Marrotte, Eric J.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

The mechanisms underlying regenerative function of endothelial progenitor cells (EPCs) are not completely understood. Since previous studies from several groups including ours suggest that biosynthesis of NO in EPCs is low, the present study was designed to determine ability of EPCs to produce and release prostacyclin (PGI 2 ). Outgrowth (“late”) EPCs were obtained from peripheral blood of healthy subjects. Enzymatic activity of eNOS was significantly lower in EPCs as compared to eNOS activity in human coronary endothelial cells (CAECs) (n=4‐6 subjects, P<0.05). In contrast, production and release of PGI 2 was four fold higher in EPCs as compared to CAECs (n=3, P<0.05). This was associated with significantly higher expression of cyclooxygenase‐1 (COX‐1) protein in EPCs whereas levels of COX‐2 protein were not different between progenitor and mature endothelial cells. Production of thromboxane A 2 and prostaglandin E 2 were low and identical in EPCs and CAECs. Most importantly, inhibition of COX isoforms with indomethacin impaired pro‐angiogenic effect of EPCs as assessed by in vitro tube formation assay (n=4‐6, P<0.05). Cell proliferation was also significantly reduced after inhibition of COX isoforms with indomethacin or inactivation of PGI 2 ‐synthase by siRNA (n=4‐6, P<0.05). Our findings suggest that production and release PGI 2 is an important mechanism contributing to regenerative capability of EPCs.