Acute respiratory tract infections: A potential trigger for the acute coronary syndrome

Abstract

Clinical studies suggest that acute respiratory tract infection (ARTI) may be a risk factor for the acute coronary syndrome (ACS). ARTI is associated with an increased risk for ACS up to 2 weeks prior to a cardiac event. The mechanism that may underlie this association is unclear. Infections are thought to play a role in the progression and instability of atherosclerotic plaques, resulting in plaque rupture, sudden constriction, and/or blockage of coronary arteries. Inflammation, endothelial dysfunction and thrombotic activation seem to play an important role in this. Influenza vaccination may reduce the risk of ACS in patients with coronary artery disease. Future studies will provide more information about the underlying mechanisms of infection‐related ACS.

• Acute coronary syndrome
• inflammation
• plaque rupture
• respiratory infection
• vaccination

Abbreviations
ACS	=	acute coronary syndrome
ARTI	=	acute respiratory tract infection
CAD	=	coronary artery disease
CRP	=	C‐reactive protein
CVA	=	cerebrovascular accident
CVD	=	cardiovascular disease
HDL	=	high‐density lipoprotein
HTN	=	hypertension
IHD	=	ischemic heart disease
LDL	=	low‐density lipoprotein
MI	=	myocardial infarction
PCA	=	primary cardiac arrest
PCI	=	percutaneous coronary intervention
SARS	=	severe acute respiratory syndrome

Introduction

The acute coronary syndrome (ACS) is a leading cause of death in industrialized countries 1. Although the incidence and mortality have declined with the advent of medical therapies and preventive strategies, more than 1 million Americans suffer from ACS each year 2. ACS describes a spectrum of clinical conditions ranging from ST segment elevation myocardial infarction (MI) to non‐ST segment elevation MI and unstable angina (ACS without enzyme or marker release) 3. ACS is caused by narrowing and/or obstruction of the coronary arteries mainly due to rupture of atherosclerotic plaques. The severity of coronary arterial obstruction and the volume of affected myocardium determine the characteristics of clinical presentation 4. Inflammation plays a central role in the development of atherosclerosis and in the occurrence of ACS 5, 6. Acute infections may play a major part in this process 7–11. A range of infectious agents have been linked to atherosclerosis, including cytomegalovirus, Chlamydia pneumoniae, and more recently the influenza virus 12–14. By rapidly increasing inflammation in the coronary arteries, acute infections may trigger destabilization and possible rupture of vulnerable plaques 15. The effects on the coronary wall can be either direct (seeding of the microbe) or indirect (inflammatory cytokines) 14–17. In this study we assessed the association between acute respiratory tract infection (ARTI) and risk of ACS. Also, we reviewed the possible mechanisms by which ARTI may affect the risk of vascular events. We searched PubMed, ScienceDirect, and Ovid, using all relevant articles published from the 1980s to present.

Key messages

• Acute respiratory tract infections are associated with the acute coronary syndrome, when infected within 14 days prior to event.

• A possible underlying mechanism may include infection‐induced destabilization and rupture of atherosclerotic plaques.

• Vaccination for acute respiratory tract infections, and influenza in particular, may prevent the infection‐associated increase of the acute coronary syndrome.

Respiratory infections and risk for acute coronary syndrome

Clinical reports have noted that up to one‐third of acute MI are preceded by a respiratory infection 15–22. The occurrence of ACS undergoes seasonal variation, with a peak during the winter period 23, 24. A possible causal link is the greater number of respiratory infections in winter 25–27. Patient‐control studies suggest that a significant number of patients were infected with the influenza virus just before the onset of ACS 18, 28, 29. Also, during epidemic outbreaks of influenza in Europe and the United States in the early 1900s, about half of the excess mortality was related to cardiovascular diseases 30, 31.

Besides influenza, other ARTIs have also been associated with ACS. In a recently published study, Musher et al. show that patients with pneumococcal pneumonia are at increased risk (19.4%) for acute cardiac events 32. In animal studies it was shown that chickens infected with herpes virus quickly developed atherosclerotic lesions similar to human coronary artery disease 33. In human tissue it appeared that the herpes virus induced lipid accumulation in arterial smooth muscle cells, which is a characteristic feature of atherosclerosis 34. Meier et al. (n = 9571) investigated the development of MI in noninfected controls versus those who recently experienced an ARTI 10. They found that the chance of developing MI within 5 days of a respiratory infection was significantly increased (odds ratio: 3.6; 95% CI: 2.2–5.7). Those who experienced ARTI more than 2 weeks prior to an event were not at increased risk for developing an MI. In other words: during a short period after infection, the risk for MI is increased. A recent study by Smeeth et al. supports those findings. They also showed increased risks for developing stroke 11. Unfortunately, in both studies the clinical diagnosis of ARTI was not confirmed with follow‐up for viral and bacterial organisms. Therefore, symptoms like fatigue, malaise, subfebrile temperature, and angina pectoris could also have been prodroma of ACS.

Table I. Outcome studies: respiratory infections and risk of acute cardiovascular events.

Author, year (ref)	Population	Number	Period (yrs)	Parameters	Conclusions	Findings
Pesonen, 1981 18	Patients with MI and controls	99	1	ARTI versus MI	↑ ARTI within 7 days prior to MI	1 day: P<0.05 3 days: P<0.01 7 days: P<0.05
Tillett, 1983 25	Cohort (UK)	120,100	10	Influenza epidemic versus death CVD	↑ Mortality CVD	31% of excess deaths (P<0.05)
Spodick, 1984 7	Patients with MI/controls	300	1	Symptoms ARTI versus MI	↑ Symptoms of ARTI prior to MI (<14 days)	OR = 6.35
Marshall, 1988 27	New Zealand (cohort)	±5000 (deaths)	12	ARTI versus death of CVD	↑ Mortality CVD from ARTI (patients ⩾55 years old)	Male: OR: 4.5 (±1.8) female: OR: 2.7 (±1.7)
Mattila, 1989 29	Patients with MI and controls with stable angina	70	1	ARTI (symptoms and workup) versus MI	↑ Symptoms of ARTI prior to MI; workup for ARTI: no difference	P<0.05
Meier, 1998 10	Patients with MI and controls	9,571	2	ARTI (symptoms <10 days prior to event) versus MI	↑ Risk for MI	OR: 3.6 (2.2–5.7)
Smeeth, 2004 11	Patients with first MI, first CVA, and controls	39,909	14	ARTI versus MI and CVA	↑ MI and CVA (<14 days after ARTI	MI: OR = 4.95 (4.43–5.53) CVA: OR = 3.19 (2.81–3.62)
Dvorakova, 2004 35	Patients with first MI	65,000	24	Influenza versus MI	↑ MI during influenza epidemic	P<0.05
Madjid, 2007 36	Autopsies (death with or without infection)	27	11	MI, CAD, and acute systemic infections <2 weeks	↑ Macrophages and T cells in coronary artery wall; infection associated with ACS	P<0.05; P<0.05

ARTI = acute respiratory tract infections; ACS = acute coronary syndrome; CVA = cerebrovascular accident; CVD = cardiovascular disease; CAD = coronary artery disease; HTN = hypertension; IHD = ischemic heart disease; MI = myocardial infarction; OR = odds ratio.

Vaccination and risk for acute coronary syndrome

Another way to investigate whether ARTI induces an increased risk for ACS is to compare patients with and without vaccination. Several studies show that those vaccinated are at lower risk for unstable angina pectoris and MI 37, 38. Patients with a history of coronary artery disease that were vaccinated for influenza are at lower risk for developing future MI (odds ratio: 0.33; 95% CI: 0.13–0.82) 37. In a population‐based case‐control study Siscovick et al. examined whether influenza vaccination was associated with a reduced risk of out‐of‐hospital primary cardiac arrest (PCA) 38. After adjustment for demographic, clinical, and behavioral risk factors, influenza vaccination was associated with a reduced risk of PCA (odds ratio: 0.51; 95% CI: 0.33–0.79). A recent cohort study, that included 140,000 patients with a follow‐up of 2 years, assessed the effects of influenza vaccination on the risk of hospitalization for heart disease and stroke, hospitalization for pneumonia and influenza, and death from all causes, during two influenza seasons 39. They concluded that influenza vaccination was associated with a reduction in the risk of hospitalization for cardiac disease (P<0.001), cerebrovascular disease (P<0.018), pneumonia or influenza (P<0.001), and a reduction in the risk of death from all causes of 48% (P<0.001). Gurfinkel et al. performed a study in patients that underwent percutaneous coronary intervention (PCI) with the aim to test the potential beneficial effect of flu vaccination in secondary prevention of cardiovascular death. An absolute risk reduction of 6% was found (relative risk: 0.25; 95% CI: 0.07–0.86) 40. In contrast to other studies, Heffelfinger and co‐workers did not find alteration in risk of MI after influenza vaccination (odds ratio: 0.97; 95% CI: 0.75–1.26) 41. However, this study only evaluated a selection of subjects from one health maintenance organization. Other limitations of this study include the possibility of randomization bias (subjects decided to receive or not receive vaccine) and misclassification of the influenza vaccination status (some subjects may have been vaccinated elsewhere).

Vaccination for other ARTI, such as pneumococci, may also prevent ACS‐associated morbidity and mortality. In a prospective study by Christenson and colleagues (n = 100,242) both pneumococcal and influenza immunizations were associated with a lower mortality (P<0.0001) when compared with the unvaccinated cohort 42. Other studies, like those of Vila‐ Córcoles et al. 43 and Jackson et al. 44, show a similar reduction of mortality and hospitalization after pneumococcal vaccination.

Table II. Outcome studies: influenza vaccination and risk of acute cardiovascular events.

Author, year (ref)	Population	n	Period (yrs)	Parameters	Conclusions	Odds ratio (95% CI)
Naghavi, 2000 37	CAD patients	218	1	Vaccination versus MI	↓ Recurrent nonfatal MI	0.33 (0.13–0.82)
Siscovick, 2000 38	CAD patients	891	8	Vaccination versus MI	↓ Cardiac arrest	0.51 (0.33–0.79)
Nichol, 2003 39	Cohort	286,383	2	Vaccination versus CVD	↓ IHD	0.80 (0.70–0.91)
Gurfinkel, 2004 40	Randomized control study (patients with MI, unstable angina)	301	1	Vaccination versus subsequent MI, CVD death	↓ CVD death; ↓ CVD death/nonfatal MI/severe IHD	0.25 (0.07–0.86); 0.50 (0.29–0.85)
Smeeth, 2004 11	Patients with first MI, first CVA, and controls	41,407	14	Vaccination versus MI	↓ MI	0.68 (0.56–0.84)
Heffelfinger, 2006 41	Case‐control study	2,485	6	Vaccination versus MI	No difference between groups	0.98 (0.75–1.30)

CVD = cardiovascular disease; CAD = coronary artery disease; HTN = hypertension; IHD = ischemic heart disease; MI = myocardial infarction.

Atherosclerosis: the underlying etiology of ACS

The formation of atherosclerosis, the main pathology of ACS, is complex and involves endothelial dysfunction, dyslipidemia, inflammatory and immunologic factors, plaque rupture, and smoking 5. Atherosclerosis starts already in childhood and involves episodes of vascular alteration followed by incomplete healing 45.

Initial stages: from fatty streaks to atherosclerotic plaques

The initial lesion in atherosclerosis involves focal thickening of the intima with an increase in smooth muscle cells, extracellular matrix, and lipid deposition, together referred to as ‘fatty streaks’ 46. As these lesions expand, more smooth muscle cells and macrophages (‘foam cells’) migrate into the intima. This causes increased apoptosis of the smooth muscle cells in the deep layer of the fatty streak and calcification of cytoplasmic remnants. The accumulation of connective tissue, smooth muscle cells, and lipid deposition contribute to the transition of fatty streaks into atherosclerotic plaques 47. Both cellular and humoral inflammatory pathways are involved in the development of atherosclerosis 48, 49. Inflammation in the arterial wall, such as macrophages, causes the secretion of lytic enzymes that break down connective tissue, which results in tissue destruction and compromised structural integrity 50. Macrophages that have been modified by oxidized low‐density lipoprotein (LDL) release a variety of inflammatory cytokines, cellular proteases, prothrombotic molecules, and growth factors 51. Oxidized LDL causes disruption of the endothelial cell surface, resulting in endothelial dysfunction 52. Endothelial dysfunction and impaired vascular reactivity perhaps represents early large vessel disease 53. Autonomic dysfunction and altered neurotransmission may be an important determinant of vascular reactivity 54.

Plaque rupture: from atherosclerosis to acute coronary syndrome

As atherosclerotic plaques develop and expand, they acquire their own microvascular network (vasa vasorum) extending from the adventitia through the media and into the thickened intima 55. These thin‐walled vessels are prone to disruption, leading to plaque hemorrhage 56. Due to inflammation, the coagulation‐inhibiting activity of endothelial cells and the activation of fibrinolysis are decreased 57. This leads to an uncontrolled process of inflammation‐induced coagulation activation. In addition, the inflammation reaction in the coronary arteries inhibits the action of antithrombin, protein C system, and tissue factor pathway inhibitor (TFPI), three major coagulation‐inhibiting proteins, and thereby facilitates thrombosis and related complications 58. Repeated plaque rupture and thrombosis, followed by wound healing, causes progression of atherosclerosis, with an increase in plaque burden and percent stenosis and coronary artery remodeling 59. The site of the rupture of a coronary artery lesion has recently been shown to be most commonly the shoulder of the plaque, where substantial numbers of mononuclear inflammatory cells are located 60.

In contrast with stable angina pectoris, ACS (unstable angina and myocardial infarction) is typically due to rupture of plaques with less than 50% stenosis 3. The ruptured plaque(s) form thrombi that occlude one or more coronary arteries, leading to ischemia of the downstream myocardial tissue, and subsequently causing clinical symptoms.

How acute infections may trigger the acute coronary syndrome

Infectious agents have several potential effects on the pathophysiology of atherosclerosis and its clinical complications 14, 61. Clinical studies indicate that repeated and/or chronic infection with multiple pathogens (‘pathogen burden’) results in persistent chronic inflammation, a key player in the development and progression of atherosclerotic disease 62–64. Viruses or bacteria with a specific tropism for cells of the vascular wall, such as Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 2, are all thought to contribute to vascular inflammation and injury 62, 63, 65, 66. Eventually, patients infected with those pathogens are also at increased risk for death from cardiovascular disease 63, 65, 67.

Whereas most suspected infectious agents initiate or aggravate a chronic vascular or systemic inflammatory process, acute systemic infections may, instead, destabilize existing vulnerable plaques 68, 69. Systemic infections can exert acute and chronic influence on vascular walls. The effects are either direct (through seeding of the microbe in the vascular wall) or indirect (through release of inflammatory cytokines and other systemic effects) 14–17. In a recent study, Madjid and co‐workers conducted an autopsy study to investigate the pathologic effect of systemic infections on coronary artery inflammation 36. They found a significantly higher number of macrophages and T cells in the coronary adventitia and periadventitial fat and more dendritic cells in the intima and media of the infected patients compared with controls who were atherosclerotic without infection. The higher number of inflammatory cells was associated with an increase in the incidence of MI and luminal thrombosis.

Mechanisms by which acute infections may affect atherosclerotic plaques

The mechanisms by which ARTI affects the risk of ACS are not well understood. A number of etiologies have been proposed, which are summarized in Table III.

Table III. Various mechanisms by which acute infections affect arterial inflammation and atherosclerosis.

Effect	Mechanism
Plaque rupture	Acute infections and inflammation cause plaque rupture and thereby precipitating acute coronary events 70, 71.
Endothelial dysfunction	Acute infections cause endothelial dysfunction 72, 73, partly due to increased serum glucose and triglycerides levels 74, 75. Dysfunctional endothelium leads to coronary vasoconstriction, attachment of leukocytes and reduces its fibrinolytic and anticoagulant capacity 76.
↑ Coagulability	Acute infections increase the coagulability of circulating blood via leukocytosis, platelet aggregation, fibrinogen, and C‐reactive protein, decrease in antithrombin‐III, and activation of circulating leukocytes 77, 78.
↑ Plasma viscosity	Plasma viscosity can be increased during fever, especially in combination dehydration 79.
Tachycardia	An increase in heart rate in response to fever increases the statistical chance that a given cardiac contraction will lead to mechanical rupture of the plaque 80.
Psychological stress	Infection, like other illnesses, may trigger depression or anxiety, which are independent predictors of MI 81.

Acute infections induce an acute‐phase reaction that is marked by the production of inflammation mediators. This inflammation reaction results in activation of the coagulation cascade 82. Tissue factor, the most important initiator of blood coagulation, is expressed by monocytes in the atherosclerotic plaques, especially after stimulation of cytokines. In blood, tissue factor generates thrombin and fibrin. After rupture of an atherosclerotic plaque, collagen is released in blood, which activates thrombocytes. Next to thrombin and collagen, thrombocytes are also activated directly by inflammation mediators. After thrombocytes are activated, they express tissue factor to the monocytes, causing a vicious circle 83.

Causative agents of acute respiratory infections use the same mechanisms to activate endothelial cells, leukocytes, and tissue factor‐mediated blood coagulation. In vitro studies show that this results in a prethrombotic state 84, 85. Vice versa, coagulation factors also activate receptors that result in inflammation 86. Those protease‐activated receptors are found in endothelial cells, monocytes, thrombocytes, fibroblasts, and smooth muscle cells 87 and play an important role in connecting inflammation and coagulation.

Inflammation induced by ARTI also results in an increased number of cytokines and C‐reactive protein (CRP), which may cross‐react with components involved in the progression of atherosclerotic plaques. CRP is involved in the immune system by opsonization of pathogens. CRP binds to phosphorylcholine on the cell membrane of both microorganisms and apoptotic cells. It is thought that CRP also binds oxidized LDL‐cholesterol using phosphorylcholine 88. Oxidized LDL‐cholesterol initiates a local inflammatory response and thereby contributes to atherosclerotic plaque instability 89. In contrast high‐density lipoprotein (HDL)‐cholesterol normally has anti‐inflammatory characteristics. However, in mice infected with influenza it is shown that during the acute phase immune response HDL‐cholesterol loses its anti‐inflammatory abilities 17. This is thought to be the result of a systemic inflammation response rather than a direct effect of the influenza virus on HDL‐cholesterol. Those proinflammatory changes in the vascular wall could result in cellular degeneration and rupture of an existing atherosclerotic plaque 16, 90. The combination of inflammation and coagulation and its effect on the stability of atherosclerotic plaques may explain how ARTI leads to an increased risk of ACS.

Discussion

Recent research suggests that ARTI is a risk factor for ACS. The risk decreases with increasing time between ARTI and a cardiovascular event and is absent after 2 weeks. Those findings may be explained by the interaction of coagulation and inflammation agents that result in destabilization and rupture of atherosclerotic plaques. This subsequently leads to acute coronary complications, such as unstable angina pectoris, MI, and stroke. The clinical relevance of prevention of ARTI in those at risk for cardiac events is demonstrated by the fact that vaccination helps to prevent the cascade of inflammation, coagulation, plaque instability, and rupture induced by infection. Aside from a decrease in mortality, vaccination also results in a lower incidence of acute coronary syndromes.

Other ways to prevent ACS, such as the use of antibiotics, remain questionable. A number of studies show that antibiotic treatment significantly reduces adverse cardiac events in patients presenting with ACS 62, 91, 92. Recent clinical trials, however, do not show a reduction in the development of events in patients with ACS 93, 94.

Future preventive measures may include statin treatment. Recent reports suggest that statins decrease the recruitment of inflammatory cells to the coronary arteries 95, 96. Therefore statins may be useful in lowering morbidity and mortality rates among people with atherosclerotic disease during influenza epidemics.

Future studies are required to provide more information about the underlying pathophysiologic mechanisms of infection‐related ACS. A better understanding of the role of chronic and acute infections in the etiology of ACS may result in new strategies for its prevention and treatment. Given the central role of inflammation as a common final pathway for infectious agents, most acute infections have similar nonspecific, injurious effects on the coronary arteries. More severe infections, such as influenza and the severe acute respiratory syndrome (SARS), may have a more profound effect on atherosclerotic disease and could warrant separate studies 15. The hypothesis that inflammation and coagulation result in destabilization and rupture of atherosclerotic plaque and thrombosis may provide opportunities for future prevention and new ways of treatment.