BACKGROUND Aortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene. OBJECTIVES This study sought to describe aortic risk in a population with Marfan syndrome with pathogenic variants in the FBN1 gene as a function of aortic root diameter. METHODS Patients carrying an FBN1 pathogenic variant who visited our reference center at least twice were included, provided they had not undergone aortic surgery or had an aortic dissection before their first visit. Aortic events (aortic surgery or aortic dissection) and deaths were evaluated during the 2 years following each patient visit. The risk was calculated as the number of events divided by the number of years of follow up. RESULTS A total of 954 patients were included (54% women; mean age 23 years). During follow-up (91 years), 142 patients underwent prophylactic aortic root surgery, 5 experienced type A aortic dissection, and 12 died (noncardiovascular causes in 3, unknown etiology in 3, post-operative in 6). When aortic root diameter was <50 mm, risk for proven type A dissection (0.4 events/1,000 patient-years) and risk for possible aortic dissection (proven aortic dissection plus death of unknown cause, 0.7 events/1,000 patients-years) remained tow in this population that was treated according to guidelines. Three type A aortic dissections occurred in this population during the 8,594 years of follow-up, including 1 in a patient with a tubular aortic diameter of 50 mm, but none in patients with a family history of aortic dissection. The risk for type B aortic dissection in the same population was 0.5 events/1,000 patient-years. CONCLUSIONS In patients with FBN1 pathogenic variants who receive beta-blocker therapy and who limit strenuous exercise, aortic risk remains tow when maximal aortic diameter is <50 mm. The risk of type B aortic dissection is dose to the remaining risk of type A aortic dissection in this population, which underlines the global aortic risk. (C) 2020 by the American College of Cardiology Foundation.

OBJECTIVES The purpose of this study was to define the contribution of ischemic mitral regurgitation (IMR) to the occurrence of congestive heart failure (CHF) after myocardial infarction (MI). BACKGROUND After MI, CHF is a frequent and serious complication, but its determinants and, particularly, the role of IMR are poorly defined. METHODS We analyzed 173 asymptomatic patients with previous Q-wave MI ( 16 days) with echocardiographic quantitation of IMR (measuring effective regurgitant orifice [ERO] and regurgitant volume). The 102 patients with IMR were matched to 71 patients without IMR for age (71 11 years vs. 68 9 years; p 0.11), gender (76% vs. 82% males; p 0.41), and left ventricular ejection fraction (EF) (37 14% vs. 36 11%; p 0.92). RESULTS Five-year rates of CHF and of CHF or cardiac death (CD) were 36 5% and 52 5%, respectively. Independent determinants of CHF were EF, sodium plasma level, and presence and degree of IMR (p 0.0001). Five-year CHF rates were 18 5% without mitral regurgitation (MR), 53 7% with IMR, 46 9% with ERO 1 to 19 mm and 68 12% with ERO 20 mm (all p 0.0001). The adjusted relative risk of CHF was 3.65 (95% confidence interval [CI] 1.86 to 7.75) for IMR presence and 4.42 (95% CI 1.9 to 10.5) for ERO 20 mm. The adjusted relative risk of CHF/CD was 2.97 (95% CI 1.77 to 5.16) for IMR presence and 4.4 (95% CI 2.4 to 8.2) for ERO 20 mm. CONCLUSIONS After MI, incidence of CHF and of CHF/CD are high even in patients with no or minimal symptoms at baseline and are higher in patients with IMR. Congestive heart failure is independently determined by larger ERO of IMR. These data suggest that detecting and quantifying IMR is essential for risk stratification after MI. Value of IMR treatment in improving post-MI outcome should be investigated. (J Am Coll Cardiol 2005;45:260–7) ublished by Elsevier Inc. doi:10.1016/j.jacc.2004.10.030

Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.

AIMS:To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS:A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving β-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION:Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

Background Contrast-enhanced computed tomography (CT) is routinely used as a complementary technique to trans-thoracic echocardiography (TTE) for assessing thoracic aortic aneurysms (TAA). However different measures can be obtained on CT and there are no recommendations on which to use. The objective was to determine which CT measurements most closely match reference TTE measurements in Marfan patients with TAA. Methods TTE measurements were obtained using the leading edge-to-leading edge technique in end-diastole on the parasternal longitudinal view. ECG-gated CT measurements were obtained, using the inner-to-inner technique in end-diastole by double oblique reconstruction: on three-cavity view (3C), left ventricle–aorta view (LVAo), and strict transverse plane passing through the maximal diameter "cusp to commissure" and "cusp to cusp" for each cusp. CT and TTE were performed within one month. Results 44 Marfan patients (39 ± 19 years, 48% men) were included. Dilatation of the ascending aorta was maximal at the level of the sinuses (TTE diameters: mean 47.5 ± 5.3 mm). TTE diameters were similar to 3C, LVAo (mean differences: 2.2 and −0.1 mm, p = NS) and to the three "cusp to cusp" diameters (mean differences ranging from 0 to 1.1 mm, p = NS), whereas "cusp to commissure" diameters were all statistically smaller than TTE (3.6 mm, 2.9 mm and 3.7 mm, p ≤ 0.01). Conclusions Inner-to-inner "cusp to cusp" diameter measured on an ECG-gated CT should be used for comparison with 2D TTE aortic diameter at the level of the sinuses of Valsalva in patients with thoracic aortic aneurysms.

Background Severe osteoarthritis and thoracic aortic aneurysms have recently been associated with mutations in the SMAD3 gene, but the full clinical spectrum is incompletely defined. Methods All SMAD3 gene mutation carriers coming to our centre and their families were investigated prospectively with a structured panel including standardized clinical workup, blood tests, total body computed tomography, joint X-rays. Electroneuromyography was performed in selected cases. Results Thirty-four SMAD3 gene mutation carriers coming to our centre were identified and 16 relatives were considered affected because of aortic surgery or sudden death (total 50 subjects). Aortic disease was present in 72%, complicated with aortic dissection, surgery or sudden death in 56% at a mean age of 45 years. Aneurysm or tortuosity of the neck arteries was present in 78%, other arteries were affected in 44%, including dissection of coronary artery. Overall, 95% of mutation carriers displayed either aortic or extra-aortic arterial disease. Acrocyanosis was also present in the majority of patients. Osteoarticular manifestations were recorded in all patients. Joint involvement could be severe requiring surgery in young patients, of unusual localization such as tarsus or shoulder, or mimicking crystalline arthropathy with fibrocartilage calcifications. Sixty eight percent of patients displayed neurological symptoms, and 9 suffered peripheral neuropathy. Electroneuromyography revealed an axonal motor and sensory neuropathy in 3 different families, very evocative of type II Charcot-Marie-Tooth (CMT2) disease, although none had mutations in the known CMT2 genes. Autoimmune features including Sjogren’s disease, rheumatoid arthritis, Hashimoto’s disease, or isolated autoantibodies- were found in 36% of patients. Interpretation SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth.

Aims: To define, in bicuspid aortic valve (BAV), ascending aorta dilatation patterns and progression rates vs. other aortopathies (Marfan Syndrome-MFS, Annulo-Aortic-Ectasia-AAE). Methods and results: Aortic dilatation progression was evaluated in two tertiary-care centers (US and European) by repeated echocardiography ≥2 years apart in adults with BAV (n=353) matched to MFS (n=50) and AAE (n=51) for gender, blood pressure and follow-up time. At baseline, aortic dilatation was present in 87% of BAV with predominant dilatation of the tubular-ascending-aorta (60%) irrespective of BAV morphology, while predominant Valsalva-sinuses dilatation (27%) was independently linked to typical (right-left fusion) BAV morphology (p<0.04). After 3.6±1.2 years, aortic dilatation rate in BAV was higher than population-expected for all aortic levels (p=0.005) and was maximal at the tubular-ascending-aorta for BAV (0.42±0.6mm/y) and AAE (0.20±0.3mm/y), while predominant at Valsalva-sinuses for MFS (0.49±0.5mm/y). Maximal aortic dilatation rate was similar between BAV and MFS (p>0.40) and lower in AAE (p=0.02) but was heterogeneous in BAV, with 43% of BAV exhibiting no dilatation progression (vs. 20% of MFS, p=0.01) (figure). Aortic dilatation rate was not related to baseline aortic size or BAV type (all models p>0.40). Conclusion: Tubular-ascending-aorta dilatation is frequent with BAV, irrespective of valve morphology, while Valsalva-sinuses dilatation is less common and associated with typical BAV morphology. Aortic dilatation progresses slower in AAE and equally fast in BAV and MFS, with a significant proportion of BAV not progressing at all. However, patterns of aortic dilatation are different, predominant for tubular-ascending-aorta in BAV vs. Valsalva-sinuses in MFS. Baseline aortic diameter does not predict progression rate, systematic follow-up is therefore warranted in BAV patients. Different valvulo-aortic phenotypes and patterns/rates of aortic dilatation underscore possible mechanistic and outcome differences between aortopathies.

Syncope is a common medical problem with a precise definition of which one must know the words but also their justification.This is the condition that the diagnostic approach can be effective. Although usually benign, syncope can sometimes be a warning sign of a sudden cardiac death.If the search for the specific cause of syncope remains an important objective to optimize the treatment, the basic purpose of the diagnostic approach is first to reduce sudden death. It therefore requires a good risk stratification of major cardiovascular events and sudden cardiac death.Clearly identify signs that indicate potential “dangerousness” of syncope is crucial because if present, the management strategy should be “aggressive” to promptly determine the cause and treat it immediately.La syncope est un problème médical fréquent, qui répond à une définition précise dont il faut bien connaître les termes, mais aussi leur justification.C’est à ce prix et à lui seul que la démarche diagnostique peut se révéler efficace. Bien que le plus souvent bénignes, les syncopes peuvent parfois être le signe annonciateur d’une mort subite.Si la recherche de la cause précise d’une syncope reste un objectif important en vue d’optimiser le traitement, l’objectif essentiel de leur prise en charge est d’abord de diminuer la mort subite, d’où la nécessité de bien stratifier le risque rythmique.Connaître les signes qui font craindre la « dangerosité » d’une syncope est primordial car s’ils sont présents, la stratégie de prise en charge doit être « agressive » pour s’efforcer de déterminer sans tarder la cause et la traiter sans délai.

Background Bicuspid aortic valve (BAV) is related to aortic dilatation, but patterns/rates are conflicting with no comparison among aneurysms of different aetiology. We sought to define ascending aorta dilatation patterns/progression rates in BAV versus other aortopathies (Marfan syndrome (MFS), degenerative aortopathy (DA)).Design and setting Retrospective, observational study. Aortic dilatation progression was evaluated in two tertiary care centres (US and European) by repeated echocardiography >= 2 years apart in adults with BAV (n=353), matched to MFS (n=50) and DA (n=51) for gender, blood pressure, and minimum follow-up time.Results At baseline, ascending aortic dilatation was present in 87% of BAV cases: tubular ascending aorta in 60% (irrespective of BAV morphology), and Valsalva sinuses dilatation in 27% (independently linked to typical BAV morphology and male gender (p=0.0001)). After 3.6 +/- 1.2 years, the aortic dilatation rate in BAV was higher than expected for the population for all aortic levels (p=0.005) and was maximal at the tubular ascending aorta for BAV (0.42 +/- 0.6 mm/year) and DA (0.20 +/- 0.3 mm/year), and was maximal at the Valsalva sinuses for MFS (0.49 +/- 0.5 mm/year). Maximal aortic dilatation rate was similar between BAV and MFS (p>0.40) and lower in DA (p=0.02) but was heterogeneous in BAV, with 43% of BAV not progressing (vs 20% of MFS, p=0.01). Aortic dilatation rate was not proportionally related to baseline aortic size or BAV type (all models p>0.40).Conclusions In patients with BAV, tubular ascending aorta dilatation is the most common pattern and exhibits the fastest growing rate, irrespective of valve morphology and function. Dilatation of the Valsalva sinuses is less common and associated with typical BAV morphology and male gender. Aortic dilatation progresses equally fast in BAV (tubular segment) and MFS (Valsalva sinuses), but a significantly higher proportion of BAV patients does not progress at all, irrespective of BAV type. Baseline aortic diameter does not proportionally predict progression rate; systematic follow-up is therefore warranted in patients with BAV.

AIMS:We analysed reinterventions performed during long-term follow-up after percutaneous mitral commissurotomy (PMC) with a particular focus on freedom from mitral surgery and late results of repeat PMC.METHODS AND RESULTS:In 912 patients who had good immediate results of PMC (valve area ≥1.5 cm² with mitral regurgitation ≤2/4), we analysed survival without reintervention (surgery or repeat PMC) and survival without surgery alone, with a follow-up up to 20 years. The median age was 48 years, and 251 patients (27%) had calcified valves. During a median follow-up of 12 years, 351 patients (38%) underwent a reintervention: surgery was performed in 266 (76%) patients and repeat PMC in 85 (24%). Cardiovascular survival without reintervention (surgery or repeat PMC) was 38 ± 2% at 20 years. When analysing cardiovascular survival without surgery, this rate increased to 46 ± 2% at 20 years. In the 504 patients aged <50 years at the time of their initial PMC, 20-year rates were 45 ± 3% for cardiovascular survival without reintervention and 57 ± 3% for cardiovascular survival without surgery. Of the 85 patients who underwent repeat PMC, cardiovascular survival without surgery was 60 ± 7% at 10 years.CONCLUSION:After successful PMC, reintervention is frequently needed. However, almost half of the patients remained free from surgery at 20 years. Repeat PMC was performed in one out of four cases of reintervention in this study, thereby allowing for postponement of surgery in a substantial number of patients.

The indication of percutaneous mitral commissurotomy (PMC) is debated in patients (pts) with calcified mitral stenosis. We report outcome up to 20 years according to the presence and the extent of valve calcification. PMC was performed in 1024 consecutive pts between 1986 and 1995: 710 pts had non-calcified valves (NCAL group) and 314 had valve calcification (CAL group) graded from 1 (mild) to 4 (extensive) using fluoroscopy. 177 pts (57%) were grade 1, 89 (28%) grade 2 and 48 (15%) grade 3 or 4. Good immediate results (GIR), defined as final valve area ≥1.5 cm2 without mitral regurgitation >2/4, were obtained in 93% in NCAL group vs. 80% in CAL group (p<0.0001). Among CAL group, GIR were 87% for grade 1 calcification vs. 72% for grades 2,3 and 4 (p=0.01). Good functional results (GFR) were defined as survival without intervention and in NYHA class I or II. 20-year rates of GFR were 38±3% for NCAL group and 12±3% in CAL group (p<0.0001). Among pts with GIR, 20 year rates of GFR were 40±3% in NCAL group vs. 21±3% in CAL group (p<0.0001). In CAL group predictors of GFR after GIR were: younger age (p=0.003), lower NYHA class (p=0.01), sinus rhythm (p=0.0002), lower post-PMC mean gradient (p<0.0001) and a lower extent of valve calcification (p=0.015). According to the extent of valve calcification, 15-year rates of GFR after GIR were 35±4% for pts in grade 1 vs. 19±4% for pts in grades 2, 3 and 4 (p=0.01). This study further confirms the negative prognostic impact of valve calcification on immediate and long-term results of PMC. PMC may, however, be considered to defer valve surgery in selected patients. In particular, more than 1 patient out of 3 with mild calcification still benefits from PMC 15 years after GIR. Young patients with few symptoms and in sinus rhythm are likely to benefit from PMC, even with calcified valves.

Percutaneous mitral commissurotomy (PMC) has enabled patients (pts) to be treated at an earlier stage of their disease than by surgery. However, very long-term results have not been specifically studied in this context. From 1986 to 1995, 237 patients in NYHA class I or II underwent PMC in our department. Mean age was 46±12 years; 74 patients (31%) had atrial fibrillation and 22 (9%) had a history of commissurotomy. Most patients were in NYHA class II (232 pts, 98%). As assessed by echocardiography, mean valve area was 1.1±0.2 cm2 (≤1.5 cm2 in all cases); 40 patients (17%) had pliable valves and mild subvalvular disease, 145 (61%) had severe subvalvular disease, and 52 (22%) had calcified valves. PMC used a singleballoon in 5 pts, a double-balloon in 93 and the Inoue balloon in 139. After PMC, valve area increased to 1.9±0.3 cm2 as assessed by 2D echo. Severe mitral regurgitation (grade ≥3/4) occurred in 4 patients (1.7%). There were no other severe immediate complications. Good immediate results (valve area ≥1.5 cm2 without mitral regurgitation >2/4) were obtained in 223 patients (94%). The 20-year actuarial rate of survival without surgery or repeat PMC and in NYHA class I or II was 41±4% in the whole population. After good immediate results, the 20-year rate of good functional results was 42±3%. A Cox multivariate model identified 2 predictors of good late functional results after good immediate results: young age (p=0.05) and a large valve area after PMC (p=0.002). In the 142 patients aged ≤50 years, the 20-rate of good functional results was 50±6%.

Objective: To determine cardiac and obstetric outcomes among women with Marfan syndrome (MS) whose pregnancies were managed in accordance with the French national guidelines. Methods: A descriptive analysis was conducted for a prospective cohort of 18 women with MS who gave birth in the maternity unit of Bichat-Claude Bernard Hospital, Paris, France, between January 1, 1998, and May 31, 2011. The study hospital was the national referral center for MS and related diseases. Results: A total of 22 pregnancies were recorded among the study cohort. Of these, 21 were managed according to the national guidelines. One woman who was referred to the study hospital during late pregnancy was not managed according to the national guidelines; this patient experienced aortic dissection at 37 weeks. In the cohort, aortic diameter did not increase significantly during pregnancy. Vascular fetal growth restriction was observed in 7 (31.8 %) of the pregnancies. Cesarean delivery was planned for 17 (77.3%) of the pregnancies. Conclusion: Risk of aortic dissection was low among a cohort of pregnant women with MS who were managed according to the French national guidelines. (C) 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Objective We analysed long-term results of percutaneous mitral commissurotomy (PMC) performed because of mitral restenosis after previous commissurotomy.Design Follow-up of a prospective cohort.Setting Tertiary university hospital.Patients We studied 163 consecutive patients who underwent PMC because of restenosis occurring 168years after previous commissurotomy (closed-heart in 121, open-heart in 30 and PMC in 12). Mean age was 4814years; 62 patients (38%) had valve calcification. Restenosis was due to bicommissural fusion in all cases.Intervention PMC using a single or double balloon in 80 patients and the Inoue balloon in 83.Results Good immediate results (IR) (valve area 1.5cm(2) with MR2/4) were obtained in 135pts (83%). 20-year rates were 27.9 +/- 4.7% for cardiovascular survival without mitral surgery and 14.8 +/- 3.9% for good functional results (cardiovascular survival without reintervention on the mitral valve and in New York Heart Association (NYHA) class I or II). After good IR, 20-year rates were 33.2 +/- 5.5% for cardiovascular survival without surgery and 17.9 +/- 4.7% for good functional results. After good IR, multivariate predictive factors of poor late functional results were higher NYHA class (p=0.01), atrial fibrillation (p=0.0002) and higher mean mitral gradient after PMC (p=0.004).Conclusions In patients with restenosis after mitral commissurotomy, PMC provides good IR in most cases. After good IR, one patient out of three remains free from surgery and one out of five has good functional results at 20years. These findings support the use of PMC after previous commissurotomy, particularly in selected patients with few symptoms and in sinus rhythm.

Dianna Milewicz and colleagues report the identification of loss-of-function mutations in TGFB2 in individuals with familial thoracic aortic aneurysm and acute aortic dissection associated with mild systemic features of the Marfan syndrome.

Background-Optimal management, including timing of surgery, remains debated in Marfan syndrome because of a lack of data on aortic risk associated with this disease.Methods and Results-We used our database to evaluate aortic risk associated with standardized care. Patients who fulfilled the international criteria, had not had previous aortic surgery or dissection, and came to our center at least twice were included. Aortic measurements were made with echocardiography (every 2 years); patients were given systematic beta-blockade and advice about sports activities. Prophylactic aortic surgery was proposed when the maximal aortic diameter reached 50 mm. Seven hundred thirty-two patients with Marfan syndrome were followed up for a mean of 6.6 years. Five deaths and 2 dissections of the ascending aorta occurred during follow-up. Event rate (death/aortic dissection) was 0.17%/y. Risk rose with increasing aortic diameter measured within 2 years of the event: from 0.09%/y per year (95% confidence interval, 0.00-0.20) when the aortic diameter was <40 mm to 0.3% (95% confidence interval, 0.00-0.71) with diameters of 45 to 49 mm and 1.33% (95% confidence interval, 0.00-3.93) with diameters of 50 to 54 mm. The risk increased 4 times at diameters >= 50 mm. The annual risk dropped below 0.05% when the aortic diameter was >= 50 mm after exclusion of a neonatal patient, a woman who became pregnant against our recommendation, and a 72-year-old woman with previous myocardial infarction.Conclusions-Risk of sudden death or aortic dissection remains low in patients with Marfan syndrome and aortic diameter between 45 and 49 mm. Aortic diameter of 50 mm appears to be a reasonable threshold for prophylactic surgery. (Circulation. 2012;125:226-232.)