Aart Brutel de la Rivière

Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures.

Human embryonic stem cells (hESCs) can differentiate into cardiomyocytes, but the efficiency of this process is low. We routinely induce cardiomyocyte differentiation of the HES‐2 cell line by coculture with a visceral endoderm‐like cell line, END‐2, in the presence of 20% fetal calf serum (FCS). In this study, we demonstrate a striking inverse relationship between cardiomyocyte differentiation and the concentration of FCS during HES‐2‐END‐2 coculture. The number of beating areas in the cocultures was increased 24‐fold in the absence of FCS compared with the presence of 20% FCS. An additional 40% increase in the number of beating areas was observed when ascorbic acid was added to serum‐free cocultures. The increase in serum‐free cocultures was accompanied by increased mRNA and protein expression of cardiac markers and of Isl1, a marker of cardiac progenitor cells. The number of beating areas increased up to 12 days after initiation of coculture of HES‐2 with END‐2 cells. However, the number of α‐actinin–positive cardiomyocytes per beating area did not differ significantly between serum‐free cocultures (503 ± 179; mean ± standard error of the mean) and 20% FCS cocultures (312 ± 227). The stimulating effect of serum‐free coculture on cardiomyocyte differentiation was observed not only in HES‐2 but also in the HES‐3 and HES‐4 cell lines. To produce sufficient cardiomyocytes for cell replacement therapy in the future, upscaling cardiomyocyte formation from hESCs is essential. The present data provide a step in this direction and represent an improved in vitro model, without interfering factors in serum, for testing other factors that might promote cardiomyocyte differentiation.

Acute Aortic Dissection Complicating Pregnancy

BACKGROUND Acute aortic dissection occurring during pregnancy represents a lethal risk to both the mother and fetus. Our purpose was to study the prevalence, treatments, and outcome of this rare problem and to suggest therapeutic guidelines. METHODS During the past 12 years, 6 pregnant women were admitted with an acute aortic dissection. Four had a type A and 2 had a type B dissection (Stanford classification). RESULTS Two of the 4 patients with a type A dissection underwent a combined emergency operation consisting of first cesarean section and then ascending aortic repair. Cesarean section was carried out 5 days after the emergency procedure on the aorta in the third patient, and 16 weeks later in the fourth patient. All 4 fetuses were delivered alive. One fetus died 6 days later, but the other 3 are alive and well at long-term follow-up. Of the 2 patients with a type B dissection, 1 was operated on for celiac ischemia; the other was treated medically. In both cases the fetus died in utero. There were no maternal deaths in either group. CONCLUSIONS Cesarean section with concomitant aortic repair is recommended for pregnant women with a type A dissection, depending on the gestational age. The maternal hemodynamic status will determine the sequence of the two procedures. Medical treatment is advised for patients with a type B dissection, but surgical repair is indicated if complications such as bleeding or malperfusion of major side branches occur.

Exercise Performance in Patients With End-Stage Heart Failure After Implantation of a Left Ventricular Assist Device and After Heart Transplantation An Outlook for Permanent Assisting?

OBJECTIVES We sought to study exercise capacity at different points in time after left ventricular assist device (LVAD) implantation and subsequent heart transplantation (HTx). BACKGROUND The lack of donor organs warrants alternatives for transplantation. METHODS Repeat treadmill testing with respiratory gas analysis was performed in 15 men with a LVAD. Four groups of data are presented. In group A (n = 10), the exercise capacities at 8 weeks and 12 weeks after LVAD implantation were compared. In group B (n = 15), the data at 12 weeks are presented in more detail. In group C (n = 9), sequential analysis of exercise capacity was performed at 12 weeks after LVAD implantation and at 12 weeks and one year after HTx. In group D, exercise performance one year after HTx in patients with (n = 10) and without (n = 20) a previous assist device was compared. RESULTS In group A, peak oxygen consumption (Vo2) increased from 21.3+/-3.8 to 24.2+/-4.8 ml/kg body weight per min (p < 0.003), accompanied by a decrease in peak minute ventilation/ carbon dioxide production (VE/Vco2) (39.4+/-10.1 to 36.3+/-8.2; p < 0.03). In group B, peak Vo2 12 weeks after LVAD implantation was 23.0+/-4.4 ml/kg per min. In group C, levels of peak Vo2 12 weeks after LVAD implantation and 12 weeks and one year after HTx were comparable (22.8+/-5.3, 24.6+/-3.3 and 26.2+/-3.8 ml/kg per min, respectively; p = NS). In group D, there appeared to be no difference in percent predicted peak Vo2 in patients with or without a previous LVAD (68+/-13% vs. 74+/-15%; p < 0.37), although, because of the small numbers, the power of this comparison is limited (0.45 to detect a difference of 10%). CONCLUSIONS Exercise capacity in patients with a LVAD increases over time; 12 weeks after LVAD implantation, Vo2 is comparable to that at 12 weeks and one year after HTx. Previous LVAD implantation does not seem to adversely affect exercise capacity after HTx.

Transplantation of cells for cardiac repair.

The inability of adult cardiomyocytes to divide to a significant extent and regenerate the myocardium after injury leads to permanent deficits in the number of functional cells, which can contribute to the development and progression of heart failure. The transplantation of skeletal myoblasts or stem cells or cardiomyocytes derived from them into the injured myocardium is a novel and promising approach in the treatment of cardiac disease and the restoration of myocardial function. In this article, skeletal myoblasts and embryonic and bone marrow stem cells are discussed in the context of their potential therapeutic use in cardiac failure. The state of the art in both laboratory and clinic is presented. We discuss current and intrinsic limitations of cardiac cellular transplantation and suggest directions for future research.

Mitral valve surgery and atrial fibrillation: is atrial fibrillation surgery also needed?

OBJECTIVE Atrial fibrillation (AF) persisting after mitral valve surgery reduces survival due to heart failure and thrombo-embolisms, and impairs quality of life. Arrhythmia surgery for AF shows today very satisfying results and therefore mitral valve surgery with AF surgery appears appealing. This study explores whether combined surgery in view of todays results of mitral valve surgery is indicated. METHODS AND RESULTS An outcome analysis of the arrhythmia outcome of patients undergoing exclusive mitral valve surgery with or without tricuspid repair was done. Preoperative baseline characteristics including arrhythmia pattern, surgical methods and follow-up findings were reviewed. Postoperative management of AF was not protocolized. Between 1990 and 1993, 162 consecutive patients underwent mitral valve surgery; follow-up was a mean of 3.3+/-1.9 years. In-hospital and late mortality were 1 and 9%, respectively. Sinus rhythm was preserved in 40 of 57 (70%) patients with preoperative sinus rhythm whereas AF persisted in 58 of 68 (85%) of patients with preoperative chronic AF (>1 year present). Sinus rhythm without AF was observed in 10 of 29 (34%) patients with preoperative paroxysmal AF. The 4-year Kaplan-Meier survival did not differ between patients with preoperative sinus rhythm (95.2%), paroxysmal AF (89.2%) and chronic AF (82.9%) but AF persisting after surgery tended to determine survival (P=0.05). Gender, age and right ventricular pressure and tricuspid valve repair were risk factors for postoperative recurrence of AF in patients with sinus rhythm at discharge, relative risk 0.35, 1.06, 1. 04 and 2.9, respectively. CONCLUSION Current mitral valve surgery with or without tricuspid valve repair does not eliminate preoperative paroxysmal or chronic AF. Secondly, because preoperative AF did not determine survival after mitral valve surgery, whereas postoperatively persisting AF was weakly associated with survival, atrial arrhythmia surgery primarily aims to reduce morbidity due to AF. Some characteristics can identify patients with increased propensity for persisting AF after surgery. Randomized studies of AF surgery are needed to identify suitable candidates for combined surgery.

Results of Maze Surgery for Lone Paroxysmal Atrial Fibrillation

BACKGROUND If drug refractoriness to paroxysmal atrial fibrillation (PAF) occurs, arrhythmia surgery that involves channelling and the exclusion of specific atrial areas can abolish atrial fibrillation. The purpose of this study was to establish the effectiveness and safety of maze III surgery to abolish PAF. METHODS AND RESULTS Surgery was performed in 41 selected patients who had long-standing, symptomatic, drug-refractory, lone PAF. At discharge, 35 patients (85%) were arrhythmia free, and 6 patients (15%) showed PAF and paroxysmal atrial tachycardia. Death or stroke did not occur during a mean follow-up of 31+/-16 months. At the end of follow-up, 39 patients (95%) had no PAF; however, in 2 patients (5%), PAF persisted and eventually required His bundle ablation and pacing. Three months after surgery, nodal escape rhythm was observed in only 1 patient, whereas sick-sinus syndrome emerged late after surgery in 2 patients. Antiarrhythmic drugs were used in 20% of patients during follow-up. The quality of life improved markedly after surgery and remained unchanged afterward. Echocardiographic findings did not alter, but exercise capacity increased. CONCLUSIONS This pilot study demonstrates the effectiveness and safety of maze III surgery for lone PAF. In patients without sick-sinus syndrome, this intervention offers a sensible alternative to His bundle ablation and lifelong pacemaker dependency.

Survival in resected stage I lung cancer with residual tumor at the bronchial resection margin

BACKGROUND Sometimes microscopic residual tumor is found at the bronchial resection margin despite an apparently complete resection of lung cancer. This may adversely affect the patients prognosis. Its impact on survival is unclear. METHODS The records of 834 patients with resected stage I non-small cell lung cancer were studied. Patients with complete resection were assigned to the complete resection group (n = 802); patients with microscopic residual tumor at the bronchial resection margin that was accepted were assigned to the residual tumor group (n = 23). Residual tumor was classified as carcinoma in situ, mucosal residual disease, or peribronchial residual disease. RESULTS The 5-year survival in the patients in the complete resection group was 54%; it was 58% in the residual tumor group with carcinoma in situ and 27.3% in the residual tumor group with invasive tumor (mucosal residual disease or peribronchial residual disease). The difference in survival between patients in the complete resection group and patients in the residual tumor group with invasive tumor was significant (p = 0.03). CONCLUSIONS The presence of mucosal or peribronchial residual disease, but not carcinoma in situ, at the bronchial resection margin in patients with stage I non-small cell lung cancer has an adverse effect on survival.

Allograft aortic root replacement in prosthetic aortic valve endocarditis: a review of 32 patients.

BACKGROUND This study was conducted to evaluate allograft aortic root replacement in the setting of complicated prosthetic valve endocarditis with extensive annular destruction. METHODS From January 1990 through March 1996, 32 patients diagnosed with complicated prosthetic valve endocarditis underwent allograft root replacement. Mean age was 58.3 +/- 13.2 years; 23 patients were men. Mean preoperative New York Heart Association functional class was 3.4. Staphylococcus epidermidis (50%) and Enterococcus faecalis (19%) were the predominant causative microorganisms. Annular abscesses were found in 26 patients (81%), aortic-mitral discontinuity in 14 patients (43%), and left ventricular-aortic discontinuity in 11 patients (34%). A cryopreserved allograft was used in 31 patients (97%) and a fresh antibiotic-treated allograft was used in 1 patient (3%). Mean aortic cross-clamp time was 150 +/- 29 minutes. Mean duration of the postoperative antibiotic treatment was 38.5 +/- 11.8 days. RESULTS There were three operative deaths (9.4%); causes of death were multiorgan failure in 2 patients (6.2%) and low cardiac output in 1 patient (3.2%). Six patients (18%) had complete heart block (4 patients already before the operation), 3 patients (9.4%) had temporary respiratory insufficiency, and 1 patient (3.2%) needed temporary hemodialysis. Mean follow-up was 37.4 +/- 22.4 months. Two late deaths occurred: 1 patient had recurrent endocarditis, leading to a false aneurysm, and died at reoperation; another patient died of lung cancer. Actuarial 5-year survival was 87.3% (70% confidence interval, 76.8% to 97.8%); actuarial 5-year freedom from recurrent endocarditis was 96.5% (70% confidence interval, 90.0% to 100%). CONCLUSIONS Allograft aortic root replacement is a valuable technique in the complex setting of prosthetic valve endocarditis with involvement of the periannular region. Mortality and morbidity are low.

Long-term survival after bronchial sleeve resection: univariate and multivariate analyses.

BACKGROUND Long-term results after bronchial sleeve resection remain controversial, especially in relation to nodal involvement. In a previous report, there were no 10-year survivors among patients with N1 or N2 disease. METHODS From 1960 to 1989, 145 patients underwent bronchial sleeve resection for a bronchogenic tumor. Follow-up was updated until the end of 1994, so the minimum follow-up was 5 years for surviving patients. A univariate analysis and a multivariate analysis were performed. RESULTS For the whole group, 5-year, 10-year, and 15-year survival rates were 46%, 33%, and 22%, respectively. The median survival time was 53 months. Five-year and 10-year survival rates for the 71 patients with no disease were 62% and 51%, respectively; for the 58 patients with N1 disease, 31% and 10%; and for the 16 patients with N2 disease, 5-year and 7-year survival rates were 31% and 13%. There was a highly significant difference in survival between patients with no and N1 or N2 disease but not between those with N1 and N2 disease. Multivariate analysis showed only nodal stage and patient age to be significant factors in relation to survival. CONCLUSIONS Long-term results after bronchial sleeve resection are influenced chiefly by nodal stage. A significantly lower survival is found in patients with N1 and N2 disease, and most of these patients die of distant metastases.

A 23-year experience with composite valve graft replacement of the aortic root.

BACKGROUND This is a retrospective study of early and long-term results of composite valve graft replacement of the aortic root. METHODS AND RESULTS Between July 1974 and July 1997, 244 patients underwent aortic root replacement with a composite valve graft. Mean age was 54+/-15 years. The inclusion technique was used in 178 patients (73.0%), the open technique in 65 (26.5%), and the Cabrol II technique in 1 patient (0.5%). Hospital mortality was 7.8% (70% confidence limit, 6.1% to 9.5%). Independent determinants of hospital mortality were preoperative creatinine level more than 150 micromol/L (p = 0.04), prolonged cardiopulmonary bypass time (p = 0.006), intraoperative technical problems (p = 0.048), and year of operation (p = 0.015). Follow-up was 99.6% complete, median 96 months (range, 2 to 256 months). Fifty-seven patients (25.3%; 70% confidence limit, 22.4% to 28.2%) died during follow-up. Cumulative survival at 5, 10, and 20 years was 76%, 62%, and 33%. Independent risk factors for late death were postoperative complications (p = 0.027), technique for coronary reattachment (p = 0.028), and concomitant aortic arch operation (p = 0.01). Twenty patients (8.8%; 70% confidence limit, 7.0% to 10.6%) underwent reoperation on the aortic root. Estimated freedom from reoperation for pseudoaneurysms at 3 years was 96% in the inclusion group and 94% in the open group (p = 0.236). CONCLUSIONS Aortic root replacement with a composite valve graft can be performed with low hospital mortality and morbidity. Pseudoaneurysms did occur in the inclusion group, but also in the open group.