Early prognosis of unstable angina patients with positive Helicobacter pylori IgG values

Coronary atherosclerosis is a chronic inflammatory disorder, initiated and driven on by the recruitment and activation of inflammatory cells in the vascular intima, and has been linked with persistent bacterial or viral infections. Epidemiological studies have shown increased prevalence of cardiovascular diseases in patients with serological evidence of infection by intracellular pathogens such as cytomegalovirus, herpes simplex virus, chlamydia pneumoniae and helicobacter pylori among many pathogens. These organisms are reported to be associated with the pathogenesis of the cardiovascular diseases. By the same mechanisms, helicobacter pylori is likely to be associated with the short term as well as long term prognosis of the cardiovascular diseases as well. But this aspect has not been studied till now. Our study is an IJBR (2013) 04 (03) www.ssjournals.com Abstract


Introduction
Coronary atherosclerosis is a chronic inflammatory disorder, initiated and driven on by the recruitment and activation of inflammatory cells in the vascular intima, and has been linked with persistent bacterial or viral infections 1,2 . Epidemiological studies have shown increased prevalence of cardiovascular diseases in patients with serological evidence of infection by intracellular pathogens such as cytomegalovirus, herpes simplex virus, chlamydia pneumoniae and helicobacter pylori among many pathogens. These organisms are reported to be associated with the pathogenesis of the cardiovascular diseases. By the same mechanisms, helicobacter pylori is likely to be associated with the short term as well as long term prognosis of the cardiovascular diseases as well. But this aspect has not been studied till now. Our study is an effort to understand the role of helicobacter pylori on the prognosis of cardiovascular disease events.

Sampling Method
: Study sample was based on period based sampling. Patients who were positive for IgG H. pylori were taken as study subjects and similar number of patients who were negative for IgG H. pylori were taken as study controls.

Inclusion Criteria:
Patients with the clinical and the ECG features suggestive of unstable angina admitted who were positive for H. pylori IgG values were followed up for a period of 30 days. These were study subjects. Controls were the patients with clinical and the ECG features suggestive of unstable angina admitted at the Kasturba Medical College hospitals who were negative for H. pylori IgG values. They were also followed up for a period of 30 days.

Exclusion Criteria:
Patients who did not give consent to be part of the study. Patients who were not willing for follow up visits for subsequent 1 month.
Both the cases and the controls were evaluated by the following parameters. The study was carried over a period of 1 year.

Definition of Unstable angina 3
The angina pectoris or equivalent ischemic discomfort with at least one of the three features (1) It occurs at rest (or with minimal exertion) usually lasting more than 10 minutes.
(2) It is severe and of new onset (that is within the prior 4 to 6 weeks), and/or (3) It occurs with a crescendo pattern (that is distinctly more severe, prolonged, or frequent than previously.

Statistical Methods:
For the analysis of data, the SPSS-PC (Statistical Package for Social Sciences) was used. The mean and proportions were used for each continuous variable like age, total leukocyte count, ESR. For comparing mean values of cases and controls of various measures, like total leucocyte count and ESR, one-way ANOVA was used. Fisher's Exact test was used to compare distribution of risk factors like hypertension, diabetes among the cases and the controls and to compare the outcome among H. pylori positive and H. pylori negative subjects.

Results and Data analysis
Our study involved following up of the cases presenting with the features of unstable angina attending the Kasturba Medical College hospitals for 1 month. The study was carried over a period of 1 year. A total of 86 cases of unstable anginadiagnosed by clinical history and evaluated by complete blood counts, ESR, ECG and IgG H. pylori by ELISA method were followed up. The patients were regularly followed up for next 1 month and noted for the development of nonfatal myocardial infarction, cardiac failure and death. The patients undergoing coronary angiogram and revascularization were noted. Few of the patients had sudden cardiac death during the study period. The patients were put into the cases and the control group based on the titres of IgG H. pylori by ELISA. Those patients with IgG H. pylori titres of more than 40 EU/ml were taken as positive-i.e. cases and those with titres less than 40 EU/ml were taken as negative-i.e. controls. We had a total of 46 cases and 40 controls in the study. This included 51 males and 35 females [table1]. All the patients were anticoagulated with heparin on admission and were on aspirin during the follow-up period.
IJBR (2013) 04 (03) www.ssjournals.com    (2013) 04 (03) www.ssjournals.com  Table 10]. One patient each among both the groups developed cardiac failure [ Table 11]. Two cases and three controls underwent coronary revascularization procedure [ Table 12]. 2 cases and controls had sudden cardiac death during the period [ Table 13]. Among the cases, after the follow up period, five patients had composite outcome, compared with controls where three had composite outcome (i.e. more than one of the clinical study end points mentioned above).There was no statistically significant difference in the outcome among the cases compared to the controls in any of the study end points.  Analysis showed significant difference in the ESR values and total leucocyte counts of the cases and that of the controls probably indicating contribution of infection in pathogenesis of unstable angina [ Table 9].

Discussion
The incidence of the cardiovascular diseases has been increasing all over the world and studies are being conducted all over to understand the reasons for this increasing trend. Cardiovascular diseases have been proposed to be associated with chronic infections since long and the increasing trend of the cardiovascular diseases, is at least in part, probably related to the infectious etiology. Several organisms have been proposed to have causal relationship with acute coronary syndromes. Helicobacter pylori, Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenza are some of these organisms. The association between H. pylori infection and coronary artery disease was described by Mendel et al. in 1994 and has further been tested by several studies 4,5,6,7,8,9,10 . Our study was conducted because of the conflicting results available from the study results published from different parts of world and also because the lack of studies in India till now testing the effect of H. pylori seropositivity on the prognosis of the patients with unstable angina. The primary end points of our study, recurrent angina, myocardial infarction, heart failure and death were studied in unstable angina patients with and without H. pylori seropositivity for a period of 28 days. There was no significant difference in any of the outcomes between the study groups. In other words, the early prognosis of unstable angina patients with H. pylori seropositivity was not different from those with H. pylori seronegativity.
The relation between H. pylori infection and cardiovascular diseases has been studied in many of the studies. Several studies support pathogenic link between H. pylori infection and coronary atherosclerosis. H. pylori is probably directly involved in pathogenesis of coronary heart disease because the DNA of H. pylori has been found in coronary arteries of individuals with coronary artery disease 11 . Infectious agents like H. pylori are likely involved not only in the initiation of the atherosclerosis, but also in the progression of the atherosclerosis as well. This has been proved by a study by Espinola-Klein et al., who showed significant association between infectious burden and the extent of atherosclerosis and also that in individuals with advanced atherosclerosis, the future risk of death is increased by the number of infectious IJBR (2013) 04 (03) www.ssjournals.com pathogens. Study by Niccoli et al. also support the association between CagA-positive H. pylori infection and coronary atherosclerotic burden 12 . The higher infectious burden in individuals with coronary artery disease has also been supported by an Iranian study 13 . So, association of H. pylori in atherosclerosis is logically expected to be associated with worse prognosis in acute coronary events. But this was not the case in our study and early prognosis in unstable angina was un affected by H. pylori seropositivity. Probably long term prognosis is influenced to a greater extent by H. pylori seropositivity.
H. pylori, because of the pathogenetic mechanism in atherosclerosis, is likely to be related to causation of unstable angina as well as myocardial infarction. Study by Miyazaki et al 14 16 El Marshad et al. 17 showed an association between Acute Myocardial Infarction and H. pylori seropositivity. A Meta analysis by Franceschi F et al. suggests that in a subset of patients with unstable angina, an intense immune response against CagA-positive H. pylori strains might be critical to precipitate coronary instability mediated by antigen mimicry between CagA antigen and a protein contained in coronary atherosclerotic plaques 9 . But we did not observe significantly increased occurrence of myocardial infarction in subgroup of unstable angina patients with H. pylori seropositivity in our study during the one month follow up period.
But, there has been no consensus about the role of infectious agents in either causation or progression of cardiovascular diseases in all studies. A Canadian study was conducted to assess the role of C. Pneumoniae, CMV, Adenovirus, Hepatitis A and H. pylori in the development of atherosclerosis. This study found association between heart disease and C. Pneumoniae only but not with H.pylori 18 . Similarly, several others studies also have reported lack of association between Acute coronary syndromes and H. pylori infection 19,20,21,22 . Rahime Eskandarian et al. in a prospective study showed that H. pylori infection has no effect on short term prognosis of patients with ACS 23 . The same result has been observed in our study as well.
The role of infectious diseases in cardiovascular diseases has been tested in several major trials by looking for the prognosis after administering antibiotics to the individuals with acute coronary syndromes. WIZARD (Weekly Intervention with Zithromax for Atherosclerosis and Related Disorder) study 24 failed to find a long term benefit of administering Azithromycin for individuals with stable coronary artery disease, serologic evidence of C. Pneumoniae and past history of myocardial infarction. The ineffectiveness of antibiotics for prevention of secondary cardiovascular events has also been shown in ACES, 25 PROVE IT-TIMI 26 and AZACS 27 trials. But STAMINA 28 trial found that antibiotic treatment significantly reduces adverse cardiac events in patients with acute coronary syndromes, but this was independent of H. pylori or C. pneumoniae seropositivity.
There is some important link between the infectious diseases and the acute coronary syndromes as evident from the several studies quoted above, but this probably does not affect the early prognosis, which has been reflected by our study. So, the infectious agents like H. pylori may be related to the pathogenesis rather than outcome of coronary artery diseases. There is need to rethink and revise hypothesis and research strategies related to the role of infectious agents in coronary artery diseases. There is strong need to conduct research about pro-atherogenic mechanisms of infections in order to give boost for preventive cardiology. Only then there is possibility of discovering novel anti-infective agents and vaccines which will have positive impact in preventing ever increasing catastrophic cardiac coronary events all over the world.

Conclusions
The early prognosis of the patients of unstable angina with positive Helicobacter pylori IgG values is not significantly different from those with negative Helicobacter pylori IgG values.
Long term studies are needed to study the prognosis of unstable angina patients with Helicobacter pylori infection.

Limitation of Study
Angiography could not be performed on all the patients because of financial constraints, which might have helped in understanding impact of H. pylori sero-positivity on the extent of atherosclerosis, in addition to the prognosis.