Frontline Science: Low regulatory T cells predict perioperative major adverse cardiovascular and cerebrovascular events after noncardiac surgery

Abstract

Immune cells drive atherosclerotic lesion progression and plaque destabilization. Coronary heart disease patients undergoing noncardiac surgery are at risk for perioperative major adverse cardiac and cerebrovascular events (MACCE). It is unclear whether differential leukocyte subpopulations contribute to perioperative MACCE and thereby could aid identification of patients prone to perioperative cardiovascular events. First, we performed a hypothesis-generating post hoc analysis of the LeukoCAPE-1 study (n = 38). We analyzed preoperative counts of 6 leukocyte subpopulations in coronary heart disease patients for association with MACCE (composite of cardiac death, myocardial infarction, myocardial ischemia, myocardial injury after noncardiac surgery, thromboembolic stroke) within 30 d after surgery. Regulatory T cells (Tregs) were the only leukocyte subgroup associated with MACCE. We found reduced Tregs in patients experiencing MACCE versus no-MACCE (0.02 [0.01; 0.03] vs. 0.04 [0.03; 0.05] Tregs nl −1 , P = 0.002). Using Youden index, we derived the optimal threshold value for association with MACCE to be 0.027Tregs nl −1 . Subsequently, we recruited 233 coronary heart disease patients for the prospective, observational LeukoCAPE-2 study and independently validated this Treg cutoff for prediction of MACCE within 30 d after noncardiac surgery. After multivariate logistic regression, Tregs < 0.027 cells nl −1 remained an independent predictor for MACCE (OR = 2.54 [1.22; 5.23], P = 0.012).Tregs improved risk discrimination of the revised cardiac risk index based on ΔAUC (area under the curve; ΔAUC = 0.09, P = 0.02), NRI (0.26), and IDI (0.06). Preoperative Treg levels below 0.027 cells nl −1 predicted perioperative MACCE and can be measured to increase accuracy of established preoperative cardiac risk stratification in coronary heart disease patients undergoing noncardiac surgery.

Sequential Surgical Procedures in Vascular Surgery Patients Are Associated With Perioperative Adverse Cardiac Events

“…Therefore, numbers cannot be compared to histological findings in this cohort. However, our previous results (17) in connection with the current findings lead to the intriguing hypothesis that there is a connection between circulating Tregs, plaque stability and patients' outcome after surgery. Oxidative stress increases Treg apoptosis in a high fat mouse model (40) rendering this also a possible mechanism explaining the lower Treg numbers in the plaques under perioperative stress from 2nd surgery.…”

“…Low numbers of circulating Tregs are associated with atherosclerosis (39). Additionally, we have recently shown that preoperative low counts of Tregs are associated with cardiac adverse events after non-cardiac surgery (17). When looking at the atherosclerotic lesion itself, low numbers of Tregs within the plaque have been associated with plaque vulnerability (15,37).…”

“…Low numbers of regulatory T cells (Tregs) in blood, as well as in human atherosclerotic plaque, are associated with plaque vulnerability (14,15) and modulating Treg numbers in mouse models of atherosclerosis regulates progression of atherosclerotic lesion development (16). Additionally, we have recently shown that preoperative low counts of Tregs are associated with higher rates of MINS and adverse cardiovascular outcome in patients with coronary heart disease undergoing non-cardiac surgery (17).…”

Low Tregs: A targetable risk factor for life-threatening cardiovascular complications after major noncardiac surgery

“…The studies described by Scholz et al . in this issue of the Journal of Leukocyte Biology have significantly advanced our knowledge on MACCE following major noncardiac surgery, in particular the potential importance of silent cardiovascular disease (vulnerable asymptomatic atherosclerotic plaques) and the significance of Tregs.…”

“…). Importantly, Scholz et al . also provide important information on the Treg cell counts at which such effects become clinically significant.…”