Heart Outcomes Prevention Evaluation (HOPE) Infections Substudy - HOPE Infections Substudy


The goal of the study was to evaluate whether exposure to 4 infections was a prospective risk marker for cardiovascular (CV) events among patients with preexisting CV disease or at high risk of disease.

Study Design

Study Design:

Patients Enrolled: 3,168
Mean Follow Up: mean 4.5 years
Mean Patient Age: mean age 65.4 years
Female: 22%

Patient Populations:

Enrollment in the HOPE study at a Canadian site. HOPE inclusion criteria included: age >=55 and a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other CV risk factor (hypertension, elevated total cholesterol levels, low HDL cholesterol levels, cigarette smoking, or documented microalbuminuria).


HOPE exclusion criteria included: heart failure, known low ejection fraction (<0.40), use of ACE inhibitor or vitamin E, uncontrolled hypertension or overt nephropathy, or MI or stroke within 4 weeks before the study began.

Primary Endpoints:

Incident MI, stroke, or CV death

Secondary Endpoints:

MI alone, stroke alone, either combined with revascularization

Drug/Procedures Used:

The HOPE trial was a multicenter, randomized clinical trial of the angiotensin converting enzyme (ACE) inhibitor ramipril, vitamin E, both, or neither for the prevention of CV events. Baseline serological testing was performed by staff blinded to clinical outcomes in 3,168 of the 9,541 patients in the HOPE trial. Serum samples were tested for antibodies to chlamydia (C) pneumoniae, helicobacter pylori, cytomegalovirus (CMV), and hepatitis A virus (HAV).

Principal Findings:

Neither positive C pneumoniae IgG (adjusted hazard ratio, 0.87; 95% CI, 0.68, 1.10), C pneumonia IgA (adjusted HR, 1.10; 95% CI, 0.90, 1.34), H pylori IgG (HR, 0.99; 95% CI, 0.82, 1.19), nor HAV IgG (HR, 1.01; 95% CI, 0.83, 1.24) were associated with the primary endpoint of MI, stroke, or CV death (data in parentheses) or the individual endpoints of MI or stroke. However, positive CMV serostatus (>0.4 IU/mL, present in 70.4% of patients) was associated with increased CV death, MI or stroke (adjusted HR 1.24; 95% CI, 1.01, 1.53), as was a higher total pathogen score (adjusted HR for 4 versus 1 or 0=1.41; 95% CI, 1.02, 1.96). CMV was also associated with the individual endpoints of MI alone (adjusted HR 1.33, 95% CI, 1.04, 1.58) and with the primary events combined with revascularization (adjusted HR 1.17, 95% CI, 1.01, 1.36).


Among patients with preexisting or at high risk for CV disease, exposure to CMV but not to C pneumoniae, H pylori, or HAV was associated with a small but significant excess risk of MI, stroke, or CV death by 4.5 years. Likewise, total pathogen score based on these 4 infections predicted an increased risk of CV events.

Previous retrospective and case-control studies have identified an association between coronary and cerebrovascular disease with prior exposure to the bacteria C pneumoniae and helicobacter pylori, and with the viruses CMV, herpes simplex virus types 1 and 2, enteroviruses, and hepatitis A. The HOPE substudy is one of the first prospective studies to examine such relationships and, notably only the virus CMV was associated with increased CV death, MI or stroke. However, the study population in the HOPE trial was comprised of patients with preexisting or at high risk for CV disease. As such, the present study cannot address the association of these pathogens in first CV events.

Additionally, it is unknown if the infection is ongoing or resolved. Several studies have shown a stronger relationship between CV events and the sum of multiple infectious exposures (i.e., a total pathogen score), rather than individual infection exposures. The earlier studies showed that the increased risk was primarily due to seropositivity of the viral pathogens included in the score. Similar results occurred in the HOPE substudy analysis, with a total pathogen score of 4 associated with a higher risk of CV death, MI or stroke compared with a pathogen score of 0 or 1, largely driven by the CMV status. The use of other markers more specifically associated with active infection may prove to be more strongly associated with atherosclerosis progression and CV risk.


Circulation. 2003;107:251-257.

Keywords: Immunoglobulin G, Stroke, Pneumonia, Atherosclerosis, Chlamydia, Simplexvirus, Risk Factors, Cytomegalovirus, Ramipril, Peripheral Vascular Diseases, Smoking, Peptidyl-Dipeptidase A, Cholesterol, alpha-Tocopherol, Hypertension, Diabetes Mellitus

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