L.A. van Herwerden

Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in absence of atopy

Asthma is a manifestation of bronchial hyperreactivity (BHR) and forms part of the spectrum of atopic disease. Some pedigree studies of atopy have suggested linkage with the high-affinity IgE receptor (Fc epsilon RI beta) gene on chromosome 11q13, but others find no linkage. The molecular genetics of asthma and BHR have not been studied in the general population. We examined the genetic linkage of the Fc epsilon RI beta gene with clinical asthma and the underlying phenotypes of BHR (to methacholine) and atopy (defined by skinprick testing) in 123 affected sibling-pairs recruited from the general population. We found evidence of significant linkage of a highly polymorphic microsatellite marker in the fifth intron of the Fc epsilon RI beta gene to a diagnosis of asthma (18.0% excess of shared alleles, p = 0.002) and to BHR (21.7% excess of shared alleles, p = 0.001). Significant linkage was also observed in siblings sharing BHR when those with atopy were excluded (32.8% excess of shared alleles, p = 0.004). Atopy in the absence of BHR did not show significant linkage to the Fc epsilon RI beta gene (7.2% excess of shared alleles, p = 0.124). These findings suggest that mutations in the Fc epsilon RI beta gene or a closely linked gene influence the BHR underlying asthma, even in the absence of atopy.

Prognosis after aortic valve replacement with a bioprosthesis: predictions based on meta-analysis and microsimulation

BackgroundBioprostheses are widely used as an aortic valve substitute, but knowledge about prognosis is still incomplete. The purpose of this study was to provide insight into the age-related life expectancy and actual risks of reoperation and valve-related events of patients after aortic valve replacement with a porcine bioprosthesis. Methods and ResultsWe conducted a meta-analysis of 9 selected reports on stented porcine bioprostheses, including 5837 patients with a total follow-up of 31 874 patient-years. The annual rates of valve thrombosis, thromboembolism, hemorrhage, and nonstructural dysfunction were 0.03%, 0.87%, 0.38%, and 0.38%, respectively. The annual rate of endocarditis was estimated at 0.68% for >6 months of implantation and was 5 times as high during the first 6 months. Structural valve deterioration was described with a Weibull model that incorporated lower risks for older patients. These estimates were used to parameterize, calibrate, and validate a mathematical microsimulation model. The model was used to predict life expectancy and actual risks of reoperation and valve-related events after implantation for patients of different ages. For a 65-year-old male, these figures were 11.3 years, 28%, and 47%, respectively. ConclusionsThe combination of meta-analysis with microsimulation enabled a detailed insight into the prognosis after aortic valve replacement with a bioprosthesis for patients of different ages. This information will be useful for patient counseling and clinical decision making. It also could serve as a baseline for the evaluation of newer valve types.

Risk of strut fracture of Björk-Shiley valves

The incidence of and factors that predispose to outlet strut fracture of Björk-Shiley heart valves are still not known. To obtain such information a retrospective cohort study was conducted on all 2303 patients in the Netherlands with a 60 degrees convexo-concave (60 degrees CC) or a 70 degrees convexo-concave (70 degrees CC) Björk-Shiley heart valve. Patients have been followed-up for a mean of 6.6 years (range 1-4271 days). 42 cases of mechanical failure due to outlet strut fracture have been recorded-6 of the 7 patients with fracture of the aortic valve died, as did 18 of the 35 patients with fracture of the mitral valve. Multivariate analysis identified wide opening angle (70 degrees), large valve size (greater than or equal to 29 mm diameter), and young age (less than 50 years) as risk factors for outlet strut fracture. For large 70 degrees CC mitral valves the cumulative risk of outlet strut fracture after 8 years was 17.4% (95% CI 9.1-31.6). Unlike previous findings, this excessive risk applied to late as well as to early batches of valves. In patients with a large 60 degrees CC mitral valve the cumulative risk after 8 years was 4.2% (95% CI 2.7-6.5). The incidence rate of outlet strut fracture in 60 degrees CC and 70 degrees CC valves (aortic and mitral) was constant over time. Overall survival since implantation was better for patients with 60 degrees CC prostheses than for those with 70 degrees CC prostheses; the adjusted hazard ratio for mortality for patients receiving a 70 degrees CC prosthesis was 1.5 (95% CI 1.1-2.0). Together with the low (24%) necropsy rate, this ratio suggests that the reported incidence of strut fracture for the 70 degrees CC valves is an underestimate. The data indicate that prophylactic replacement of 60 degrees CC and 70 degrees CC valves is advisable for selected groups of patients. Since the case-fatality rate is 50% for emergency replacement of faulty valves, patients suspected of Björk-Shiley heart-valve failure should be referred without delay to a cardiothoracic centre.

Comparison of outcomes after aortic valve replacement with a mechanical valve or a bioprosthesis using microsimulation

Background: Mechanical valves and bioprostheses are widely used for aortic valve replacement. Though previous randomised studies indicate that there is no important difference in outcome after implantation with either type of valve, knowledge of outcomes after aortic valve replacement is incomplete. Objective: To predict age and sex specific outcomes of patients after aortic valve replacement with bileaflet mechanical valves and stented porcine bioprostheses, and to provide evidence based support for the choice of prosthesis. Methods: Meta-analysis of published results of primary aortic valve replacement with bileaflet mechanical prostheses (nine reports, 4274 patients, and 25 726 patient-years) and stented porcine bioprostheses (13 reports, 9007 patients, and 54 151 patient-years) was used to estimate the annual risks of postoperative valve related events and their outcomes. These estimates were entered into a microsimulation model, which was employed to calculate age and sex specific outcomes after aortic valve replacement. Results: Life expectancy (LE) and event-free life expectancy (EFLE) for a 65 year old man after implantation with a mechanical valve or a bioprosthesis were 10.4 and 10.7 years and 7.7 and 8.4 years, respectively. The lifetime risk of at least one valve related event for a mechanical valve was 48%, and for a bioprosthesis, 44%. For LE and EFLE, the age crossover point between the two valve types was 59 and 60 years, respectively. Conclusions: Meta-analysis based microsimulation provides insight into the long term outcome after aortic valve replacement and suggests that the currently recommended age threshold for implanting a bioprosthesis could be lowered further.

Evolution of allograft aortic valve replacement over 13 years: Results of 275 procedures

OBJECTIVE We describe our centers experience with the use of allografts for aortic valve or root replacement, illustrating the impact on outcome of the changes made in surgical and preservation techniques. METHODS Between 4/1987 and 1/2001 275 allografts were used in 267 consecutive patients to replace the aortic valve or root. All patients were prospectively followed over time. Mean patient age was 46 years (SD 16; range 0.06-83), male/female ratio was 201/74. Prior cardiac operations took place in 73 patients; 49 patients presented with active endocarditis. Pre-operative NYHA-class was III in 51%. Initially, the subcoronary technique was used (SC; N=95) while in recent years root replacement (ARR; N=180) became the technique of choice. Seven fresh (two pulmonary and five aortic) and 268 cryopreserved (four pulmonary and 264 aortic; 35 glycerol and 233 DMSO) allografts were implanted. Concomitant procedures took place in 133 (48%). RESULTS Operative mortality was 5.5% (N=15) and during follow-up (99% complete) 29 more patients died. Overall cumulative survival was 73% (95% CI 65-81%) at 9 years postoperative and significantly better for SC compared to ARR patients (P=0.005). Freedom from allograft-related reoperation (N=34) was 77% (95% CI 69-85) at 9 years, and worse in the SC compared to ARR group due to increased early technical failure (P=0.03). Freedom from reoperation for structural valve deterioration (SVD; N=22) was 81% (95% CI 73-89) at 9 years and did not differ between SC and ARR (P=0.51). Independent predictors of degenerative SVD were younger patient age (HR 0.93 with age as continuous variable; 95% CI 0.90-0.97), older donor age (HR 1.06 with age as a continuous variable; 95% CI 1.00-1.11), larger allograft diameter (HR 1.38; 95% CI 1.11-1.71) and the use of pulmonary allografts (HR 10.72; 95% CI 3.88-29.63). Calculated median time to reoperation for structural valve deterioration ranged from 23 years in a 65-year-old patient to 12 years in a 25-year-old. CONCLUSIONS Aortic valve replacement with allografts yields adequate midterm results. Although important changes have been made over the years to improve durability, allografts still have a limited life span especially in young patients.

Age thresholds for prophylactic replacement of Björk-Shiley convexo-concave heart valves. A clinical and economic evaluation.

BackgroundBjork-Shiley convexo-concave heart valves have an increased risk of mechanical failure. One might consider prophylactic rereplacement as a preventive measure to avert the disastrous consequences of these failures. We investigated the effect that prophylactic rereplacement has on survival of individual patients and on the medical costs. Methods and ResultsQuantitative estimates for the surgical risks of prophylactic replacement of Bjork-Shiley valves, long-term survival, and the risk of outlet strut fracture were derived insofar as possible from a detailed analysis of a follow-up study conducted in The Netherlands, including 2303 patients with a mean follow-up of 6.6 years. On the basis of these estimates, we calculated life expectancy with and without prophylactic replacement. For the various valve types, age thresholds were determined below which rereplacement prolongs (discounted quality-adjusted) life expectancy. We also calculated the cost per year of life gained as a function of age. The age thresholds below which prophylactic rereplacement increases life expectancy (expressed in simple future years of life) for male patients without comorbidity, if the surgical mortality after rereplacement is equivalent to that of primary replacement, are 27, 48, 51, and 65 years for small and large 60° and for small and large 700 mitral valves, respectively. For aortic valves, these age thresholds lie somewhat higher 39, 52, 56, and 76 years, respectively. Repeat analyses indicated that for women, all age thresholds lie about 1 or 2 years higher. These age thresholds decrease considerably if the surgical mortality after rereplacement is considered to be higher after prophylactic rereplacement than after primary replacement or if comorbidity is present. The costs per discounted and quality-adjusted year of life gained depend on type and position of the Bjork-Shiley convexo-concave heart valve and rise steeply as the patients age approaches the threshold for rereplacement. ConclusionsThe results of the Dutch follow-up study allow guidance for prophylactic replacement of the Bjork-Shiley convexo-concave valve on an individual basis. Rereplacement compares favorably with expectant management in some patient subgroups with both 600 and 700 valves. Age thresholds may serve as a first step in identifying patients in whom rereplacement might be beneficial.

Single-leg strut fractures in explanted Björk-Shiley valves

A retrospective follow-up study in the Netherlands on the risk of fracture of Björk-Shiley convexo-concave valves concluded that prophylactic replacement is advisable for certain groups of patients. We have examined valves explanted from twenty-two patients because they met epidemiological criteria for reoperation, with or without the presence of moderate cardiac impairment, or because there were other cardiac complaints not related to the valve. No information was available before explanation to suggest a valve defect. All patients survived their operations. Of the twenty-four valves, seven (29% [95% CI 13-52]) had fracture of one of the legs of the outlet strut (single-leg strut fracture [SLF]). Two other valves had features that suggested fatigue defects. As in the previous study, 70 degrees valves had the highest risk of SLF (five of sixteen, two aortic and three mitral). However, two of eight 60 degrees valves (both aortic) also had SLF. Current hazard calculations and explanation recommendations may need to be revised. Since several of the defective valves were welded by the same person, knowledge of manufacturing details may help in estimation of fracture risk for an individual patient.

Allograft reconstruction of the right ventricular outflow tract.

OBJECTIVE Evaluation of allograft reconstruction of the right ventricular outflow tract (RVOT). METHODS From 1986 to April 1995, 201 allografts (146 pulmonary, 55 aortic) were implanted in 189 patients for conduit reconstruction of the RVOT in congenital heart disease or in the pulmonary autograft procedure. The mean age at allograft implantation was 16 years (range 2 weeks - 54 years). The primary diagnoses of these patients were truncus arterious (n = 19, 10%), transposition of the great arteries (TGA) with ventricular septal defect (VSD) and pulmonary atresia (PA) or stenosis (PS) (n = 14, 7%), PA with VSD (n = 26, 14%), PA or PS with intact septum (n = 7, 4%), tetralogy of Fallot (n = 44, 23%), corrected TGA with PA or PS (n = 11, 6%), tricuspid atresia (n = 9, 5%), aortic valve pathology for pulmonary autograft procedure (n = 55, 29%), and miscellaneous (n = 4, 2%). The allograft implantation was a reoperation in 54 patients (29%). RESULTS The mean follow-up was 2.5 years (range 4 weeks-9 years). Six patients died in hospital (3.2%). Patient survival at 5 years was 91% (95% CL 86-95%). Freedom from all valve-related events (2 deaths, 17 reoperations, one endocarditis), as determined during reoperation or autopsy at 5 years was 78% (95% CL 65-86%). Freedom from structural allograft failure was 83% (2 deaths, 12 reoperations, 95% CL 70-90%). Allografts implanted for congenital right heart defects failed earlier than allografts used for pulmonary autograft procedures (P = 0.05). Aortic allografts showed structural failure more often than pulmonary allografts (P = 0.05). There were more valve-related events in patients of a younger age at implantation (P = 0.02) and in those allograft valves from younger donors (P = 0.004). CONCLUSIONS Allograft RVOT reconstruction is an adequate surgical therapy. The allograft should preferably be pulmonary. A younger age at implantation is a risk factor for allograft failure. Donor age may be a thus-far underestimated risk factor for allograft degeneration.

Short-term and 5-year outcome after primary isolated coronary artery bypass graft surgery: results of risk stratification in a bilocation center

OBJECTIVE We retrospectively investigated the short and mid-term outcome of non-emergent primary isolated coronary artery bypass graft (CABG) surgery in relation to risk stratification in the fully equipped university location (FE) and the low volume, limited facility location (LVLF) of our department. METHODS Between September 1995 and December 1996, 832 patients were referred to our department to undergo a primary isolated CABG operation. The surgical team selected 482 patients (58%) as being at low-risk. These were treated in the LVLF hospital. The other 350 patients with mixed-risk were treated in the FE hospital. The selection consisted primarily of exclusion of patients with moderate or poor left ventricular function, severe COPD or renal impairment, from surgery in the LVLF location. Finally, the prognostic value of the EuroSCORE and the Parsonnet score was tested on our patient population. RESULTS Overall in-hospital mortality was 1.6% (13 patients). One patient died in the LVLF group (0.2%) and 12 patients (3.4%) in the FE group. LVLF patients experienced less complications during the hospital period compared to the FE patients (5 versus 21%; P=0.0001). The Parsonnet risk model and the EuroSCORE risk model showed both a good relation with in-hospital mortality. After discharge, an increased risk of late mortality was observed up to 1 year postoperative in the FE group compared to the LVLF group (2.7 versus 0.5%; P=0.01). Risk factors for 5-year mortality were pre-operative renal impairment (blood creatinine >150 micromol/l) (hazard ratio (HR): 2.8; 95% confidence interval (CI): 1.4-5.5), diabetes (HR: 2.1; 95% CI: 1.3-3.5), impaired LVEF (HR: 1.9; 95% CI: 1.2-3.0), COPD (HR: 1.9; 95% CI: 1.1-3.5) and older age (HR: 1.07 per year; 95% CI: 1.01-1.10). Lipid-lowering therapy was a predictor of lower mortality at 5-years (HR: 0.5; 95% CI: 0.4-0.9). CONCLUSION By careful decision making, selection of low-risk patients for a low volume and limited facility location resulted in excellent in-hospital survival with very low complication rates.

Determinants of survival after surgery for mitral valve regurgitation in patients with and without coronary artery disease

Mortality and its determinants were assessed in 181 consecutive patients undergoing primary mitral valve surgery for pure mitral regurgitation with coronary artery disease (MR + CAD, 79 patients) or without (MR no CAD, 102 patients). Early mortality (C10% vs. 3%) and 6-year estimate of survival (55% +/- 7.1% vs. 82% +/- 4.4%) were significantly different. Mortality was not significantly different in patients with CAD + MR of an ischemic (49 patients) or a non-ischemic etiology (30 patients). Multivariate testing using Cox regression models of overall mortality in patients with MR + CAD indicated that preoperative renal dysfunction, high right atrial pressure, ejection fraction less than 45% as well as qualitatively reduced left ventricular function and left ventricular end-diastolic volume index greater than 120 ml/m2 are associated with decreased survival. Multivariate testing in patients with MR no CAD only identified insertion of a mechanical prosthesis and a degenerative etiology of mitral valve disease as independent predictors of survival. Thus, a common denominator of preoperative pathology (renal dysfunction) and indices of right and left ventricular dysfunction determined overall survival of patients with MR + CAD. Survival of patients with MR no CAD was determined by the valve prosthesis and the etiology of valve disease.