Jos A. Bekkers

Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections

Background Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-β signaling. Objectives This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. Methods We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. Results Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands. Conclusions Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

Direct Proof of Endo-Epicardial Asynchrony of the Atrial Wall During Atrial Fibrillation in Humans

Background—The presence of focal fibrillation waves during atrial fibrillation (AF) can, besides ectopic activity, also be explained by asynchronous activation of the atrial endo- and epicardial layer and transmurally propagating fibrillation waves. To provide direct proof of endo-epicardial asynchrony, we performed simultaneous high-resolution mapping of the right atrial endo- and epicardial wall during AF in humans. Method and Results—Intraoperative mapping of the endo- and epicardial right atrial wall was performed during (induced) AF in 10 patients with AF (paroxysmal: n=3; persistent: n=4; and longstanding persistent: n=3) and 4 patients without a history of AF. A clamp made of 2 rectangular 8×16 electrode arrays (interelectrode distance 2 mm) was inserted into the incision in the right atrial appendage. Recordings of 10 seconds of AF were analyzed to determine the incidence of asynchronous endo-epicardial activation times (≥15 ms) of opposite electrodes. Asynchronous endo-epicardial activation ranged between 0.9 and 55.9% without preference for either side. Focal waves appeared equally frequent at endocardium and epicardium (11% versus 13%; P=0.18). Using strict criteria for breakthrough (presence of an opposite wave within 4 mm and ⩽14 ms before the origin of the focal wave), the majority (65%) of all focal fibrillation waves could be attributed to endo-epicardial excitation. Conclusions—We provided the first evidence for asynchronous activation of the endo-epicardial wall during AF in humans. Endo-epicardial asynchrony may play a major role in the pathophysiology of AF and may offer an explanation why in some patients therapy fails.

Acute type A aortic dissection: long-term results and reoperations

OBJECTIVESnThe objective of this study was to report long-term results and incidence of reoperations after surgery for acute type A dissection.nnnMETHODSnAll 232 consecutive patients who underwent surgery for acute type A aortic dissection from 1972 to April 2011 were included. Patient, procedural and follow-up information was obtained from hospital records.nnnRESULTSnMean age was 57.9 years (standard deviation 13.4 years), 64% were male. In 157 patients, the native aortic valve was preserved, 75 underwent aortic valve replacement (valved conduit 49, aortic allograft 16, mechanical prosthesis 8 and bioprosthesis 2). Thirty-, 60- and 90-day mortalities were 18.1% (n = 42), 19.8% (n = 46) and 21.6% (n = 50), and decreased over time. Thirty-day mortality in the period 2007-11 was 12.5%. During follow-up of hospital survivors (mean duration 7.2 years, range 0.2-25.7 years), 64 patients died. Risk factors for 30-day mortality were preoperative resuscitation and longer cardiopulmonary bypass time. The use of circulatory arrest and biological glue was associated with a lower 30-day mortality. Actuarial survival was 53.4% (95% confidence interval [CI] 45.8-61.0%) after 10 and 29.3% (95% CI 29.9-48.7%) after 15 years. Late survival was comparable for patients with preserved native valves versus patients with various types of valve replacement. Forty-three patients underwent 47 reoperations; for aortic valve insufficiency in 17 patients (12 native valve, 5 allograft), recurrent aortic dissections or aneurysms in 27 and other cardiac operations in 3 . Actuarial freedom from aortic valve reoperation at 10 years was 85.6% for patients with a preserved native aortic valve, 84.8% after allograft implantation and 100% after prosthetic replacement (Tarone-Ware test P = 0.13). Aortic valve preservation in patients presenting with severe aortic insufficiency was associated with an increased risk of aortic valve reoperation.nnnCONCLUSIONSnAcute type A dissection in the current era is associated with a decreasing acceptable operative mortality risk and has a satisfactory long-term survival for hospital survivors. These factors were both involved were associated with a lower 30-day mortality. A substantial proportion of patients will require reoperations on the aortic valve or the aorta.

Autograft and pulmonary allograft performance in the second post-operative decade after the Ross procedure: insights from the Rotterdam Prospective Cohort Study

AIMSnThe objective of the present study was to report our ongoing prospective cohort of autograft recipients with up to 21 years of follow-up.nnnMETHODS AND RESULTSnAll consecutive patients (n = 161), operated between 1988 and 2010, were analysed. Mixed-effects models were used to assess changes in echocardiographic measurements (n = 1023) over time in both the autograft and the pulmonary allograft. The mean patient age was 20.9 years (range 0.05-52.7)-66.5% were male. Early mortality was 2.5% (n = 4), and eight additional patients died during a mean follow-up of 11.6 ± 5.7 years (range 0-21.5). Patient survival was 90% [95% confidence interval (CI), 78-95] up to 18 years. During the follow-up, 57 patients required a re-intervention related to the Ross operation. Freedom from autograft reoperation and allograft re-intervention was 51% (95% CI 38-63) and 82% (95% CI 71-89) after 18 years, respectively. No major changes were observed over time in autograft gradient, and allograft gradient and regurgitation. An initial increase of sinotubular junction and aortic anulus diameter was observed in the first 5 years after surgery. The only factor associated with an increased autograft reoperation rate was pre-operative pure aortic regurgitation (AR) (hazard ratio 1.88; 95% CI 1.04-3.39; P= 0.037).nnnCONCLUSIONnWe observed good late survival in patients undergoing autograft procedure without reinforcement techniques. However, over half of the autografts failed prior to the end of the second decade. The reoperation rate and the results of echocardiographic measurements over time underline the importance of careful monitoring especially in the second decade after the initial autograft operation and in particular in patients with pre-operative AR.

Reported Outcome After Valve-Sparing Aortic Root Replacement for Aortic Root Aneurysm: A Systematic Review and Meta-Analysis

Valve-sparing aortic root techniques have progressively gained ground in the treatment of aortic root aneurysm and aortic insufficiency. By avoiding anticoagulation therapy they offer a good alternative to composite graft replacement. This systematic review describes the reported outcome of valve-sparing aortic root replacement, focusing on the remodeling and reimplantation technique. A systematic literature search on the characteristics of and outcomes after valve-sparing aortic root replacement revealed 1,659 articles. The inclusion criteria were a focus on valve-sparing aortic root replacement in adults with aortic root aneurysm, presentation of survival data, and inclusion of at least 30 patients. Data were pooled by inverse variance weighting and analyzed by linear regression. Of 1,659 articles published between January 1, 2000, and January 1, 2014, 31 were included (n = 4,777 patients). The mean age at operation was 51 ± 14.7 years, and 14% of patients had a bicuspid aortic valve. The reimplantation technique was used in 72% and remodeling in 27% (1% other). No clinical advantage in terms of survival and reoperation of one technique over the other was found. Cusp repair was performed in 33%. Pooled early mortality was 2% (n = 103). During follow-up (21,716 patient-years), 262 patients died (survival 92%), and 228 (5%) underwent reoperation, mainly valve replacement. Major adverse valve-related events were low (1.66% patient-years). Preoperative severe aortic valve regurgitation showed a trend toward higher reoperation rate. Remodeling and reimplantation techniques show comparable survival and valve durability results, providing a valid alternative to composite valve replacement. The heterogeneity in the data underlines the need for a collaborative effort to standardize outcome reporting.

Trends and outcomes of valve surgery: 16-year results of Netherlands Cardiac Surgery National Database

OBJECTIVESnThe aim was to describe procedural volumes, patient risk profile and outcomes of heart valve surgery in the past 16 years in Netherlands.nnnMETHODSnThe Dutch National Database for Cardio-Thoracic Surgery includes approximately 200 000 cardiac operations performed between 1995 and 2010. Information on all valve surgeries (56 397 operations) was extracted. We determined trends for changes in procedural volume, demographics, risk profile and in-hospital mortality of valve operations. Because of incomplete data in the first years of registration, the total number of operations in those years was estimated using Poisson regression. For a subset from 2007 to 2010, follow-up data were available. Survival status was obtained through linkage with the national Cause of Death Registry, and survival analysis was performed using Kaplan-Meier method. Information on discharge and readmissions was obtained from the National Hospital Discharge Registry.nnnRESULTSnThe annual volume of heart valve operations increased by more than 100% from an estimated 2431 in 1995 to 5906 in 2010. Adjusted for population size in Netherlands, the number of operations per 100 000 adults increased from 20 in 1995 to 43 in 2010. In 2010, frequently performed valve surgery included the following: 34.6% isolated aortic valve (AoV) replacement, 21.8% AoV replacement and coronary artery bypass grafting (CABG), 14.6% isolated mitral valve surgery (repair or replacement) and 9.1% mitral valve and CABG. In AoV surgery, an increasing use of bioprostheses in all age categories is observed. In mitral valve surgery, 75.4% was performed by repair rather than replacement in 2010. In-hospital mortality for all valve surgery decreased significantly from 4.6% in 2007 to 3.6% in 2010, whereas the mean logistic EuroSCORE remained stable (median 5.8, P = 1.000). Thirty-day mortality after all valve surgery was 3.9% and 120-day mortality was 6.5%. At 1 year, survival after all valve surgery was 91.6% and a reoperation had been performed in 1.6%. The median postoperative length of stay was 7 days (interquartile range (IQR) 5-11) in the primary hospital and 11 days (IQR 8-16), including subsequent stay, in the secondary hospital.nnnCONCLUSIONSnThe results of this study provide a comprehensive overview of valve surgery trends and outcomes in Netherlands. The number of heart valve operations performed in Netherlands has increased since 1995. The significant decrease in mortality and unchanged EuroSCORE between 2007 and 2010 might reflect a general improvement of the safety of valve surgery.

Bentall Procedure: A Systematic Review and Meta-Analysis

BACKGROUNDnThe Bentall procedure is considered the gold standard in the treatment of patients requiring aortic root replacement. An up-to-date overview of outcomes after the Bentall procedure is lacking.nnnMETHODSnWe conducted a systematic review and meta-analysis of characteristics of and long-term outcome after the Bentall procedure with a mechanical valve prosthesis. Pooling was performed using the inverse variance method within a random-effects model. Outcome events are reported as linearized occurrence rates (percentage per patient year) with 95% confidence intervals.nnnRESULTSnIn total, 46 studies with 7,629 patients (mean age, 50 years; 76% men) were selected. Pooled early mortality was 6% (422 patients). During a mean follow-up of 6 years (49,175 patient-years), the annual linearized occurrence rate for late mortality was 2.02% (1.77%- 2.31%; 892 patients), for aortic root reoperation it was 0.46% (0.36%-0.59%), for hemorrhage it was 0.64% (0.47%-0.87%), for thromboemboli it was 0.77% (0.60%-1.00%), for endocarditis it was 0.39% (0.33%-0.46%), and for major adverse valve-related events it was 2.66% (2.17%-3.24%). Operations performed in more recent years were associated with lower rates of aortic root reoperation (betaxa0= -0.452; pxa0= 0.015).nnnCONCLUSIONSnThis systematic review illustrates that rates of aortic root reoperation after the Bentall procedure have decreased over the years. However, late mortality, major bleeding, and thromboembolic complications remain a concern. This report may be used to benchmark the potential therapeutic benefit of novel surgical approaches, such as valve-sparing aortic root replacement.

Aortic root reoperations after pulmonary autograft implantation.

OBJECTIVEnTo report the results of aortic root reoperations after pulmonary autograft implantation.nnnMETHODSnAll consecutive patients in our prospective Ross research database were selected for analysis, and additional information for patients requiring reoperation was obtained from the hospital records.nnnRESULTSnFrom 1988 to 2009, 155 pulmonary autograft operations were performed. During this period, 41 patients required reoperation for aortic root dilatation and/or autograft valve insufficiency, in 8 patients combined with pulmonary allograft dysfunction. The freedom from autograft reoperation rate was 86% (standard error, 3.3%) after 10 years and 52% (standard error, 6.6%) after 15 years. The median interval to reoperation was 15.3 years. During reoperation, 39 patients underwent aortic root replacement (mechanical conduit, 31; stentless root, 2; allograft, 3; and valve sparing, 3), and 2 patients underwent valve replacement. In 8 patients this was combined with pulmonary allograft replacement. The technical difficulties encountered included bleeding at the sternal re-entry in 5 patients. No 30-day mortality occurred. The postoperative complications included reexploration for persistent blood loss in 3 patients and cerebrovascular accident in 3 patients. Two patients died during the follow-up period. The survival rate after reoperation was 94% (standard error, 4.1%) at 5 years.nnnCONCLUSIONSnAn increasing number of patients requires reoperation after pulmonary autograft implantation. These reoperations can be done with very low mortality and morbidity and excellent follow-up results.

Re-operations for aortic allograft root failure: experience from a 21-year single-center prospective follow-up study §

OBJECTIVEnThe study aims to report results of re-operations after aortic allograft root implantation.nnnMETHODSnAll consecutive patients in our prospective allograft database, who underwent aortic allograft root implantation, were selected for analysis, and additional information for patients who subsequently underwent re-operation was obtained from hospital records.nnnRESULTSnFrom 1989 to 2009, 262 aortic allograft root implantations were performed. Thirty-day mortality was 5.7%. During follow-up, 69 patients died. The actuarial survival was 77.0% (95% confidence interval (CI) 71-83%) after 10 years, and 65.1% (95% CI 57-74%) after 14 years. A total of 52 patients required re-operation. The actuarial freedom from allograft re-operation was 82.9% (Standard Error (SE) 2.9%) after 10 years and 55.7% (SE 5.7%) after 14 years. The actuarial median time to re-operation was 14.8 years. The indications for re-operation were structural valve dysfunction in 46 patients, endocarditis in two patients and non-structural valve dysfunction in four patients. The re-operations included 23 aortic valve replacements (mechanical prostheses 20 and bioprostheses 3), 27 aortic root replacements (mechanical conduits 21, aortic allografts five, and biological conduit one), one trans-apical valve implantation and one primary closure of a false aneurysm. The additional procedures were mitral valve repair (N = 5), mitral valve replacement (N = 1), ascending aortic replacement (N = 5), and coronary artery bypass grafting (CABG) (N = 4; in two patients unforeseen). Thirty-day mortality after re-operation occurred in two patients (3.9%). Five patients died during follow-up. The survival after re-operation was 87.1% (SE 5.5%) after 1 year and 79.3% (SE 7.4%) after 9 years.nnnCONCLUSIONSnRe-operations after aortic allograft root implantation will be required in a substantial and growing number of patients. These re-operations, although technically demanding, can be performed with satisfying results.

Autograft or allograft aortic valve replacement in young adult patients with congenital aortic valve disease

AIMSnWe analysed the outcome of young adults with congenital aortic valve disease who underwent allograft or autograft aortic valve or root replacement in our institution and evaluated whether there is a preference for either valve substitute.nnnMETHODS AND RESULTSnBetween 1987 and 2007, 169 consecutive patients with congenital aortic valve disease aged 16-55, participating in our ongoing prospective follow-up study, underwent 63 autograft and 106 allograft aortic valve replacements (AVRs). Mean age was 35 years (SD 10.8), 71% were males. Aetiology was 71% bicuspid valve, 14% other congenital, and 15% BV endocarditis. Twenty-two percent underwent previous cardiac surgery; 11% had an ascending aorta aneurysm. Two patients died in hospital. During follow-up six more patients died and 45 patients required valve-related re-operations. Thirteen-year survival was 97% for autograft and 93% for allograft recipients, 13 year freedom from valve-related re-operation was 63% for autograft and 69% for allograft patients.nnnCONCLUSIONnIn patients with congenital aortic valve disease, autograft and allograft AVR show comparable satisfactory early and long-term results, with the increasing re-operation risk in the second decade after operation remaining a major concern.