Relationship of Atherosclerotic Plaque Structure with the History of COVID-19 in Patients Undergoing Coronary Computed Tomographic Angiography.

Although there is no sign of reinfection, individuals who have a history of coronavirus disease 2019 (COVID-19) may experience prolonged chest discomfort and shortness of breath on exertion. This study aimed to examine the relationship between atherosclerotic coronary plaque structure and COVID-19. This retrospective cohort comprised 1269 consecutive patients who had coronary computed tomographic angiography (CCTA) for suspected coronary artery disease (CAD) between July 2020 and April 2021. The type of atherosclerotic plaque was the primary outcome. Secondary outcomes included the severity of coronary stenosis as determined via the Coronary Artery Disease-Reporting and Data System (CAD-RADS) classification and the coronary artery calcium (CAC) score. To reveal the relationship between the history of COVID-19 and the extent and severity of CAD, propensity score analysis and further multivariate logistic regression analysis were performed. The median age of the study population was 52 years, with 53.5% being male. COVID-19 was present in 337 individuals. The median duration from COVID-19 diagnosis to CCTA extraction was 245 days. The presence of atherosclerotic soft plaque (OR: 2.05, 95% confidence interval [CI]: 1.32-3.11, P = 0.001), mixed plaque (OR: 2.48, 95% CI: 1.39-4.43, P = 0.001), and high-risk plaque (OR: 2.75, 95% CI: 1.98-3.84, P < 0.001) was shown to be linked with the history of COVID-19 on the conditional multivariate regression analysis of the propensity-matched population. However, no statistically significant association was found between the history of COVID-19 and the severity of coronary stenosis based on CAD-RADS and CAC score. We found that the history of COVID-19 might be associated with coronary atherosclerosis assessed via CCTA.

Computed tomography and nuclear medicine for the assessment of coronary inflammation: clinical applications and perspectives.

There is increasing evidence that in patients with atherosclerotic cardiovascular disease (ASCVD) under optimal medical therapy, a persisting dysregulation of the lipid and glucose metabolism, associated with adipose tissue dysfunction and inflammation, predicts a substantial residual risk of disease progression and cardiovascular events. Despite the inflammatory nature of ASCVD, circulating biomarkers such as high-sensitivity C-reactive protein and interleukins may lack specificity for vascular inflammation. As known, dysfunctional epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) produce pro-inflammatory mediators and promote cellular tissue infiltration triggering further pro-inflammatory mechanisms. The consequent tissue modifications determine the attenuation of PCAT as assessed and measured by coronary computed tomography angiography (CCTA). Recently, relevant studies have demonstrated a correlation between EAT and PCAT and obstructive coronary artery disease, inflammatory plaque status and coronary flow reserve (CFR). In parallel, CFR is well recognized as a marker of coronary vasomotor function that incorporates the haemodynamic effects of epicardial, diffuse and small-vessel disease on myocardial tissue perfusion. An inverse relationship between EAT volume and coronary vascular function and the association of PCAT attenuation and impaired CFR have already been reported. Moreover, many studies demonstrated that 18F-FDG PET is able to detect PCAT inflammation in patients with coronary atherosclerosis. Importantly, the perivascular FAI (fat attenuation index) showed incremental value for the prediction of adverse clinical events beyond traditional risk factors and CCTA indices by providing a quantitative measure of coronary inflammation. As an indicator of increased cardiac mortality, it could guide early targeted primary prevention in a wide spectrum of patients. In this review, we summarize the current evidence regarding the clinical applications and perspectives of EAT and PCAT assessment performed by CCTA and the prognostic information derived by nuclear medicine.

Elevated FAI Index of Pericoronary Inflammation on Coronary CT Identifies Increased Risk of Coronary Plaque Vulnerability after COVID-19 Infection.

Inflammation is a key factor in the development of atherosclerosis, a disease characterized by the buildup of plaque in the arteries. COVID-19 infection is known to cause systemic inflammation, but its impact on local plaque vulnerability is unclear. Our study aimed to investigate the impact of COVID-19 infection on coronary artery disease (CAD) in patients who underwent computed tomography angiography (CCTA) for chest pain in the early stages after infection, using an AI-powered solution called CaRi-Heart®. The study included 158 patients (mean age was 61.63 ± 10.14 years) with angina and low to intermediate clinical likelihood of CAD, with 75 having a previous COVID-19 infection and 83 without infection. The results showed that patients who had a previous COVID-19 infection had higher levels of pericoronary inflammation than those who did not have a COVID-19 infection, suggesting that COVID-19 may increase the risk of coronary plaque destabilization. This study highlights the potential long-term impact of COVID-19 on cardiovascular health, and the importance of monitoring and managing cardiovascular risk factors in patients recovering from COVID-19 infection. The AI-powered CaRi-Heart® technology may offer a non-invasive way to detect coronary artery inflammation and plaque instability in patients with COVID-19.

The potential role of SARS-CoV-2 infection in acute coronary syndrome and type 2 myocardial infarction (T2MI): Intertwining spread.

Coronavirus disease 2019 (COVID-19) is a novel pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has been shown that SARS-CoV-2 infection-induced inflammatory and oxidative stress and associated endothelial dysfunction may lead to the development of acute coronary syndrome (ACS). Therefore, this review aimed to ascertain the link between severe SARS-CoV-2 infection and ACS. ACS is a spectrum of acute myocardial ischemia due to a sudden decrease in coronary blood flow, ranging from unstable angina to myocardial infarction (MI). Primary or type 1 MI (T1MI) is mainly caused by coronary plaque rupture and/or erosion with subsequent occlusive thrombosis. Secondary or type 2 MI (T2MI) is due to cardiac and systemic disorders without acute coronary atherothrombotic disruption. Acute SARS-CoV-2 infection is linked with the development of nonobstructive coronary disorders such as coronary vasospasm, dilated cardiomyopathy, myocardial fibrosis, and myocarditis. Furthermore, SARS-CoV-2 infection is associated with systemic inflammation that might affect coronary atherosclerotic plaque stability through augmentation of cardiac preload and afterload. Nevertheless, major coronary vessels with atherosclerotic plaques develop minor inflammation during COVID-19 since coronary arteries are not initially and primarily targeted by SARS-CoV-2 due to low expression of angiotensin-converting enzyme 2 in coronary vessels. In conclusion, SARS-CoV-2 infection through hypercytokinemia, direct cardiomyocyte injury, and dysregulation of the renin-angiotensin system may aggravate underlying ACS or cause new-onset T2MI. As well, arrhythmias induced by anti-COVID-19 medications could worsen underlying ACS.

Study of common hypertriglyceridaemia genetic variants and subclinical atherosclerosis in a group of women with SLE and a control group.

OBJECTIVE: SLE is associated with increased cardiovascular risk (CVR). High serum concentrations of triglyceride-rich lipoproteins and apolipoprotein B-rich particles constitute the characteristic dyslipidaemia of SLE. METHODS: A cross-sectional study was conducted to study the relationship between genetic variants involved in polygenic hypertriglyceridaemia, subclinical atherosclerosis and lipoprotein abnormalities. 73 women with SLE and 73 control women age-matched with the case group were recruited (age range 30-75 years). Serum analysis, subclinical atherosclerosis screening studies for the detection of plaque, and genetic analysis of the APOE, ZPR1, APOA5 and GCKR genes were performed. RESULTS: Triglyceride concentrations and the prevalence of hypertension, dyslipidaemia and carotid atherosclerosis were higher in women with SLE than in the control group. Multivariate logistic regression showed that CC homozygosity for the GCKR rs1260326 gene (OR=0.111, 95% CI 0.015 to 0.804, p=0.030) and an increase of 1 mmol/L in triglyceride concentrations were associated with a greater risk of carotid plaque in women with SLE (OR=7.576, 95% CI 2.415 to 23.767, p=0.001). CONCLUSIONS: GCKR CC homozygosity (rs1260326) and serum triglyceride concentrations are independently associated with subclinical carotid atherosclerosis in women with SLE. Subclinical carotid atherosclerosis is also more prevalent in these women compared with the control group. The study of GCKR rs1260326 gene variants may contribute to more precise assessment of CVR and modulation of the intensity of lipid-lowering treatment in patients with SLE.

Measurement of epicardial adipose tissue using non-contrast routine chest-CT: a consideration of threshold adjustment for fatty attenuation.

BACKGROUND: Epicardial adipose tissue (EAT) is known as an important imaging indicator for cardiovascular risk stratification. The present study aimed to determine whether the EAT volume (EV) and mean EAT attenuation (mEA) measured by non-contrast routine chest CT (RCCT) could be more consistent with those measured by coronary CT angiography (CCTA) by adjusting the threshold of fatty attenuation. METHODS: In total, 83 subjects who simultaneously underwent CCTA and RCCT were enrolled. EV and mEA were quantified by CCTA using a threshold of (N30) (- 190 HU, - 30 HU) as a reference and measured by RCCT using thresholds of N30, N40 (- 190 HU, - 40 HU), and N45 (- 190 HU, - 45 HU). The correlation and agreement of EAT metrics between the two imaging modalities and differences between patients with coronary plaques (plaque ( +)) and without plaques (plaque ( -)) were analyzed. RESULTS: EV obtained from RCCT showed very strong correlation with the reference (r = 0.974, 0.976, 0.972 (N30, N40, N45), P < 0.001), whereas mEA showed a moderate correlation (r = 0.516, 0.500, 0.477 (N30, N40, N45), P < 0.001). Threshold adjustment was able to reduce the bias of EV, while increase the bias of mEA. Data obtained by CCTA and RCCT both demonstrated a significantly larger EV in the plaque ( +) group than in the plaque ( -) group (P < 0.05). A significant difference in mEA was shown only by RCCT using a threshold of N30 (plaque ( +) vs ( -): - 80.0 ± 4.4 HU vs - 78.0 ± 4.0 HU, P = 0.030). The mEA measured on RCCT using threshold of N40 and N45 showed no significant statistical difference between the two groups (P = 0.092 and 0.075), which was consistent with the result obtained on CCTA (P = 0.204). CONCLUSION: Applying more negative threshold, the consistency of EV measurements between the two techniques improves and a consistent result can be obtained when comparing EF measurements between groups, although the bias of mEA increases. Threshold adjustment is necessary when measuring EF with non-contrast RCCT.

Safety and feasibility study of non-invasive robot-assisted high-intensity focused ultrasound therapy for the treatment of atherosclerotic plaques in the femoral artery: protocol for a pilot study.

INTRODUCTION: Peripheral arterial disease (PAD) is an atherosclerotic disease leading to stenosis and/or occlusion of the arterial circulation of the lower extremities. The currently available revascularisation methods have an acceptable initial success rate, but the long-term patency is limited, while surgical revascularisation is associated with a relatively high perioperative risk. This urges the need for development of less invasive and more effective treatment modalities. This protocol article describes a study investigating a new non-invasive technique that uses robot assisted high-intensity focused ultrasound (HIFU) to treat atherosclerosis in the femoral artery. METHODS AND ANALYSIS: A pilot study is currently performed in 15 symptomatic patients with PAD with a significant stenosis in the common femoral and/or proximal superficial femoral artery. All patients will be treated with the dual-mode ultrasound array system to deliver imaging-guided HIFU to the atherosclerotic plaque. Safety and feasibility are the primary objectives assessed by the technical feasibility of this therapy and the 30-day major complication rate as primary endpoints. Secondary endpoints are angiographic and clinical success and quality of life. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained in 2019 from the Medical Ethics Committee of the University Medical Center Utrecht, the Netherlands. Data will be presented at national and international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL7564.

Deficiency of B vitamins leads to cholesterol-independent atherogenic transformation of the aorta (preprint)

Background: Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in-vivo models of atherosclerosis that resemble the human situation. Methods: : Aortic specimens obtained from balloon injured rabbits fed either diet deficient in B vitamins, supplemented with 1% cholesterol or combined diet were subjected to ex vivo MRI, myographical, biomechanical, microscopical and histological analysis. Lipoproteins were analyzed by FPLC. Findings: We developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development even at low balloon pressure. Already in the absence of hypercholesterolemia, B vitamin deficiency results in accumulation of macrophages and lipids in the aorta, impairment of its biomechanical properties and disorganization of aortic collagen. Combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity of the aorta. Interpretation: Our findings suggest that deficiency of B vitamins leads to atherosclerotic transformation of the aorta already in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence. Funding This work was funded by the Austrian Science Fund (FWF) (Projects P31105 and P33672), the EU project NanoAthero and BioTechMed-Graz.

Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self.

BACKGROUND: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. METHODS: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. RESULTS: In addition to macrophages, we found a high proportion of αß T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αß T cells (CD4

Lung Opacity and Coronary Artery Calcium Score: A Combined Tool for Risk Stratification and Outcome Prediction in COVID-19 Patients.

PURPOSE: To assess and correlate pulmonary involvement and outcome of SARS-CoV-2 pneumonia with the degree of coronary plaque burden based on the CAC-DRS classification (Coronary Artery Calcium Data and Reporting System). METHODS: This retrospective study included 142 patients with confirmed SARS-CoV-2 pneumonia (58 ± 16 years; 57 women) who underwent non-contrast CT between January 2020 and August 2021 and were followed up for 129 ± 72 days. One experienced blinded radiologist analyzed CT series for the presence and extent of calcified plaque burden according to the visual and quantitative HU-based CAC-DRS Score. Pulmonary involvement was automatically evaluated with a dedicated software prototype by another two experienced radiologists and expressed as Opacity Score. RESULTS: CAC-DRS Scores derived from visual and quantitative image evaluation correlated well with the Opacity Score (r=0.81, 95% CI 0.76-0.86, and r=0.83, 95% CI 0.77-0.89, respectively; p<0.0001) with higher correlation in severe than in mild stage SARS-CoV-2 pneumonia (p<0.0001). Combined, CAC-DRS and Opacity Scores revealed great potential to discriminate fatal outcomes from a mild course of disease (AUC 0.938, 95% CI 0.89-0.97), and the need for intensive care treatment (AUC 0.801, 95% CI 0.77-0.83). Visual and quantitative CAC-DRS Scores provided independent prognostic information on all-cause mortality (p=0.0016 and p<0.0001, respectively), both in univariate and multivariate analysis. CONCLUSIONS: Coronary plaque burden is strongly correlated to pulmonary involvement, adverse outcome, and death due to respiratory failure in patients with SARS-CoV-2 pneumonia, offering great potential to identify individuals at high risk.

Non-invasive coronary imaging in patients with COVID-19: A narrative review.

SARS-CoV-2 infection, responsible for COVID-19 outbreak, can cause cardiac complications, worsening outcome and prognosis. In particular, it can exacerbate any underlying cardiovascular condition, leading to atherosclerosis and increased plaque vulnerability, which may cause acute coronary syndrome. We review current knowledge on the mechanisms by which SARS-CoV-2 can trigger endothelial/myocardial damage and cause plaque formation, instability and deterioration. The aim of this review is to evaluate current non-invasive diagnostic techniques for coronary arteries evaluation in COVID-19 patients, such as coronary CT angiography and atherosclerotic plaque imaging, and their clinical implications. We also discuss the role of artificial intelligence, deep learning and radiomics in the context of coronary imaging in COVID-19 patients.

Aortic vulnerability to COVID-19: is the microvasculature of vasa vasorum a key factor? A case report and a review of the literature.

Arterial thromboembolic complications reported in patients with COVID-19 infection suggested that SARS-CoV-2 can trigger atherosclerotic plaque vulnerability. While endothelial cells in healthy subjects protect against thrombus formation, after injury they show prothrombotic activity. In addition, it has been hypothesized that "cytokine storm" might stimulate the production of neo-platelets triggering an abnormal "immunothrombosis" responsible for the hypercoagulable state induced in COVID-19 patients. The aim of this study is to report a case of severe COVID-19 infection characterized by the occurrence of microthrombosis in the vasa vasorum of the aorta. A 67-year-old male patient, in good health status and without comorbidities, who underwent a severe COVID-19 infection with fatal outcome, showed scattered aortic atherosclerotic plaques, characterized by multiple occlusive micro-thromboses in the vasa vasorum, spread out lymphocytic infiltrates and foci of endotheliitis and endothelial detachment. This case report confirms the previously described thrombotic involvement of vasa vasorum in COVID-19. The occurrence of the synchronous damage involving both the lumen surface (endothelial dysfunction, endotheliitis and endothelial detachment) and the adventitia (inflammation and occlusive thrombosis of vasa vasorum) could be the key points related to the fatal outcome of the SARS-CoV-2 patients. In our opinion, vasa vasorum thrombosis may thus initiate an atherogenic process that could be characterized by a much more rapid development.

Coronavirus disease 2019 and stroke.

The multisystem nature of coronavirus disease 2019 has become increasingly clear over the course of the pandemic. Both the neurological and vascular systems are affected, impacting acute stroke. This impact can be conceptualised as direct and indirect effects of the disease. The direct effects of coronavirus disease 2019 on stroke are thought to relate to receptor-mediated tissue invasion and the marked inflammatory response to the presence of the virus. These effects include coagulopathies, endotheliitis, systemic inflammation and atherosclerotic plaque instability, with possibly long-term cardiovascular effects. The indirect effects impact all aspects of stroke care delivery. These extend far beyond the direct effects of coronavirus disease 2019, and represent an essential focus for stroke systems of care. In this article, we detail the impact of coronavirus disease 2019 on acute stroke.

The Delivery of Nitric Oxide in the Cardiovascular System: Implication for Clinical Diagnosis and Therapy (preprint)

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of Coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in cardiovascular system, the clinical applications centered on the NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process based on the clinical images and mathematical modeling to assess the endothelial function and vulnerability of atherosclerotic plaque. Then, the emerging bioimaging technologies that have the potential to directly measure the arterial NO concentration were discussed, including the Raman spectroscopy and electrochemical sensor. Aside from the diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the inhaled NO therapy to treat the pulmonary hypertension and COVID-19, stem cell therapy and NO-releasing platform to treat endothelial dysfunction and atherosclerosis.

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease.

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient's immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.

Acute Viral Illnesses and Ischemic Stroke: Pathophysiological Considerations in the Era of the COVID-19 Pandemic.

The severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the correlation with this viral illness and increased risk of stroke. Although it is too early in the pandemic to know the strength of the association between COVID-19 and stroke, it is an opportune time to review the relationship between acute viral illnesses and stroke. Here, we summarize pathophysiological principles and available literature to guide understanding of how viruses may contribute to ischemic stroke. After a review of inflammatory mechanisms, we summarize relevant pathophysiological principles of vasculopathy, hypercoagulability, and hemodynamic instability. We will end by discussing mechanisms by which several well-known viruses may cause stroke in an effort to inform our understanding of the relationship between COVID-19 and stroke.

Role of vitamin D in the pathogenesis of atheromatosis.

BACKGROUND AND AIMS: Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE-/- mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability. METHODS AND RESULTS: In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet administration. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease. CONCLUSIONS: The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies.

COVID-19-convalescence phase unmasks a silent myocardial infarction due to coronary plaque rupture.

Increased risk of cardiovascular complications during and post-COVID-19 infection is more and more recognized-including myocarditis, arrhythmias, and myocardial infarctions (MIs). The mechanisms leading to these complications are direct virus-induced injuries, as well as potential thrombotic and inflammatory-induced mechanisms. To the latter, inflammatory plaque instability and plaque rupture are discussed entities contributing to MI-induced post-COVID-19 complications. Our case report describes the first time, when a temporary impairment of LVEF in the COVID-19-convalescence phase unmasks a silent MI due to coronary plaque rupture by using invasive (OCT) and non-invasive (CMR) modalities. Myocardial infarction might be an important differential diagnosis to consider in deteriorating patients with COVID-19, especially if dyspnoea persists after acute infection.

Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque.

BACKGROUND: Immune checkpoint inhibitors (ICIs) 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 2-year period after and the control period as the 2-year period before 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. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. 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 (hazard ratio, 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 2 years (adjusted hazard ratio, 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%/y before 6.7%/y after). 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 before, during, and after treatment should be considered among patients on an ICI.