The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele.

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.

Marfan Sartan: a randomized, double-blind, placebo-controlled trial.

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 ß-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. ß-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

Reinterventions after percutaneous mitral commissurotomy during long-term follow-up, up to 20 years: the role of repeat percutaneous mitral commissurotomy.

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.

Aortic event rate in the Marfan population: a cohort study.

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 ß-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.

Late results of percutaneous mitral commissurotomy up to 20 years: development and validation of a risk score predicting late functional results from a series of 912 patients.

BACKGROUND: Long-term follow-up after percutaneous mitral commissurotomy enables predictive factors of late results to be identified. METHODS AND RESULTS: Late results of percutaneous mitral commissurotomy were assessed in 1024 consecutive patients. Good immediate results, defined as valve area ≥1.5 cm(2) without mitral regurgitation >2/4, were obtained in 912 patients (89%). These 912 patients were randomly split into 2 cohorts comprising 609 and 303 patients that were used to develop and validate, respectively, a scoring system predicting late functional results. The 20-year rate of good functional results (survival without cardiovascular death, mitral surgery, or repeat percutaneous mitral commissurotomy and in New York Heart Association class I or II) was 30.2 ± 2.0%. A multivariable Cox model identified 7 predictive factors of poor late functional results: higher final mean gradient (P<0.0001), interaction between age and final mitral valve area (P<0.0001) showing that the impact of valve area decreases with age, interaction between sex and valve calcification (P<0.0001) showing that the impact of valve anatomy is stronger in men, and interaction between rhythm and New York Heart Association class showing an impact of New York Heart Association class only in patients in atrial fibrillation (P<0.0001). A 13-point score enabled 3 risk groups to be defined, corresponding to predicted good functional results of 55.1%, 29.1%, and 10.5% at 20 years in the validation cohort. CONCLUSIONS: Twenty years after percutaneous mitral commissurotomy in a population of patients with varied characteristics, 30% still had good functional results. Prediction of late functional results is multifactorial and strongly determined by age and the quality of immediate results. A simple validated scoring system is useful for estimating individual patient outcome.

Dissection in Marfan syndrome: the importance of the descending aorta.

AIMS: To better characterize patients with Marfan syndrome who have survived an acute aortic dissection and to estimate the risks of events in the descending aorta. Up until now, this portion of the aorta has not been well studied but is gaining importance due to improved patient survival. METHODS AND RESULTS: We report a retrospective cohort of 100 Marfan patients who survived an aortic dissection. Dissection occurred in either the ascending aorta (AscAo) (n = 37), the descending aorta (DescAo) (n = 20), or both (As + DescAo, n = 43). During a mean follow-up of 9.8 ± 6.0 years (complete for 88% of the patients), 17 patients died and 52 had a clinical event (new aortic dissection, surgery, ischaemia, haemorrhage), 60% of which involved the descending aorta. Event-free survival was similar whatever the location of the aortic dissection. However, a better event-free survival was observed when no dissected portion of the aorta remained after surgery, which was the case in 62% (23/37) of the AscAo patients (30% incurred an event vs. 86%; P = 0.008 by log-rank test). Interestingly, the diameter of the ascending aorta was below the surgical threshold in 60% of the patients who incurred a dissection of the descending aorta, and within the normal range in 25%. CONCLUSION: The descending aorta may dissect whatever the diameter of the ascending aorta. The descending aorta is the location of most late clinical events after any dissection of the aorta. The rate of clinical events is much lower when all the dissected aorta has been removed in patients with AscAo dissection.

Real-time 3D transoesophageal measurement of the mitral valve area in patients with mitral stenosis.

AIMS: Planimetry measured by two-dimensional transthoracic echocardiography (TTE, MVA2D) is the reference method for the evaluation of the severity of mitral stenosis (MS) but requires experienced operators and good echocardiographic windows. Real-time three-dimensional transoesophageal echocardiography (3D-TEE, MVA3D) may overcome these limitations but its accuracy has never been evaluated. METHODS AND RESULTS: We prospectively enrolled 80 patients (58±15 years, 86% female) referred for MS evaluation who underwent, within 1 week, a clinically indicated TTE and TEE. MVA2D was measured by experienced operators (Level III), MVA3D by one experienced and one non-experienced (Level I) operators blinded of any clinical or TTE information. MVA3D measured by the experienced operator [1.11±0.32 cm2; median, 1.1 cm2; range (0.45-2.20)] did not differ from and correlated well with MVA2D [1.10±0.34 cm2; median, 1.05 cm2; range (0.45-2.30)], P=0.87; r=0.79, P<0.0001; ICC=0.79) and mean difference between methods was small (+0.004±0.21 cm2). MVA3D measured by the non-experienced operator [1.08±0.34 cm2; median 1.02 cm2; range (0.45-2.23)] also did not differ from and correlated well with MVA2D measured by experienced operators (P=0.25; r=0.86, P<0.0001; mean difference -0.02±0.18 cm2; ICC=0.86). Intra and interobserver variability were 0.02±0.25 and 0.01±0.33 cm2. CONCLUSION: 3D-TEE provides accurate and reproducible MVA measurements similar to 2D planimetry performed by experienced operators. Thus, 3D-TEE could be considered as a second-line alternative tool for the evaluation of MS severity in patients with poor echocardiographic windows or for team less accustomed to evaluate MS patients.

Cardiovascular manifestations in men and women carrying a FBN1 mutation.

AIMS: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. METHODS AND RESULTS: A total of 1,013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11-34), male gender 53%] had data suitable for analysis. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94-97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67-81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [≤ 30 years: 57% (95% CI: 52-63) vs. 50% (95% CI: 45-55), P = 0.0076] and aortic events [≤ 30 years: 21% (95% CI: 17-26) vs. 11% (95% CI: 8-16), P < 0.0001; adjusted HR: 1.4 (1.1-1.8), P = 0.005]. The prevalence of mitral valve (MV) prolapse [≤ 60 years: 77% (95% CI: 72-82)] and MV regurgitation [≤ 60 years: 61% (95% CI: 53-69)] also increased steadily with age, but surgery limited to the MV remained rare [≤ 60 years: 13% (95% CI: 8-21)]. No difference between genders was observed (for all P> 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend = 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend = 0.01). CONCLUSION: The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation.

Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders.

BACKGROUND: TGFBR2 mutations were recognized recently among patients with a Marfan-like phenotype. The associated clinical and prognostic spectra remain unclear. METHODS AND RESULTS: Clinical features and outcomes of 71 patients with a TGFBR2 mutation (TGFBR2 group) were compared with 50 age- and sex-matched unaffected family members (control subjects) and 243 patients harboring FBN1 mutations (FBN1 group). Aortic dilatation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% versus 79%, respectively) but was highly variable. The incidence and average age for thoracic aortic surgery (31% versus 27% and 35+/-16 versus 39+/-13 years, respectively) and aortic dissection (14% versus 10% and 38+/-12 versus 39+/-9 years) were also similar in the 2 groups. Mitral valve involvement (myxomatous, prolapse, mitral regurgitation) was less frequent in the TGFBR2 than in the FBN1 group (all P<0.05). Aortic dilatation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (P=0.002). The rate of death was greater in TGFBR2 families before diagnosis but similar once the disease had been recognized. Most pregnancies were uneventful (without death or aortic dissection) in both TGFBR2 and FBN1 families (38 of 39 versus 213 of 217; P=1). Seven patients (10%) with a TGFBR2 mutation fulfilled international criteria for Marfan syndrome, 3 of whom presented with features specific for Loeys-Dietz syndrome. CONCLUSIONS: Clinical outcomes appear similar between treated patients with TGFBR2 mutations and individuals with FBN1 mutations. Prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 gene mutation.

Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome.

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 (9.1 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 low 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 low when maximal aortic diameter is <50 mm. The risk of type B aortic dissection is close to the remaining risk of type A aortic dissection in this population, which underlines the global aortic risk.

Usefulness of the right parasternal view and non-imaging continuous-wave Doppler transducer for the evaluation of the severity of aortic stenosis in the modern area.

AIMS: Evaluation of the severity of the aortic stenosis (AS) is based on echocardiographic assessment of peak velocity/mean transaortic pressure gradient (MPG) by continuous-wave Doppler and calculation of the aortic valve area (AVA) using the continuity equation. Pioneering echocardiographic studies have shown that MPG should be measured from the apical and right parasternal views using non-imaging continuous-wave Doppler transducer (NI-CWD). Nowadays, ultrasound systems are often sold without NI-CWD due, at least partially, to the improvement of two-dimensional continuous-wave Doppler transducers (2D-CWD). Whether this evolution translated into misevaluation of AS severity was uncertain. Our aim was to evaluate the additional diagnostic value of the use of NI-CWD and the right parasternal view for the evaluation of AS severity in the modern area. METHODS AND RESULTS: We prospectively evaluated MPG and AVA using the 2D-CWD (apical view) and the NI-CWD (right parasternal view) in 100 patients (78 +/- 5 years, 65% male) consecutively enrolled in an ongoing prospective study. Aortic stenosis severity was graded as mild (AVA > or = 1.5 cm(2)), moderate (1-1.5 cm(2)), or severe (AVA < 1 cm(2)). Misclassification was defined as at least a one grade difference and DeltaAVA > 0.15 cm(2) (twice the intra-observer variability). Feasibility of the 2D-CWD was 100%, MPG 20 +/- 13 mmHg, and AVA 1.52 +/- 0.45 cm(2). Fifty-three per cent had a mild AS, 34% a moderate AS, and 13% a severe AS. Using the NI-CWD, feasibility was 85%, MPG 25 +/- 16 mmHg, AVA 1.33 +/- 0.41 cm(2) (both P < 0.005 compared with 2D-CWD). Thirty-five per cent (n = 30) had a mild AS, 46% (n = 39) a moderate AS, and 19% (n = 16) a severe AS. Using only the 2D-CWD and the apical view, 21 patients (21%) would have been misclassified: 17 as mild instead of moderate AS and 4 as moderate instead of severe AS. In those misclassified patients, MPG was 9 +/- 6 mmHg higher with the NI-CWD and 33% had an MPG difference >10 mmHg. CONCLUSION: The use of the NI-CWD and the right parasternal view must be performed to evaluate AS severity, especially in case of discrepancy between symptoms and AS severity or for precise evaluation of AS progression.

Contemporary surgical or percutaneous management of severe aortic stenosis in the elderly.

AIMS: To assess patient characteristics, therapeutic options, and their results in patients referred to a tertiary centre with on-site capabilities for surgical and percutaneous valvular interventions for the management of severe symptomatic aortic stenosis (AS). METHODS AND RESULTS: Sixty-six consecutive patients >70 years (83 +/- 6 years) were referred for severe AS. Their mortality risk predicted by the logistic European System for Cardiac Operative Risk Evaluation and the Society of Thoracic Surgeons-Predicted Risk of Mortality scores were on average 20 +/- 14% and 17 +/- 7%, respectively. Thirty-nine patients (59%) were considered at high-risk for surgery or inoperable after multidisciplinary evaluation: 12 (31%) underwent a transfemoral aortic valve implantation and 27 were considered unsuitable and treated medically (n = 16) or with valvuloplasty (n = 7), or were re-directed towards surgery (n = 4). The 27 other patients underwent valve replacement. In-hospital mortality was 9% (6 of 66). There were three hospital deaths in patients treated percutaneously, two in those treated medically, and one after surgery. At 6 months, 10% (6 of 60) of the survivors died: two after valvuloplasty and four after medical treatment. CONCLUSION: A large proportion of elderly patients referred for management of severe AS have a high-risk profile. The availability of percutaneous valvular interventions increases the number of those who are offered interventions.

[Dystrophic aortic insufficiency]. / Insuffisance aortique dystrophique.

Dystrophic AR is the combination of two features including ascending aorta enlargement and aortic regurgitation due to change in aortic root geometry Marfan syndrome, an inherited connective tissue disorder, is the most frequent genetic aetiology of dystrophic AR. The main clinical manifestations involve the cardiovascular, ocular and skeletal system. Aortic dilatations and ruptures are the most serious complications. Thus management of the disease require frequent follow-up visit with measurement of aorta diameters, examination of family members, medical treatment with beta blockers and evaluation of the need of surgery based on dilatation of ascending aorta and on tolerance of aortic regurgitation.

Quantitative determinants of the outcome of asymptomatic mitral regurgitation.

BACKGROUND: The clinical outcome of asymptomatic mitral regurgitation is poorly defined, and the treatment is uncertain. We studied the effect on the outcome of quantifying mitral regurgitation according to recent guidelines. METHODS: We prospectively enrolled 456 patients (mean [+/-SD] age, 63+/-14 years; 63 percent men; ejection fraction, 70+/-8 percent) with asymptomatic organic mitral regurgitation, quantified according to current recommendations (regurgitant volume, 66+/-40 ml per beat; effective regurgitant orifice, 40+/-27 mm2). RESULTS: The estimated five-year rates (+/-SE) of death from any cause, death from cardiac causes, and cardiac events (death from cardiac causes, heart failure, or new atrial fibrillation) with medical management were 22+/-3 percent, 14+/-3 percent, and 33+/-3 percent, respectively. Independent determinants of survival were increasing age, the presence of diabetes, and increasing effective regurgitant orifice (adjusted risk ratio per 10-mm2 increment, 1.18; 95 percent confidence interval, 1.06 to 1.30; P<0.01), the predictive power of which superseded all other qualitative and quantitative measures of regurgitation. Patients with an effective regurgitant orifice of at least 40 mm2 had a five-year survival rate that was lower than expected on the basis of U.S. Census data (58+/-9 percent vs. 78 percent, P=0.03). As compared with patients with a regurgitant orifice of less than 20 mm2, those with an orifice of at least 40 mm2 had an increased risk of death from any cause (adjusted risk ratio, 2.90; 95 percent confidence interval, 1.33 to 6.32; P<0.01), death from cardiac causes (adjusted risk ratio, 5.21; 95 percent confidence interval, 1.98 to 14.40; P<0.01), and cardiac events (adjusted risk ratio, 5.66; 95 percent confidence interval, 3.07 to 10.56; P<0.01). Cardiac surgery was ultimately performed in 232 patients and was independently associated with improved survival (adjusted risk ratio, 0.28; 95 percent confidence interval, 0.14 to 0.55; P<0.01). CONCLUSIONS: Quantitative grading of mitral regurgitation is a powerful predictor of the clinical outcome of asymptomatic mitral regurgitation. Patients with an effective regurgitant orifice of at least 40 mm2 should promptly be considered for cardiac surgery.

Risk, determinants, and outcome implications of progression of mitral regurgitation after diagnosis of mitral valve prolapse in a single community.

To analyze the evolution of mitral regurgitation (MR) after the diagnosis of mitral valve prolapse in community patients, 285 residents of Olmsted County, Minnesota, diagnosed with mitral valve prolapse without severe MR were studied. MR grade was assessed at diagnosis and at follow-up 1,663 +/- 1,079 days later using Doppler echocardiography. The progression of MR was defined as an increase of > or =1 MR grade. The patients' mean age was 56 +/- 22 years, 57% were women, and the mean ejection fraction was 60 +/- 9%. Between diagnostic and follow-up echocardiography, 108 patients showed progression of MR, 39 of whom had progression > or =1 grade. The mean overall MR grade increased from 0.4 +/- 0.7 to 0.9 +/- 1.1 (p <0.01). The progression of MR was observed in all subsets, irrespective of age, gender, prolapse localization, leaflet thickening, and initial MR grade. However, multivariate analysis identified age (p <0.01) and initial MR grade (p = 0.01) as independent predictors of progression. In addition, MR progression was associated with greater left atrial enlargement (p <0.001), ventricular dilatation (p = 0.02 for increase in end-diastolic and end-systolic diameters), and a worse outcome (adjusted p = 0.001). In conclusion, in patients with mitral valve prolapse, MR progression was observed over time in all clinical and anatomic subsets and was associated with more severe ventricular and atrial remodeling and worse outcome.

Nitrous oxide inhalation for transoesophageal echocardiography: an alternative to benzodiazepine sedation?

AIMS: Transoesophageal echocardiography (TEE) is usually performed using benzodiazepine sedation, which is a limiting factor for elderly patients or those with respiratory insufficiency. Kalinox, an equimolar mixture of nitrous oxide and oxygen, with no depressive respiratory action and fast reversible effects, seems ideally suited for performing TEE but has never been evaluated. The aim of the present study was to evaluate the TEE feasibility and efficiency using Kalinox compared with the standard care using benzodiazepine. METHODS AND RESULTS: We prospectively enrolled 80 consecutive patients referred for TEE. In the 35 first patients, TEE was performed using intravenous benzodiazepine (Midazolam) and in the 45 last patients using Kalinox (nasal delivery). Pain and tolerance induced by the examination were evaluated on a 0-10 scale. Remembrance of the examination by the patient and quality of the TEE by the operator were also evaluated. All TEEs were performed by the same experienced operator. TEE duration was not different (6 +/- 3 vs. 7 +/- 4 min, respectively, P = 0.57). Patients in the Kalinox group felt TEE to be more difficult (P = 0.005) and remembered the procedure more clearly (P < 0.0001) but pain experience was not different (7 vs. 9% had a pain score >or=5, respectively, P = 0.75). Percentage of patients who agreed to have a second TEE if necessary was slightly lower (77 vs. 94%, respectively, P = 0.04). The operator judged TEE quality satisfactory in similar proportions (76 vs. 68%, respectively, P = 0.44). CONCLUSION: These preliminary results show that TEE using Kalinox is feasible, provides similar pain relief despite more discomfort for the patient, and acceptable conditions for the operator. Thus, Kalinox use could be considered as an alternative to benzodiazepine sedation for patients intolerant to benzodiazepines such as elderly or respiratory-insufficient patients.

Surgical correction of mitral regurgitation in the elderly: outcomes and recent improvements.

BACKGROUND: In the elderly, mitral regurgitation (MR) is frequent, but surgery risks are considered high. Benefits and indications of MR surgery are uncertain in the elderly. METHODS AND RESULTS: Baseline characteristics, outcome, and trends for surgical results improvement were analyzed in elderly patients (> or = 75 years of age; n=284) operated on for MR in 1980 to 1995 compared with younger patients (65 to 74 years of age, n=504; and <65 years of age, n=556). Preoperatively, class III to IV symptoms, atrial fibrillation, coronary disease, creatinine, and comorbidity index were more severe in elderly patients (all P<0.002). In the long term after surgery, observed survival stratified by age (> or = 75, 65 to 74, <65 years) was lower in elderly than in younger patients (at 5 years, 57+/-3%, 73+/-2%, and 85+/-2%, respectively; P<0.001), but ratios of observed to expected survival were similar (83%, 85%, and 88%, respectively). In multivariate analysis adjusted to expected survival, elderly patients showed no difference in life expectancy restoration compared with younger patients (adjusted hazard ratio, 0.89; 95% confidence interval, 0.73 to 1.30; P=0.54). Temporal trends showed that risk of operative mortality, although higher in elderly patients (P<0.001), declined markedly for all ages (27% to 5% in those > or = 75 years of age, P<0.01; 21% to 4% in those 65 to 74 years of age, P<0.01; and 7% to 2% in those <65 years of age, P=0.06), with a parallel decline in low cardiac output and length of hospital stay. Over time, valve repair feasibility increased in all age groups (30% to 84% overall and 31% to 93% in degenerative MR; P<0.0001). CONCLUSIONS: Elderly patients undergoing MR surgery display more severe preoperative characteristics and incur higher operative risks than younger patients. However, restoration of life expectancy after surgery is similar in elderly and younger patients, and outstanding recent surgical improvements particularly benefited elderly patients. Thus, elderly patients with MR can now carefully be considered for surgery before refractory heart failure is present.

B-type natriuretic peptide in organic mitral regurgitation: determinants and impact on outcome.

BACKGROUND: B-type natriuretic peptide (BNP) activation observed in cardiac diseases is a predictor of poor outcome; however, in organic mitral regurgitation (MR), BNP determinants and prognostic value are unknown. METHODS AND RESULTS: We prospectively enrolled 124 patients with chronic organic MR (aged 63+/-15 years, 60% males) in whom we measured BNP level and simultaneously quantified MR degree, left ventricular (LV) remodeling, and left atrial (LA) volumes and analyzed long-term outcome. Baseline BNP level (54+/-67 pg/mL, median 31 pg/mL) was associated univariately with multiple clinical and echocardiographic characteristics, but in multivariate analysis, independent determinants of BNP, beyond age and sex (both P< or =0.01), were LV end-systolic volume index, LA volume, atrial fibrillation, and symptoms (all P<0.02). Conversely, MR degree was not independently associated with BNP. During follow-up, patients with high versus low BNP (> or =31 versus <31 pg/mL) displayed lower survival rates (at 5 years, 72+/-10% versus 95+/-5%, P=0.03) and higher rates of the combined end point of death and heart failure (at 5 years, 42+/-10% versus 16+/-7%, P=0.03). In multivariate analysis, with adjustment for age, sex, functional class, MR severity, and ejection fraction, BNP was independently predictive of mortality (hazard ratio per 10 pg/mL, 1.23 [95% CI 1.07 to 1.48], P=0.004) and of death or heart failure (hazard ratio per 10 pg/mL, 1.09 [95% CI 1.001 to 1.19], P=0.04). CONCLUSIONS: BNP activation in organic MR reflects primarily ventricular and atrial consequences rather than degree of MR. Higher BNP level in patients with organic MR independently predicts adverse events under conservative management. Therefore, BNP activation in organic MR is an emerging biomarker of severity of MR consequences and of poor clinical outcome, and its assessment should be considered in the clinical evaluation and risk stratification of patients with MR.