High prevalence of ventricular repolarization abnormalities in people carrying TGFßR2 mutations.

Mutations in the TGFßR2 gene have been associated with a life threatening risk of aortic dissection but no arrhythmic death has been previously reported. Two young females carrying a TGFßR2 mutation, initially diagnosed as Marfan syndrome or Loeys Dietz syndrome, presented sudden death with autopsy ruling out dissection. The ECGs of the 2 Sudden Cardiac Deaths revealed profound ventricular repolarization abnormalities with a sinusoidal T-U morphology associated with normal left ventricular ejection fraction. These data strongly suggest sudden cardiac arrhythmic deaths and prompted us to systematically study the repolarization pattern in the patients with TGFßR2 mutations. ECG findings from 58 mutation carriers patients (TGFßR2 group) were compared with those of 46 non-affected first degree relatives (control group). TGFßR2 mutation was associated with ventricular repolarization abnormalities in 47% of patients (p < 0.001 vs. controls), including a 19.6 ms (95%CI 8.7; 30.5) QTc interval prolongation compared to the non-affected first degree relatives (p < 0.001), higher prevalence of abnormal U waves (16% vs. 2%), and sinusoidal T-U morphology (10% vs. 0%). TGFßR2 mutations can be associated with abnormal ventricular repolarization pattern, longer QT interval than non-carrier relatives and an increased risk for sudden death.

Eclipsed mitral regurgitation: an unusual cause of acute heart failure.

AIMS: So far, a total of five patients with eclipsed mitral regurgitation (MR) have been reported in the literature by three different teams. The aim of this article was to detail clinical and echocardiographic characteristics, and outcome of patients presenting eclipsed MR. METHODS AND RESULTS: We defined eclipsed MR as spontaneous appearance, at rest, from 1 min to the next of an acute restriction in the motion of mitral leaflets preventing coaptation and leading to massive MR in patients with normal left ventricular end-diastolic diameter, left ventricular ejection fraction >45%, and baseline MR ≤2. Spontaneous regression occurred within 30 min, and no obvious trigger such as acute hypertension, new-onset arrhythmia, or myocardial ischaemia is present. Clinical data, ECG, echocardiographic data, surgery report, and follow-up status of six patients with eclipsed MR are reported: all were post-menopausal women with median age of 74 [57-80] years presenting hypertension (4/6), chronic kidney disease (5/6), or chronic anaemia (4/6). Five out of six patients experienced acute pulmonary oedema requiring hospitalization and underwent mitral valve replacement because of heart failure recurrence. Two patients died in the first days after surgery while the three others are free of symptoms at, respectively, 56, 18, and 10 months follow-up. CONCLUSION: Eclipsed MR is a clinical and echocardiographic syndrome responsible for heart failure with preserved EF. It is presently underdiagnosed and should be evoked in cases of recurrent acute pulmonary oedema without obvious trigger, in particular in patients presenting discordant evaluation of MR severity over time.

[Respiratory manifestations of Marfan's syndrome]. / Manifestations respiratoires du syndrome de Marfan.

Marfan's syndrome is a rare genetic disorder caused by a mutation of the gene FBN1, coding for the protein fibrillin-1. Cardiovascular, musculoskeletal and ophthalmic manifestations are the most commonly observed, but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing, affects 5 to 11% of patients. Rib cage abnormalities (pectus excavatum or pectus carinatum) and apical blebs may contribute to their occurrence. Treatment does not require any specific procedure but there is an increased risk of recurrence. Pectus excavatum affects up to 60% of the patients, without any functional impairment in most cases. Surgery may be required (using the Nuss procedure) in case of cardiovascular or psychological symptoms. Marfan's syndrome is frequently associated with obstructive sleep apnoea, which may itself contribute to aortic dilatation. Some studies suggest a potential role of craniofacial abnormalities in the pathogenesis of sleep apnea in these patients. Pulmonologists should consider Marfan's syndrome when treating patients for recurrent spontaneous pneumothorax or rib cage abnormalities, since early detection of cardiac abnormalities improves the prognosis significantly.

What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

OBJECTIVES: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. METHODS: Two different questionnaires were produced. RESULTS: Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. CONCLUSION: This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request.

[Recent progress in Marfan syndrome]. / Nouveautés dans le syndrome de Marfan.

For 20 years, the clinical, genetic and therapeutic knowledge of Marfan syndrome made great progress. The new classification, allowing the diagnosis and published in 2010, is easier to use. The diagnosis remains sometimes difficult particularly during childhood, because of the great variability of expression of the disease, from neonatal Marfan syndrome, to a weak clinical expression and especially because of the evolution of the signs with the age, which no classification takes into account. The search for amutation in the FBN1 gene is long and expensive and must be reserved only for patients having a very strong diagnostic suspicion. The therapeutics is preventive and based on patient education, limitation of the sport, beta blockade therapy, regular echocardiography as well as aorta replacement. New treatments are at present on approval but did not make the proof of their efficiency. The global care of the patient, by taking into account difficulties about genetic origin of the disease, aesthetic and psychological consequences, allows an improvement of the quality of life.

The new Ghent criteria for Marfan syndrome: what do they change?

The diagnosis of Marfan syndrome (MFS) is challenging and international criteria have been proposed. The 1996 Ghent criteria were adopted worldwide, but new diagnostic criteria for MFS were released in 2010, giving more weight to aortic root aneurysm and ectopia lentis. We aimed to compare the diagnosis reached by applying this new nosology vs the Ghent nosology in a well-known series of 1009 probands defined by the presence of an FBN1 mutation. A total of 842 patients could be classified as MFS according to the new nosology (83%) as compared to 894 (89%) according to the 1996 Ghent criteria. The remaining 17% would be classified as ectopia lentis syndrome (ELS), mitral valve prolapse syndrome or mitral valve, aorta, skeleton and skin (MASS) syndrome, or potential MFS in patients aged less than 20 years. Taking into account the median age at last follow-up (29 years), the possibility has to be considered that these patients would go on to develop classic MFS with time. Although the number of patients for a given diagnosis differed only slightly, the new nosology led to a different diagnosis in 15% of cases. Indeed, 10% of MFS patients were reclassified as ELS or MASS in the absence of aortic dilatation; conversely, 5% were reclassified as MFS in the presence of aortic dilatation. The nosology is easier to apply because the systemic score is helpful to reach the diagnosis of MFS only in a minority of patients. Diagnostic criteria should be a flexible and dynamic tool so that reclassification of patients with alternative diagnosis is possible, requiring regular clinical and aortic follow-up.

[Hormonal theory of heart failure with altered systolic function]. / Théorie hormonale de l'insuffisance cardiaque à fonction systolique altérée.

Heart failure (HF) is a major cause of morbidity and mortality in the developed countries. Hospital discharges and deaths from HF are regularly increasing. Therapies initially aimed at reversing hemodynamic abnormalities in HF, increasing cardiac output, decreasing intracardiac pressures, and blocking vasoconstriction. However, none of these therapies improved survival and some actually increased mortality. Now therapies for HF related to left ventricular systolic dysfunction have focused on counteracting compensatory neurohormonal activation. Several neurohormonal activations are present in HF supporting hemodynamics, but they appear to be deleterious in the long term on the myocardium, increasing progression of the HF and mortality. Blocking the renin-angiotensin-aldosterone system and the sympathetic system are now the mainstay of medical therapy in HF related to systolic dysfunction as they decrease mortality, hospitalisation rate and improve quality of life. Hence, the approach to patient with chronic heart failure should differ from that of patient with acute heart failure.

[NT-proBNP in practice: from chemistry to medicine]. / NT-proBNP en pratique "De la biologie à la clinique".

Since the introduction of routine assay for natriuretic peptides, there are a growing number of clinical applications for those new tests. Numerous studies have defined analytical characteristics and clinical interest of NT-proBNP assay. Originally limited to acute heart failure diagnosis in the emergency room, NT-proBNP assay has now a wide number of applications. This literature review presents the "state of art" of this marker, detailing NT-proBNP physiological recent knowledge and its recognized or investigated clinical applications.

[NT-proBNP in practice: from chemistry to medicine]. / NT-proBNP en pratique "de la biologie à la clinique".

Since introduction of routine assay for natriuretic peptides, there are a growing number of clinical applications for those new tests. Numerous studies have defined analytical characteristics and clinical interest of NT-proBNP assay. Originally limited to acute heart failure diagnosis in the emergency room, NT-proBNP assay has now a wide number of applications. This review presents the "state of art" of this marker, detailing NT-proBNP physiological recent knowledge and its recognized or investigated clinical applications.

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion.

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.

Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.

Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands.

BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.

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.

Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

[The best of cardiac failure in 2006]. / L'essentiel de 2006 en insuffisance cardiaque.

This year, several studies performed were justified by the increasing importance of diastolic dysfunction, while the systolic dysfunction remains stable. Its prognosis, previously considered as benign, is similar to heart failure due to systolic dysfunction. Studies are difficult in this field and we are often satisfied by imperfect results: PEP CHF, limited by the enrollment issue, showed only a trend for a beneficial effect of ACE-inhibitors. However the study can be considered as significant if only limited to the first year of follow-up, which can be justified. The second major field of research is resynchronization therapy: echocardiographic studies keep on providing asynchrony criteria. The benefit is greater in case of less extended fibrosis, and if the heart disease is non-ischemic, and if the paced zone does not contain fibrosis. Finally, a promising study on the interest of left ventricular discharge by a long-term circulatory assistance in case of severe systolic dysfunction should be cited.

Muscle strength and body composition in adult women with Marfan syndrome.

OBJECTIVE: The purpose of this study was to assess skeletal muscle function and body composition in a group of women with Marfan syndrome compared with matched controls. METHODS: The 21 women who were receiving follow-up for Marfan syndrome at our institution, were free of major cardiovascular disease, and consented to the study performed isokinetic and isometric knee extension and flexion maximal strength tests and had their body composition evaluated using dual-energy X-ray absorptiometry (DEXA). The same assessments were done in 19 matched controls. RESULTS: A significant decrease in lean leg mass with no change in total soft-tissue leg mass was noted in the patients compared with the controls. Peak torque values for the quadriceps and hamstring muscle groups were decreased in the patients, but only quadriceps strength was significantly reduced after normalization for lean leg mass. CONCLUSION: The muscle strength reduction in Marfan patients was not fully explained by a decrease in lean leg mass, suggesting qualitative skeletal-muscle alterations related to abnormal fibrillin expression in muscle connective tissue.