**Abstract**

Endothelial cells play a critical role in maintaining the integrity of vascular structure and function. Endothelial dysfunction is closely associated with the development and progression of cardiovascular diseases (CVDs) like hypertension (HTN) and atherosclerosis. Gut microorganisms significantly contribute to atherosclerosis and related CVDs. *Helicobacter pylori* (*H. pylori*) colonizes in human gastric epithelium in a significant portion of general population in the world. Patients with *H. pylori* infection have significantly increased risk for CVDs including atherosclerosis, HTN, coronary heart disease, and cerebrovascular disease especially in younger patients (< 65 years old). *H. pylori* infection significantly impairs vascular endothelial function through multiple mechanisms including increased reactive oxygen species production and oxidative stress, inflammation, decreased nitric oxide formation, modification of the expression of cytokines and microRNAs, abnormalities of lipid and glucose metabolisms, and exosomes-mediated pathways. Endothelial dysfunction associated with *H. pylori* infection is reversible in both animal model and human subjects. Accumulating data suggests that *H. pylori* infection is an important risk factor for endothelial dysfunction and CVDs especially in young patients. Screening young male population for *H. pylori* infection and treating accordingly could be an effective approach for early prevention of CVDs especially premature atherosclerosis associated with *H. pylori* infection.

**Keywords:** *Helicobacter pylori*, atherosclerosis, endothelial dysfunction, cardiovascular disease, exosomes

### **1. Introduction**

Atherosclerosis is among the principal contributors to cardiovascular diseases (CVDs) especially coronary artery diseases (CAD) and stroke [1]. Despite in-depth understanding of the traditional cardiovascular risk factors including diabetes mellitus (DM), hypertension (HTN), hyperlipidemia, smoking, and obesity, and effective control of these known risk factors, CVDs remain the leading cause of mortality and morbidity in developed countries including the US [2, 3]. It is worrisome that the decline of all cardiovascular mortality rate has been slowing down since 2011 [4]. It is very problematic that patients presenting with ST elevation myocardial infarction over the past 20 years are getting younger [5], and the total number of death from CAD and stroke is projected to increase by

about 18% by 2030 [6]. Clearly, there are other risk factors that have not been defined, and yet contribute significantly to the development and progression of atherosclerosis and related CAD and stroke.

Gut microorganisms significantly contribute to the development of atherosclerosis and related CVDs [7–9]. The microaerophilic Gram-negative bacterium *Helicobacter pylori* (*H. pylori*) colonizes in the epithelium of human stomach in a significant portion of general population in the world with the infection rate ranging from 30% - 50% in developed countries up to 80% in developing countries especially in Asia [10, 11]. Most patients with *H. pylori* infection have no symptoms clinically [12]. However, *H. pylori* infection could cause progressive damage to gastric mucosa, and is closely associated with a number of important diseases including (but not limited to) chronic gastritis, peptic ulcers, and gastric cancer [13]. Recent data indicate that *H. pylori* infection could also contribute to some important extra gastrointestinal diseases such as hematological diseases (especially idiopathic thrombocytopenia), neurological abnormalities, dermatological pathologies, and autoimmune disorders like inflammatory bowel diseases, chronic liver disease, and DM [14–22]. Thus, *H. pylori* infection is a significant cause of morbidity and mortality in humans. In 2005, Dr. Barry Marshall and Dr. Robin Warren were awarded the Nobel Prize in Physiology for their pioneering work on *H. pylori*.

Growing evidences indicate that *H. pylori* infection could also contribute to CVDs. A recent meta-analysis with a large population showed that *H. pylori* infection increased the risk of adverse cardiovascular events by 51%, mostly due to myocardial infarction and cerebrovascular disease [23]. Data also suggests that *H. pylori* infection increases the risk of coronary heart diseases (CHD) and related events predominantly in a patient's early life [24], and is positively associated with HTN [25, 26]. In this chapter, efforts will be focused on: 1) brief overview on the association of *H. pylori* infection and CVDs; 2) relationship between *H. pylori* infection and atherosclerosis; 3) *H. pylori* infection and endothelial dysfunction; 4) role of exosomes in mediating the effect of *H. pylori* infection on endothelial function, and 5) significance and clinical implications.
