Role of acute infection in triggering acute coronary syndromes

Review

Role of acute infection in triggering acute coronary syndromes Vicente F Corrales-Medina, Mohammad Madjid, Daniel M Musher

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.

Introduction Coronary artery disease is the leading cause of death worldwide.1 Acute coronary syndromes, which include unstable angina and acute myocardial infarction, are the most feared complication of coronary artery disease. We2–5 and others6–8 have shown that acute infections are associated with, and appear to have a role in causing, the development of acute coronary syndromes. In our Review, we provide an overview of the pathophysiology of coronary artery disease and acute coronary syndromes and review the in-vitro, animal, and human studies that clarify the role of acute infection in triggering these syndromes. The putative roles of Chlamydophila pneumoniae, cardiotropic viruses (eg, coxsackie), and chronic infections (including periodontal disease) in these conditions are beyond the scope of this Review.

Atherosclerosis: an inflammatory disease Atherosclerosis is an inflammatory condition that begins with endothelial injury. A variety of stimuli including raised concentration of cholesterol in blood, exposure to tobacco, diabetes mellitus, hypertension, or rheological stress alter endothelial function, increasing permeability to low-density lipoproteins and allowing the migration of leucocytes (particularly monocytes and lymphocytes) into the arterial intima.9–12 Within the arterial wall, low-density lipoproteins are biochemically modified into their oxidized form (oxLDL) that induces more endothelial dysfunction and intimal inflammation.11 Infiltrating monocytes differentiate into macrophages that recognise and internalise oxLDL to eventually become lipid-laden foam cells, the hallmark cellular component of atheromas.11 Infiltrating CD4 T cells, likewise, interact with oxLDL and other antigens.11 These inflammatory cells proliferate and secrete cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products,10 whereas macrophages also produce enzymes (ie, metalloproteases) that degrade components of the extracellular matrix.10,11 Ongoing inflammation promotes the death of macrophages and smooth muscle www.thelancet.com/infection Vol 10 February 2010

cells, and their necrotic debris help to continue the inflammatory process.10 The result is the progression of so-called fatty streaks, the earliest morphological stage of atheromas, into advanced atherosclerotic lesions composed of two basic elements: a lipid-rich core that, in addition to extracellular lipid droplets, comprises foam cells, other inflammatory cells, collagen fibres, calcified nodules, microvessels (from neovascularisation), and necrotic debris; and a covering component of smooth muscle cells with a fibrous cap made of extracellular-matrix proteins (figure 1).12,13

Acute coronary syndrome Slowly growing atherosclerotic plaques cause progressive coronary obstruction that eventually can lead to effort angina. Most acute coronary syndromes, however, arise from thrombotic complications at the site of lesions that were not necessarily haemodynamically significant (ie, those causing less than 50% stenosis of a coronary artery).14 The surface of these lesions becomes disrupted, exposing underlying thrombogenic elements (collagen, phospholipids, tissue factor, and platelet-adhesive matrix molecules) that lead to the formation of an acute or subacute thrombus.15–17 Plaque disruption alone, however, is not enough for the development of a cardiac ischaemic event.15,18 Instead, the obstructive nature of the thrombus (partial vs total), degree of stenosis, presence of vasoconstriction, adequacy of the coronary perfusion pressure, and balance between the metabolic demand and supply of the cardiac muscle, ultimately determine the evolution of an acute coronary event (figure 2).16,18–23 Autopsy studies show that rupture of the fibrous cap is responsible for about 70% of acute coronary syndromes, whereas erosion of the plaque with exposure of an area of denuded endothelium accounts for most of the remaining 30%.24

Lancet Infect Dis 2010; 10: 83–92 Division of Infectious Diseases, Department of Medicine, University of Ottawa, ON, Canada (V F Corrales-Medina MD); Departments of Medicine (M Madjid MD, Prof D M Musher MD) and Molecular Virology and Microbiology (Prof D M Musher), Baylor College of Medicine, Houston, TX, USA; Infectious Disease Section, Medical Care Line, Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, USA (Prof D M Musher); Department of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA (M Madjid); and the Atherosclerosis Research Laboratory, Texas Heart Institute at St Luke’s Episcopal Hospital; Houston, TX, USA (M Madjid) Correspondence to: Prof Daniel M Musher, Baylor College of Medicine, Infectious Disease Section, Room 4B-370, Michael E DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030, USA [email protected]

Triggering by acute infections Inflammation has a central role in triggering acute coronary syndromes.25 The development of acute coronary syndromes is preceded by high concentrations of 83

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Endothelium

Smooth-muscle cell T cell Lipid core Foam cell

Fibrous cap

Figure 1: Advanced coronary atherosclerotic lesion An advanced coronary lesion has two main components: a lipid-rich core, containing lipid droplets, inflammatory cells, and collagen fibres and a covering made of smooth muscle cells and a fibrous cap.

inflammatory markers in the blood, such as C-reactive protein, neutrophil myeloperoxidase, procalcitonin, and white blood cells.26–29 When compared with patients with stable coronary artery disease, patients with acute coronary syndromes have higher inflammatory activity across the entire coronary bed and, aside from the culprit lesion (ie, the lesion causing the coronary obstruction responsible for the coronary event), many other plaques with disrupted surfaces.25,30–32 However, irrespective of the mechanism of disruption (rupture vs erosion), culprit lesions have more infiltrating inflammatory cells (ie, macrophages, T cells, and neutrophils) than other lesions in the coronary tree.33–35 These cells contribute to the development of acute coronary syndromes by producing cytokines, proteases, coagulation factors, oxygen radicals, and vasoactive molecules that increase endothelial damage, disrupt the fibrous cap, and start the formation of thrombi.11 Acute infections, in addition to eliciting systemic inflammatory responses, can also have direct inflammatory effects on atherosclerotic plaques and coronary arteries. In mice deficient of apolipoprotein E, a wellestablished animal model of atherosclerosis, infection with influenza virus promotes acute inflammation, smooth muscle cell proliferation, and fibrin deposition in atherosclerotic plaques in a manner similar to that in coronary plaques after fatal acute myocardial infarction.36 People dying of acute systemic infections have a substantially higher number of macrophages and T cells in the coronary adventitia and periadventitial fat, and 84

more dendritic cells in the intima and media than people who died without infection.37 The formation of platelet thrombi at the surface of complicated coronary plaques is an essential step in the evolution of acute coronary syndrome,15,18 and acute infections can promote the development of thrombi in various ways.38 Platelets can be directly activated by pathogens and the inflammatory response that they elicit.39,40 Additionally, acute infections can cause coronary vasoconstriction and further narrow the lumen in atherosclerotic coronary segments, stimulating shearinduced platelet activity.22,41,42 These effects can all be enhanced by increased concentrations of endogenous catecholamines.43 Severe sepsis is associated with high circulating concentrations of tissue factor without a compensatory increase in the activity of counter-regulatory pathways.44 In this setting, changes in antithrombin activity,45,46 concentrations of activated protein C,47 and plasminogen activator inhibitor type-148 can all contribute to further deregulation of the coagulation system. Acute infections also cause or exacerbate dysfunction of the endothelium, impairing its normal anticoagulant properties.49,50 That prothrombotic changes are seen in healthy individuals with subclinical endotoxaemia49,51,52 or mild infections53,54 supports the idea that this interplay is not necessarily restricted to severe infections. Increased sympathetic activity, changes in the circulatory volume, and variations in systemic and coronary vascular tone can all produce surges of biomechanical stress on coronary plaques, triggering their disruption.17,42,55 The www.thelancet.com/infection Vol 10 February 2010

Review

A

Several mechanisms trigger the disruption of an advanced coronary lesion. The disrupted surface exposes underlying thrombogenic material. Plaque disruption alone is not sufficient for the development of an acute coronary syndrome.

• Increased coronary and systemic inflammation • Increased biomechanical stress • Vasoconstriction

• Increased procoagulant conditions • Increased platelet activation • Vasoconstriction • Endothelial dysfunction

Acute infections

B

Thrombogenic conditions (local and systemic) determine thrombus formation.

• Increased metabolic demand • Hypoxaemia • Hypotension • Vasoconstriction

D

C The occlusive nature of the thrombus (total vs partial), the degree of stenosis, the presence of vasoconstriction, the coronary perfusion pressure, and the myocardial metabolic balance (demand vs supply) determine the evolution of an acute coronary syndrome.

Figure 2: Triggering of acute coronary syndromes by acute infections The conditions created by acute infections can cause an advanced coronary lesion (A) to progresses to a disrupted coronary lesion (B) and then a thrombosed coronary lesion (C). This can ultimately cause an acute coronary syndrome (D).

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Study design

Sample size

Exposure

Spodick (1984)62

Case–control

150 cases, 150 controls

Respiratory infection†

Finding OR 2·2 (p<0·02)

Meier (1998)63

Case–control

1922 cases, 7649 controls

Respiratory infection†

OR 3·0 (95% CI 2·1–4·4)

Meier (1998)63

Case cross-over 74 cases

Respiratory infection†

RR 2·7 (1·6–4·7) for the probability of the infection in the 10 days vs 1 year before the index myocardial infarction

Meyers (2004)64

Case–control

335 cases, 199 controls

Respiratory infection†

OR 2·4 (1·1–5·4)

Smeeth (2004)6

Self-controlled case series

20 921 cases

Respiratory infection†

IRR 4·9 (4·4–5·5) on days 1–3, 3·2 (2·8–3·6) on days 4–7, 2·8 (2·5–3·1) on days 8–14, 2·0 (1·8–2·1) on days 15–28, and 1·4 (1·3–1·5) on days 29–91

Clayton (2005)65

Case–control

119 cases, 214 controls

Respiratory infection†

OR 1·0 (0·5–1·9)

Baylin (2007)66

Case cross-over 499 cases

Respiratory infection†

RR 1·5 (0·9–2·4) for the probability of the infection in the 10 days vs 1 year before the index myocardial infarction

Clayton (2008l)8

Case–control

11 155 cases, 11 155 controls

Respiratory infection†

OR 2·1 (1·4–3·2) on days 1–7, 1·9 (1·4–2·6) on days 8–28, 1·2 (0·9–1·5) on days 29–91

Nicholls (1977)67

Case–control

38 cases, 21 controls

Influenza-like illness

OR 1·7 (0·5–5·6)

Ponka (1981)68

Case–control

49 cases, 37 controls

Influenza-like illness

OR 1·2 (0·3–4·4)

Mattila (1998)69

Case–control

40 cases, 71 controls

Influenza-like illness

OR 2·9 (0·9–9·5)

Zheng (1998)70

Case cross-over 2264 cases

Influenza like-illness

OR 2·4 (1·7–3·4) for the probability of myocardial infarction 1 day vs 7 days from the onset of the infection

Porter (1999)71

Case–control

20 cases, 118 controls

Influenza (viral antigen in lung tissue)

OR 1·0 (0·1–8·6)

Pesonen (2008)72

Case–control

110 cases, 323 controls

Influenza-like illness

OR 3·8 (1·4–10·8)

Ramirez (2008)73

Observational

500 cases

Community-acquired pneumonia

5·8% in-hospital Incidence of acute myocardial infarction; OR 4·2 (1·1–16·3) for myocardial infarction in patients experiencing early clinical failure of medical treatment vs patients who do not

Corrales-Medina (2009)5

Cohort study

206 cases, 395 controls

Bacterial communityacquired pneumonia

OR 8·5 (3·4–22·2)

Corrales-Medina (2009)5

Self-controlled case series

37 cases

Bacterial communityacquired pneumonia

IRR 47·6 (24·5–92·5) for days 1–15

Corrales-Medina (2009)2

Self-controlled case series

42 cases

Staphylococcus aureus bacteraemia

IRR 7·9 (CI 3·9–15·9) for days 1–15

Meier (1998)63

Case–control

1922 cases, 7649 controls

Urinary tract infection

OR 1·2 (0·3–4·7)

Sims (2005)74

Case–control

100 patients with acute coronary syndrome and 100 patient with stable coronary heart disease

Pyuria

OR 3·0 (1·3–6·8)

Smeeth (2004)6

Self-controlled case series

10 448 cases

Urinary tract infection

IRR 1·7 (1·3–2·1) on days 1–3, 1·6 (1·3–2·0) on days 4–7, 1·2 (1·0–1·5) on days 8–14, 1·3 (1·2–1·5) 15–28, and 1·2 (1·1–1·3) on days 29–91

Baylin (2007)66

Case cross-over 101 cases

Gastroenteritis

RR 2·08 (1·31–3·28) for the probability of the infection in the 10 days vs 1 year before index myocardial infarction

Adapted from Warren-Gash and colleagues.7 OR=odds ratio. RR=relative risk. IRR=incidence rate ratio. *Ecological studies and other studies were not included in this table if there was no analysis of risk. †Including acute exudative pharyngitis;75 pneumonia, influenza, acute bronchitis or “chest infections”;6 respiratory symptoms with fever and pleuritic chest pain;65 nasal congestion, rhinorrhoea, sore throat, head cold and cough with or without fever,62 respiratory symptoms consistent with infection;64,66,69 non-specific acute upper-respiratory infection, bronchitis, pneumonia or chesty productive cough;63 and acute bronchitis, pneumonia, and productive cough.8

Table 1: Clinical studies of acute infections and acute coronary syndromes*

hyperdynamic cardiovascular response, high metabolic demands, hypovolaemia (poor intake, fever, hyperventilation), hypervolaemia (fluid replacement and renal failure related to sepsis), and variations in peripheral vascular resistance (septic state and endogenous and exogenous catecholamines) common to serious infections56 can all contribute to this effect. In addition to reducing the blood flow through stenotic coronary segments, coronary vasoconstriction might compress the atheromatous core and force its intraluminal rupture,55,57 and contribute to plaque erosion.58 Acute 86

worsening of endodothelial function caused by acute infection and inflammation can amplify coronary vasoconstrictive responses49 or cause paradoxical reactions to stimuli that otherwise produce vasodilatation.22,49 Animal studies suggest that bacterial products directly induce coronary vasoconstriction.59,60 Decreased central blood pressure, as in severe sepsis, impairs perfusion through stenotic coronary segments,23 whereas hypoxaemia and increased cardiac metabolic demands can contribute further to the development of myocardial ischaemia.61 www.thelancet.com/infection Vol 10 February 2010

Review

Study design

Sample size

Case–control

109 cases, 109 controls Influenza vaccine

Siscovick (2000)86 Case–control

Naghavi (2000)85

Exposure

Outcome

Finding

Acute myocardial infarction OR 0·33 (95% CI 0·13–0·82)

342 cases, 549 controls Influenza vaccine

Primary cardiac arrest

OR 0·51 (0·33–0·79)

Jackson (2002)87

Cohort study

1378 survivors of first myocardial infarction

Influenza vaccine

Recurrent myocardial infarction

HR 1·18 (0·76–1·75)

Nichol (2003)88

Cohort study

140 055 patients (cohort A)

Influenza vaccine

Admission to hospital for ischaemic heart disease

OR 0·8 (0·7–0·91)

Nichol (2003)88

Cohort study

146 328 patients (cohort B)

Influenza vaccine

Admission to hospital for ischaemic heart disease

OR 0·9 (0·78–1·03)

Gurfinkel (2004)89 Randomised controlled trial

301 patients with coronary heart disease

Influenza vaccine

Cardiovascular death

RR 0·34 (0·17–0·71)

Gurfinkel (2004)89 Randomised controlled trial

301 patients with coronary heart disease

Influenza vaccine

Cardiovascular death plus myocardial infarction

RR 0·59 (0·4–0·86)

Meyers (2004)64

Case–control

335 cases,199 controls

Influenza vaccine

Acute myocardial infarction OR 0·9 (0·6–1·35)

Smeeth (2004)6

Self–controlled case series

20 486 cases

Influenza vaccine

Acute myocardial infarction IRR 0·75 (0·60–0·94) on days 1–3, 0·68 (0·56–0·84) on days 4–7, 0·73 (0·63–0·85) on days 8–14, 0·87 (0·79–0·96) on days 15–28, and 1·03 (0·98–1·09) on days 29–91

Heffelfinger (2006)90

Case–control

750 cases, 1735 controls

Influenza vaccine

Acute myocardial infarction OR 0·97 (0·75–1·27)

Ciszewski (2008)91

Randomised controlled trial

658 patients with coronary heart disease

Influenza vaccine

Cardiovascular death

HR 1·06 (0·15–7·56)

Ciszewski (2008)91

Randomised controlled trial

658 patients with coronary heart disease

Influenza vaccine

Cardiovascular death, acute myocardial infarction, or coronary revascularisation

HR 0·54 (0·29–0·99)

Keller (2008)92

Meta–analysis of randomised controlled trials

959 patients with coronary heart disease

Influenza vaccine

Cardiovascular death

RR 0·39 (0·20–0·77)

Keller (2008)92

Meta–analysis 959 patients with of randomised coronary heart disease controlled trials

Influenza vaccine

Acute myocardial infarction RR 0·85 (0·44–1·62)

Meyers (2004)64

Case–control

335 cases,199 controls

Pneumococcal vaccine

Acute myocardial infarction OR 0·89 (0·6–1·33)

Smeeth (2004)6

Self–controlled case series

5925 cases

Pneumococcal vaccine

Acute myocardial infarction IRR 0·49 (0·19–1·32) on days 1–3, 1·11 (0·63–1·96) on days 4–7, 1·22 (0·81–1·84) on days 8–14, 1·15 (0·85–1·55) on days 15–28, and 1·1 (0·95–1·28) on days 29–91

Lamontagne (2008)93

Case–control

335 cases,199 controls

Pneumococcal vaccine

Acute myocardial infarction OR 0·53 (0·40–0·70)

Smeeth (2004)6

Self–controlled case series study

7966 cases

Tetanus vaccine

Acute myocardial infarction IRR 1·1 (0·62–1·92) on days 1–3, 1·16 (0·72–1·87) on days 4–7, 0·97 (0·66–1·44) on days 8–14, 0·89 (0·66–1·19) on days 15–28, and 1·07 (0·94–1·21) on days 29–91

Swerdlow (2003)94

Observational

37 901 people that were vaccinated

Smallpox vaccine

5 vs 2 (0·6–5·4*) Observed vs expected (on the basis of historical cohorts) number of ischaemic cardiac events in the 3 weeks after vaccination

Adapted from Warren-Gash and colleagues.7 OR=odds ratio. HR=hazard ratio. RR=relative risk. IRR=incidence rate ratio. *95% predicted interval.

Table 2: Clinical studies of vaccination and acute coronary syndromes

In summary, the host response to acute infections can trigger, hasten, or facilitate acute coronary syndromes not only on the basis of generalised inflammatory and thrombogenic changes, but also local effects on coronary arteries and atherosclerotic lesions.

Clinical studies Strong evidence supports an association between acute coronary syndromes and acute respiratory infections www.thelancet.com/infection Vol 10 February 2010

(table 1). Both acute respiratory infections and acute coronary syndromes vary with the seasons, peaking in the winter.76,77 Acute respiratory symptoms shortly precede up to a third of acute coronary syndromes.8,62,63,65,69,75,78 Large and well-designed retrospective studies consistently find a two-fold to three-fold increase in the risk for acute coronary syndromes within 1–2 weeks after a respiratory infection.6,8,63 These studies also show that this risk increase is higher during the first few days after the infection 87

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(nearly five-fold from baseline in the first 72 h) and falls over time, but can still remain significant at 3 months.6,8 For decades increased morbidity and mortality related to acute coronary syndromes and other cardiac conditions have been recognised during influenza epidemics,4,79–82 with up to a half of all excess deaths during these periods attributable to cardiovascular causes.83 In a study of 34 000 autopsies, Madjid and colleagues4 showed that myocardial infarction is 30% more likely to happen during influenza season versus off-season weeks. Many observational studies7 further support this association. Moreover, a large retrospective study84 showed that early treatment of influenza in patients with established cardiovascular disease was associated with a 60% reduction in the risk of recurrent cardiovascular events, including acute coronary syndromes, in the month after the diagnosis of the infection. Vaccination against influenza seems to reduce the risk of acute coronary syndromes (table 2). Four retrospective studies,6,85,86,88 one of which included nearly 300 000 people, found a reduction in the rate of acute coronary syndromes in patients who had received influenza vaccine, although three other, small-scale studies did not.64,87,90 Two prospective randomised clinical trials89,91,95,96 suggested that influenza vaccine reduced the risk of coronary events by 50%, but two recent meta-analyses7,92 concluded that the validity of these results was limited by the small number patients and cardiovascular events in each study. Nevertheless, their agreement with previous observations85,86,88 has led to recommendations that influenza immunisation be given to people with coronary and other atherosclerotic vascular disease.97 After we reported a 5–7% incidence of acute coronary syndrome in patients with bacteraemic and nonbacteraemic pneumococcal pneumonia,3,98 several other studies confirmed this observation.5,73,99 Recently, we noted that patients with bacterial pneumonia, when compared with a control group admitted to the hospital for other diagnoses, had a nearly eight-fold increase in the risk for acute coronary syndromes in the 15 days after admission.5 Further analysis with a self-controlled case series found that, again, the increased risk was transient and was more striking (greater than 100-fold over baseline) during the first 3 days after admission.5 Ramirez and colleagues73 reported that 15% of patients with severe community-acquired pneumonia had acute myocardial infarction at hospital admission; moreover, myocardial infarction eventually developed in 20% of patients who were admitted with a less severe infection but where treatment failed.100 A large case–control study suggested that pneumococcal vaccination is associated with a greater than 50% decrease in the rate of myocardial infarction during the 10 years after the immunisation (table 2).93 Several case reports have described acute coronary syndromes in patients with low coronary risk in the setting of bacteraemic infections with various pathogens including 88

Capnocytophaga canimorsus,101–104 Neisseria meningitidis,105,106 and Staphylococcus aureus.107 Some investigators have reported an incidence of acute coronary syndromes of about 4% in the month after an episode of bacteraemia.108,109 Using the self-controlled case series method, we showed a 35-fold increase risk of a coronary event in the 2 days after the documentation of S aureus bacteraemia compared with the 6 months before and after the event.2 Two retrospective studies63,74 on the link between urinary tract infections and acute myocardial infarction found conflicting results. However, in the largest study (10 000 patients) of this association, Smeeth and colleagues6 showed that the risk of myocardial infarction increased by 66% in the 3 days after the diagnosis of the infection and remained substantially raised up to 1 month after this event. In 491 people that survived a first time myocardial infarction, the presence of a clinical syndrome consistent with gastroenteritis within 6 days before the coronary event was associated with a doubling in the risk of acute coronary syndromes in patients who had three or more coronary risk factors.66 Although vaccination with killed viruses or microbial constituents causes an inflammatory response, such vaccines have has not been linked to the development of acute coronary syndromes6 and, in fact, in the case of influenza vaccine, they can be protective (table 2). Smallpox vaccine, however, uses a live vaccinia virus that infects the person receiving the vaccine. After the US civilian smallpox vaccination programme started in 2003, ten cases of acute coronary syndromes within 4 weeks of vaccination were reported among the 37 901 people that were vaccinated. A statistical analysis suggested an increased susceptibility to acute coronary syndromes, and it was recommended that people with known underlying heart disease or three or more known cardiac risk factors were not vaccinated.94,110

The argument of causality Differentiating causal relations from those based on bias, chance, or confounding is often challenging and elusive. Sir Austin Bradford Hill, in 1965,111 summarised nine guiding principles that provide a framework for this process (strength of association, temporal relation, consistency, coherence, analogy, biological plausibility, biological gradient, experimental evidence, and specificity). On the basis of these principles we argue that there is a causal relation between acute respiratory infections and acute coronary syndromes. Acute respiratory infections are associated with a significant increase in the risk for acute coronary syndromes (strength of association).4–6,8,62,63,80 The increase is transient and highest in the few days after the infection (temporal relation).5,6,8 These findings are consistent in studies involving several populations, done by different investigators, and using diverse designs and statistical analyses (consistency).4–6,8,62,63,80 www.thelancet.com/infection Vol 10 February 2010

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The possibility that acute infections trigger acute coronary syndromes agrees with existing scientific knowledge since both conditions have similar seasonality (winter peaks),77 they tend to happen in populations with similar traits (elderly people, patients with chronic respiratory or cardiac conditions, people that smoke, people with diabetes, etc), and they share pathophysiological pathways in the immune, coagulation, and vascular systems (coherence). Acute infections can trigger other vascular events (eg, stroke)6,112 in a way analogous to acute coronary syndromes and, similarly, acute coronary syndromes can be triggered by other exposures (eg, air pollution, heavy exercise, sexual activity, emotional stress, etc)113–117 in a way analogous to acute infections (analogy). The mechanisms by which acute infections can trigger acute coronary syndromes, discussed in the previous sections and summarised in figure 2, make biological sense (biological plausibility). There is a greater risk of acute coronary syndromes after lower respiratory tract infections than after less severe urinary tract infections6 and, in the case of pneumonia, the risk is further raised when the infection is more severe or has a complicated course (biological gradient).73 Two randomised clinical trials91,95,96 suggest that vaccination against influenza decreases the risk of acute coronary syndromes (experimental evidence). Although an ideal causal link should consist of a single exposure leading to a single outcome and vice versa (specificity), this criterion is rarely met even in well-established causal relations (eg, tobacco and lung cancer or alcohol and liver cirrhosis); and in view of the other characteristics of the association, its absence does not disqualify our argument.118 From this analysis we can infer that acute respiratory infections, more likely than not, have a role in triggering acute coronary syndromes. These syndromes, however, are multifactorial and no cause is either necessary or sufficient to trigger them. Instead, acute infections need to be viewed as components of a web of causation119 in which complex interactions with other known and unknown contributing factors, each with their own causation webs, ultimately determine the development of the coronary event.

Future directions We have reviewed the evidence that acute infections, especially respiratory infections, trigger acute coronary syndromes. This association is supported by pathophysiological observations, and epidemiological and clinical findings. Because a large proportion of acute respiratory infections such as influenza and pneumonia tend to happen in patients at higher risk for coronary disease, this association deserves attention by the medical community. Future investigations should characterise the biological pathways underlying the association between acute infection and acute coronary syndromes; the development www.thelancet.com/infection Vol 10 February 2010

Search strategy and selection criteria In addition to reviewing our own files on specific infections, infecting organisms, inflammation, and acute coronary syndromes, we searched published work, with no language restrictions, within Ovid/Medline, PubMed, and the Cochrane database (date limits were from 1950 to Dec 5, 2009). The search terms used, singly and in combination, were “atherosclerosis”, “coronary heart disease”, “coronary disease”, “acute coronary syndrome”, “myocardial infarction”, “angina”, “cardiovascular death”, “cardiac death”, “inflammation”, “infection”, “pneumonia”, “respiratory infection”, “gastroenteritis”, “diarrhea”, “bacteria”, and “virus”. We supplemented the search with the references cited in selected articles and correspondence with other colleagues. All relevant articles were discussed by the authors for their inclusion in the final paper.

of an animal model will be of great value for this purpose. At the same time, efforts should be directed at the development of methods to identify people at the highest risk of acute coronary syndromes after an acute infection. Such methods will allow targeted and efficient evaluation of strategies for preventing these complications. These strategies should include, but not be limited to, avoidance of infection (not only through vaccination but personal hygiene, use of masks and hand sanitisers, and, to the extent possible, avoidance of close contact with sick people); earlier recognition and faster treatment of acute infections; the preferential use of aspirin, given the crucial role of thrombosis in acute coronary syndromes, rather than nonsteroidal anti-inflammatory drugs in patients who develop acute respiratory or other infections; and the expanded use of statins, because they have antiinflammatory effects that can reduce the inflammatory burden of these infections within arteries.120 Greater awareness of the association between acute infections and acute coronary syndromes will encourage further research into ways of protecting large numbers of patients at high risk. Contributors VFC-M, MM, and DMM designed and created the Review, and analysed the data. VFC-M also acquired the data and elaborated the figures. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We thank Karla Absi-Delgado for her invaluable contribution to the creation of the figures and the Medical Media Department of the Michael E DeBakey VA Medical Center for assisting with their preparation. This work was partly funded by the Department of Veterans Affairs through the Merit Review Program for DMM. Funds from this source were used for financial support of VFC-M in his role as Research Fellow at Baylor College of Medicine under the direction of DMM. References 1 Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747–57.

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