Patients at elevated cardiovascular risk are prone to perioperative cardiovascular complications, like myocardial injury after non-cardiac surgery (MINS). We have demonstrated in a mouse model of atherosclerosis that perioperative stress leads to an increase in plaque volume and higher plaque vulnerability. Regulatory T cells (Tregs) play a pivotal role in development and destabilization of atherosclerotic plaques. For this exploratory post-hoc analysis we identified 40 patients recruited into a prospective perioperative biomarker study, who within the inclusion period underwent sequential open vascular surgery. On the basis of protein markers measured in the biomarker study, we evaluated the perioperative inflammatory response in patients' plasma before and after index surgery as well as before and after a second surgical procedure. We also analyzed available immunohistochemistry samples to describe plaque vulnerability in patients who underwent bilateral carotid endarterectomy (CEA) in two subsequent surgical procedures. Finally, we assessed if MINS was associated with sequential surgery. The inflammatory response of both surgeries was characterized by postoperative increases of interleukin-6,−10, Pentraxin 3 and C-reactive protein with no clear-cut difference between the two time points of surgery. Plaques from CEA extracted during the second surgery contained less Tregs, as measured by Foxp3 staining, than plaques from the first intervention. The 2nd surgical procedure was associated with MINS. In conclusion, we provide descriptive evidence that sequential surgical procedures involve repeat inflammation, and we hypothesize that elevated rates of cardiovascular complications after the second procedure could be related to reduced levels of intraplaque Tregs, a finding that deserves confirmatory testing and mechanistic exploration in future populations.

Introduction: Vascular surgery patients are at risk of myocardial injury after non-cardiac surgery (MINS) associated with perioperative mortality. Underlying mechanisms are largely unknown. In animal models surgery combined with blood loss promotes atherosclerotic lesion progression and plaque destabilization. It is unknown whether repetitive surgery contributes to cardiac risk in patients. Hypothesis: Repetitive surgical procedures in vascular surgery patients are associated with increased MINS rates. Methods: With IRB approval, after obtaining informed consent, pre- and day-1 post-operative (OP) plasma samples were collected from 663 patients undergoing elective aortic-, peripheral vascular or carotid surgery. High-sensitive cardiac troponin T (hs-cTNT) (Roche) was measured pre- and post-OP. Additional 3 rd generation cTnT or hs-cTNT measurements were prompted on clinical suspicion for acute coronary syndrome. MINS was defined as any new (delta ≥50%) hs-cTNT ≥50 ng/L or 3 rd gen. cTnT >0.03 ng/mL. Data are presented as median (inter quartile range (IQR)) and were compared using Wilcoxon matched-pairs signed tank test. Incidence of the combined endpoint between 1 st and 2 nd surgeries was compared using one-sided chi square test. p<0.05 was considered significant. Results: We identified 40 patients with two repetitive surgical procedures. For 37 patients pre- and post-OP blood samples were available. Median time between surgeries was 53 (43.5-208) days. There were no statistical differences in pre-OP medication or risk factors. Pre-OP hs-cTNT values were slightly higher prior to the 2 nd procedure (1 st vs. 2 nd procedure, 11.2 (6.6-19.9) vs 12.6 (7.9-31.3) ng/l, n=37, p<0.05). One patient experienced MINS after the 1 st surgery. Five patients reached the endpoint after the 2 nd procedure (1 st vs 2 nd procedure, n=37, p<0.05). Conclusions: In vascular patients repetitive surgery is associated with myocardial injury. The underlying mechanisms need to be examined in more detail. However, clinicians should recognize the elevated cardiovascular risk associated with repetitive operations. Among other things, prophylactic strategies for prevention of perioperative cardiac events should focus on patients undergoing repetitive operations.