or another category of physician (6%). Seventy percent of patients received three or more different classes of heart failure medications. Diuretics were prescribed to 71%, angiotensin converting enzyme inhibitors to 54% and digitalis to 35% of the population. Beta-blockers were given to only 14% of the patients. In patients aged over 80 years, only 45% received angiotensin converting enzyme inhibitors., Conclusion: This survey of ambulatory heart failure patients confirms that the disease is predominantly observed in elderly patients, and associated with prolonged and recurrent hospitalisations. The underuse of recommended therapeutic classes including angiotensin converting enzyme inhibitors and beta-blockers deserves further investigation.

An enquiry was undertaken amongst 71 cardiologists in 1999 evaluating 600 ambulatory patients with cardiac failure (64% men; mean age 73 years; NYHA Class I: 9%, Class II: 52%, Class III: 33%, Class IV: 6%). Cardiac failure is commoner in men (81%) before the age of 70. After the age of 80, the tendency is inversed (53% of women). Fifty-two per cent of patients had a history of hospital admission for cardiac failure: 26% in the year before the enquiry (on average 13.1 days' hospital stay). On inclusion, the diagnosis was made 4.2 +/- 4.6 years previously and the patients had been followed up for an average of 3.04 +/- 3.3 years. The diagnosis of cardiac failure was made by the cardiologist (57%), the general practitioner (37%), or another category of physician (6%). Eight per cent of patients were treated with a single drug before inclusion, 22% had a bi-therapy and 70% a polytherapy. The most frequently prescribed drugs were: diuretics (71%), angiotensin converting enzyme (ACE) inhibitors (54%) and digitalis (35%). The prescription of betablockers was only reported in 14% of the population. In the over-80's, only 45% of patients were prescribed ACE inhibitors. These results confirm that ambulatory patients with cardiac failure are mainly in NYHA Classes II and III, that the pathology concerns elderly patients and that it is the cause of recurrent hospital admission. The prescription of diuretics is the main therapy in all NYHA Classes. ACE inhibitors were only prescribed in 2/3 of patients and in less than half of patients over 80 years of age. The prescription of betablockers remains marginal. The reason for the underprescription of recommended drugs (International Recommendations) would justify further investigation.

Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.

Unlabelled: Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease characterised by ventricular hypertrophy, with predominant involvement of the interventricular septum. It is a monogenic disease with a high level of genetic heterogeneity (nine genes and more than 110 mutations reported so far). We describe a family with a new R869G mutation in the beta -myosin heavy chain gene (MYH7). This mutation was found in the heterozygous status in both parents and in the homozygous status in the two children. A haplotype analysis on the MYH7 locus with microsatellite markers showed that the same haplotype is transmitted within the family, suggesting a founder effect. Clinically, the father was asymptomatic with mild left ventricular hypertrophy on echocardiography. The mother had a mild form of hypertrophic cardiomyopathy and remained asymptomatic until 60 years old when an atrial fibrillation occurred. For the two children, clinical diagnosis was performed at 12 and 8 years and atrial fibrillation occurred at 17 years. For both children, the evolution was characterized by left ventricle (LV) systolic dysfunction and a severe dilatation of the left atrium before 40 years of age., Conclusions: In this family, a new R869G mutation in the MYH7 gene was found. Interestingly, a mutation was found at the homozygous status for the first time in FHC. This finding suggests that this particular mutation is compatible with life, but for homozygous subjects, age at onset of symptoms was earlier and the disease much more severe than in the heterozygous subjects, suggesting a gene-dose effect., (Copyright 2000 Academic Press.)

Heart failure is becoming, in France as in other countries, a major public health problem, occurring in elderly patients with concurrent disease. A general overview of the current care of heart failure patients in France is provided in this article, and some ideas about possible ways of improving the present management of heart failure.

Objective: This study investigated whether, among a population of cardiac patients, there is a preferential association between idiopathic cardiomyopathy (CMP) and Panic Disorder (PD)., Methods: A total of 93 patients with cardiac failure, 50 of them with CMP, 43 with other cardiac diseases, underwent a standard psychiatric examination using the MINI neuropsychiatric interview., Results: While half of the subjects met the criteria for a psychiatric disorder, PD was no more prevalent in the CMP group compared to other patients., Conclusion: This study confirms the high prevalence of psychiatric pathology, particularly anxiety, mood, and alcohol-related disorders, in patients with cardiac failure. However, previous findings on the specific association between CMP and PD could not be replicated.

The occurrence of stroke after the post-operative period of cardiac transplantation is a rare event, and the role of the cardiac transplant in these patients, who often have various vascular risk factors, is unclear. We reviewed the clinical records of 303 consecutive patients with orthotopic cardiac transplantation performed from March 1985 to December 1996 and selected those who developed a stroke over the first 2 months postoperatively, in order to evaluate the frequency and the mechanisms of late cerebrovascular complications. Four patients had presented cerebral infarct and two intracranial hemorrhage. The overall risk of late cerebrovascular complications was 2.6p.100 at 5 years. Ischemic stroke was related to cardiac embolus in one patient, lacunar infarction in another, and was of undetermined etiology in two cases. In addition to vascular risk factors prior to transplantation and the development of intracardiac thrombus, immunosuppressive therapy, the surgical procedure and cardiac rejection may play a role in the occurrence of stroke in such patients.

The aim of this update is to review the role of digitalis and betablockers in the treatment of chronic cardiac failure. The role of digitalis is unquestioned in the treatment of chronic cardiac failure complicated by atrial fibrillation resistant to attempts at reduction. Digoxin, with a shorter half-life, is preferred to digitalis. When in sinus rhythm, digoxin is indicated in association with diuretics and angiotensin converting enzyme inhibitors, to improve the quality of life without demonstrable effects on survival. Betablockers now have a recognised place in the treatment of chronic cardiac failure in association with diuretics and angiotensin converting enzyme inhibitors. The compilation of the US-Carvedilol HF Trial have shown a 67% reduction in mortality at 6 months. Carvedilol has been officially approved for use in this indication. Some betablockers are under evaluation, regarding positive results in term of mortality, some clinical trials have been stopped. This review emphasises the changes in prescribing habits of digitalis, and mostly betablockers, in chronic cardiac failure.

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.

Many systems have been proposed to evaluate the functional incapacity caused by chronic cardiac failure. The classification of the New York Heart Association (NYHA) is the best known. It is subjective, poorly reproducible and has a poor predictive value on effort. The authors propose a Specific French Scale of Activity with the object of a more accurate functional evaluation of cardiac failure, easier to use by the doctor and more specific to French patients and their life styles. A French multicentre study was set up in hospital departments by the French Society of Cardiology working group on Cardiomyopathy and Cardiac Failure to assess this new classification with respect to the NYHA classification and peak VO2 (Weber's classification). Eight centres participated in the study. A total of 124 patients with chronic cardiac failure and a mean age of 61 years (102 men) were included. Cardiac failure was due to ischaemic heart disease in 72 cases, hypertension in 10 cases, dilated cardiomyopathy in 40 cases and aortic regurgitation in 2 cases. Eighty-two patients underwent a double evaluation using the French Scale: 40 patients by 2 physicians and 42 patients by a physician and a nurse. Good reproducibility was found between the assessment by the 2 physicians in 35 cases (87%) and between the physician and nurse in 30 cases (71%). When compared with peak VO2, the classification was concordant in 47% of cases using the NYHA and in 61% of cases using the French Scale, with variation of one class in 40% of cases with the NYHA and 35% of cases with the French Scale. These results show good reproducibility and correspondence of classification with the exercise test which was better using the French Scale than the NYHA classification.

Chronic cardiac failure is a common complication of coronary artery disease and hypertension. It is observed above all in the elderly and represents a high public health cost, mainly due to hospital admissions. The education of patients with cardiac failure, and their families', will contribute to an improved cost/efficacy ratio of the management of this pathology. This educative process comprises a simple description of cardiac failure, its symptoms and aetiologies. Dietary advice is very important (salt intake, drinks...). Physical exercise, which is not contraindicated, should be adapted to the degree of functional impairment and the same applies to travelling and voyages. Medical treatment should be clearly explained, mode of action, dosage, expected benefit, side effects... Finally, the possible progression of the disease should be explained if arrangements have to be made. The possibility of cardiac transplantation should be discussed if the subject is young. Although the risk of sudden death is not usually spoken about, this common complication of cardiac failure justifies consideration and widespread instruction of cardiopulmonary ressuscitation.

Aim: The aim of the study was to evaluate electrocardiography and echocardiography in the diagnosis of familial hypertrophic cardiomyopathy in children, using the genetic status as the criterion of reference., Methods and Results: We analysed 35 children (<18 years) from 13 families with identified mutations: 16 were genetically affected (11.2 +/- 3 years), 19 unaffected (13.1 +/- 2.8 years). Conventional major diagnostic criteria were: left ventricular wall thickness >95% confidence interval on the echocardiogram; abnormal Q waves, left ventricular hypertrophy (voltage >95th percentile), or marked ST-T changes on the electrocardiogram. Twenty-two minor electrocardiographic and echocardiographic criteria were also analysed. Using major criteria, the specificity of the electrocardiogram and echocardiogram was excellent (100% for both) but sensitivity was particularly low (38% and 50% respectively). However, when four relevant additional criteria (QRS axis, left atrium dimension, intraventricular septum/posterior wall ratio, E/A wave ratio) were taken into account, sensitivity increased to 88% and specificity remained high (95%)., Conclusions: (1) Familial hypertrophic cardiomyopathy was diagnosed in only approximately 50% of genetically affected children by conventional electrocardiographic and/or echocardiographic criteria. (2) Relevant additional diagnostic criteria were selected so that nearly all children considered as healthy carriers of a mutation (based on conventional criteria) could be identified with excellent specificity.

Background: Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis., Methods and Results: We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02)., Conclusions: These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.

Aims: It is not known whether the apparent normality of echocardiographic examination results, in subjects bearing a mutation for hypertrophic cardiomyopathy but without ultrasonic left ventricular hypertrophy, is due to incomplete phenotypic expression, or inaccurate echocardiographic criteria. The aim of this study was to search for echocardiographic abnormalities in these patients., Methods and Results: Echocardiography was performed in 100 subjects from two families with a mutation in the beta-MHC (720) or My-BPC (714) genes. We compared genetically affected subjects with an apparently normal left ventricle (thickness < 13 mm) (20 patients), and nonaffected first-degree relatives (61 normal subjects). (1) Patients had a thicker left ventricular wall (9.7 +/- 1.4 vs 8.9 +/- 1.4 mm, P = 0.03), a greater indexed mass (107 +/- 18 vs 97 +/- 17 g. m-2, P = 0.03), a larger left atrium (27 +/- 9 vs 23 +/- 10 mm3, P = 0.09) and lower wall stress (78 +/- 11 vs 89 +/- 15 10(3) dynes. cm-2, P = 0.002); these differences were highly significant after adjustment for height, age and systolic blood pressure either for wall thickness (P = 0.000003), mass (P = 0.005) or atrial volume (P = 0.001), and the ventricular systolic dimension appeared smaller (P = 0.01); (2) results remained significant (P < 0.01) when a lower cut-off value (< or = 11 mm) or only adults (> or = 18 years) were considered; (3) a subanalysis of Family 714 (13 patients, 25 normals matched for sex, age and height) showed the same trends., Conclusion: In familial hypertrophic cardiomyopathy, genetically affected subjects with an apparently normal heart by echocardiography show slight ultrasonic structural and functional left ventricular modifications, suggesting that the phenotype of the disease is a continuous spectrum from normal structure to typical hypertrophy.

Myxoid heart disease is frequently encountered in the general population. It corresponds to an etiologically heterogeneous group of diseases, idiopathic mitral valve prolapse (IMVP) being the most common form. A rarely observed form of myxoid heart disease, X-linked myxomatous valvular dystrophy (XMVD), is inherited in an X-linked fashion and is characterized by multivalvular myxomatous degeneration; however, the histopathological features of the mitral valve do not differ significantly from the severe form of IMVP. In this article, we describe the genetic analysis of a large family in which XMVD is associated with a mild hemophilia A. The coagulation factor VIII gene position in Xq28 provided a starting point for the genetic study, which was conducted by use of polymorphic markers. Two-point linkage analysis confirmed this localization, and a maximum LOD score of 6.57 was found at straight theta=0 for two polymorphic microsatellite markers, INT-3 and DXS1008, the first one being intronic to the factor VIII gene. Haplotype analysis of this chromosomal region allowed the definition of an 8-cM minimal interval containing the gene for XMVD, between DXS8011 and Xqter.

Plasma noradrenaline is little used in evaluating the prognosis of cardiac failure because of the theoretical necessity of interrupting treatment for a few days before blood sampling. The present study reevaluated the prognostic value of this parameter with blood sampling performed during treatment and then 48 hours after withdrawal of treatment in 192 patients with chronic stable cardiac failure at an advanced stage (64% of patients in Classes III or IV with an average ejection fraction of 28.5 +/- 13.5%). During follow-up (average 43 months) there were 51 deaths and 17 transplants. None of the patients were lost to follow-up. Univariate analysis of 52 variable observers during the initial phase of evaluation found in decreasing order of predictive value for death plasma noradrenaline levels before and after withdrawal of treatment for 48 hours. Serum sodium, age, systolic mean and diastolic pulmonary artery pressures. In multivariate analysis: noradrenaline with or without withdrawal of treatment, hyponatraemia and systolic pulmonary artery pressure. Actuarial survival curves distinguished the following parameters: noradrenaline levels became predictive at concentrations of over 210 pg/mL and there was a significant difference in survival with respect to 4 levels of serum noradrenaline (with or without treatment) > 300 pg/mL, 300 to 600 pg/mL and > 900 pg/mL. This serum noradrenaline measured without withdrawal of treatment (especially angiotensin converting enzyme inhibitors) is a powerful predictor of mortality, carrying a progressively poorer prognosis as the concentration increases.

Background: The gene involved in familial hypertrophic cardiomyopathy on chromosome 11 was recently identified as the cardiac myosin binding protein-C (MyBP-C) gene. The phenotype of two families associated with mutation in this gene is described here and compared to that of five families with mutations in the beta-myosin heavy chain gene., Methods and Results: In adults (n = 33) bearing a splice acceptor site mutation in the MyBP-C gene, penetrance of familial hypertrophic cardiomyopathy was incomplete (69%) and ventricular hypertrophy mild. Among 37 clinical, electrocardiographic and echocardiographic parameters analysed, the only difference with the beta-MHC group (n = 35) was a shorter acceleration time of systolic flow in the pulmonary artery (P < 0.05). Sensitivity and specificity of diagnostic criteria were similar for the two genes. Cumulative survival rate for the splice acceptor site mutation (90% at 50 years old) was mid-way between that observed with a malignant (Arg403Leu: 42%) and a benign mutation (Arg403Trp: 100%) in the beta myosin heavy chain gene (P = 0.002)., Conclusions: The detailed phenotype associated with a mutation in the MyBP-C gene was no different from that associated with mutations in the beta myosin heavy chain gene, except for prognosis which appeared more benign. These preliminary results suggest that there is no locus-specific genotype-phenotype correlation for the two genes analysed.

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.

The mere recognition of cardiac failure should not be the sole diagnostic aim. Diagnosis must also include the search for the underlying cause of cardiac failure and for its precipitating causes, as well as the assessment of its severity. Each step is essential because it contributes to the choice of an appropriate treatment. Full diagnosis take into account disease history, physical examination, electrocardiogram and chest X-ray; in addition, informations provided by cardiac echography play an increasing role in the assessment of cardiac failure.

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.

Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both structural and regulatory roles. The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). Detailed characterization of the MYBPC3 gene is essential for studies on gene regulation, analysis of the role of MyBP-C in cardiac contraction through the use of recombinant DNA technology, and mutational analyses of FHC. The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing. The MYBPC3 gene comprises > 21,000 base pairs and contains 35 exons. Two exons are unusually small in size, 3 bp each. We found six new mutations associated with FHC in seven unrelated French families. Four of these mutations are predicted to produce truncated cardiac MyBP-C polypeptides. The two others should each produce two aberrant proteins, one truncated and one mutated. The present study provides the first organization and sequence for an MyBP-C gene. The mutations reported here and previously in MYBPC3 result in aberrant transcripts that are predicted to encode significantly truncated cardiac MyBP-C polypeptides. This spectrum of mutations differs from the ones previously observed in other disease genes causing FHC. Our data strengthen the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant cardiac disease for which the penetrance remains a much-debated issue. Since the recent identification of the genes involved in the disease, the penetrance of FHC has not been reassessed in a large genotyped population. The aim of our study was therefore to evaluate it, according to age and sex, in ten families with previously identified mutations. Among 178 individuals we studied, 90 were genetically affected (9 different mutations in 3 genes). We found that penetrance, assessed by classical echocardiographic and electrocardiographic criteria, was (1) incomplete: 69%; (2) age-related: 55% between 10 and 29 years old, 75% between 30 and 49 y. and 95% over 50 y.; (3) greater in males than in females: 77% vs 58%, age-adjusted odds ratio: 3.98, CI 95%: 1.34 to 11,48; (4) similar for the genes analyzed. The consequences of these results for genetic counseling and linkage analyses are discussed.

Ambulatory mechanical left ventricular assistance has become a reality but clinical experience of long-term tolerance is limited for setting up a randomised trial comparing this technique with cardiac transplantation. On the other hand, it is justified in proposing this long-term circulatory assistance to a subgroup of patients on the waiting list for transplantation but who have little chance of being transplanted before irreversible multivisceral failure sets in. Some specific contraindications to left ventricular mechanical assistance should be respected. After implantation of a portable system, the possibility of being reinscribed on the waiting list for cardiac transplantation should be envisaged if the patient so wishes.

Of the three physiopathological types of cardiomyopathy, dilated, hypertrophic and restrictive, it is the first which characteristically shows major left ventricular systolic dysfunction. The left ventricular volumes are increased, the ventricle becomes spherical and global ejection fraction decreases with diffuse or segmental wall motion abnormalities. The left ventricular mass is increased in an excentrical fashion with wall thinning. Isovolumic contraction is slower, the ejection time is shorter and, above all, the indices of contractility such as maximal velocity of the contractile elements ... are very abnormal and do not improve after positive inotropic stimulation.

Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximal LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity.

Unlabelled: Familial hypertrophic cardiomyopathy (HCM) has been poorly studied, although it may represent 50% of all HCM. We studied 346 subjects belonging to 20 unrelated families. Patients were considered affected in view of left ventricular (LV) wall thickness. One hundred twenty-seven adults were considered affected, id est. had a left ventricular wall thickness (LVWT) > 13 mm, whereas 123 had a LVWT > 15 mm, suggesting that the cut-off value is usually not critical. Within affected patients, 95% had an asymmetrical HCM (interventricular septum/left posterior wall thickness > 1.3 mm), whereas 84% had a ratio > 1.5. Distribution of the affected patients according with Maron's classification are in keeping with published studies about sporadic forms. Doppler derived isovolumetric relaxation time was prolonged in HCM (105 +/- 23 vs 88 +/- 16 msec, P < 0.001), and the ratio peak velocity of A wave over peak velocity of E wave was significantly lower in affected individuals (0.99 +/- 0.56 vs 0.83 +/- 0.46, P < 0.05). None of the 24 children studied (10 +/- 3 years) were considered affected according to echocardiographic criteria., Conclusion: Echocardiography is the obligatory first step during genetic study for recognizing familial HCM. It allows classification in adults but not in children. Doppler estimate of diastolic function may be helpful in the future to recognize genetically affected subjects with normal or subnormal echocardiographic examination.

An echocardiographic Study of 322 adults (age: 40 +/- 16 years), belonging to 20 families with hypertrophic cardiomyopathy (HCM), was undertaken. Affected subjects had a LV diastolic wall thickness > 13 mm. The patients were classified according to the distribution of left ventricular hypertrophy (LVH) and by Maron's classification: 189 subjects were normal, 127 were affected and 6 could not been classified. By Maron's classification: 3% were type I, 33% were type II, 58% were type III and 6% were type IV. LVH was asymmetrical in 95% of cases (septum/posterior wall ratio > 1.3). The familial distribution of LVH of the 4 families in which HCM was genetically related to different loci (chromosome 11, 14 exon 13, 14 exon 8, fifth locus); the LVH was analysed from two short axis LV parasternal views and each plane was divided into 5 segments. The distribution of LVH was said to be identical between two first degree relations when all the same segments were affected, similar when they differed by only 1 or 2 segments and different when they differed by 3 or more segments. In the 26 pairs studied, LVH was identical in 2/26 (8%), similar in 11/26 (42%) and different in 13/26 (50%). Familial HCM usually gives rise to asymmetrical LVH affecting the septum and free wall. An identical distribution in 50% of affected first degree relatives.

Hypertrophic cardiomyopathy is familial in about 50% of cases and is transmitted in the autosomal dominant mode. The first morbid gene implicated in the disease was the gene coding the beta myosin heavy chain (beta MHC) on chromosome 14. However, only 30% of families have this genetic abnormality. Recently, three new loci have been identified on chromosomes 1q3, 11p13-q13 and 15q2. In order to determine whether other genes could be implicated in the disease a linkage analysis study was performed in a West Indian family. The method is based on the analysis of the distribution of the disease in the family and the microsatellite markers. The microsatellites used were those which recognised the 4 loci previously mentioned and 4 new markers situated and arranged with respect to known microsatellites. The results show that in the family studied, the disease did not concord with the markers of the beta MHC gene or with those recognising the loci on chromosomes 1q3, 11p13-q13 and 15q2. There is, therefore, a fifth gene implicated in familial HCM. The heterogeneity of the disease seems even greater than originally thought.

Mitochondrial cytopathies are due to genetic anomalies in the oxidative phosphorylation enzymes (excepting Krebs cycle, pyruvate and certain other mitochondrial enzymes). Recently discovered, these diseases have a characteristic heterogeneous clinical expression because of the ubiquitous nature of this intracellular organelle. We observed a case in a 16-year-old girl who had cytochrome C oxidase deficiency. The child was born to non-consanguinous parents and had a healthy brother. The first manifestation of the disease was a systolic murmur heard at the age of 4 years. Progressively, exertion dyspnoea, lipothymia with cyanose led to the first echocardiography at 8 years revealing non-obstructive cardiomyopathy. Functional inadaptation of cardiac performance worsened requiring various symptomatic treatments. At the age of 16, the symptomatology included lower limb fatigue and the diagnosis of a metabolic disease was entertained. Phosphorylase A and B activity and phosphokinase activity were normal. High lactic acid levels after exertion suggested a mitochondrial enzyme deficiency. The diagnosis of cytochrome C oxidase deficiency was confirmed by spectrophotometric and polarographic assay of mitochondria from a peripheral muscle biopsy. Treatment with riboflavin, ascorbic acid, factor P, menadione, carnitine and iron sulfate has currently provided some symptomatic improvement. In patients with unexplained cardiomyopathy, the diagnosis of mitochondrial cytopathy should be entertained if oxidoreduction potentials (lactate/pyruvate ratio) are perturbed. The diagnosis is confirmed by enzyme studies of fresh muscle mitochondria. Currently therapeutic prospects are at best very poor. Genetic counselling may be advisable.

Several mutations within the gene coding for the cardiac beta myosin heavy chain (designed MYH7) have been shown to be responsible for Familial Hypertrophic Cardiomyopathy (FHC) in several families, and evidence of genetic heterogeneity has been reported. To investigate the MYH7 gene as the cause of the disease in a small family with FHC, inheritance of the disease and chromosome 14 q11-q12 markers haplotype were studied, exons coding for the head domain of the cardiac beta myosin heavy chain (beta MHC) were analysed for mutations by MDE gel electrophoresis, and sequenced. We report a mutation within exon eight of the MYH7 gene at a very conserved amino acid at position 232, which results in the conversion of an asparagine to serine. This residue Asn-232 is located in a MHC area that has been recently identified as a critical site for ATPase activity. According to recent results on the three-dimensional structure of the myosin head or subfragment-1 (S1), Asn-232 is located in an alpha-helix which forms part of the nucleotide binding pocket. Although this mutation affects an active site, it seems to be associated with a favourable prognosis and a weak penetrance in this family.

A study was made of iatrogenic complications (IC) occurring in the department of cardiology of the Nantes Teaching Hospital Group between May 31, 1990 and June 1, 1991. One hundred and fifty eight IC were seen during this period, i.e. an annual incidence of 4.4%. There were 4 deaths following and IC, i.e. an annual mortality rate of 0.11%. Five other IC had serious though non-fatal consequences. Taken in general, IC appeared to be benign and of various origins. Drugs were responsible for almost half of IC and invasive investigations for one third. Application of a simple and single preventive approach is difficult in view of the diversity of causes. The solution lies in part in awareness and education concerning the problem, in which a permanent register system like ours certainly has a role to play.