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

Abstract

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.

Modulation of Peripheral CD4+CD25+Foxp3+ Regulatory T Cells Ameliorates Surgical Stress-Induced Atherosclerotic Plaque Progression in ApoE-Deficient Mice

“…We recently demonstrated, that coronary artery disease patients with low preoperative Treg counts face a higher risk of major adverse cardiovascular and cerebrovascular events after non-cardiac surgery (26). We further provided evidence that increased cardiovascular risk associated to sequential surgical procedures may be due to reduced levels of intraplaque Tregs (27). Here, we explore whether preoperatively low Treg counts further accelerate perioperative destabilization of atherosclerotic plaques and whether preoperative Treg expansion has the potential to limit surgical stress-induced atherosclerosis progression.…”

Biomarkers and Cellular Biology in Perioperative Medicine

“…Surgical procedures alter tissue integrity; are associated with pain and activation of the sympathetic nervous system; and sometimes, cause exposure to foreign materials used during the surgery or implanted perioperatively. Those factors have been demonstrated to induce a number of inflammatory reactions [ 1 , 2 , 3 ]. Depending on the magnitude of such perioperative trauma, the molecular and cellular impacts on homeostasis can be tremendous and can follow a bi-phasic course with perioperative inflammatory surge as well as postoperative injury-associated immunosuppression, which occur in a significant number of patients and lead to adverse outcome [ 2 , 4 , 5 , 6 ].…”

“…Those factors have been demonstrated to induce a number of inflammatory reactions [ 1 , 2 , 3 ]. Depending on the magnitude of such perioperative trauma, the molecular and cellular impacts on homeostasis can be tremendous and can follow a bi-phasic course with perioperative inflammatory surge as well as postoperative injury-associated immunosuppression, which occur in a significant number of patients and lead to adverse outcome [ 2 , 4 , 5 , 6 ]. The use of cardiopulmonary bypass (CPB), for example, may aggravate perioperative immunosuppression.…”

Editorial: Targeting innate and adaptive immunity for improvement of cardiovascular disease

“…Atherosclerosis is the leading underlying pathology of cardiovascular disease, and shares many features with other chronic inflammatory conditions. The concept of bone marrow derived macrophages destabilizing atherosclerotic lesions has been widely accepted, and recent scientific findings have broadened our understanding on how every part of the immune system plays a role in vascular inflammation ( Chinetti-Gbaguidi et al, 2015 ; Engelen et al, 2022 ) and how stressors such as perioperative inflammation impact on atherosclerosis ( Janssen et al, 2015 ; Janssen et al, 2020 ).…”

“…

Editorial on the Research Topic Targeting innate and adaptive immunity for improvement of cardiovascular diseaseAccording to the WHO's Global Health Estimates 2019, the deleterious complications of cardiovascular disease, in particular ischemic heart disease and stroke, account for 27% of deaths worldwide, rendering it the single most detrimental disease globally.Extensive effort has been put into preventive interventions, such as anti-smoking campaigns, educational programs for dietary changes and exercise to improve overall cardiovascular health and prevent development of cardiovascular risk factors already in preschool students (Gupta and Wood, 2019;Santos-Beneit et al, 2022).Pharmacological interventions so far mainly focused on modulation of blood pressure, hyperlipidemia and glucose metabolism, as well as antithrombotic therapy, but further optimization has stalled (Arnett et al, 20192019;Fang et al, 2021).Atherosclerosis is the leading underlying pathology of cardiovascular disease, and shares many features with other chronic inflammatory conditions. The concept of bone marrow derived macrophages destabilizing atherosclerotic lesions has been widely accepted, and recent scientific findings have broadened our understanding on how every part of the immune system plays a role in vascular inflammation (Chinetti-Gbaguidi et al, 2015;Engelen et al, 2022) and how stressors such as perioperative inflammation impact on atherosclerosis (Janssen et al, 2015;Janssen et al, 2020).The CANTOS trial, published in 2017, was the first to prove that an antiinflammatory therapy by targeting interleukin-1β with a monoclonal antibody is sufficient to reduce recurrence of cardiovascular events (Ridker et al, 2017). This breakthrough was followed by promising interventions with colchicine in 2019 and

…”