**3.** *Helicobacter pylori* **infection and carotid atherosclerosis**

The relationship between *H. pylori* infection and atherosclerosis has been inconsistent and sometimes controversial with the findings from a strong positive association, and a mild association, to no association [27, 34–36]. Compared to those without *H. pylori* infection, patients with *H. pylori* infection, especially with CagA**+** *H. pylori*, have much higher incidence of atherosclerosis (29% vs. 63%) [37], and acute ischemic stroke (45% vs. 77%) [17]. The prevalence of serologically confirmed *H. pylori* infection was significantly higher in patients with angiographically documented CAD, supporting a positive association between *H. pylori* infection and CAD [38–40]. However, a meta-analysis with inclusion of 18 epidemiological studies and over 10,000 patients showed no positive relationship between *H. pylori* infection and CAD [41]. In contrast, the data supporting a positive relationship between *H. pylori* infection and carotid atherosclerosis with increased carotid intima-media thickness (CIMT) were consistent in most of the studies with patients [17, 42–45]. The reason(s) for the significant difference in consistency on the relationship between *H. pylori* infection and CAD vs. carotid atherosclerosis is unclear. It could be very likely due to the different imaging modalities used for the detections of CAD (using coronary angiogram) and carotid atherosclerosis (using carotid ultrasound). Carotid ultrasound could easily detect early atherosclerotic lesions without significant loss of vascular lumen, while coronary angiogram could not. In a recent study, the investigators used cardiac multidetector computed tomography to identify subclinical coronary atherosclerotic lesions in healthy subjects without clinical CVD, and found that patients with current *H. pylori* infection was 3-fold more likely to have subclinical and yet significant coronary atherosclerosis than the patients without *H. pylori* infection [15]. One of the major features of atherosclerosis is thickening of the intima-media in the arteries that could not be detected with angiogram. Carotid artery is considered an early site of atherosclerosis, and superficially located. Thus, carotid ultrasound examination is an ideal and sensitive non-invasive image modality to diagnose and monitor the

progression of atherosclerosis [46], although it has not been widely used clinically for atherosclerosis screening at this point.

Recently, a large patient database of 17,613 adult patients with carotid ultrasound examination and a 13C-urea breath *H. pylori* test was analyzed [47]. Based on the study designs, the patients were divided into two groups: a cross-sectional study for single measurement group, and a retrospective cohort study for the patients with follow up measurements up to 5 years. Patients were excluded from the study if any of the following conditions was present: 1) history of *H. pylori* eradication, 2) use of any antibiotics, proton pump inhibitors, or H2-receptor blockers 3 months before the tests, 3) age < 20 or > 70 years, 4) connective tissue diseases or immunological diseases, 5) mental disorders, 6) asthma or COPD, 7) hematological disorders, 8) thyroid diseases, 9) malignancies, 10) recent (within 3 months) or chronic infection (over 3 months) except *H. pylori* infection, 11) congestive heart failure, and 12) abnormal liver or kidney function. Patients with CAD were not excluded from the study since carotid atherosclerosis and CAD share similar risk factors, and it was felt that exclusion of the subjects with CAD could remove the subgroup population who might be at increased risk for carotid atherosclerosis with *H. pylori* infection, leading to potential selection bias. Of note, the patients with CAD accounted only for about 3% of all participating subjects for this study, and there was no stroke in the patients in the database.

The data showed that, after adjusting for age, sex, body mass index, lipid profile, HTN, DM, and smoking, *H. pylori* infection was an independent risk factor for carotid atherosclerosis in male patients ≤50 years, but not in older males or females (OR of 1.229, p = 0.009). The data also demonstrated that *H. pylori* infection was associated with a significant increase in CIMT for males, not females. To further evaluate the relationship between *H. pylori* infection and carotid atherosclerosis, the investigators studied the 5 years follow up data on additional 2,042 subjects with and without *H. pylori* infection for progression on the prevalence of carotid atherosclerosis with annual carotid ultrasound examination and a 13C-urea breath test. The data showed that for males with age of <50 years, there was a 22.5% increase in the prevalence of carotid atherosclerosis in the subjects with *H. pylori* infection compared with the ones without *H. pylori* infection. These data demonstrated that *H. pylori* infection selectively increased the risk for carotid atherosclerosis in young males under 50 years old [47]. However, how *H. pylori* infection could lead to atherosclerosis, and why only in young males is unknown.
