Could vaccinations prevent myocardial infarction?

Could Vaccinations Prevent Myocardial Infarction? David G. Meyers,

MD, MPH,

n a recent report, Naghavi and coworkers1 determined the frequency of antecedent influenza vaccination in 218 of their patients with coronary heart disease during the months of October 1997 through March 1998. Among 109 patients who experienced an acute myocardial infarction (AMI) in that period, the percentage who had been vaccinated in that current season was 47% versus 71% among 109 patients with coronary heart disease without AMI (odds ratio 0.33, 95% confidence interval 0.13 to 0.82, p ⫽ 0.017). They suggested that vaccination against influenza might reduce the risk of AMI. The public health implications, if their observation is correct, are tremendous. Although the idea that vaccination could beneficially impact on AMI is novel and seemingly unfounded, there is a surprising amount of observational evidence to support the hypothesis. Disruption of the so-called “vulnerable plaque” with resultant intravascular thrombosis often leads to unstable coronary syndromes and most ischemic strokes.2 Plaque disruption and intraluminal thrombosis is not a random event. Purported triggers of plaque disruption have been reported in nearly 50% of patients with AMI.3 Plaque disruption is most likely caused by surges in sympathetic activity with a sudden increase in blood pressure, pulse rate, heart contraction, and coronary blood flow. Thrombosis then occurs on plaques when the systemic thrombotic tendency is high, as with platelet hyperaggregability or hypercoagulability, or thrombus may abnormally persist because of impaired fibrinolysis. It was first observed in the 1920s that acute vascular events occur more frequently in winter months.4 Since then, similar observations have been made in several temperate but geographically diverse areas.5 In 300,000 deaths from the Canadian Mortality Database, the incidence of fatal AMI and ischemic stroke was increased 19% and 20%, respectively, in January compared with the trough in September.6 A total of 259,891 cases of AMI from the Second National Registry of Myocardial Infarction, which occurred between July 1, 1994, and July 31, 1996, were analyzed by season.7 The incidence of AMI was 53% greater in winter than in summer, with case fatality rates follow-

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From the Division of Cardiovascular Disease, Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, Kansas. Manuscript received October 9, 2001; revised manuscript received and accepted November 21, 2001. Address for reprints: David Meyers, MD, MPH, Division of Cardiovascular Disease, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160-7378. E-mail: dmeyers@ kumc.edu. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 March 15, 2002

and Peter D. Jurisich,

DO

ing a similar seasonal pattern. Conversely, in a subtropical region with no seasonal temperature extremes, no seasonal variation of the incidence of AMI was observed.8 The winter peaks in AMI mortality have been correlated with temperature and shown to be greater among those with less personal protection from temperature extremes.9 Whereas no mechanism has been elucidated, many physiologic and biochemical changes associated with plaque disruption and intravascular thrombosis are known to correlate with temperature or season. Sympathetic tone, blood pressure, myocardial oxygen consumption, red blood cell count, hematocrit, platelet count, blood viscosity, and white blood cell count are all increased in winter.10 Cholesterol, ␣ antitrypsin, ␤ thromboglobulin, plasma cortisol, and C-reactive protein also increase in winter.11,12 Components of the clotting system show winter elevations including fibrinogen, factor VII activity, and platelet factor 4, while the fibinolytic system concurrently reaches a seasonal trough.13 Could the seasonal changes observed in both AMI incidence and relevant biochemical factors be due to seasonal infections? Systemic infection produces changes similar to those observed in cold weather. The link between infection and inflammation on the one hand and the immune response and coagulation on the other hand is phylogenetically ancient. Systemic infection results in elevations in blood pressure, white blood cell count, total and low-density lipoprotein cholesterol, tumor necrosis factor, interleukin-1, C-reactive protein, and fibrinogen.14 These changes certainly could either precipitate plaque disruption or predispose to intravascular thrombosis. In 1981, Pesonen and Siitonen15 were the first to call attention to an association between respiratory infections and AMI. This was followed in the United States by a matched case-control study,16 which showed an odds ratio of 2.1 for antecedent upper respiratory symptoms among patients with AMI. In a nested case-control study of 1,922 cases and 7,649 matched controls, significantly more cases (2.8%) than controls (0.9%) recalled having an acute respiratory tract infection in the 10 days before their index AMI (odds ratio 3.6, 95% confidence interval 2.2 to 5.7).17 In a database of 2,264 persons with AMI, 19% reported a flu-like illness or infection in the week preceding their AMI.18 To avoid recall bias, a nested case-control study of 3,172 male farmers used office records of visits to confirm that those with recurrent or chronic upper respiratory infections were at increased 0002-9149/02/$–see front matter PII S0002-9149(01)02346-3

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risk of AMI (odds ratio 1.3).19 It has been observed that deaths for “organic heart disease” were increased after the influenza epidemics in the United States in the early 1900s and in London between 1952 and 1965.20,21 Using national health statistics for the United States, Gordon and Thom22 showed a correlation between monthly deaths from ischemic heart disease and deaths from influenza and pneumonia. They observed a spike in ischemic heart disease mortality that corresponded to a spike in influenza incidence. They suggested that most of the observed decrease in ischemic heart disease mortality in the 1960s might be attributable to epidemic fluctuations on the incidence of upper respiratory infections. But in contrast, the Minnesota Heart Survey found no correlation between coronary heart disease trends and influenza epidemics.23 Community-living persons have 1.5 to 5.6 upper respiratory infections per year, primarily in winter months.24 Seven to 12% of persons, aged 50 to 60 years, are infected each year, as are 13% to 16% of those aged ⬎60 years. In adults, ⬎85% of upper respiratory infections are viral including rhinovirus in 36% of cases, influenza A in 25%, influenza B in 13%, parainfluenza in 9%, respiratory syncytial virus in 9%, adenovirus in 4%, and others in 4%.23 Influenza virus was isolated in 7.6/1,000 adults and peaked in November through April.25 Overall, influenza virus infects 5% to 40% of the general population each year. A review the efficacy of influenza vaccination noted a 50% reduction of incident disease in a metaanalysis of 23 cohort studies of “flu-like illness.”26 A similar 50% reduction in incident influenza was seen in a randomized clinical trial of the vaccine.27 Despite the 1976 to 1977 outbreak of GuillainBarre´ syndrome, which was possibly associated with the swine influenza (A/New Jersey) vaccine, influenza vaccine has been remarkably safe. Two randomized, placebo-controlled, blinded clinical trials with a total of 2,655 participants found no difference in occurrence of systemic symptoms 2 to 7 days after vaccination.28,29 The United States Army observed no increased incidence of Guillain-Barre´ syndrome among vaccinated soldiers between 1980 and 1988. Similarly, the national Vaccine Adverse Event Reporting System identified no increased risk of vaccine-associated Guillain-Barre´ syndrome in the United States between 1992 and 1994.30 They noted an incidence of 1 to 2 cases/1,000,000 or 1 additional case of Guillain-Barre´ syndrome per million persons vaccinated against influenza. What would be the public health impact if influenza vaccination really did protect against AMI? About 800,000 AMIs occur in the United States each year. Between 3% and 19% of persons with AMI report an antecedent upper respiratory illness.24 Thirty-eight percent of upper respiratory illnesses are due 724 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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to influenza A or B.23 Influenza vaccine is efficacious in 50% of recipients.26 Thus, between 4,256 and 26,600 AMIs yearly could be prevented. The absolute risk reduction of between 0.5% and 3.3% translates into a number needed to treat of 200 and 30, respectively. This compares favorably with other prevention strategies. If all persons aged ⬎65 years were vaccinated each year, it would cost between $2,500 and $12,050 per myocardial infarction prevented. Naghavi et al1 proposed several possible mechanisms for the beneficial effect of influenza vaccination. First, influenza might stimulate inflammation of plaque, thus contributing to rupture. Second, influenza might activate other pre-existing infections such as herpes simplex virus or Chlamydia pneumoniae, which in turn could contribute to plaque rupture. Influenza-induced cytokines could stimulate macrophage proliferation, resulting in activation of matrix metalloproteinases. Influenza could directly cause endothelial dysfunction. Platelet aggregation and increased coagulability occur with influenza. Fever and dehydration may lead to increased plasma viscosity. Influenza causes increased serum levels of glucose and triglycerides, which promote endothelial dysfunction. Influenza causes fever that, by increasing shear force of the endothelium, might promote plaque rupture. And last, illness due to influenza might produce psychological stress, which is associated with AMI. These proposed mechanisms could apply broadly to all infections. Thus, would a similar benefit be produced by pneumococcal vaccination? Ischemic nonembolic stroke appears also to have a mechanism involving plaque rupture and thrombosis. Could vaccination also prevent stroke? Of course, the hypothesis suggested by the important observational study of Naghavi et al1 needs to be confirmed in a prospective manner. Yet, given the extremely positive risk/benefit ratio and extraordinarily low cost of vaccination, the possibility of preventing AMI (and possibly stroke) may be an added reason for widespread influenza vaccination of adults.

1. Naghavi M, Barlas Z, Siadaty S, Naguib S, Madjid M, Casscells W. Associ-

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