Background-Bicuspid aortic valve is frequent and is reported to cause numerous complications, but the clinical outcome of patients diagnosed with normal or mildly dysfunctional valve is undefined. Methods and Results-In 212 asymptomatic community residents from Olmsted County, Minn (age, 32Ϯ20 years; 65% male), bicuspid aortic valve was diagnosed between 1980 and 1999 with ejection fraction Ն50% and aortic regurgitation or stenosis, absent or mild. Aortic valve degeneration at diagnosis was scored echocardiographically for calcification, thickening, and mobility reduction (0 to 3 each), with scores ranging from 0 to 9. At diagnosis, ejection fraction was 63Ϯ5% and left ventricular diameter was 48Ϯ9 mm. Survival 20 years after diagnosis was 90Ϯ3%, identical to the general population (Pϭ0.72). Twenty years after diagnosis, heart failure, new cardiac symptoms, and cardiovascular medical events occurred in 7Ϯ2%, 26Ϯ4%, and 33Ϯ5%, respectively. Twenty years after diagnosis, aortic valve surgery, ascending aortic surgery, or any cardiovascular surgery was required in 24Ϯ4%, 5Ϯ2%, and 27Ϯ4% at a younger age than the general population (PϽ0.0001). No aortic dissection occurred. Thus, cardiovascular medical or surgical events occurred in 42Ϯ5% 20 years after diagnosis. Independent predictors of cardiovascular events were age Ն50 years (risk ratio, 3.0; 95% confidence interval, 1.5 to 5.7; PϽ0.01) and valve degeneration at diagnosis (risk ratio, 2.4; 95% confidence interval, 1.2 to 4.5; Pϭ0.016; Ͼ70% events at 20 years). Baseline ascending aorta Ն40 mm independently predicted surgery for aorta dilatation (risk ratio, 10.8; 95% confidence interval, 1.8 to 77.3; PϽ0.01). Conclusions-In the community, asymptomatic patients with bicuspid aortic valve and no or minimal hemodynamic abnormality enjoy excellent long-term survival but incur frequent cardiovascular events, particularly with progressive valve dysfunction. Echocardiographic valve degeneration at diagnosis separates higher-risk patients who require regular assessment from lower-risk patients who require only episodic follow-up. (Circulation. 2008;117:2776-2784.)

The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62LNKG2AKIR) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.

Background-Mitral valve (MV) repair is preferred over replacement in clinical guidelines and is an important determinant of the indication for surgery in degenerative mitral regurgitation (MR). Yet, the level of evidence supporting current recommendations is low, and recent data cast doubts on its validity in the current era. Accordingly, the aim of the present study was to analyze very long-term outcome after MV repair and replacement for degenerative MR with a flail leaflet. Methods-MIDA is a multicenter registry enrolling patients with degenerative MR with a flail leaflet in 6 tertiary European and US centers. We analyzed the outcome after MV repair (n=1,709) and replacement (n= 213), overall, by propensity score matching and by inverse probability-of-treatment weighting. Results-At baseline, patients undergoing MV repair were younger, had more comorbidities and were more likely to present with a posterior leaflet prolapse than those undergoing MV replacement. After propensity score matching as well as after inverse probability-of-treatment weighting, the 2 treatments groups were balanced and absolute standardized differences were usually below 10%, indicating adequate match. Operative mortality (defined as a death occurring within 30 days from surgery or during the same hospitalization) was lower after MV repair than after replacement, both in the entire (1.3 vs 4.7%; p<0.001) and in propensity-matched population (0.2% vs 4.4%; p<0.001). During a mean follow-up of 9.2 years, 552 deaths were observed, of which 207 were of cardiovascular origin. Twenty-year survival was better after MV repair than after MV replacement, both in the entire (46% vs 23%, p<0.001) and in matched population (41% vs 24%, p<0.001). Similar superiority of MV repair were obtained in patients' subsets based on age, sex or any stratification criteria (all p<0.001). MV repair was also associated with reduced incidence of reoperations and valve-related complications.Conclusions-Among patients with degenerative MR with a flail leaflet, referred to mitral surgery, MV repair was associated with lower operative mortality, better long-term survival and fewer valve-related complications compared to MV replacement.