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Cardiovascular disease (CVD) is the leading cause of death globally, and is rising in many countries. The WHO estimates that 18 million people die annually from CVD, and the majority of these are a result of heart attack and stroke 1. The association between CVD and influenza has long been recognized, with a peak in CVD mortality during the winter months, corresponding with peaks of influenza activity 2. Coronary artery disease is an inflammatory condition, and influenza more than any other infection has been strongly associated with triggering of acute coronary events 3. The postulated mechanism is that influenza causes systemic inflammation and release of various cytokines, which result in a prothrombotic state, disruption of coronary artery endothelium and acute thrombus formation in a diseased artery which may not otherwise be critically stenosed 3. The infection also acts by causing hypoxia, tachycardia, vasoconstriction and direct effects on the myocardium, the combined effect of which may precipitate acute myocardial infarction (AMI) 3.
Respiratory infection and AMI
A number of studies show that influenza is associated with AMI 4-7. In a meta-analysis of available case-control studies, we showed that influenza infection doubles the risk of AMI 4. In a prospective study, we tested patients admitted with AMI for influenza and found that almost 10% of AMI patients had undiagnosed, unrecognised influenza infection as an antecedent event 5. An influenza infection may occur up to a week prior to AMI, and the diagnosis may not be considered when a patient presents with an acute coronary event. A17-fold increase in risks of developing angiographically confirmed MI was reported by a recent Australian study within 1-7 days following respiratory infection. Lower, but increased RR of 13.5 (95%CI 10.2-17.7) was also observed when the analysis was limited to mild, upper respiratory tract infection of self-reported symptoms for the same period in the study.8
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Herpes zoster infection and AMI
Apart from respiratory infections, few studies have shown an association between cardiovascular events/AMI following herpes zoster (HZ) infection. Rate of MI was reported, an increase of 1.7 fold within a week after diagnosis of HZ infection in a self-controlled case series conducted in the United States of older adults aged 65 years and over.9 An increased, and higher risk (59%) in developing MI was reported compared to other cardiovascular events and stroke with HZ cases compared to controls (non-HZ group) conducted in a large population-based study using a propensity score-matching analysis by a Korean study recently.10 Thus MI is a famous known outcome factor of high morbidity and mortality especially in middle aged and older adults with identified infective causes or pathogens.
CVD and influenza vaccine
If influenza precipitates AMI, then it logically follows that vaccination against influenza may have a protective effect. There is, in fact a large body of evidence from both RCT and observational studies which suggests that influenza vaccine protects against AMI 4. We were the first to calculate vaccine effectiveness against AMI, and found that influenza vaccine effectiveness was 45% against AMI 5. The pooled vaccine effectiveness against AMI calculated from all available studies is 29% 4. From observational studies, it is estimated that influenza vaccine could provide vaccine effectiveness of 19 – 45 % against myocardial infarction 5,11,12. In addition, the vaccine effectiveness is more evident in AMI patients with early seasonal influenza vaccination compared to midseason vaccination (21% vs 12%) in a large matched case-control study conducted in the United Kingdom 12.
Given the high burden of CVD worldwide, a vaccine effectiveness of this range can have a substantial population health benefit in preventing AMI 5. Influenza vaccine is postulated to prevent AMI by preventing influenza infection and the resulting pathological mechanisms outlined above. There is also evidence that influenza vaccine results in antibodies which cross-react with bradykinin receptors, as yet another protective mechanism 13.
Compelling evidence continues to accumulate, with many studies reporting the benefits of influenza vaccine on cardiovascular events and its relative reduction in patients with AMI 14,15. Pooled data from small randomized controlled trials show a relative reduction of 50% in cardiovascular deaths, and 43% in cardiovascular events, with 54% protection for patients who have an acute coronary syndrome within 12 months 16. However, small sample sizes of the available RCTs, as well as with variable study outcomes reported in these studies are a limitation. We have already argued the need for a large randomised controlled trial to better inform policy and practice 17. Currently, a multicenter, registry-based randomised clinical trial is underway with over 4,000 participants to determine the effect of influenza vaccine to all-cause death and cardiovascular events at one year period after in-house influenza vaccination compared to placebo.18 The study finding could provide the valuable information of influenza vaccine against MI in the target population.
We showed that the vaccine effectiveness of influenza vaccine as a coronary prevention of 15-45% against AMI, makes it comparable to accepted strategies such as smoking cessation (32-43% efficacy), use of statins (19-30% efficacy), and use of anti-hypertensive drugs (17-25% efficacy) 3. A paradigm shift is required to view influenza vaccination as another available strategy for secondary prevention of AMI in addition to accepted measures such as statins.
Relationship of vaccine with other preventive measures
Another interesting association between influenza and AMI includes the use of statins. Recent studies have suggested an interaction between statins and influenza vaccine which reduce the benefits of vaccination 19,20. The role of confounding in these studies is unclear, and more research is required to understand this relationship. However, statins have also been proposed as a protective therapy during pandemic influenza due to their anti-inflammatory properties 21. In addition, a reduced risk of MI was also reported in patients who had regular cardiac medications.8 An additive effect of influenza vaccine in such population would be large if the target population have annual flu vaccination plus other cardiovascular preventive strategies for both primary and secondary prevention of cardiovascular events at high-risk population. More in-depth researches are needed to answer these questions.
Influenza vaccine is safe, effective and relatively cheap. It has already shown to be highly cost-effective, even without considering the prevention of AMI 22. Cost-effectiveness studies which include AMI prevention need to be conducted. There is enough evidence available to guide policy, and most immunization policies do in fact recommend influenza vaccination for patients with CVD. Despite influenza vaccine being recommended in many countries for patients with CVD 23, it has not made its way into practice as a routine measure to protect patients at-risk, with vaccination rates in patients with CVD being low 24. It has been shown that clinicians in general have a low awareness of adult vaccination, and are not strong advocates for vaccination in adults 25,26. Improved clinician awareness of the benefits of influenza vaccine in prevention of CVD events is needed to take advantage of vaccination as low hanging fruit for prevention of AMI.
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10. Kim M-C, Yun S-C, Lee H-B, et al. Herpes Zoster Increases the Risk of Stroke and Myocardial Infarction. Journal of the American College of Cardiology. 2017;70(2):295-296.
11. Hsu S-Y, Chen F-L, Liaw Y-P, Huang J-Y, Nfor ON, Chao D-Y. A Matched Influenza Vaccine Strain Was Effective in Reducing the Risk of Acute Myocardial Infarction in Elderly Persons: A Population-Based Study. Medicine. 2016;95(10):e2869.
12. Siriwardena AN, Gwini SM, Coupland CA. Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study. CMAJ. 2010;182(15):1617-1623.
13. Veljkovic V, Glisic S, Veljkovic N, et al. Influenza vaccine as prevention for cardiovascular diseases: Possible molecular mechanism. Vaccine. 2014;32(48):6569-6575.
14. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J. 2008;29(11):1350-1358.
15. Gurfinkel EP, de la Fuente RL, Mendiz O, B M. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J. 2004;25(1):25-31.
16. LeBras MH, Barry AR. Influenza Vaccination for Secondary Prevention of Cardiovascular Events: A Systematic Review. Can J Hosp Pharm. 2017;70(1):27-34.
17. MacIntyre RC, Heywood AE, Kovoor P. Influenza virus vaccine reduces risk of ischemic events: time for a large-scale randomized trial? Future cardiology. 2014;10(1):35-37.
18. Fröbert O, Götberg M, Angerås O, et al. Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial. A registry-based randomized clinical trial. American Heart Journal. 2017;189:94-102.
19. Tumpey TM, Garcia-Sastre A, Taubenberger JK, et al. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol 2005;79:14933-14944.
20. Fessler MB, Young SK, Jeyaseelan S, et al. A role for hydroxy-methylglutaryl coenzyme A reductase in pulmonary inflammation and host defense. Am J Respir Crit Care Med 2005;171:606-615.
21. Fedson DS. Pandemic Influenza: A Potential Role for Statins in Treatment and Prophylaxis. Clinical Infectious Diseases. 2006;43(2):199-205.
22. Newall AT, Scuffham PA, Kelly H, Harsley S, MacIntyre CR. The cost-effectiveness of a universal influenza vaccination program for adults aged 50–64 years in Australia. Vaccine. 2008;26(17):2142-2153.
23. CDC. Centers for Disease Control and Prevention. Flu and Heart Disease & Stroke.Available at https://www.cdc.gov/flu/heartdisease/index.htm. Accessed 19 April, 2017.
24. Madjid M1, Alfred A, Sahai A, Conyers JL, Casscells SW. Factors contributing to suboptimal vaccination against influenza: results of a nationwide telephone survey of persons with cardiovascular disease. Tex Heart Inst J. 2009;36(6):546-552.
25. Raina MacIntyre C, Menzies R, Kpozehouen E, et al. Equity in disease prevention: Vaccines for the older adults – a national workshop, Australia 2014. Vaccine. 2016;34(46):5463-5469.
26. MacIntyre CR. Elderly vaccination—The glass is half full. Health. 2013;5:80-85.
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