Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study.

BACKGROUND: Patients with Fabry disease (FD) show left ventricular hypertrophy (LVH) mimicking hypertrophic cardiomyopathy (HCM) of sarcomeric origin and might benefit, if detected early, from specific enzyme replacement therapy. The prevalence of FD in patients with LVH of 13 mm or greater, screened using the leucocyte alpha-galactosidase A (α-gal A) activity test, a technique that is difficult to apply routinely, ranged from 0% to 6%. OBJECTIVE: To screen systematically for FD in patients with a diagnosis of HCM (LVH ≥15 mm) in primary cardiology practice, a validated, physician-friendly α-gal A assay was used on dried blood spots using a filter paper test. DESIGN AND PATIENTS: A cohort of 392 adults (278 men) followed for HCM were screened for FD. A standard blood test was used for confirmation in nine men in whom the α-gal A result was 40% or less. RESULTS: Four men (1.5%; 1.8% of men ≥40 years vs 0% <40 years; all with α-gal A <30%), but no women, were diagnosed with FD. Index cases presented with diffuse but asymmetric LVH, with severe obstruction in one case and frequent high-grade atrioventricular conduction block necessitating a pacemaker in three cases. Family screening identified eight additional cases. Genotyping was performed successfully on DNA extracted from the filter papers. CONCLUSION: In male patients diagnosed as having HCM, pure FD cardiac variants are not exceptional and can be specifically identified using a simple filter-paper test. The sensitivity of this test is low in female patients.

Functional impairment of von Willebrand factor in hypertrophic cardiomyopathy: relation to rest and exercise obstruction.

BACKGROUND: Hypertrophic obstructive cardiomyopathy submits blood to conditions of high shear stress. High shear stress impairs von Willebrand factor (VWF) and promotes abnormal bleeding in aortic stenosis. We sought to evaluate VWF impairment and its relationships to baseline or exercise obstruction in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Outflow obstruction was evaluated by rest and exercise echocardiography in 62 patients with HCM (age 44+/-16 years, 40 males). HCM was considered obstructive in 28 patients with rest or exercise peak gradient >or=30 mm Hg. Blood was sampled to assess VWF. History of bleeding was recorded. Baseline median (25th to 75th percentile) peak gradient was 11 (5-62) mm Hg. Shear-induced platelet adhesion was impaired in patients with obstructive HCM. The ratio of VWF-collagen-binding activity to antigen and the percentage of high-molecular-weight multimers of VWF were lower in patients with obstructive HCM than in those with nonobstructive HCM (0.49 [0.43 to 0.59] versus 0.82 [0.73 to 1.03] and 5.0% [3.9% to 7.2%] versus 11.7% [10.8% to 12.5%], respectively; both P<0.0001). Platelet adhesion time, VWF-collagen-binding activity-to-antigen ratio, and the percentage of high-molecular-weight multimers correlated closely and independently with peak gradient (r=0.81, r=-0.68, and r=-0.89, respectively; all P<0.0001). According to receiver operating characteristic curves, a peak gradient threshold of 15 mm Hg at rest and 35 mm Hg during exercise was sufficient to impair VWF. Conversely, VWF function tended to improve with a decrease in peak gradient. Obstructive HCM patients had a trend toward abnormal spontaneous bleeding. CONCLUSIONS: In obstructive HCM, VWF impairment is frequent and is closely and independently related to the magnitude of outflow obstruction. A resting peak gradient of 15 mm Hg is sufficient to impair VWF. VWF abnormalities might favor abnormal bleeding in this setting.

Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.

AIMS: Idiopathic dilated cardiomyopathy (DCM) is a cardiac disorder characterized by left ventricular dilatation and impaired systolic contraction. It is a major cause of heart failure and heart transplantation. DCM is of genetic origin in approximately 30% of cases and genetically heterogeneous with the identification of numerous disease genes. However, many new disease genes remain to be discovered. Focusing on gene products located in the sarcomere of cardiomyocytes as disease-causing candidates, we screened the gene encoding the sarcomeric Z-band protein myopalladin (MYPN, OMIM 608517) for mutation. METHODS AND RESULTS: We sequenced the coding region in 114 (65 familial and 49 sporadic cases) independent DCM patients' DNA and functionally analysed the identified mutations. We identified four independent heterozygous mutations in two families (R1088H and I83fsX105) and two sporadic cases (V1195M, P1112L). For the three missense mutations, the substituted amino acids were conserved among species. All mutations were absent from 400 control subjects. Specific immunolabelling of heart tissue from a proband carrying the R1088H mutation showed a decreased localization of myopalladin at the Z-band area of left ventricular cardiac myofibrils. Analysis of the effects of the mutations after transfection in rat neonate cardiomyocytes indicated sarcomere disorganization and premature cell death associated with the V1195M and P1112L myopalladin expression. Allele-specific expression analysis of mRNA from a patient harbouring the I83fsX105 mutation indicated the absence of the mutated transcript, suggesting a haploinsufficiency mechanism. CONCLUSION: Based on genetic, histological, and functional evidence, we identified a new gene associated with DCM and observed mutations in 3-4% of cases in a population of European descent.

Aspirin does not adversely affect survival in patients with stable congestive heart failure treated with Angiotensin-converting enzyme inhibitors.

BACKGROUND: Experimental studies and retrospective analyses of mortality trials with angiotensin-converting enzyme inhibitors (ACE-Is) have suggested that aspirin may reduce the beneficial effect of these drugs. The aim of this study was to assess a possible detrimental effect of aspirin on survival in stable patients with left ventricular systolic dysfunction who had congestive heart failure and had been treated with ACE-Is. METHODS AND RESULTS: We performed a retrospective analysis in 755 consecutive stable patients with left ventricular systolic dysfunction. A Cox regression model was used to select independent predictors of survival and to test for a possible interaction between aspirin and ACE-Is with an adjustment to differences in clinical characteristics in subgroups of patients. Of the 755 patients, 328 (43.4%) had proven ischemic cardiomyopathy, 693 patients (91.8%) were receiving ACE-Is, and 317 patients were receiving aspirin (mean [+/- SD] dose, 183 +/- 65 mg/d; 74% of the patients receiving < or = 200 mg/d). During a median follow-up period of 1,996 days, there were 273 cardiac-related deaths, 14 urgent transplantations, 71 nonurgent transplantations, and 46 noncardiac-related deaths, and 3 patients were lost to follow-up. The cardiovascular mortality rates were 11.5% and 19.0%, respectively, at 1 and 2 years. There were no interactions among aspirin, ACE-Is, and survival in the overall population (p = 0.21), or in subgroups of patients with ischemic cardiomyopathy (p = 0.41) or with nonischemic cardiomyopathy (p = 0.74). CONCLUSIONS: In this population of stable patients with left ventricular systolic dysfunction, our retrospective analysis did not demonstrate any interaction between the use of aspirin and survival in patients receiving ACE-Is.

Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

BACKGROUND: Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. METHODS AND RESULTS: The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients ( approximately 63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. CONCLUSIONS: These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.

Antiphospholipid antibodies and the risk of thromboembolic events in valvular heart disease.

OBJECTIVE: To investigate the role of antiphospholipid antibodies (aPLs) in subsequent thromboembolic events and mortality in a prospective follow-up of 89 patients with severe, nonspecific valvular heart disease. PATIENTS AND METHODS: Between November 1, 1993, and March 31, 1994, 89 patients with valvular heart disease were assessed for the presence of anticardiolipin antibodies and lupus anticoagulant. The primary end point was thromboembolic events, and the secondary end points were cardiovascular mortality and overall mortality. RESULTS: All patients were followed up for a mean of 59 months; 1 patient (without aPLs) was lost to follow-up. Nineteen patients had increased titers of aPLs. Thromboembolic events were significantly more frequent in the aPL-positive group than in the aPL-negative group (7/19 [37%] vs 8/70 [11%]; P=.01). Cardiovascular mortality tended to be higher in the aPL-positive group than in the aPL-negative group (3 [16%] vs 6 [9%]; P = .40). However, in multivariate Cox analysis, presence of aPLs was not an independent risk factor for thromboembolic events. CONCLUSION: Our results suggest that patients with severe valvular heart disease and aPLs have an increased risk for developing thromboembolic events.

Influence of diabetes mellitus on heart failure risk and outcome.

Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure. THE STUDIES LINKING DIABETES MELLITUS (DM) WITH HEART FAILURE (HF) : The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy. TREATMENT OF HEART FAILURE IN DIABETIC PATIENTS : The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients.