Jean-Pierre Gueffet

Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.

Background— Myxomatous dystrophy of the cardiac valves affects ≈3% of the population and remains one of the most common indications for valvular surgery. Familial inheritance has been demonstrated with autosomal and X-linked transmission, but no specific molecular abnormalities have been documented in isolated nonsyndromic forms. We have investigated the genetic causes of X-linked myxomatous valvular dystrophy (XMVD) previously mapped to chromosome Xq28. Methods and Results— A familial and genealogical survey led us to expand the size of a large, previously identified family affected by XMVD and to refine the XMVD locus to a 2.5-Mb region. A standard positional cloning approach identified a P637Q mutation in the filamin A (FLNA) gene in all affected members. Two other missense mutations (G288R and V711D) and a 1944-bp genomic deletion coding for exons 16 to 19 in the FLNA gene were identified in 3 additional, smaller, unrelated families affected by valvular dystrophy, which demonstrates the responsibility of FLNA as a cause of XMVD. Among carriers of FLNA mutation, the penetrance of the disease was complete in men and incomplete in women. Female carriers could be mildly affected, and the severity of the disease was highly variable among mutation carriers. Conclusions— Our data demonstrate that FLNA is the first gene known to cause isolated nonsyndromic MVD. This is the first step to understanding the pathophysiological mechanisms of the disease and to defining pathways that may lead to valvular dystrophy. Screening for FLNA mutations could be important for families affected by XMVD to provide adequate follow-up and genetic counseling.

Clinical characteristics of a familial inherited Myxomatous valvular dystrophy mapped to Xq28

OBJECTIVES The purpose of this study was to describe the phenotypic characteristics of an inherited myxomatous valvular dystrophy mapped to Xq28. BACKGROUND Myxomatous valve dystrophies are a frequent cause of valvular diseases, the most common being idiopathic mitral valve prolapse. They form a group of heterogeneous diseases difficult to subclassify. The first mapping of the gene for a myxoid valvular dystrophy to Xq28 allowed investigation of the phenotype of affected members in a large family and characterization of the disease. METHODS Among the 318 members in the pedigree, 89 agreed to participate in this study. Phenotypic characteristics were investigated using clinical examination, transthoracic echocardiography and biological analysis (F.VIII activity). Genetic status was based on haplotype analysis. RESULTS Among 46 males, 9 were hemizygous to the mutant allele and had an obvious mitral and/or aortic myxomatous valve defect, and 4 had undergone valvular surgery. All had typical mitral valve prolapse associated in six cases with moderate to severe aortic regurgitation. The valve defect cosegregated with mild hemophilia A (F.VIII activity = 0.32 +/- 0.05). The 37 remaining males had normal valves and normal F.VIII activity. Heterozygous women were identified on the basis of their haplotypes. Among the 17 women heterozygous to the mutant allele, moderate mitral regurgitation was present in 8, associated with mild mitral valve prolapse in 1 and aortic regurgitation in 3, whereas 2 women had isolated mild aortic regurgitant murmur. In heterozygotes, the penetrance value was 0.60 but increased with age. CONCLUSION X-linked myxomatous valvular disease is characterized by mitral valve dystrophy frequently associated with degeneration of the aortic valves affecting males and, to a lower severity, females. The first localization of a gene for myxomatous valvular diseases is the first step for the subclassification of these diseases.

Valvular heart disease associated with benfluorex

MOTS CLES Benfluorex ; Fibrose valvulaire ; Amphetamines ; A 57-year-old woman was referred for dyspnoea during mild exercise, especially during the past year. Electrocardiogram and chest X-ray demonstrated no significant anomaly. Ntpro brain natriuretic peptide was moderately elevated to 319 ng/L (range: 0—290 ng/L). Echocardiographic examination showed normal left ventricle function and anatomy, mild regurgitations of the aortic and mitral valves and a severe regurgitation of the tricuspid valve (Figs. 1 and 2), with an estimated systolic pulmonary pressure of 60mmHg. Themechanism of the valvular regurgitations corresponded to valvular fibrosis and subsequently restriction motion. Right heart catheterization confirmed pulmonary arterial hypertension with normal pulmonary wedge pressure and cardiac output. Thoracic tomodensitometry ruled out pulmonary embolism. There was also no clinical or biological evidence for a carcinoid syndrome. The patient had no previous medical history, but she had taken benfluorex (150mg tid) for the past 8 years because of excessive weight (159 cm, 82 kg) and hypertriglyceridaemia. In addition to withdrawal of the drug, and because of elevated right atrial pressure, we

Molecular risk stratification in advanced heart failure patients

Risk stratification in advanced heart failure (HF) is crucial for the individualization of therapeutic strategy, in particular for heart transplantation and ventricular assist device implantation. We tested the hypothesis that cardiac gene expression profiling can distinguish between HF patients with different disease severity. We obtained tissue samples from both left (LV) and right (RV) ventricle of explanted hearts of 44 patients undergoing cardiac transplantation or ventricular assist device placement. Gene expression profiles were obtained using an in‐house microarray containing 4217 muscular organ‐relevant genes. Based on their clinical status, patients were classified into three HF‐severity groups: deteriorating (n= 12), intermediate (n= 19) and stable (n= 13). Two‐class statistical analysis of gene expression profiles of deteriorating and stable patients identified a 170‐gene and a 129‐gene predictor for LV and RV samples, respectively. The LV molecular predictor identified patients with stable and deteriorating status with a sensitivity of 88% and 92%, and a specificity of 100% and 96%, respectively. The RV molecular predictor identified patients with stable and deteriorating status with a sensitivity of 100% and 96%, and a specificity of 100% and 100%, respectively. The molecular prediction was reproducible across biological replicates in LV and RV samples. Gene expression profiling has the potential to reproducibly detect HF patients with highest HF severity with high sensitivity and specificity. In addition, not only LV but also RV samples could be used for molecular risk stratification with similar predictive power.

Drug-induced aortic valve stenosis: An under recognized entity

BACKGROUND We have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS. METHODS Herein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient >15mmHg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria. RESULTS Twenty-five (19 females, mean age 62years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/-13mmHg. Aortic regurgitation was ≥ mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD. CONCLUSION The association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS.

0049: FDG-PET imaging for the management of suspected inflammatory cardiomyopathies beyond cardiac sarcoidosis: a single center initial experience

Purpose FDG-positron emission tomography (PET) has high diagnostic accuracy in cardiac sarcoidosis (CS). Beyond CS, the non invasive diagnosis of inflammatory cardiomyopathies (IC) is challenged by a lower diagnostic performance of usual tools as magnetic resonance imaging (MRI). Methods 17 consecutive patients with suspected IC had a FDG-PET to detect myocardial inflammation. From all clinical data including PET, we classified patients in either CS or non-CS and respective PET data were compared. The clinical impact of adding PET in the non-CS group was evaluated by comparing diagnosis and management proposed by an expert blind to PET with final diagnosis and management actually held in practice. Results 6 patients had CS, all with positive PET. In the 11 non-CS patients, 7 had a positive PET. All had MRI late gadolinium enhancement in FDG uptake areas, suggesting a true positivity of PET for the presence of inflammation. PET data were all significantly different between CS and nonCS patients with positive PET, particularly the coefficient of variation of cardiac SUV which is an index of heterogeneity of FDG uptake was significantly greater in CS patients (0,4 vs 0,17 p Conclusion Some patients with suspected IC had a positive FDG-PET in favour of myocardial inflammation, with a different pattern from that observed in CS. Adding PET to usual diagnostic tools led to a decrease of possible IC diagnosis that turned in excluded IC. These preliminary data suggest a potential role of PET for the non-invasive diagnosis of IC that will need further investigations. Download : Download high-res image (89KB) Download : Download full-size image Abstract 0049 – Figure: FDG uptake concordant with MRI-LGE

0326: Prediction of right ventricular failure after cardiac transplantation: a recipient transcriptomic study

Background Right ventricle failure (RVF) is a frequent and severe complication after cardiac transplantation. However, risk stratification for RVF is poorly achieved. Development of transcriptomic biomarkers for outcome prediction in cardio-vascular diseases is promising. Aim To identify right ventricular gene expression signature associated to RVF and to define a transcriptomic biomarker that could predict post-transplantation RVF. Methods Recipient RV myocardial samples of 44 patients transplanted from February 1998 to November 2002 in our center were collected. We retrospectively identified patients with (RVF group) and without (CTL group) post-transplantation RVF. A 4035-gene expression profile was obtained for all patients. Differentially expressed genes between RVF and CTL groups were identified and a molecular RVF predictor was used to determine for each patient a RVF prediction score (RVFs). Results 9 (20%) and 18 (41%) patients were classified in RVF and CTL groups respectively. As compared to CTL group, RVF patients showed higher pre-operative bilirubin level and higher post-operative death rate. Molecular RVF predictor included 75 differentially expressed genes. Using this predictor, risk for post-transplantation RVF was 2.8-fold greater if RVFs was >0.5 (CI 95%: 1.243-6.305). Sensitivity and specificity of RVFs were 0.778 and 0.889, respectively. Using receiver operating characteristic analysis, RVFs area under curve (AUC) was significantly greater than AUC of commonly used RVF predictors (pulmonary vascular resistance, trans-pulmonary gradient). Conclusion Gene expression profiling of recipient right ventricle could be used to predict post-transplantation RVF. Transcriptomic biomarkers should be further investigated as a new tool for selection of cardiac transplant candidates.

0282: Rest and exercise pulmonary hypertension in hypertrophic cardiomyopathy

Background Heart failure (HF) symptoms, related to pulmonary capillary hypertension, are frequent in hypertrophic cardiomyopathy (HCM). Pulmonary hypertension (PH) is the consequence of left ventricular (LV) diastolic pressure elevation and/or functional mitral regurgitation. We aimed to evaluate determinants and prognostic significance of rest and exercise in HCM. Methods and results We included 235 patients referred for clinical work-up of HCM. Rest pulmonary artery systolic pressure (PASP) was measurable in 214 (91%) patients (48±16 years, 161 males). A symptom-limited semi-supine bicycle exercise was carried out in 188 patients. PASP was measurable during exercise in 108 patients (57%). Resting PH (≥36mmHg) was present in 56 patients (26.2%) and exercise PH (≥60mmHg) in 38 patients (35.2%). Mutivariate correlates of rest PASP were sinus rhythm (β=–0.15, P=0.021), LV obstruction tract (LVOT) peak gradient (β=0.22, P=0.001) and left atrial volume (β=0.39, P Conclusion In patients with HCM, the main determinants of rest PH are sinus rhythm, LVOT peak gradient and left atrium volume. Determinants of exercise PH are rest PASP, grade of MR and rest LVOT gradient. Rest and exercise PH predict a poor outcome in HCM.

098 Misclassified out of proportion post-capillary pulmonary hypertension associated with heart failure and preserved ejection fraction

Introduction: Out of proportion post-capillary pulmonary hypertension (resulting from left-sided heart failure, group 2 of the World Health Organisation of Pulmonary Hypertension (PH) classification.) is a well known hemodynamic entity described in the past in mitral stenosis, but also concern patients with leftside heart failure and preserved ejection fraction (HFpEF). The prevalence is probably underestimated because a part of this population is addressed to the PH center and misdiagnosed group 1 PH of WHO classification.

Endocardite infectieuse à hémocultures négatives

Resume Les endocardites a hemocultures negatives posent un probleme diagnostique, therapeutique et pronostique. Nous rapportons le cas d’un homme de 57 ans avec pour seul antecedent un rhumatisme articulaire aigu. En aout 2000, decouverte d’une thrombose veineuse surale du membre inferieur droit sans facteur favorisant retrouve. Mise en route d’un traitement par AVK. En octobre 2000, mise en evidence d’une occlusion du tronc tibio-peronier droit et d’une thrombose suspendue de l’artere poplite gauche dans un contexte de claudication du membre inferieur droit. Une EI est suspectee apres 2 autres episodes emboliques et sur l’antecedent rhumatismal. Ce diagnostic est confirmee par ETO : fuite aortique associee a des vegetations de 8 mm. Les hemocultures sont negatives. Un interrogatoire policier a la recherche d’une porte d’entree fait suspecter une maladie de Whipple devant la notion d’arthralgies associees a une diarrhee intermittente avec perte de poids et ceci malgre des biopsies jejunales negatives. Le diagnostic sera pose sur la valvule aortique resequee pour remplacement par homogreffe et sur la relecture des thrombi reseques anterieurement. Examen anatomopathologique : reaction inflammatoire a predominance macrophagique avec inclusions PAS positives cytoplasmiques. Confirmation par immunohistochimie avec Ac anti-tropheryma whipplei et par PCR. Conclusion La maladie de Whipple doit etre evoquee devant toute EIHN avec contexte evocateur (diarrhee, perte de poids, arthralgies). L’examen anatomopathologique reste primordial et peut etre complete par biologie moleculaire. L’atteinte cardiaque au cours du Whipple n’est pas rare. Le pronostic reste sombre si une antibiotherapie adaptee et au long cours n’est pas mise en place rapidement.