**7. Significance and clinical implications**

It is very concerning that cardiovascular mortality has been increasing since 2010 especially for males for unknown reasons [6]. It is also reported that the patients with ST elevation myocardial infarction over the past 20 years are getting younger [5]. The reasons for this reverse trend in cardiovascular mortality and mobility have yet to be defined. *H. pylori* infection selectively increased the risk for carotid atherosclerosis in young male patients (≤ 50 years), not in older males or female patients. A recent study [33] that analyzed a large database with a study population of 208,196 showed that the mortality rate was significantly lower in patients with early eradication of *H. pylori* infection. The cumulative CAD rate was significantly decreased in younger patients (<65 years old) with *H. pylori* eradication therapy within 1 year of infection compared to those patients without eradication at all. Interestingly, the treatment of *H. pylori* eradication did not have a benefit in older patients (>65 years old). These data strongly suggested that *H. pylori* infection could be a significant risk factor for endothelial dysfunction, atherosclerosis and CAD in young patients, and could provide a potential explanation for young patients who develop CAD without a clear etiology. It is unclear why *H. pylori* infection does not increase the risk for atherosclerosis for patients older than 50 years. It is possible that other significant risk factors like DM, HTN, and hyperlipidemia play a dominant role that could mask the contribution of *H. pylori* infection to the development and progression of atherosclerosis in this age group of patients. Further studies are needed to investigate the mechanism(s) on the selective effect of *H. pylori* infection on atherosclerosis in young population.

There are substantial sex differences in many CVDs including (but not limited to) myocardial infarctions, heart failure, hypertension, and cardiac hypertrophy [88]. It is well known that premenopausal women are relatively protected from CVDs when compared to men. Typically, women are almost 10 years older than men when they have their first myocardial infarction [89]. It was believed that the decreased cardiovascular morbidity and mortality in young females was due to possible cardio-protective effects of estrogen [90]. However, several large clinical studies, including the HERS trials and the Women's Health Initiative study [91, 92] showed that hormone replacement therapies (HRT) had no cardiovascular benefit in post-menopausal women. In contrast, there might have been an increased risk of CAD during the first year of HRT, and there was an increased risk of nonfatal ventricular arrhythmias among the women on HRT [91]. Thus, the mechanism(s) for decreased CVD risk in premenopausal women is still unclear. The prevalence of *H. pylori* infection was the same in males and females, and yet, *H. pylori* infection only increased the risk for carotid atherosclerosis in male patients≤50 years, not in older males or female patients. It is possible that the significant sex and age difference in the development of atherosclerosis associated with *H. pylori* infection may be one of the reasons for decreased risk for CAD in young females. Further studies are needed to confirm these findings with both patients and experimental animal models.

Currently available data strongly suggest that *H. pylori* infection is an important risk factor for endothelial dysfunction and CVDs especially in young male population. The available data also provide solid evidence to support screening young male population for *H. pylori* infection once a year and treating accordingly for early prevention of CVDs especially premature atherosclerosis associated with *H. pylori* infection.
