Study of the efficacy and safety of losartan versus atenolol for aortic dilation in patients with Marfan syndrome

Introduction and objectives

Marfan syndrome is an inherited disease of the connective tissue. Recent trials have indicated the use of losartan (a transforming growth factor beta inhibitor) in these patients prevents aortic root enlargement. The aim of our clinical trial is to assess the efficacy and safety of losartan versus atenolol in the prevention of progressive dilation of the aorta in patients with Marfan syndrome.

Methods

This is a phase III clinical trial conducted in two institutions. A total of 150 subjects diagnosed with Marfan syndrome, aged between 5 and 60 years, of both sexes, and who meet the Ghent diagnostic criteria will be included in the study, with 75 patients per treatment group. It will be a randomized, double blind trial with parallel assignment to atenolol versus losartan (50 mg per day in patients below 50 kg and 100 mg per day in patients over 50 kg). Both growth and distensibility of the aorta will be assessed with echocardiography and magnetic resonance. Follow-up will be 3 years.

Conclusions

Efficacy of losartan versus atenolol in the prevention of progressive dilation of the aorta, improved aortic distensibility, and prevention of adverse events (aortic dissection or rupture, cardiovascular surgery, or death) will be assessed in this study. It will also show the possible treatment benefits at different age ranges and with relation to the initial level of aortic root dilation.Full English text available from: www.revespcardiol.org     

Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome

Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = ?0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = ?0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m², p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.     

β受体阻滞剂治疗马方综合征主动脉根部扩张的临床观察

目的观察长效β受体阻滞剂氨酰心安对儿童和青少年马方综合征(MFS)主动脉根部扩张的临床治疗效果。方法15例临床诊断明确的MFS患者,药物治疗组7例,年龄3.5～2(011.5±5.7)岁,另外8例未用药物作为对照组。应用UCG测定用药前、后主动脉根部最大直径,记录用药前后身高、体重,按回归方程计算出体表面积,进而得出主动脉根部增长速度、增长指数和年增长指数,以及应用氨酰心安的剂量。结果两组在性别、年龄、随访时间、体表面积和家族史差异无统计学意义。用药组根据个体化服用氨酰心安(0.81±0.32)mg·kg-·1d-1,随访时间1.4～3.(32.47±0.68)年,服药后安静心率由(93±9)次/min降为(74±8)次/min,其主动脉根部直径年增长速度[(2.33±0.82)mmvs(.5.30±1.89)mm)]和年增长指数[(1.14±1.09)mmv(s4.85±3.07)mm)明显慢于对照组(P<0.05)。随访期间有2例治疗无效,表现为主动脉窦进行性扩张并反流而行改良带瓣管道置换术。结论β受体阻滞剂氨酰心安对大多数儿童和青少年马方综合征的主动脉根部具有明显延缓扩张的效果,但对主动脉窦部已中-重度扩张者无效。     

Usefulness of tissue doppler imaging for assessing aortic wall stiffness in children with the Marfan syndrome

The purpose of this study was to assess wall motion velocities of the abdominal aorta using tissue Doppler imaging (TDI) in 12 patients with Marfan syndrome and 30 age-matched normal controls. The patients with Marfan syndrome displayed an increased aortic stiffness index in the abdominal aorta, and significant relationships were observed between wall motion velocities of the abdominal aorta and the aortic stiffness index. Thus, TDI analyzes aortic expansion and contraction velocities and allows the identification of abdominal aortic stiffness in patients with Marfan syndrome.     

Surgical management of the aortic root in patients with Marfan syndrome

BACKGROUND AND AIM OF THE STUDY: Surgical aortic root reconstruction techniques are standard therapy to avoid catastrophic vascular events in patients with Marfan syndrome with a dilated and/or dissected aortic root. The study aim was to evaluate the long-term results of aortic root reconstruction. METHODS: Eighty-three patients (54 males, 29 females; mean age 37+/-17 years) fulfilling strict Ghent criteria for Marfan syndrome underwent aortic root surgery between 1971 and 2001. Of these patients, 65 (78%) underwent a composite valve conduit repair and 18 (22%) a valve-sparing aortic root reconstruction. Six patients (7%) suffered from an acute type A dissection, and 16 (19%) a chronic type A dissection. RESULTS: In-hospital and 30-day mortality was 3.6% (n = 3). Morbidity included stroke (1.2%; n = 1), perioperative myocardial infarction (1.2%; n = 1) and reoperation for bleeding (10%; n = 8). Of 21 late deaths, the cause was cardiac in nine cases. Actuarial survival at 5, 10, 15 and 20 years was 84% (95% CI 76-93%), 73% (CI 61-86%), 59% (CI 45-77%) and 43% (CI 26-72%), respectively. Multivariate predictors for late death were postoperative dysrhythmias and need for inotropes (p < or =0.01). Freedom from reoperation at 5, 10, 15 and 20 years was 86% (CI 78-95%), 69% (CI 56-85%), 53% (CI 38-74%) and 48% (CI 23-71%), respectively. Multivariate predictors for reoperation were preoperative mitral valve prolapse and an initial valve-sparing aortic procedure (p < or =0.05). In the composite valve conduit patients, freedom from thromboembolism was 88% (CI 76-100%), and from endocarditis was 99% (CI 93-100%) at 15 years. CONCLUSION: Composite valve conduit replacement of the aortic root in patients with Marfan syndrome offers a durable result, with low mortality and long-term complication rates. Reoperation was most commonly required for cardiac and vascular disease unrelated to the initial operation and in patients undergoing a valve-sparing aortic root procedure.     

Long-term outcomes after aortic root replacement for patients with Marfan syndrome

BackgroundA diversity of surgical strategies are used to treat Marfan syndrome patients with aortic disease. We sought to evaluate the long-term efficiency of aortic root replacement (ARR) for patients with Marfan syndrome.MethodsData were collected from 131 patients with Marfan syndrome and aortic disease who underwent ARR in our center. We retrospectively analyzed the long-term outcomes of these patients, among whom 68 had been diagnosed with aortic aneurysm (AA) and had undergone ARR. The remaining 63 patients had aortic dissection (AD); of these, 35 underwent ARR for limited ascending AD, while the others underwent ARR and total arch replacement combined with frozen elephant trunk (FET). Risk factors for survival and reoperation were identified.ResultsThe operative mortality rate was 4.58%. Age >40 years was the sole risk factor for operative mortality. During follow-up, 12 deaths occurred. Patients aged <25 years and female patients were more prone to late death than were other patients. Indications for reoperation were noted in 22 patients, and the risk factors were age <30 years and female sex. At 5 years, the survival rate was 92.96%, and the freedom from reoperation rate was 88.36%. At 10 years, the survival rate was 85.25%, and the freedom from reoperation rate was 71.75%. The survival and freedom from reoperation rates were significantly higher in patients with AD than in those with AA. Specifically, chronic AD was a greater risk factor for late survival than was acute AD in patients with Marfan syndrome.ConclusionsFor patients with Marfan syndrome and aortic disease, ARR can be safely performed and results in low operative mortality and favorable long-term survival. Young and female patients have a higher risk for late death and reoperation. To prevent AD, surgical intervention should be promptly implemented following the diagnosis of aortic sinus dilation.     

Cognitive function in hypertensives treated with atenolol or propranolol

Study objective:To test reports that beta blockers, particularly lipopbilic forms, impair cognitive function and cause psychiatric disturbances. Design:Randomized, double-blind, controlled crossover trial with eight-week treatment periods. Patients:Sequential sample of 43 male veterans, with untreated diastolic blood pressures (DBP) between 90 and 110 mmHg, aged 35–64 years. Interventions:Propranolol-LA, 80-mg tablets, or atenolol, 50-mg tablets, were given daily, incremented by one tablet at weekly intervals until DBP ≤90 mmHg. Hydrochlorothiazide was added, if necessary. Main results:Repeated-measures ANOVA was performed on all cognitive tests. Cognitive test performance was not affected by beta blocker therapy in seven of nine tests and was enhanced on Trail Making Test. Performance was impaired only on Digit Cancellation. Neither Speilberger’s State Trait Anxiety Inventory nor the Beck Depression Inventory was affected by either beta blocker. Conclusions:Atenolol or propranolol therapy does not impair cognitive function or contribute significantly to psychiatric side effects. Received from the Veterans Administration Medical Center, Portland Division and Oregon Health Sciences University, Portland, Oregon. Presented at the annual meeting of the Society of General Internal Medicine, April 28, 1989. Supported by a Veterans Administration Merit Review Grant, Ayerst Laboratories, and Stuart Pharmaceuticals.     

Usefulness of stenting in aortic coarctation in patients with the Turner syndrome

We report our experience with stent implantation for treatment of aortic coarctation in patients with Turner syndrome. Ten consecutive patients with Turner syndrome and aortic coarctation (median age 12 years, range 9 to 24) underwent coarctation stenting. Of these, 6 patients were treated for isolated coarctation and 4 for recurrent coarctation (3 after balloon dilation and 1 after balloon dilation and surgical repair). Bare metal stents were implanted in 7 patients and covered stents in 3. Immediately after stent implantation, peak systolic gradient decreased from 46.1 ± 24.3 to 1.9 ± 2.1 mm Hg (p <0.001). Aortic diameter at coarctation site increased from 5.1 ± 3.2 to 15.3 ± 2.0 mm after stenting (p <0.001). There were no deaths or procedure-related complications. During a median follow-up of 30.5 months, no patient developed restenosis. Two patients developed late aortic aneurysms at the coarctation site. In conclusion, stent implantation for aortic coarctation in patients with Turner syndrome appears to be a safe and effective alternative to surgical repair. Larger cohorts and longer-term follow-up are required to determine the effects of the procedure on the aortic wall.     

Comparison of the pattern of aortic dilation in children with the Marfan's syndrome versus children with a bicuspid aortic valve

Marfan's syndrome (MS) and bicuspid aortic valves (BAVs) are associated with aortic dilation. Despite their histologic similarities, the 2 diseases differ with regard to the location of maximal aortic dilation. Echocardiographic analysis of aortic dimensions was performed in children with MS, children who had aortic dilation in the setting of nonstenotic BAVs (peak gradient <16 mm Hg), and healthy controls. Data on 25 patients with MS, 31 with BAVs, and 65 controls were analyzed. Subjects with BAVs had greater dimensions at all levels of the aortic root compared with normal controls. Patients with BAVs also had greater dilation than those with MS at the level of the annulus and the ascending aorta, with dilation often extending cranially beyond the region of measurement. Conversely, patients with MS had more focal dilation at the sinuses of Valsalva compared with controls and patients with BAVs. In conclusion, despite similar histologic abnormalities, the anatomic pattern of aortic dilation differs in children with MS and BAVs.     

Effect of long-term beta-blockade on aortic root compliance in patients with Marfan syndrome.

BACKGROUND: This study was undertaken to assess the effect of long-term beta-blockade on the aortic root stiffness index and distensibility in patients with Marfan syndrome. METHODS: Aortic root stiffness index and distensibility were calculated according to the formulas of Stefanadis and Hirai, respectively, with 2-dimensional guided M-mode echocardiogram before and after an average of 26 months of atenolol administration. RESULTS: Twenty-three asymptomatic patients were studied (11 men and 12 women, aged 31 +/- 14.2 years). The follow-up was 4 +/- 2.2 years. The dose of atenolol was individualized (mean 43.5 +/- 21.6 mg/d). Heart rate decreased from 79 +/- 9 beats/min to 64 +/- 9 beats/min (P =. 01), and systolic blood pressure decreased from 124 +/- 13 mm Hg to 114 +/- 2 mm Hg (P =.01). Distensibility increased from 1.85 +/- 0. 70 x 10(-6) cm2/dynes-1 to 2.21 +/- 0.76 x 10-6 cm2/dynes-1 (P =.02), and the stiffness index decreased from 9.68 +/- 3.78 to 8.85 +/- 3. 15 ( P =.2). Two groups of responses to treatment were identified. Compared with baseline values 15 (65%) patients who responded to treatment had increased distensibility and decreased stiffness index of the aortic root (P =.05). Eight patients (35%) who did not respond to treatment had no significant change. Body weight >91 kg and baseline end-diastolic aortic root diameter >40 mm were significantly associated with no response (P =.05). Two patients in the nonresponding group had echocardiographic progression of aortic insufficiency. CONCLUSIONS: There was a heterogeneous response in the aortic root elastic properties after long-term treatment with atenolol in asymptomatic patients with Marfan syndrome. Stiffness index and distensibility are more likely to respond when the baseline end-diastolic aortic root diameter is <40 mm.     

马方综合征并发主动脉夹层临床特征分析

目的 :探讨马方综合征并发主动脉夹层临床特征。方法 :收集主动脉夹层患者 79例 ,按其不同易患因素分为两组 :马方综合征组 ,4 4例 ;高血压组 35例 ,对两组患者的临床资料进行对比分析。结果 :马方综合征并发主动脉夹层临床特征 :①平均年龄 [(36 .2± 12 .6 )岁 ]小于高血压组患者 [(5 8.3± 11.3)岁 ](P <0 .0 5 ) ;②首发症状以心功能不全多见 ,常并发马方综合征的其他系统损害表现 ;③典型的胸痛较少见 ,发生比例低于高血压组 (P <0 .0 5 ) ;④A型主动脉夹层和主动脉根部扩张多见 ,而主动脉粥样硬化少见 (P <0 .0 5 ) ;⑤马方综合征组住院死亡率 (2 0 .5 % )低于高血压组 (4 5 .7% ) (P <0 .0 5 )。结论 :马方综合征并发主动脉夹层在年龄、临床表现及预后具有不同于高血压并发主动脉夹层的特点 ,处理两类患者时应注意其差别。     

Aortic stiffness and diameter predict progressive aortic dilatation in patients with Marfan syndrome.

AIM: Patients with Marfan syndrome may develop dissection due to progressive dilatation in the entire aorta, which is not always predictable by mere anatomic assessment of the aortic diameter, especially of the descending aorta. The aim of this study was to identify the predictive value of aortic stiffness on the occurrence of dissection and progressive aortic dilatation. METHODS AND RESULTS: In 78 non-operated patients with Marfan syndrome (mean age 31+/-8 years, mean aortic root diameter 43+/-6 mm, range 31-55 mm) aortic stiffness and diameters were assessed by magnetic resonance imaging (MRI) at multiple levels. After a median follow-up of 71 months (25-75%: 68-72 months) a second MRI was performed and the incidence of aortic dissection and progressive aortic dilatation, defined as mean aortic diameter increase >1 mm/year was determined. During follow-up, 4 (5%) of 78 patients developed an aortic dissection (1 type A, 2 type B, and 1 infra-renal dissection). Twenty (26%) of the 78 patients had progressive aortic root dilatation. There were 5 (6%) patients with progressive descending thoracic aortic dilatation and 6 (7%) with progressive abdominal aortic dilatation. Multivariate logistic regression analysis revealed that local distensibility was an independent predictor of progressive thoracic descending aortic dilatation (OR=4.14, 95% CI, 1.02-16.7). For progressive aortic root and abdominal aortic dilatation local initial diameter appeared to be the major predictor (OR=1.37, 95% CI, 1.16-1.62; OR=1.36, 95% CI, 1.09-1.69, respectively). CONCLUSION: In patients with Marfan syndrome both aortic diameter and aortic distensibility are independent predictors of progressive aortic dilatation. For optimal risk assessment and monitoring of patients with Marfan syndrome, both aortic stiffness and diameter should be assessed at least annually.     

Acute aortic dissection in a female patient with Marfan syndrome

The group of patients with the Marfan syndrome is used to suffer from aneurysm and dilatation of the ascendent aorta, therefore the reason echocardiography examination is necessary. But in spite of this, although the dimensions (measures) are stable, we do really not know when the dissection appeared. This complication is the most usual cause of death these patients. But if we recognize the diagnosis in time and if we treat it correctly, this complication can be treated with the great difference in mortality. That is while we must think of this possible complication in case of atypical breast ache. The following case describes the acute dissection of the aorta in the proximal and also descendent part together with the acute aortal significant regurgitation and the volume overload of the left chamber appeared on female--patient with the Marfan syndrome.