Spark That Lights the Fire: Infection Triggers Cardiovascular Events.

Atherosclerosis is a complex pathology resulting from a dysfunctional endothelium, activated leukocytes, macrophages, and lipid‐laden foam cells, implying a wealth of different actors driving plaque disruption. Classically, all of these actors have been considered acting chronically (ie, the so‐called cardiovascular risk factors such as hypertension, diabetes mellitus, etc.)1; however, acute triggers have also been identified recently. Among these, infections have been associated with cardiovascular events.2, 3 In this issue of the Journal of the American Heart Association (JAHA), Cowan et al4 shed more light on this relationship. Inflammation has been described as a causal link between traditional cardiovascular risk factors and modification of the arterial wall, which leads to atherosclerosis and cardiovascular events such as myocardial infarction (MI) and stroke.1 Clinically, autoimmune diseases characterized by a hyperinflammatory status such as systemic lupus erythematosus,5 rheumatoid arthritis,6 and psoriasis7 are also associated with increased cardiovascular risk. Mechanistically, this association has indeed been confirmed by elegant experimental approaches with various other inflammatory insults. The boosted inflammation in the immediate post‐MI period causes progression of atherosclerosis lesions (enlarged necrotic core size, increased protease activity, and enhanced inflammatory cell infiltration) in apolipoprotein E knock‐out mice subjected to experimental MI8 mediated via augmented inflammation and increased sympathetic activity. Enhanced inflammation is also the central mechanism of atherosclerotic progression after other insults, both acute (orthopedic surgery)9 or chronic (prolonged stress).10 The necessary role of inflammation in the worsening of atherosclerosis after MI has been mechanistically corroborated by several studies showing mitigation of atherosclerosis progression by the inhibition of essential inflammatory pathways such as adhesion molecules11 and NLRP3 inflammasome.12 This hypothesis has also been clinically confirmed because the clinical trial CANTOS (Canakinumab Anti‐Inflammatory Thrombosis Outcomes Study) demonstrated that anti‐inflammatory therapy targeting the interleukin‐1β innate immunity pathway with canakinumab led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid‐level lowering.13 Infections, both acute and chronic, are one of the main triggers of inflammation, thus it is not far‐fetched to hypothesize that infections could also elicit cardiovascular events. This has been demonstrated in the clinical setting given that patients with chronic infections such as Helicobacter pylori 14 also experienced more cardiovascular events. The role of acute infections as triggers for cardiovascular events has been recently investigated. While several recent retrospective clinical observations found an increased incidence of MI after community‐acquired pneumonia (CAP), this was further confirmed by a prospective multicenter cohort of 2344 unselected patients with CAP2 showing that the 30‐day incidence of heart failure, arrhythmia, and MI was 21%, 10% and 3%, respectively, with this risk peaking in the first 2 days of hospitalization. Additional prospective data in hospitalized CAP patients15, 16 found even higher MI rates, with half of CAP patients showing high levels of hs‐TnT (High‐sensitivity cardiac Troponin T) while 11% of CAP patients additionally showed electrocardiographic signs of MI and clinical symptoms on top of the high hs‐TnT levels. Of note, this MI incidence of 11%17 was higher than in previous reports (3% as reported by Corrales‐Medina2), which is probably explained by the use of hs‐TnT (a more sensitive marker of myocardial injury than the CK (Creatine Kinase) that was used in previous studies2) and by the fact that the levels of hs‐TnT were measured not only at hospital baseline but also every 12 hours during hospital admission.2 An analysis of even larger populations (5888 patients in the Cardiovascular Health Study and 15 792 in the ARIC (Atherosclerosis Risk in Communities) study confirmed that CAP was associated with increased risk of cardiovascular events.17 Increased MI risk is not circumscribed to CAP, but it also extends to other types of respiratory infections. Large retrospective epidemiological studies involving >33 000 patients found an increase in MI risk after acute respiratory infections.18, 19, 20 This link is further supported because influenza vaccination is associated with a reduced risk of MI and stroke, both in retrospective studies21 and in clinical trials,22 and because early treatment of influenza in patients with established CVD was associated with a 60% decrease in the MI risk.23 Furthermore, the authors of the present article4 have previously expanded this field by demonstrating that infections do not only increase the risk of MI but also the risk of stroke.3 Of the utmost importance, infections also increase the risk for heart failure2, 24 and not only for MI. The main hypothesis to explain this association is the infection‐triggered enhancement in inflammation that boosts atherosclerosis and prompts plaque rupture. Atherosclerosis is an inflammatory disease; acute infections not only elicit systemic inflammatory responses but can also have direct inflammatory effects on atherosclerotic plaques, increasing their vulnerability. In atherosclerotic apolipoprotein E knockout mice, influenza virus infection promotes acute inflammation in the atheromata (infiltration of plaques with macrophages and T lymphocytes) and superimposed fibrin deposition, similar to unstable plaques after MI.25 Coronary artery tone abnormalities may also be involved, as increased vasoconstrictive responses were observed in animals injected with staphylococcal alpha‐toxins.15 Other factors may likely contribute: tachycardia shortens diastole (when coronary perfusion occurs); decreased central blood pressure (as in severe sepsis) impairs myocardial perfusion through stenotic coronary segments; hypoxemia and increased cardiac metabolic demands (secondary to tachycardia and catecholamine release) can contribute to development of myocardial ischemia.15 Furthermore, infections increase platelet aggregation15 and higher in vivo markers of platelet activation (soluble CD40L, soluble P‐selectin, and TxB2 levels) in CAP patients,16 thus suggesting that CAP may increase platelet activation which in turn may be the cause of MI. This platelet hyper‐reactivity may be explained because Gram‐positive bacteria induce platelet aggregation and formation of platelet‐neutrophil complexes and, in response to lipopolysaccharide from Gram‐negative bacteria, platelets bind more avidly to fibrinogen under flow conditions in a Toll‐like receptor‐4‐dependent manner.15 The main mechanisms responsible for triggering an episode of CVD after infections are summarized in Table. Table 1 Mechanism Involved in Triggering Cardiovascular Events After Acute Infections