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Review Article
U
ntil the early 20th century, the human life expectancy was From the Michael E. DeBakey Veterans
less than 50 years, and infections were often fatal. Only in the past cen- Affairs Medical Center and Baylor Col-
lege of Medicine, Houston (D.M.M.); Na-
tury have humans, on average, lived long enough for cardiovascular dis- tional Institute of Allergy and Infectious
ease to develop regularly and have antimicrobial therapies made survival from Diseases, National Institutes of Health,
infection the norm. Furthermore, sophisticated techniques for assessing myocar- Bethesda, MD (M.S.A.); and the Ottawa
Hospital Research Institute and Univer-
dial damage have evolved during the past 50 years. It is therefore not surprising sity of Ottawa, Ottawa (V.F.C.-M.). Ad-
that an association between acute infections and myocardial infarction has been dress reprint requests to Dr. Musher at
appreciated only in the past few decades. We will review the evidence that acute Infectious Disease Section, Rm. 4B-370,
Veterans Affairs Medical Center, 2002
bacterial and viral infections are associated with an increased risk of myocardial Holcombe Blvd., Houston, TX 77030, or
infarction in the short, intermediate, and long term, and we will then discuss at daniel.musher@va.gov.
mechanisms that might explain this association. N Engl J Med 2019;380:171-6.
DOI: 10.1056/NEJMra1808137
Copyright © 2019 Massachusetts Medical Society.
Shor t-Ter m R isk of M yo c a r di a l Infa rc t ion A sso ci ated
w i th Acu te Infec t ions
Excess mortality from cardiovascular disease during influenza epidemics was first
recognized early in the 20th century, but the specific association of influenza and
other infections with myocardial infarction was not characterized until decades
later.1 An increase in the short-term risk of myocardial infarction has been de-
scribed in association with influenza, pneumonia, acute bronchitis, and other
chest infections.2-5 A recent study showed an increase in the risk of myocardial
infarction during the week after laboratory-confirmed infection with influenza
virus, respiratory syncytial virus, or other respiratory viruses, to a risk that was
six, four, and three times higher, respectively, than the risk during the year before
or after the onset of infection.5
In a retrospective case series6 and, subsequently, in a prospective study,7 Musher
(one of the authors of this review article) and colleagues found a rate of myocar-
dial infarction of 7 to 8% among patients who were hospitalized for pneumococ-
cal pneumonia. The association between pneumonia and myocardial infarction
was confirmed in patients with Haemophilus influenzae pneumonia and in those with
pneumonia from any cause.8-12 The risk of myocardial infarction associated with
pneumonia peaks at the onset of infection and is proportional to the severity of
illness.9,11,12 A self-controlled case series involving U.S. veterans showed a remark-
able increase in the risk of myocardial infarction during the first 15 days after
hospitalization for acute bacterial pneumonia, to a risk that was 48 times higher
than that in any 15-day period during the year before or after the onset of infec-
tion.8 An increase in the short-term risk of myocardial infarction has also been
described in association with urinary tract infection2 and bacteremia.13
Intimal cells
Thickened
fibrin
Foamy
macrophages Disrupted
smooth-muscle cells
T lymphocytes
Lipid deposits
Accumulated
metalloproteinases Lipid core: cholesterol crystals,
and peptides other lipids, and calcium
“demand ischemia” (Fig. 3B). Inflammation and of acute infection have not distinguished between
fever increase the metabolic needs of peripheral type 1 and type 2 myocardial infarction, but de-
tissues and organs. The resulting increase in mand ischemia should explain only a small pro-
heart rate shortens the filling time during dias- portion of infection-related myocardial infarction
tole, thereby compromising coronary perfusion, events that occur in the short-term postinfection
which occurs mainly in this part of the cardiac period and none beyond that period.
cycle.32 In older adults, cardiac metabolic mismatch Studies in animals have suggested a third pos-
may be increased by coronary stenosis from sible mechanism by which infection might ad-
chronic plaques and possibly by toxin-mediated versely affect cardiac function. Experimentally
vasoconstriction.33 If pneumonia is the inciting induced pneumococcal bacteremia has caused
infection, blood oxygen levels may fall because cardiac lesions that are characterized by vacuol-
of ventilation–perfusion defects, thereby further ization and loss of myocytes without accumula-
limiting oxygen supply to the myocardium. Sep- tion of inflammatory cells; these changes are
tic shock, if it occurs, has a substantial adverse associated with elevated troponin levels, arrhyth-
effect on the coronary blood supply. Most studies mias, and the presence of abnormalities on
Trapping of
red cells
LUMEN Platelets
Fibrin
Neutrophils
↑Procoagulants
Activated platelets Oxidative
damage
Figure 4. Features Present after Cardiac Involvement
in Acute Infection.
Shown is an example of direct myocardial involvement
in pneumococcal pneumonia. In the heart of a patient
who was treated with antibiotic agents but still died
Fibrin
from pneumococcal pneumonia, there are disrupted
Inflammatory cells myocytes and there is a relative absence of neutrophil
Neutrophils infiltration.21 In addition, in experimentally induced in-
Extracellular traps fection and without treatment, microcolonies of Strep-
Metalloproteinases tococcus pneumoniae were present.21
Peptidases
ceived pneumococcal polysaccharide vaccine than tients who were not receiving these drugs.42,43 A
among those who had not.40 The lack of a more 7 to 8% risk of myocardial infarction among
prominent effect may reflect the decline in the patients who are hospitalized for pneumonia cer-
prevalence of pneumococcal pneumonia in recent tainly provides support for prospective testing
decades.41 of such agents for the prevention or mitigation of
myocardial infarction. Likewise, the use of statins
and other antiinflammatory agents, even in the
Sum m a r y
absence of a specific indication, could be exam-
Practitioners may be able to influence the risk of ined in patients who are considered to be at high
postinfection myocardial infarction if they re- risk by virtue of high Framingham risk scores or
main mindful of the increased risk of myocar- the presence of severe infection. The use of such
dial infarction during and after acute infections prophylaxis might also be examined in patients
and if they do not dismiss elevated troponin who have severe sepsis of any cause.
levels as “troponin leak.” Among patients with Finally, because the risk of other cardiovascu-
acute infection who have clinical indications for lar events — such as heart failure, arrhythmias,
statins and aspirin, these medications should be and strokes — also increases after acute infec-
continued (if the patient is already receiving tion, the mechanisms that account for these as-
them) or may be initiated if no contraindications sociations need to be characterized. This is espe-
are present. cially important in the case of heart failure,
because after pneumonia the risk of worsening
heart failure is even higher than the risk of myo-
F u t ur e Dir ec t ions
cardial infarction. An integrated understanding
Whether statins and drugs that inhibit platelet of the interplay between acute infections and the
activation offer a benefit to all patients with cardiovascular system should facilitate efforts to
acute infection — even those who do not have reduce the risk of myocardial infarction and other
known clinical indications for these treatments cardiovascular events after acute infections.
— is an issue worthy of clinical investigation. No potential conflict of interest relevant to this article was
Observational studies have shown a lower risk of reported.
postpneumonia myocardial infarction among pa- Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
tients who were receiving glucocorticoids and We thank Dr. Glenn Levine for his thoughtful comments on
drugs that block angiotensin than among pa- an earlier version of the manuscript.
References
1. Collins SD. Excess mortality from ter laboratory-confirmed influenza infec- 10. Violi F, Cangemi R, Falcone M, et al.
causes other than influenza and pneumo- tion. N Engl J Med 2018;378:345-53. Cardiovascular complications and short-
nia during influenza epidemics. Public 6. Musher DM, Alexandraki I, Graviss term mortality risk in community-acquired
Health Rep (1896-1970) 1932;47:2159-79. EA, et al. Bacteremic and nonbacteremic pneumonia. Clin Infect Dis 2017;64:1486-
2. Smeeth L, Thomas SL, Hall AJ, Hub- pneumococcal pneumonia: a prospective 93.
bard R, Farrington P, Vallance P. Risk of study. Medicine (Baltimore) 2000;79:210- 11. Ramirez J, Aliberti S, Mirsaeidi M, et al.
myocardial infarction and stroke after 21. Acute myocardial infarction in hospital-
acute infection or vaccination. N Engl J 7. Musher DM, Rueda AM, Kaka AS, ized patients with community-acquired
Med 2004;351:2611-8. Mapara SM. The association between pneu- pneumonia. Clin Infect Dis 2008;47:182-7.
3. Clayton TC, Thompson M, Meade TW. mococcal pneumonia and acute cardiac 12. Corrales-Medina VF, Alvarez KN,
Recent respiratory infection and risk of events. Clin Infect Dis 2007;45:158-65. Weissfeld LA, et al. Association between
cardiovascular disease: case-control study 8. Corrales-Medina VF, Serpa J, Rueda hospitalization for pneumonia and subse-
through a general practice database. Eur AM, et al. Acute bacterial pneumonia is quent risk of cardiovascular disease. JAMA
Heart J 2008;29:96-103. associated with the occurrence of acute 2015;313:264-74.
4. Warren-Gash C, Geretti AM, Hamil- coronary syndromes. Medicine (Baltimore) 13. Dalager-Pedersen M, Søgaard M,
ton G, Rakhit RD, Smeeth L, Hayward AC. 2009;88:154-9. Schønheyder HC, Nielsen H, Thomsen
Influenza-like illness in acute myocardial 9. Corrales-Medina VF, Musher DM, RW. Risk for myocardial infarction and
infarction patients during the winter wave Wells GA, Chirinos JA, Chen L, Fine MJ. stroke after community-acquired bactere-
of the influenza A H1N1 pandemic in Cardiac complications in patients with mia: a 20-year population-based cohort
London: a case-control study. BMJ Open community-acquired pneumonia: inci- study. Circulation 2014;129:1387-96.
2013;3(5):e002604. dence, timing, risk factors, and associa- 14. Warren-Gash C, Hayward AC, Heming-
5. Kwong JC, Schwartz KL, Campitelli tion with short-term mortality. Circulation way H, et al. Influenza infection and risk
MA, et al. Acute myocardial infarction af- 2012;125:773-81. of acute myocardial infarction in England
and Wales: a CALIBER self-controlled case tion in atherosclerotic coronary arteries: rus myocarditis in mice: light and elec-
series study. J Infect Dis 2012;206:1652-9. clues to the triggering effect of acute in- tron microscopic, virologic, and hemody-
15. Warren-Gash C, Blackburn R, Whita- fections on acute coronary syndromes. Tex namic study. Am J Pathol 1990;136:409-19.
ker H, McMenamin J, Hayward AC. Labo- Heart Inst J 2007;34:11-8. 35. Oseasohn R, Adelson L, Kaji M. Clini-
ratory-confirmed respiratory infections as 25. Semeraro N, Ammollo CT, Semeraro F, copathologic study of thirty-three fatal
triggers for acute myocardial infarction Colucci M. Sepsis, thrombosis and organ cases of Asian influenza. N Engl J Med
and stroke: a self-controlled case series dysfunction. Thromb Res 2012;129:290-5. 1959;260:509-18.
analysis of national linked datasets from 26. Rose JJ, Voora D, Cyr DD, et al. Gene 36. Corrales-Medina VF, Musher DM,
Scotland. Eur Respir J 2018;51:1701794. expression profiles link respiratory viral Shachkina S, Chirinos JA. Acute pneumo-
16. Bergh C, Fall K, Udumyan R, Sjöqvist infection, platelet response to aspirin, and nia and the cardiovascular system. Lancet
H, Fröbert O, Montgomery S. Severe in- acute myocardial infarction. PLoS One 2013;381:496-505.
fections and subsequent delayed cardio- 2015;10(7):e0132259. 37. Feldman C, Anderson R. Community-
vascular disease. Eur J Prev Cardiol 2017; 27. Mangold A, Alias S, Scherz T, et al. acquired pneumonia: pathogenesis of acute
24:1958-66. Coronary neutrophil extracellular trap bur- cardiac events and potential adjunctive
17. Ou SM, Chu H, Chao PW, et al. Long- den and deoxyribonuclease activity in ST- therapies. Chest 2015;148:523-32.
term mortality and major adverse cardio- elevation acute coronary syndrome are 38. Drosatos K, Lymperopoulos A, Ken-
vascular events in sepsis survivors: a nation- predictors of ST-segment resolution and nel PJ, Pollak N, Schulze PC, Goldberg IJ.
wide population-based study. Am J Respir infarct size. Circ Res 2015;116:1182-92. Pathophysiology of sepsis-related cardiac
Crit Care Med 2016;194:209-17. 28. Cangemi R, Casciaro M, Rossi E, et al. dysfunction: driven by inflammation, en-
18. Jafarzadeh SR, Thomas BS, Warren DK, Platelet activation is associated with myo- ergy mismanagement, or both? Curr Heart
Gill J, Fraser VJ. Longitudinal study of the cardial infarction in patients with pneu- Fail Rep 2015;12:130-40.
effects of bacteremia and sepsis on 5-year monia. J Am Coll Cardiol 2014;64:1917-25. 39. Udell JA, Zawi R, Bhatt DL, et al. As-
risk of cardiovascular events. Clin Infect 29. Yende S, D’Angelo G, Kellum JA, et al. sociation between influenza vaccination
Dis 2016;63:495-500. Inflammatory markers at hospital dis- and cardiovascular outcomes in high-risk
19. Libby P. Mechanisms of acute coro- charge predict subsequent mortality after patients: a meta-analysis. JAMA 2013;310:
nary syndromes and their implications for pneumonia and sepsis. Am J Respir Crit 1711-20.
therapy. N Engl J Med 2013;368:2004-13. Care Med 2008;177:1242-7. 40. Ren S, Newby D, Li SC, et al. Effect of
20. Otsuka F, Joner M, Prati F, Virmani R, 30. Yende S, D’Angelo G, Mayr F, et al. the adult pneumococcal polysaccharide
Narula J. Clinical classification of plaque Elevated hemostasis markers after pneu- vaccine on cardiovascular disease: a sys-
morphology in coronary disease. Nat Rev monia increases one-year risk of all-cause tematic review and meta-analysis. Open
Cardiol 2014;11:379-89. and cardiovascular deaths. PLoS One 2011; Heart 2015;2(1):e000247.
21. Brown AO, Mann B, Gao G, et al. 6(8):e22847. 41. Musher DM, Abers MS, Bartlett JG.
Streptococcus pneumoniae translocates 31. Vallance P, Collier J, Bhagat K. Infec- Evolving understanding of the causes of
into the myocardium and forms unique tion, inflammation, and infarction: does pneumonia in adults, with special atten-
microlesions that disrupt cardiac function. acute endothelial dysfunction provide a tion to the role of pneumococcus. Clin
PLoS Pathog 2014;10(9):e1004383. link? Lancet 1997;349:1391-2. Infect Dis 2017;65:1736-44.
22. Mauriello A, Sangiorgi G, Fratoni S, 32. Ferro G, Duilio C, Spinelli L, Liucci 42. Cangemi R, Falcone M, Taliani G, et al.
et al. Diffuse and active inflammation oc- GA, Mazza F, Indolfi C. Relation between Corticosteroid use and incident myocar-
curs in both vulnerable and stable plaques diastolic perfusion time and coronary ar- dial infarction in adults hospitalized for
of the entire coronary tree: a histopatho- tery stenosis during stress-induced myo- community-acquired pneumonia. Ann Am
logic study of patients dying of acute myo- cardial ischemia. Circulation 1995;92:342-7. Thorac Soc 2018 September 6 (Epub ahead
cardial infarction. J Am Coll Cardiol 2005; 33. Sibelius U, Grandel U, Buerke M, et al. of print).
45:1585-93. Staphylococcal alpha-toxin provokes cor- 43. Mortensen EM, Nakashima B, Cornell
23. Kaynar AM, Yende S, Zhu L, et al. Ef- onary vasoconstriction and loss in myo- J, et al. Population-based study of statins,
fects of intra-abdominal sepsis on athero- cardial contractility in perfused rat hearts: angiotensin II receptor blockers, and angio-
sclerosis in mice. Crit Care 2014;18:469. role of thromboxane generation. Circula- tensin-converting enzyme inhibitors on
24. Madjid M, Vela D, Khalili-Tabrizi H, tion 2000;101:78-85. pneumonia-related outcomes. Clin Infect
Casscells SW, Litovsky S. Systemic infec- 34. Kotaka M, Kitaura Y, Deguchi H, Dis 2012;55:1466-73.
tions cause exaggerated local inflamma- Kawamura K. Experimental influenza A vi- Copyright © 2019 Massachusetts Medical Society.