Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Mode of presentation and mortality amongst patients hospitalized with heart failure? A report from the First Euro Heart Failure Survey.

BACKGROUND: Heart failure is heterogeneous in aetiology, pathophysiology, and presentation. Despite this diversity, clinical trials of patients hospitalized for HF deal with this problem as a single entity, which may be one reason for repeated failures. METHODS: The first EuroHeart Failure Survey screened consecutive deaths and discharges of patients with suspected heart failure during 2000-2001. Patients were sorted into seven mutually exclusive hierarchical presentations: (1) with cardiac arrest/ventricular arrhythmia; (2) with acute coronary syndrome; (3) with rapid atrial fibrillation; (4) with acute breathlessness; (5) with other symptoms/signs such as peripheral oedema; (6) with stable symptoms; and (7) others in whom the contribution of HF to admission was not clear. RESULTS: The 10,701 patients enrolled were classified into the above seven presentations as follows: 260 (2%), 560 (5%), 799 (8%), 2479 (24%), 1040 (10%), 703 (7%), and 4691 (45%) for which index-admission mortality was 26%, 20%, 10%, 8%, 6%, 6%, and 4%, respectively. Compared to those in group 7, the hazard ratios for death during the index admission were 4.9 (p ≤ 0.001), 4.0 (p < 0.001), 2.2 (p < 0.001), 2.1 (p < 0.001), 1.4 (p < 0.04) and 1.4 (p = 0.04), respectively. These differences were no longer statistically significant by 12 weeks. CONCLUSION: There is great diversity in the presentation of heart failure that is associated with very different short-term outcomes. Only a minority of hospitalizations associated with suspected heart failure are associated with acute breathlessness. This should be taken into account in the design of future clinical trials.

Abdominal obesity is associated with ineffective control of cardiovascular risk factors in primary care in France.

AIM: Insufficient control of cardiovascular risk factors is observed in primary care. The goal of the present study was to evaluate the association of abdominal obesity with achievement of treatment targets for HbA(1c), LDL cholesterol, triglycerides, HDL cholesterol and blood pressure in primary care. METHODS: In this cross-sectional observational epidemiological study, primary-care practitioners completed a questionnaire covering demographic and socioeconomic data, medical history, drug treatment, and clinical and biological characteristics for 3351 patients (1630 men and 1721 women). Therapeutic targets were HbA(1c) <7%, LDL cholesterol <1.6g/L, triglycerides <1.5 g/L and SBP/DBP <140/90 mmHg. Multivariate analyses were performed to assess the relationship between waist circumference and a lack of cardiovascular risk-factor control. RESULTS: The patients' mean ages were 58+/-14 years and 55+/-16 years for men and women, respectively. A large waist circumference was positively and significantly (P<0.0001 for all) associated with diabetes, hypercholesterolaemia, hypertriglyceridaemia, low HDL cholesterol and hypertension. The prevalence of patients not achieving therapeutic targets increased across waist-circumference quartiles. For treated patients, the odds ratios (95% CI) (adjusted for age, gender, education, smoking status and medical specialty) for not achieving treatment targets were 17.6 (2.2-142) for triglycerides, 2.8 (1.3-6.1) for HbA(1c) and 1.4 (0.9-2.0) for blood pressure on comparisons with extreme quartiles of waist-circumference distribution. CONCLUSION: In primary care, a lack of control of triglycerides, HbA(1c) and, to a lesser extent, blood pressure increases with waist circumference independently of confounders. This suggests that abdominal obesity is associated of poor results in the treatment of diabetes and hypertriglyceridaemia.

[Heart failure in men and women: important differences in the diagnostic workup and treatment]. / Hartfalen bij mannen en vrouwen: belangrijke verschillen in diagnostiek en behandeling.

OBJECTIVE: To determine gender differences in diagnostic workup and treatment of patients with heart failure. DESIGN: Retrospective. METHOD: The data of 8914 patients (of whom 4166 women; 47%) with confirmed heart failure, who participated in the Euro Heart Survey on Heart Failure (EHS-HF) were analysed. RESULTS: On average, the women in the study were older than the men (75 versus 68 years) and less often suffered from a coronary heart disease (56 versus 66%). Women were more likely to have hypertension (59 versus 49%), diabetes mellitus (29 versus 26%), or valvular heart disease (42 versus 36%). Fewer women had an ultrasonographic evaluation of ventricular function (59 versus 74%) and, among those investigated, fewer had left ventricular systolic dysfunction (44 versus 72%). These observed results remained stable after adjustment for age and other possible confounding variables. Medication with a documented positive impact on survival, i.e. angiotensin converting enzyme (ACE) inhibitors, beta-blocking drugs and the diuretic spironolactone, was prescribed less often to women than men. Women, however, received symptomatic medication such as other diuretics and digoxin more often than men. CONCLUSION: Men and women with heart failure differed with respect to a number of relevant clinical characteristics. Clinicians should take good note of this and take measures to prevent differences in patient care.

Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts.

Expression of the two sarcomeric actins, alpha-skeletal and alpha-cardiac, is regulated in the rodent heart in response to developmental, hormonal, and hemodynamic stimuli. Little is known in man, except that both isogenes were found to be coexpressed in three adult ventricles. In this report, we investigated the isoactin mRNA composition in ventricles from 21 control patients (4 fetal, 5 juvenile, 12 adult) and from 15 patients undergoing cardiac transplantation (5 idiopathic dilated cardiomyopathies, 5 ischemic myopathies with myocardial infarcts, 5 diverse etiologies) by two different and complementary techniques: RNA dot blot analysis with specific cDNA probes, and primer extensions with an oligonucleotide common to alpha-cardiac and alpha-skeletal actins. In the case of dot blot analysis, quantification of each isoform was performed by using as standards RNA transcripts obtained from cloned human alpha-actin sequences, and the total amount of sarcomeric actin mRNA was evaluated as a function of total poly(A+)RNA. We found that both isogenes are always coexpressed, and that the isoactin pattern changes during development. In utero and in neonatal hearts, alpha-skeletal actin mRNA represents less than or equal to 20% of sarcomeric actins, it increases to 48 +/- 6% during the first decade after birth and becomes the predominant isoform of adult hearts (60.4 +/- 8.5%). The 15 adult failing hearts exhibited the same isoactin pattern as the control ones (62.84 +/- 11.06%), and there was no difference in expression between patients with dilated cardiomyopathy or ischemic heart disease. These observations demonstrate that cardiac development in man, in contrast to rodent heart, is characterized by an up-regulation of the skeletal actin gene, the expression of which does not change in hypertrophied and failing hearts, and suggest that the actin and myosin heavy chain families are independently regulated in human heart.

Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure.

A decrease in the myocardial level of the mRNA encoding the Ca2(+)-ATPase of the sarcoplasmic reticulum (SR) has been recently reported during experimental cardiac hypertrophy and failure. To determine if such a deficit occurs in human end-stage heart failure, we compared the SR Ca2(+)-ATPase mRNA levels in left (LV) and right ventricular (RV) specimens from 13 patients undergoing cardiac transplantation (6 idiopathic dilated cardiomyopathies; 4 coronary artery diseases with myocardial infarctions; 3 diverse etiologies) with control heart samples using a rat cardiac SR Ca2(+)-ATPase cDNA probe. We observed a marked decrease in the mRNA for the Ca2(+)-ATPase relative to both the 18S ribosomal RNA and the myosin heavy chain mRNA in LV specimens of patients with heart failure compared to controls (-48%, P less than 0.01 and -47%, P less than 0.05, respectively). The LV ratio of Ca2(+)-ATPase mRNA to 18S RNA positively correlated with cardiac index (P less than 0.02). The RV ratio correlated negatively with systolic, diastolic and mean pulmonary arterial pressures (P less than 0.02, P less than 0.02, and P less than 0.01, respectively). We suggest that a decrease of the SR Ca2(+)-ATPase mRNA in the myocardium plays an important role in alterations of Ca2+ movements and myocardial relaxation reported during human end-stage heart failure.

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

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

[A familial form of conduction defects associated with a PRKAG2 gene mutation]. / Une forme familiale de troubles conductifs associés à une mutation du gène PRKAG2.

Conduction defects are usually secondary to elective aging of the conduction pathways. However, some familial and genetic forms are now being described. Here we report a particular electrocardiographic pattern in four members of the same family over three generations, naturally leading to the suspicion of a hereditary origin. The ECG appearance is very specific and includes conduction defects (RBBB and occasionally left anterior hemiblock), short PR interval, pseudo appearance of atrial hypertrophy, and occasionally sinus dysfunction or supraventricular extrasystole. Gene analysis identified a R302Q mutation of the gamma2 subunit producing AMP protein kinase, coded by the gene PRKAG2. This is a wrong sense mutation present in the heterozygous state in each of those displaying the ECG anomalies, and is transmitted in an autosomal dominant fashion. The clinical picture here appears to constitute a clinical entity distinct from those previously described as being associated with mutations of the PRKAG2 gene, without any left ventricular hypertrophy or Wolff-Parkinson-White syndrome.

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

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

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

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

[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.

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

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

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

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.

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.