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Acute coronary syndromes are a leading cause of morbidity and mortality worldwide. The mechanisms underlying the triggering of these events are diverse and include increased coronary and systemic inflammatory activity, dominant prothrombotic conditions, increased biomechanical stress on coronary arteries, variations in the coronary arterial tone, disturbed haemodynamic homoeostasis, and altered myocardial metabolic balance. There is experimental evidence that acute infections can promote the development of acute coronary syndromes, and clinical data strongly support a role for acute infections in triggering these events. In our Review, we summarise the pathogenesis of coronary artery disease and present the evidence linking acute infections with the development of acute coronary syndromes. Greater awareness of this association is likely to encourage research into ways of protecting patients who are at high risk.

Background. Previous reports suggest that community-acquired pneumonia (CAP) is associated with an enhanced risk of cardiovascular complications. However, a contemporary and comprehensive characterization of this association is lacking. Methods. In this multicenter study, 1182 patients hospitalized for CAP were prospectively followed for up to 30 days after their hospitalization for this infection. Study endpoints included myocardial infarction, new or worsening heart failure, atrial fibrillation, stroke, deep venous thrombosis, cardiovascular death, and total mortality. Results. Three hundred eighty (32.2%) patients experienced intrahospital cardiovascular events (CVEs) including 281 (23.8%) with heart failure, 109 (9.2%) with atrial fibrillation, 89 (8%) with myocardial infarction, 11 (0.9%) with ischemic stroke, and 1 (0.1%) with deep venous thrombosis; 28 patients (2.4%) died for cardiovascular causes. Multivariable Cox regression analysis showed that intrahospital Pneumonia Severity Index (PSI) class (hazard ratio [HR], 2.45, P = .027; HR, 4.23, P < .001; HR, 5.96, P < .001, for classes III, IV, and V vs II, respectively), age (HR, 1.02, P = .001), and preexisting heart failure (HR, 1.85, P < .001) independently predicted CVEs. One hundred three (8.7%) patients died by day 30 postadmission. Thirty-day mortality was significantly higher in patients who developed CVEs compared with those who did not (17.6% vs 4.5%, P < .001). Multivariable Cox regression analysis showed that intrahospital CVEs (HR, 5.49, P < .001) independently predicted 30-day mortality (after adjustment for age, PSI score, and preexisting comorbid conditions). Conclusions. CVEs, mainly those confined to the heart, complicate the course of almost one-third of patients hospitalized for CAP. More importantly, the occurrence of CVEs is associated with a 5-fold increase in CAP-associated 30-day mortality.

Although traditionally regarded as a disease confined to the lungs, acute pneumonia has important effects on the cardiovascular system at all severities of infection. Pneumonia tends to affect individuals who are also at high cardiovascular risk. Results of recent studies show that about a quarter of adults admitted to hospital with pneumonia develop a major acute cardiac complication during their hospital stay, which is associated with a 60% increase in short-term mortality. These findings suggest that outcomes of patients with pneumonia can be improved by prevention of the development and progression of associated cardiac complications. Before this hypothesis can be tested, however, an adequate mechanistic understanding of the cardiovascular changes that occur during pneumonia, and their role in the trigger of various cardiac complications, is needed. In this Review, we summarise knowledge about the burden of cardiac complications in adults with acute pneumonia, the cardiovascular response to this infection, the potential effects of commonly used cardiovascular and anti-infective drugs on these associations, and possible directions for future research.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem. Two investigators searched MEDLINE, Scopus, and EMBASE for observational studies of immunocompetent adults with clinical and radiological evidence of CAP that reported any of the following: overall cardiac complications, incident heart failure, acute coronary syndromes (ACS), or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria, enroll their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. Studies with focus on nosocomial or health care-associated pneumonia were not included. Review of 2,176 citations yielded 25 articles that met eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eight cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7% (confidence interval [CI] 13.9-22.2), 14.1% (9.3-20.6), 5.3% (3.2-8.6), and 4.7% (2.4-8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods but only six (24%) provided a definition for them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes. Major cardiac complications occur in a substantial proportion of patients with CAP. Physicians and patients need to appreciate the significance of this association for timely recognition and management of these events. Strategies aimed at preventing pneumonia (i.e., influenza and pneumococcal vaccination) in high-risk populations need to be optimized. Further research is needed to understand the mechanisms underlying this association, measure the impact of cardiac complications on other CAP outcomes, identify those patients with CAP at high risk of developing cardiac complications, and design strategies to prevent their occurrence in this population.

Residual inflammation in cardiovascular organs is thought to be one of the catalysts for the increased risk of cardiovascular complications seen following pneumonia. To test this hypothesis, we investigated changes in plaque characteristics and inflammatory features in ApoE −/− mouse aorta and heart following pneumonia. Male ApoE −/− mice were fed a high fat diet for 8 weeks before intranasal inoculation with either Streptococcus pneumoniae serotype 4 (test group) or phosphate buffered saline (control group). Mice were sacrificed at 2-, 7- and 28-days post-challenge. Changes in plaque burden and characteristics in aortic root and thoracic aorta were characterized by Oil red O and Trichrome stains. Inflammatory changes were investigated by FDG-PET imaging and immunofluorescence staining. We found TIGR4-infected mice present with increased plaque presence in the aortic root and thoracic aorta at 2- and 28-days post-inoculation, respectively. Aortic wall remodelling was also more pronounced in mice challenged with pneumococci at 28 days post-inoculation. Aortic root plaques of infected mice had reduced collagen and smooth muscle cells, consistent with an unstable plaque phenotype. Pneumonia alters plaque burden, plaque characteristics, and aortic wall remodelling in ApoE −/− mice. These effects caused by Streptococcus pneumoniae TIGR4, may contribute to the increased risk of cardiovascular complications seen in survivors of this infection.

Among patients who are hospitalized for pneumococcal pneumonia, the incidence of myocardial infarction is 7 to 8%. The true incidence of postinfection myocardial infarction may be higher than estimated, given the practice of attributing elevated troponin levels to “troponin leak.”

To derive and validate a clinical rule that stratifies the risk of cardiac complications in patients hospitalized for community-acquired pneumonia (CAP) and compare its performance to the pneumonia severity index (PSI) score. Two cohorts of patients hospitalized for CAP were selected for the study. We used regression techniques in the derivation cohort (1343 patients enrolled in the Pneumonia Patient Outcomes Research Team study between October 1991 and March 1994) to generate a prediction rule that we validated in the validation cohort (608 patients enrolled in the Dissemination of Guidelines for Length of Stay study between February 1998 and March 1999). Discrimination and reclassification analyses compared its performance against the PSI score. A prediction model for cardiac complications in the derivation cohort included age, 3 preexisting conditions, 2 vital signs, and 7 common laboratory or radiographic parameters. Discrimination (C statistic, 0.81; 95% CI, 0.78-0.84) and calibration (Hosmer-Lemeshow goodness-of-fit test, χ2=13.0; P=.11) were good. We derived a point score system from this model that when applied to the validation cohort also had good discrimination (C statistic, 0.78; 95% CI, 0.74-0.83) and calibration (Hosmer-Lemeshow, χ2=9.0; P=.34). On the basis of this score, we defined 4 categories of incremental risk of cardiac complications. The incidence of cardiac complications across risk categories increased linearly (from lowest to highest) in both the derivation (3.0%, 17.8%, 35.2%, and 72.2%) and validation (5.0%, 8.2%, 28.3%, and 48.9%) cohorts (Cochran-Armitage linear trend test, P<.01). The new score outperformed the PSI score in predicting cardiac complications in the validation cohort (C statistic, 0.78 vs 0.74; P=.03; proportion of patients correctly reclassified by the new score, 44%). We derived and validated a clinical rule that accurately stratifies the risk of cardiac complications in patients hospitalized for CAP.

Pneumonia is associated with high risk of heart failure (HF) in the short term (30 days) postinfection. Whether this association persists beyond this period is unknown. We studied 5,613 elderly (≥65 years) adults enrolled in the Cardiovascular Health Study between 1989 and 1994 at 4 US communities. Participants had no clinical diagnosis of HF at enrollment, and they were followed up through December 2010. Hospitalizations for pneumonia were identified using validated International Classification of Disease Ninth Revision codes. A centralized committee adjudicated new-onset HF events. Using Cox regression, we estimated adjusted hazard ratios (HRs) of new-onset HF at different time intervals after hospitalization for pneumonia. A total of 652 participants hospitalized for pneumonia during follow-up were still alive and free of clinical diagnosis of HF by day 30 posthospitalization. Relative to the time of their hospitalization, new-onset HF occurred in 22 cases between 31 and 90 days (HR 6.9, 95% CI 4.46-10.63, P < .001), 14 cases between 91 days and 6 months (HR 3.2, 95% CI 1.88-5.50, P < .001), 20 cases between 6 months and 1 year (HR 2.6, 95% CI 1.64-4.04, P < .001), 76 cases between 1 and 5 years (HR 1.7, 95% CI 1.30-2.12, P < .001), and 71 cases after 5 years (HR 2.0, 95% CI 1.56-2.58, P < .001). Results were robust to sensitivity analyses using stringent definitions of pneumonia and extreme assumptions for potential informative censoring. Hospitalization for pneumonia is associated with increased risk of new-onset HF in the intermediate and long term. Studies should characterize the mechanisms of this association in order to prevent HF in elderly pneumonia survivors.

IntroductionInflammation plays a central role in atherosclerosis development and subsequent cardiovascular complications, including heart attack and stroke. Patients with inflammatory conditions such as community-acquired pneumonia (CAP) present with an elevated risk of cardiovascular events, which is likely driven by unresolved systemic inflammation. Targeting this heightened inflammatory burden may present a novel therapeutic strategy to attenuate heart attack risk in CAP survivors. Icosapent ethyl (IPE), an omega-3 fatty acid, demonstrates both pro-resolving and cardioprotective properties. The Targeting Vascular Inflammation In Patients with CAP (TIN-CAP) trial aims to evaluate the efficacy of IPE in mitigating vascular inflammation in CAP survivors.Methods and analysisTIN-CAP is a multicentre, randomised, double-blind, placebo-controlled trial. Eligible adults diagnosed with CAP in hospital or the emergency department will complete baseline assessments within 14 days of diagnosis including 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT angiography, bloodwork and quality of life evaluation (EuroQol – 5 Dimensions (EQ-5D)). Participants will then be randomised 1:1 to receive IPE (4 g/day) or placebo for 6 months. Follow-up visits will occur at 30 days (bloodwork and EQ-5D only) and 6 months. The primary endpoint is the change in FDG uptake in the ascending aorta from baseline to 6 months between IPE and placebo groups. Secondary endpoints include FDG uptake in the bone marrow, spleen, lungs and other vasculature, in addition to major adverse cardiac events and quality of life assessments. An initial lead-in cohort of 18 patients will be enrolled to assess recruitment, imaging feasibility and IPE tolerability prior to full trial enrolment. These patients will remain blinded and will be included in the final analysis (Vanguard design).Ethics and disseminationThe TIN-CAP trial has been approved provincially by the Clinical Trials Ontario Research Ethics Board (approval number: 5045). Participants will provide written informed consent prior to enrolment. Study findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberNCT06710080.

Epidemiological analyses demonstrate that pneumonia survivors have a higher risk of myocardial infarction than people with similar load of risk factors for atherosclerotic cardiovascular disease (ASCVD) but without pneumonia. This may be due to a higher baseline burden of ASCVD in patients with pneumonia that is not captured by the accounting of known ASCVD risk factors in epidemiological analyses or to unfavorable accelerating effects of pneumonia on atherosclerosis. We analyzed data from the Multi-Ethnic Study of Atherosclerosis. We identified 54 participants that were hospitalized for pneumonia during study follow-up and that also had assessment of coronary artery calcium (CAC, an objective marker of coronary atherosclerotic burden) before and after this hospitalization. We matched them to 54 participants who were not hospitalized for pneumonia but that had CAC assessments at the same study visits as the pneumonia cases. We compared baseline CAC scores and their progression between groups. Baseline CAC scores were similar in both groups (median [IQR]; 6.3 [0-356.8] in pneumonia participants vs. 10.8 [0-178.3] in controls; p = 0.25). After a median of 4.8 years, the direction and magnitude of CAC score change, and the slope of CAC score progression between groups was also similar (median change [IQR], 21.8 [0 to 287.29] in participants with pneumonia versus 15.8 [0 to 140.94] in controls, p = 0.28; difference in slope, 7.7, 95% CI -9.0 to 24.6, p = 0.18). However, among participants with high baseline ASCVD risk (i.e. ACC/AHA 10-year risk estimate ≥7.5%), participants with pneumonia showed a larger increase in CAC scores (median change [IQR]; 159.10 [38.55-407.34] versus 48.72 [0.97-246.99] in controls; p = 0.02) and a trend towards a steeper slope of CAC score progression (difference in slope, 19.7, 95% CI -6.6 to 45.6, p = 0.07). Pneumonia may accelerate the progression of atherosclerosis in people with high baseline ASCVD risk.