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Change in body weight and activity composite score over the course of 5 months in the primary experimental protocol, chronic sepsis survival model. The analysis was performed in animals that underwent sham or cecal ligation and puncture (CLP) surgery (six per time point and nine per time point, respectively) and analyzed by two-way analysis of variance (*P < 0.001).
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IntroductionSepsis and other infections are associated with late cardiovascular events. Although persistent inflammation is implicated, a causal relationship has not been established. We tested whether sepsis causes vascular inflammation and accelerates atherosclerosis.Methods
Prospective randomized animal studies at a university research laborator...
Citations
... To date, few alternative multiple comorbidities animal models of acute pneumonia infection and atherosclerosis have been described (13,17,(42)(43)(44)(45), and a model of unstable plaque (46). In contrast to the model in the present study, these other models utilise surgical intervention (46), viral pathogens (e.g., influenza virus) (43), alternative routes of infection (e.g., intraperitoneal) that are more relevant to sepsis than pneumonia (44), intervene with antibiotics to improve mortality (13,17), or do not describe the lung pathology associated with the infectious challenge (13,17). ...
... To date, few alternative multiple comorbidities animal models of acute pneumonia infection and atherosclerosis have been described (13,17,(42)(43)(44)(45), and a model of unstable plaque (46). In contrast to the model in the present study, these other models utilise surgical intervention (46), viral pathogens (e.g., influenza virus) (43), alternative routes of infection (e.g., intraperitoneal) that are more relevant to sepsis than pneumonia (44), intervene with antibiotics to improve mortality (13,17), or do not describe the lung pathology associated with the infectious challenge (13,17). The model of the present study utilises a low infectious dose to establish infection with S. pneumoniae, the most important bacterial cause of pneumonia in humans (25,47,48), via intranasal inoculation; hence, being representative of the pneumococcal infection that is acquired via the respiratory route in humans. ...
Acute pneumonia is characterised by a period of intense inflammation. Inflammation is now considered to be a key step in atherosclerosis progression. In addition, pre-existing atherosclerotic inflammation is considered to play a role in pneumonia progression and risk. In the present study, a multiple comorbidities murine model was used to study respiratory and systemic inflammation that results from pneumonia in the setting of atherosclerosis. Firstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE -/- mice were fed a high-fat diet prior to administering intranasally 105 colony forming units of TIGR4 or phosphate-buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by magnetic resonance imaging (MRI) and positron emission tomography (PET). Mice were euthanised and investigated for changes in lung morphology and changes in systemic inflammation using ELISA, Luminex assay and real-time PCR. TIGR4-inoculated mice presented with varying degrees of lung infiltrate, pleural effusion and consolidation on MRI at all time points up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4-inoculated mice up to 28 days PI. The majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4-inoculated mice displayed significantly increased inflammatory gene expression [interleukin (IL)-1β and IL-6] in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7 and 28 days PI respectively. The mouse model developed by the authors presents a discovery tool to understand the link between inflammation related to acute infection such as pneumonia and increased risk of cardiovascular disease observed in humans.
... Survivors of severe sepsis had higher rates of cardiovascular complications, including myocardial infarction (MI), ischemic stroke (IS) and venous thromboembolism (VTE) (6)(7)(8)(9)(10). The increased risk of these post-sepsis cardiovascular complications has been attributed to a variety of pathophysiologic mechanisms, including immunoparalysis, depression of ventricular function, arrhythmia, organ ischemia related to increased oxygen demand, procoagulant changes in the blood, endothelial dysfunction, impaired adrenergic response at the cardiomyocyte level, cardiomyocyte apoptosis, mitochondrial dysfunction and accelerated atherosclerosis (11)(12)(13)(14). ...
Background:
Patients with sepsis are at increased risk for cardiovascular complications, including myocardial infarction (MI), ischemic stroke (IS), and venous thromboembolism (VTE). Our objective is to assess whether genetic risk score (GRS) can differentiate risk for these complications.
Methods:
A population-based prospective cohort of 483,177 subjects, derived from the UK Biobank, was followed for diagnosis of sepsis and its complications (MI, IS, and VTE) after the study recruitment. GRS for each complication was calculated based on established risk-associated single nucleotide polymorphisms (SNPs). Time to incident MI, IS, and VTE was compared between subjects with or without sepsis and GRS risk groups using Kaplan-Meier log-rank test and Cox-regression analysis.
Results:
During an average of 12.6 years of follow-up, 10,757 (2.23%) developed sepsis. Patients with sepsis had an overall higher risk than non-sepsis subjects for each complication, but the risk differed by time after a sepsis diagnosis; exceedingly high in short-term (0-30 days), considerably high in mid-term (31 days to 2 years), and reduced in long-term (>2 years). Furthermore, in White subjects, GRS was a significant predictor of complications, independent of sepsis and other risk factors. For example, GRSMI further differentiated their risk in patients with sepsis; 3.49, 4.73, and 9.03% in those with low- (<0.5), intermediate- (0.5-1.99), high- GRSMI (≥2.0), Ptrend < 0.001.
Conclusion:
Risk for post-sepsis cardiovascular complications differed considerably by time after a sepsis diagnosis and GRS. These findings, if confirmed in other ancestry-specific populations, may guide personalized management for preventing post-sepsis cardiovascular complications.
... Some studies found that the associated mediators may include endotoxin, inflammatory cytokines Fig. 2 The forest plot shows in-hospital mortality between septic patients with and without sepsis-induced cardiomyopathy (SIC). SIC is non-statistically associated with higher risk of in-hospital mortality among septic patients (such as tumor necrosis factor α and interleukin-1), nitric oxide, mitochondrial dysfunction, downregulation of β-adrenergic receptors, and decreasing myofibril response to calcium and histone release [6,42]. However, these mediators were mainly observed at the acute sepsis stage, and the duration of the impact of these chemical mediators and reactions on the myocardium is still arbitrary. ...
Background
The implication of sepsis-induced cardiomyopathy (SIC) to prognosis is controversial, and its association with mortality at different stages remains unclear. We conducted a systematic review and meta-analysis to understand the association between SIC and mortality in septic patients.
Methods
We searched and appraised observational studies regarding the mortality related to SIC among septic patients in PubMed and Embase from inception until 8 July 2021. Outcomes comprised in-hospital and 1-month mortality. We adopted the random-effects model to examine the mortality risk ratio in patients with and without SIC. Meta-regression, subgroup, and sensitivity analyses were applied to examine the outcome’s heterogeneity.
Results
Our results, including 20 studies and 4,410 septic patients, demonstrated that SIC was non-statistically associated with increased in-hospital mortality, compared to non-SIC (RR 1.28, [0.96–1.71]; p = 0.09), but the association was statistically significant in patients with the hospital stay lengths longer than 10 days (RR 1.40, [1.02–1.93]; p = 0.04). Besides, SIC was significantly associated with a higher risk of 1-month mortality (RR 1.47, [1.17–1.86]; p < 0.01). Among SIC patients, right ventricular dysfunction was significantly associated with increased 1-month mortality (RR 1.72, [1.27–2.34]; p < 0.01), while left ventricular dysfunction was not (RR 1.33, [0.87–2.02]; p = 0.18).
Conclusions
With higher in-hospital mortality in those hospitalized longer than 10 days and 1-month mortality, our findings imply that SIC might continue influencing the host’s system even after recovery from cardiomyopathy. Besides, right ventricular dysfunction might play a crucial role in SIC-related mortality, and timely biventricular assessment is vital in managing septic patients.
... The coagulation-promoting state associated with acute infection raises the likelihood of coronary artery thrombosis at the site of plaque breakdown even more 17,22,24) . Factors that contribute to coronary thrombosis include increased platelet activity, increased production of procoagulants, hypercoagulability, and endothelial dysfunction 10,17,[28][29][30] . AMI can also occur when the metabolic demands of myocardial cells exceed the capacity of the blood to supply oxygen. ...
Objective: The goal of this nationally matched longitudinal study was to investigate the relationship between acute myocardial infarction (AMI) and pyogenic spondylitis (PS) in Korea.Methods: We collected patient data from the National Health Insurance Service Health Screening cohort from January 1, 2004 to December 31, 2015. PS was classified using the International Classification of Diseases codes M46.2 (osteomyelitis), M46.8 (inflammatory spondylopathy), M49.2 (enterobacterial spondylitis), and M49.3 (enterobacterial spondylitis) (spondylopathy in other infectious and parasitic diseases). The PS group had a total of 628 patients. The control group included 3,140 people. Utilizing the Kaplan-Meier technique, the groups’ AMI rates were estimated. A Cox proportional-hazards regression analysis was used to compute the hazard ratio for AMI.Results: After controlling for age and sex, the hazard ratio for AMI in the PS group was 2.241 (95% confidence interval [CI], 1.112-4.516). The adjusted hazard ratio in the PS group was 2.138 after controlling for demographics and concomitant medical conditions (95% CI, 1.056-4.318). In a subgroup analysis, the AMI percentages were substantially greater in the PS group in women over 65, those with diabetes, and in non-hypertension and non-dyslipidemia subgroups. Conclusion: This nationwide longitudinal study found that PS patients had an elevated risk of AMI.
... The bacterial infection that related to AMI also include urinary tract bacterial infection [3] and bacteremia [6]. The potential mechanisms include the increasing of in ammatory activity in atheromatous plaques after an infectious stimulus [7], the augment of the risk of coronary thrombosis at sites of plaque in the prothrombotic, procoagulant state that is associated with acute bacterial infection [8,9], the up regulation of the metabolic needs of peripheral tissues and organs [10], and the cardiac lesions that are characterized by vacuolization and loss of myocytes without accumulation of in ammatory cells caused by pneumococcal bacteremia [11]. Patients with AMI usually manifest fever at admission, as well as elevation of CRP and leucocytes counts, but it does not necessarily mean that an bacterial infection is present [12,13]. ...
... Based on previous studies, Serious bacterial infection of AMI patients was not only resulted in longer hospital stay, but also associated with signi cantly higher rates of 90-day death [15]. Among the possible mechanisms is an increase in in ammation in atheromatous plaques during infection [7]. When an acute bacterial infection causes a prothrombotic, procoagulant state, the risk of coronary thrombosis increases [8,9]. ...
Background
As a trigger of acute myocardial infarction (AMI), bacterial infection usually accompanies with AMI, and will lead to worse outcomes of AMI patients. We aimed to assess the prognosis of AMI with concomitant bacterial infection and find out the best laboratory examinations to recognize it.
Methods
All patients hospitalized for an AMI in cardiology department were prospectively included. Patients were stratified into those with or without concomitant bacterial infection. Outcomes and laboratory examinations were compared between groups in unadjusted and adjusted analyses.
Results
Among the 456 patients hospitalized for AMI, 120 (26%) had a concomitant diagnosis of bacterial infection. Out-comes in hospital were worse in patients with bacterial infection (more acute heart failure: 61.7% vs. 22.6%, p < 0.001, and higher all-cause mortality in hospital: 15% vs. 3.9%, p < 0.001). In the Receiver Operating Curves (ROC) of biomarkers of AMI and concomitant bacterial infection, Areas under the Receiver Operating Curves (AUC) for c-reaction protein (CRP) and CRP to Platelet Ratio (CRP/PLA) were higher than Neutrophil to Lymphocyte Ratio (NLR) and leucocyte count. (0.852(0.81–0.89) mg/L, 0.848(0.81–0.89) *10− 9mg, p < 0.001). The sensitivity of CRP and the Specificity of CRP/PLA were the highest (80% and 88%). After adjusting for confounders, CRP/PLA (> 0.08) was associated with a fivefold increased risk of bacterial infection when compared with other biomarkers (OR (95%CI) = 5.62 (2.64–11.96), p < 0.001). CRP (> 8.05) was also associated with a higher risk of bacterial infection (OR (95%CI) = 4.02 (1.81–5.85), p = 0.001).
Conclusions
Bacterial infection will lead to worse outcomes of AMI patients, including in-hospital mortality and heart failure. It is the first time to use the CRP/PLA to distinguish AMI with concomitant bacterial infection from other AMI patients. The combination of CRP > 8.05 mg/L and CRP/PLA > 0.08*10− 9mg was the best hallmark of AMI with concomitant bacterial infection.
... Sepsis is increasingly recognized as a risk factor for new cardiovascular events, with approximately onethird of sepsis survivors hospitalized for cardiovascular complications in the year following sepsis (9)(10)(11). Animal models show that sepsis can rapidly result in atherosclerosis (12), myocardial fibrosis (13,14), and heart failure (13), similar to long-term exposure to traditional cardiovascular risk factors, but through additional mechanisms of acute inflammation-accelerated atheroma formation, direct infectious myocardial injury, and cardiac fibrosis. Importantly, the relative contributions of presepsis and intrasepsis risk factors that may predispose patients to cardiovascular events following a sepsis hospitalization are unclear. ...
... Although prior research has identified sepsis as a potential cardiovascular risk factor (9,12,27,28), few studies have evaluated the incremental value of adding sepsis characteristics as cardiovascular risk predictors. Our findings that intrasepsis factors performed as well as, or better than, presepsis cardiovascular risk predictors and that models combining presepsis and intrasepsis factors substantially improved risk prediction for postsepsis cardiovascular events, raises the possibility that specific characteristics of sepsis may play a role in cardiovascular disease progression. ...
Objectives:
Sepsis survivors face increased risk for cardiovascular complications; however, the contribution of intrasepsis events to cardiovascular risk profiles is unclear.
Setting:
Kaiser Permanente Northern California (KPNC) and Intermountain Healthcare (IH) integrated healthcare delivery systems.
Subjects:
Sepsis survivors (2011-2017 [KPNC] and 2018-2020 [IH]) greater than or equal to 40 years old without prior cardiovascular disease.
Design:
Data across KPNC and IH were harmonized and grouped into presepsis (demographics, atherosclerotic cardiovascular disease scores, comorbidities) or intrasepsis factors (e.g., laboratory values, vital signs, organ support, infection source) with random split for training/internal validation datasets (75%/25%) within KPNC and IH. Models were bidirectionally, externally validated between healthcare systems.
Interventions:
None.
Measurements and main results:
Changes to predictive accuracy (C-statistic) of cause-specific proportional hazards models predicting 1-year cardiovascular outcomes (atherosclerotic cardiovascular disease, heart failure, and atrial fibrillation events) were compared between models that did and did not contain intrasepsis factors. Among 39,590 KPNC and 16,388 IH sepsis survivors, 3,503 (8.8%) at Kaiser Permanente (KP) and 600 (3.7%) at IH experienced a cardiovascular event within 1-year after hospital discharge, including 996 (2.5%) at KP and 192 (1.2%) IH with an atherosclerotic event first, 564 (1.4%) at KP and 117 (0.7%) IH with a heart failure event, 2,310 (5.8%) at KP and 371 (2.3%) with an atrial fibrillation event. Death within 1 year after sepsis occurred for 7,948 (20%) KP and 2,085 (12.7%) IH patients. Combined models with presepsis and intrasepsis factors had better discrimination for cardiovascular events (KPNC C-statistic 0.783 [95% CI, 0.766-0.799]; IH 0.763 [0.726-0.801]) as compared with presepsis cardiovascular risk alone (KPNC: 0.666 [0.648-0.683], IH 0.660 [0.619-0.702]) during internal validation. External validation of models across healthcare systems showed similar performance (KPNC model within IH data C-statistic: 0.734 [0.725-0.744]; IH model within KPNC data: 0.787 [0.768-0.805]).
Conclusions:
Across two large healthcare systems, intrasepsis factors improved postsepsis cardiovascular risk prediction as compared with presepsis cardiovascular risk profiles. Further exploration of sepsis factors that contribute to postsepsis cardiovascular events is warranted for improved mechanistic and predictive models.
... To date, few alternative multiple comorbidities animal models of acute infection and atherosclerosis have been described (10,(20)(21)(22). In contrast to our model, these other models utilise viral pathogens (e.g., influenza virus (21) It has been proposed that the introduction of a respiratory infection leads to a mounting synergistic inflammatory response that could lead to adverse cardiovascular events . ...
... ), alternative routes of infection (eg: intraperitoneal) that are more relevant to sepsis than pneumonia(22), intervene with antibiotics to improve mortality(10), or do not describe the lung pathology associated with the infectious challenge(10,20). Our model utilises a low infectious dose to establish infection with S. pneumoniae, the most important bacterial cause of pneumonia in humans(23-25), via intranasal inoculation; hence, being representative of the pneumococcal infection that is acquired via the respiratory route in humans. ...
Background: Inflammation is a risk factor for atherosclerosis progression. Hospitalisation for pneumonia is associated with increased risk of cardiovascular disease. Herein, we describe a multiple comorbidities murine model to study the impact of bacterial pneumonia on atherosclerosis. Methods: Firstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE-/- mice were fed a high-fat diet prior to administering intranasally 105 colony forming units of TIGR4 or phosphate buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by MRI and PET. Mice were euthanised and investigated for changes in systemic inflammation and changes in lung morphology using ELISA, Luminex assay and real-time PCR. Results: TIGR4 inoculated mice presented with varying degrees of lung infiltrate, pleural effusion and consolidation on MRI at all timepoints up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4 inoculated mice up to 28 days PI. Majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4 inoculated mice displayed significantly increased inflammatory gene expression (IL-1β & IL6) in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7- and 28- days PI respectively. Conclusions: Our mouse model presents a discovery tool to understand the link between acute infections, including pneumonia, and increased cardiovascular disease risk in humans with inflammation as the mechanistic catalyst.
... The inflammatory mediators C-reactive protein and interferon-gamma were found to enhance the expression of macrophage tissue factor levels that may contribute to the hypercoagulable state in coronary disease [14]. Inflammatory cells may infiltrate the coronary bed and plaques that have disrupted surfaces, and these cells produce cytokines, proteases, and coagulation factors, which increase endothelial damage, disrupt the fibrous cap, and initiate the formation of thrombi [30,31]. Moreover, platelets can be directly activated by systemic inflammation [32]. ...
Gastroenteritis promotes the development of systemic inflammation and a hypercoagulable state. There are limited data regarding the association between gastroenteritis and acute myocardial infarction (AMI). We aimed to evaluate the risk of AMI after an episode of gastroenteritis. In this nested case-control study, we selected patients who were hospitalized for AMI (N = 103,584) as a case group during 2010-2017 and performed propensity score matching (case-control ratio 1:1) to select eligible controls from insurance research data in Taiwan. We applied multivariable logistic regressions to calculate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of AMI associated with recent gastroenteritis within 14 days before AMI. We also compared the outcomes after AMI in patients with or without gastroenteritis. A total of 1381 patients (1.3%) with AMI had a prior episode of gastroenteritis compared to 829 (0.8%) among the controls. Gastroenteritis was significantly associated with a subsequent risk of AMI (adjusted OR: 1.68, 95% CI: 1.54-1.83), which was augmented in hospitalizations for gastroenteritis (adjusted OR: 2.50, 95% CI: 1.20-5.21). The outcomes after AMI were worse in patients with gastroenteritis than in those without gastroenteritis, including increased 30-day in-hospital mortality (adjusted OR: 1.28, 95% CI: 1.08-1.52), medical expenditure, and length of hospital stay. Gastroenteritis may act as a trigger for AMI and correlates with worse post-AMI outcomes. Strategies of aggressive hydration and/or increased antithrombotic therapies for this susceptible population should be further developed.
... In mouse atherosclerosis models, Ly6C hi monocytes are predisposed to accumulating in plaques, play a key role in driving atherogenesis and are in general considered to be more in ammatory as compared to Ly6C lo monocytes (43,44). Sepsis is associated with upregulation of endothelial cell adhesion molecules including ICAM-1 and VCAM-1, and this mechanism may also contribute to the accumulation of monocytes within plaques following pneumonia (45,46). Transcriptomic analysis of plaque macrophages suggested that infection led to the differential expression of very few genes 2 weeks post pneumonia. ...
... Other limitations include not assessing the effect of pneumonia on other immune cells that may be found in plaques (including T lymphocytes and neutrophils), investigating the effect of only one S. pneumoniae serotype and only using male mice in the nal model. In contrast to our ndings, abdominal sepsis in ApoE −/− mice aged 22-24 weeks which had been fed an atherogenic diet for 16 weeks prior to infection resulted in an acceleration of atherosclerotic plaque formation over a 5 month period (45). This abdominal sepsis model further differed from ours in that atherogenic diet was continued following infection. ...
Background
Despite epidemiological associations between community acquired pneumonia (CAP) and myocardial infarction, mechanisms that modify cardiovascular disease during CAP are not well defined. In particular, largely due to a lack of relevant experimental models, the effect of pneumonia on atherosclerotic plaques is unclear. We describe the development of a murine model of the commonest cause of CAP, Streptococcus pneumoniae pneumonia, on a background of established atherosclerosis. We go on to use our model to investigate the effects of pneumococcal pneumonia on atherosclerosis.
Methods
C57BL/6J and ApoE−/− mice were fed a high fat diet to promote atherosclerotic plaque formation. Mice were then infected with a range of S. pneumoniae serotypes (1, 4 or 14) with the aim of establishing a model to study atherosclerotic plaque evolution after pneumonia and bacteraemia. Laser capture microdissection of plaque macrophages enabled transcriptomic analysis.
Results
Intratracheal instillation of S. pneumoniae in mice fed a cholate containing diet resulted in low survival rates following infection, confirming increased susceptibility to severe infection. Optimization steps resulted in a final model of male ApoE−/− mice fed a Western diet then infected by intranasal instillation of serotype 4 (TIGR4) S. pneumoniae followed by antibiotic administration. This protocol resulted in high rates of bacteremia (88.9%) and survival (88.5%). Pneumonia resulted in increased aortic sinus plaque macrophage content 2 weeks post pneumonia but not at 8 weeks, and no difference in plaque burden or other plaque vulnerability markers were found at either time point. Microarray and qPCR analysis of plaque macrophages identified downregulation of two E3 ubiquitin ligases, Huwe1 and Itch, following pneumonia. Treatment with atorvastatin failed to alter plaque macrophage content or other plaque features.
Conclusions
Without antibiotics, ApoE−/− mice fed a high fat diet were highly susceptible to mortality following S. pneumoniae infection. The major infection associated change in plaque morphology was an early increase in plaque macrophages. Our results also hint at a role for the ubiquitin proteasome system in the response to pneumococcal infection in the plaque microenvironment.
... In ApoE −/− mice infected with influenza A virus, histological analyses showed increased inflammatory macrophage and T-cell accumulation in atherosclerotic plaques (195) and post-mortem analyses showed enrichment in myeloid-and T-cells in the coronary adventitia of patients who died from acute infection (196). Intra-abdominal sepsis accelerated atherosclerosis within only 24 h in ApoE-KO mice, in part mediated by increased lesional TNF, IL-6 and CCL2 (197). Endotoxemia upregulated the chemoattractant Leukotriene B4 (LTB4) in aortas of ApoE −/− mice, which caused neutrophil invasion and subsequent enhanced collagen digestion, necrosis, and rapid destabilization in plaques (198). ...
Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed.
