|Year : 2014 | Volume
| Issue : 2 | Page : 106-109
A case-control study examining association between infectious agents and acute myocardial infarction
Sunanda N Shrikhande1, Sanjay P Zodpey2, Himanshu Negandhi3
1 Associate Professor, Department of Microbiology, Indira Gandhi Government Medical College, Nagpur, Maharashtra, India
2 Director - Public Health Education, Public Health Foundation of India, New Delhi, India
3 Assistant Professor, Indian Institute of Public Health, New Delhi, India
|Date of Web Publication||12-May-2014|
Sunanda N Shrikhande
A/303, Amar Enclave, Prashant Nagar, Ajni, Nagpur - 440 015, Maharashtra
Source of Support: Indian Clinical Epidemiology Network., Conflict of Interest: None
| Abstract|| |
Background: Coronary heart disease is multi-factorial in origin and its burden is expected to rise in developing countries, including India. Evidence suggests that the inflammation caused by infection is associated with the development of atherosclerosis and heart disease. An increasing number of clinical and experimental studies point to a contribution of various infectious organisms to the development of atherosclerosis in humans. Acute myocardial infarction (AMI) is associated with atherosclerosis. Objectives: The objective of the following study is to study the association between Helicobacter pylori, Chlamydia pneumoniae and C-reactive protein (CRP) with AMI. Materials and Methods: This group-matched case-control study was carried out in Government Medical College, Nagpur, Maharashtra, India. The study compared the risk of occurrence of AMI (outcome) if subjects were ever-infected with H. pylori or C. pneumoniae; and their CRP positivity (exposure). Incident cases of myocardial infarctions in a tertiary care hospital were included as cases. Results: The study recruited 265 cases and 265 controls and detected an odds ratio (OR) of 2.50 (95% confidence interval [CI]: 1.69-3.70) and an OR of 2.50 (95% CI: 1.71-3.65) for C. pneumoniae and H. pylori, respectively. Raised CRP levels had an OR of 3.85 (95% CI: 2.54-5.87). Conclusion: Although our study indicates the role of infections in the etiology of AMI in study population, the relative public health impact of these agents in the overall prevalence of AMI needs urgent research attention.
Keywords: Acute myocardial infarction, Atherosclerosis, Case-control study, Infection
|How to cite this article:|
Shrikhande SN, Zodpey SP, Negandhi H. A case-control study examining association between infectious agents and acute myocardial infarction. Indian J Public Health 2014;58:106-9
|How to cite this URL:|
Shrikhande SN, Zodpey SP, Negandhi H. A case-control study examining association between infectious agents and acute myocardial infarction. Indian J Public Health [serial online] 2014 [cited 2017 Nov 17];58:106-9. Available from: http://www.ijph.in/text.asp?2014/58/2/106/132285
| Introduction|| |
By 2020, cardiovascular diseases (CVD) will not only be the leading cause of mortality and disability globally; the burden of disease is expected to rise to 140-160 million disability-adjusted life years annually. Developing countries are expected to bear about 80% of this total global burden of disease in 2020.  During the period of years between 1990 and 2020, ischemic heart disease is also anticipated to increase by 120% for women and 137% for men in developing countries, compared with age-related increases of 30-60% in developed countries. , CVDs and diabetes have a higher age-standardized adult mortality rate by cause in South-East Asia Region (324 in South-East Asia vs. 245 globally for ages 30-70/100,000 population). 
The role of persistent bacterial and viral infections in the outcome of coronary heart disease (CHD) has been evaluated by some researchers.  Evidence suggests that the inflammation caused by infection is associated with the development of atherosclerosis and CHD. , The mechanisms linking infection to atherosclerosis have been listed by Sessa et al.  Early studies demonstrated that an experimental infection of germ-free chickens with the avian herpes virus produced an arterial disease resembling human atherosclerosis.  Since, then associations have since been reported of human CHD with certain Gram-negative bacteria (Helicobacter pylori and Chlamydia pneumoniae) and with cytomegalovirus.  While, some studies report evidence of bacteria or viruses in atheromatous and nonatheromatous blood vessels, most studies are sero-epidemiological studies based on antibody measurements. C-reactive protein (CRP) is produced by the liver and its level rises when there is inflammation throughout the body.  The CRP levels rise with inflammation. This is a general test to check for inflammation in the body. An increasing number of clinical and experimental studies point to a contribution of various infectious organisms to the development of atherosclerosis in humans. Against this background and the fact that no comprehensive evidence is available on the role of above stated infections in the outcome of CHD in Indians, we undertook a hospital-based pair-matched case-control study with the objective to investigate the association between H. pylori antibody positivity/C. pneumoniae antibody positivity and CRP with acute myocardial infarction (AMI).
| Materials and Methods|| |
A group-matched case-control study was carried out in the Intensive Cardiac Care Unit and cardiology ward of Government Medical College Hospital, Nagpur, Maharashtra, India over 2 years between 2004 and 2005. The study procedures outlined in the modified Declaration of Helsinki  were adhered throughout the study. The institutional ethics committee also cleared the study. The Government Medical College Hospital, Nagpur, Maharashtra, India is a tertiary care hospital catering to patients from Central India.
All consecutive incident cases of AMI admitted to these two wards were eligible for inclusion as cases. Those consenting to participate were enrolled within 24 h of onset of symptoms. A case was diagnosed as AMI if two out of the three criteria (clinical symptoms, electrocardiogram changes and raised enzyme levels) were positive. Cases of AMI with cardiogenic shock or cases with chronic illnesses like untreated hyper or hypothyroidism, renal disease or malignancies were excluded as these conditions could alter patient lifestyle or risk factors for AMI. Each case was matched with one control. The cases and controls were group-matched for age (±2 years), gender and socio-economic status, and they were selected from patients admitted in the hospital for other conditions not related to CHD or its risk factors. The exclusion criteria for controls additionally included any diagnosis of heart disease or history of exertional chest pain.
The sample size of 265 cases and 265 controls was calculated to attain 80% power. The sample size was calculated based on the information available in the literature. The sample size of 265 cases and equal number of controls was required for attaining 80% power. The sample size was calculated using Schesselmen's approach  and it was checked by using the two-sample proportion formula. The risk level of interest was expressed as the odds ratio (OR). A one-sided alpha was assumed as the lack of risk is not of interest. The sample size provided the study with 80% power to detect the risk level associated with the factor. It was assumed that the prevalence of the risk factors in the general population, represented by the controls will be not <10% and not >25%. It was assumed that a level <10% will not be of interest for mass intervention. If the level is higher than 25%, the power will not be affected. Taking the OR as 2 and a 10% exposure level in the controls, 250 individuals are needed in each group. A pretested study questionnaire acquired information on participants' risk factors for AMI. A single trained research associate who was blinded to the study objective administered the questionnaire during the hospital stay of the subjects. IgG antibodies to H. pylori in human serum were quantitatively determined (Genix HP IgG EIA test kit) and IgG antibodies specific to C. pneumoniae infection were also detected (Ani Labsystems' C. pneumoniae IgG test). The measurement of IgG antibodies was carried out in Department of Microbiology and CRP levels were measured in Department of Biochemistry, Government Medical College, Nagpur, Maharashtra, India.
Simultaneous data entry was carried out in Excel spreadsheet. Descriptive analysis was carried out to present the summary statistics. Bi-variate analysis was carried out as per the method described by Greenberg and Ibrahim.  Crude OR with 95% confidence interval (CI) and Person's Chi-square was calculated for all three risk factors.
| Results|| |
The present case-control study included 265 cases of AMI and 265 controls. [Table 1] shows the distribution of study subjects by matching factors. Over two-third of the cases of AMI were from urban areas. [Table 2] shows the results of bi-variate analysis for the three infectious agents included in the study with their OR. The current study investigated the association of C. pneumoniae and H. pylori with AMI. Both these infections were found to be significantly associated with AMI. Similarly, raised levels of CRP were also significantly associated with AMI. The study detected an OR of 2.50 (1.69-3.70) and an OR of 2.50 (95% CI: 1.71-3.65) for C. pneumoniae and H. pylori, respectively suggesting that AMI patients with IgG positive for these infections are 2.5 times more likely to suffer from AMI. Raised CRP levels had an OR of 3.85 (95% CI: 2.54-5.87), suggesting that patients with raised CRP levels are 3.85 times more likely to suffer from AMI.
|Table 2: Bi-variate analysis (Chi-square, P value) and ORs (95% CI) for AMI risk factors|
Click here to view
| Discussion|| |
Published evidence from studies suggests biological plausibility of our study findings. C. pneumoniae may participate in the pathogenesis of atherosclerosis through immune activation and the initiation of a chronic inflammatory state in the infected arterial wall. C. pneumoniae has been detected in atherosclerotic plaques  and in serum of patients with coronary artery disease. It induces foam cells (the hallmark of early atherosclerosis) and markedly accelerates this disease process in animal models. However, data from another recent Indian study found that there was no direct evidence of the involvement of C. pneumoniae and other infective agents and viruses in coronary artery disease; however, suggested the possibility that such infections produce an indirect adverse effect on the lipid profile.  Kowalski et al.  have reported that the H. pylori seropositivity was significantly higher in the coronary artery disease group than in controls without coronary artery disease, the OR being 4.3 for H. pylori in coronary artery disease.
A case-control design has been recommended by the earlier studies  to examine this problem. Our study included hospital-based controls, thereby enhancing the motivation of controls and impacting study feasibility. A potential disadvantage was that this population might not be representative of the general population. Methodologically, the recruitment used in the current research ensured that cases and controls were drawn from the same catchment area, and met a fundamental criterion that cases and controls were selected from the same source population. Despite concerns about potential biases from hospital-based controls, the results obtained from several major case-control studies on this subject have been consistent with results from the cohort studies.
A substantial proportion of patients with coronary artery disease does not have traditional risk factors , of the disease. The results of this study suggest that microbial agents may be involved in the pathogenesis of myocardial infarction. In the background of scarce Indian data, this study has attempted to bridge the gap. However, considering the wide variation in the prevalence of these microbial agents in different parts of the country further research using multi-centric case-control studies across the country could be undertaken for more detailed investigation. If similar association between these agents and AMI is observed in other studies, it will have far-reaching implications for the prevention and treatment of AMI.
Systemic antibody titers demonstrating previous exposure to infectious pathogens with persistently positive serology represent candidate markers for chronic, persistent infection. The seropositivities in the present study might have resulted from acute/recent infection or from chronic/persistent/repeated infections. CRP has been reported to be elevated in patients with acute ischemia and MI. However, as past information about CRP level of the patients was not enquired/available and CRP levels were studied only after the current AMI, raised CRP may be the outcome of MI and not a risk factor. The present design and methods did not permit us to examine this facet of the relationship.
Although, our study indicates the role of infections in the etiology of AMI in study population, an examination of the relative public health impact of these agents in the overall prevalence of AMI needs research attention. Although, associations detected in this study may not imply causation, the study findings need to be further examined in larger studies to establish etiology.
| Acknowledgments|| |
The researchers acknowledge the support of Indian Clinical Epidemiology Network in conducting this study. However, they had no role in the collection, analysis and interpretation of data; in writing the manuscript or in submitting the manuscript for publication.
| References|| |
|1.||Murray CJ, Lopez AD. Alternative visions of the future. In: Murray CJ, Lopez AD, editors. Summary: The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Disease, Injuries and Risk Factors in 1990 and Projected to 2020. Boston, USA: Harvard School of Public Health; 1996. p. 325-96. |
|2.||Leeder S, Raymond S, Greenberg H, Liu H, Esson K. A Race against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: Trustees of Columbia University; 2004. |
|3.||Gaziano TA, Reddy KS, Paccaud F, Horton S, Chaturvedi V. Cardiovascular disease. Disease Control Priorities in Developing Countries. 2 nd ed. New York: Oxford University Press; 2006. p. 645-62. |
|4.||WHO. World Health Statistics 2013. Geneva: World Health Organization; 2013. |
|5.||Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: Is there a link? Lancet 1997;350:430-6. |
|6.||Ross R. Atherosclerosis - An inflammatory disease. N Engl J Med 1999;340:115-26. |
|7.||Sessa R, Di Pietro M, Santino I, del Piano M, Varveri A, Dagianti A, et al. Chlamydia pneumoniae infection and atherosclerotic coronary disease. Am Heart J 1999;137:1116-9. |
|8.||Fabricant CG, Fabricant J, Litrenta MM, Minick CR. Virus-induced atherosclerosis. J Exp Med 1978;148:335-40. |
|9.||C Reactive Protein. Available from: http://www.nlm.nih.gov/medlineplus/ency/article/003356.htm. [Last cited on 2014 Feb 01]. |
|10.||Carlson RV, Boyd KM, Webb DJ. The revision of the declaration of Helsinki: Past, present and future. Br J Clin Pharmacol 2004;57:695-713. |
|11.||Schlesselman JJ. Case-Control Studies: Design, Conduct, Analysis. New York: Oxford University Press; 1982. |
|12.||Greenberg RS, Ibrahim MA. The case-control study. In: Holland WW, Detels R, Knox G, editors. Text-Book of Public Health. Oxford: Oxford University Press; 1985. p. 123-43. |
|13.||Fazio G, Giovino M, Gullotti A, Bacarella D, Novo G, Novo S. Atherosclerosis, inflammation and Chlamydia pneumoniae. World J Cardiol 2009;1:31-40. |
|14.||Padmavati S, Gupta U, Agarwal HK. Chronic infections & coronary artery disease with special reference to Chalmydia pneumoniae. Indian J Med Res 2012;135:228-32. |
|15.||Kowalski M, Konturek PC, Pieniazek P, Karczewska E, Kluczka A, Grove R, et al. Prevalence of Helicobacter pylori infection in coronary artery disease and effect of its eradication on coronary lumen reduction after percutaneous coronary angioplasty. Dig Liver Dis 2001;33:222-9. |
|16.||Pearson TA, Smith SC Jr, Poole-Wilson P. Cardiovascular specialty societies and the emerging global burden of cardiovascular disease: A call to action. Circulation 1998;97:602-4. |
|17.||Fong IW. Emerging relations between infectious diseases and coronary artery disease and atherosclerosis. CMAJ 2000;163:49-56. |
[Table 1], [Table 2]