Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque

Abstract

Background: Immune checkpoint inhibitors (ICI) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events. Methods: The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls, matched by age, a history of cardiovascular events and cancer type. In a second design, a case-crossover analysis was performed with an "at-risk period" defined as the two-year period after and the "control period" as the two-year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated. Results: In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 3.3 [95% CI, 2.0-5.5]; P <0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at two years (adjusted HR, 4.8 [95% CI, 3.5-6.5]; P <0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids. Conclusions: Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI.

Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity

“…Whether the acute coronary syndrome was coincidental or secondary to ICI therapy is unknown; however, given the role of checkpoint proteins in plaque stabilization, we suspect it is related. Additionally, recent study showed that use of ICIs is associated with an increase in myocardial infarction rate as well as atherosclerotic plaque progression by computed tomography [ 34 ]. In our study, of the 15 patients with elevated troponin, 7 had a left heart catheterization (LHC) to exclude ischemia.…”

CD8+ T Cells in Atherosclerosis

“…The combined treatment of mice with immune checkpoint inhibitors targeting both PD-1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), or CTLA inhibition alone, increased both CD4 + effector T cell and CD8 + cytotoxic T cell numbers in the arterial wall of hyperlipidemic mice [ 93 ]. A recent clinical study furthermore demonstrated that cardiovascular events were higher after initiation of immune checkpoint inhibitor treatment, potentially mediated by accelerated progression of atherosclerosis [ 94 ]. The exact contribution of CD4 + versus CD8 + T cells to the proatherogenic effects of immune checkpoint inhibitors is still unclear, but understanding their specific roles in mediating vascular inflammation and injury may help to design strategies to antagonize these effects in patients treated with checkpoint inhibitors in cancer therapy.…”

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis

“… 3 6–10 There are several potential cardiac adverse effects associated with ICIs but the focus on myocarditis is due to the morbidity and mortality associated with that diagnosis. 11 12 Specifically, data from multiple groups report a mortality ranging from 17% to 50%. 3 6 7 13 In comparison, the mortality of non-ICI myocarditis is far less than 5%.…”