The role of hydrogen in the prevention and treatment of coronary atherosclerotic heart disease

Coronary atherosclerotic heart disease (CHD) is a primary cardiovascular disease caused by atherosclerosis (AS), which is characterized by chronic inflammation and lipid oxidative deposition. Molecular hydrogen (H2) is an effective anti-inflammatory agent and has potential to ameliorate glycolipid metabolism disorders, which is believed to exert beneficial effects on the prevention and treatment of CHD. It is suggested that H2 reduces inflammation in CHD by regulating multiple pathways, including NF-κB inflammatory pathway, pyroptosis, mitophagy, endoplasmic reticulum (ER) stress, and Nrf2 antioxidant pathway. Additionally, H2 may improve glycolipid metabolism by mediation of PI3K and AMPK signalling pathways, contributing to inhibition of the occurrence and development of CHD. This review elaborates pathogenesis of CHD and evaluates the role of H2 in CHD. Moreover, possible molecular mechanisms have been discussed and speculated, aiming to provide more strategies and directions for subsequent studies of H2 in CHD.

Introduction

The incidence of cardiovascular disease is increasing along with the rapid development of the economy and the aging of the global population. It is estimated that cardiovascular disease caused more than 17.7 million deaths, accounting for 31% of global deaths, according to a 2015 report from the World Health Organization (WHO) (Roth et al., 2017). Coronary atherosclerotic heart disease (CHD) is one of the primary cardiovascular diseases in the clinic characterized by myocardial ischaemia and hypoxia due to atherosclerosis (AS)-induced coronary artery stenosis or occlusion. Common symptoms include angina pectoris, myocardial infarction, arrhythmia, and heart failure. Generally, the development of CHD depends on the degree and number of coronary atherosclerotic stenoses and is highly related to risk factors for AS, including dyslipidaemia, diabetes, obesity, hypertension, and family inheritance (Fan and Watanabe, 2022).

Clinical treatment strategies for CHD mainly include pharmacotherapy, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) (Anderson et al., 2016). Drugs for CHD can be classified as nitrates, antiplatelets, anticoagulants, β blockers and calcium channel blockers, based on their specific mechanisms of action (Goldstein, 1997; Inzitari et al., 2005; Lam et al., 2018). Normative pharmacotherapy can ameliorate recurrent ischaemia and improve the clinical symptoms of patients. However, the administration of drugs is always limited by side effects, insufficient efficacy, and contraindication of drug combinations. From the perspective of traditional Chinese medical science, medicinal ingredients and prescriptions that can activate blood circulation and remove blood stasis are suggested for CHD treatment (Yang et al., 2022). However, Traditional Chinese medicine lacks unified medication standards due to its wide variety, complex composition and unclear pharmacology. On the other hand, although PCI and CABG can significantly reduce the mortality and recurrence rate of complex coronary heart disease or acute cardiac events (Neumann et al., 2018), complications are formidable, especially in elderly patients who are prone to postoperative adverse cardiovascular events. Surgical effect can also be affected by multiple factors, such as equipment, technology, postoperative care and individual differences (Knuuti et al., 2020). Cutting edge approaches such as gene therapy (Korpela et al., 2021), immunotherapy (Rurik et al., 2021) and stem cell therapy (Kandaswamy and Zuo, 2018) showing great advantages of target specificity, fewer side effects and remarkable efficacy, however remain underdeveloped in view of the high cost and difficulties in clinical trial design and implementation.

As a colourless and odourless gas in nature with low molecular weight and strong ability to disperse, hydrogen (H2) has become a research hotspot in the medical field since it was first discovered to selectively reduce reactive oxygen species and oxygen free radicals in cells by Ohsawa in 2007 (Ohsawa et al., 2007). Being easily obtained by hydrolysis and accessible to all kinds of people with no significant adverse reactions reported thus far, it has been repeatedly demonstrated with broad anti-inflammatory and antioxidant effects and a significant role in regulating metabolic activities and maintaining the homeostasis of the cardiovascular system in recent years. Thus, applications have been made in conditions such as AS, glycolipid metabolism disorders, myocardial ischaemia/reperfusion (MI/R) injury, myocardial transplant injury and cardiovascular hypertrophy (Zhang et al., 2018). Given the well performance in research on cardiovascular diseases, H2 is considered as a special but promising drug for CHD prevention and treatment.

This review presents existing knowledge on the pathogenesis of CHD and highlights the effects and possible molecular mechanisms of H2 treatment on CHD.

Section snippets

Main pathogenesis of CHD

As the pathological basis of CHD, atherosclerosis is characterized by lipid deposition under the arterial wall and accumulation of T cells and macrophages caused by endothelial cell damage (Tousoulis et al., 2014). Long-term aggregation can cause bleeding, rupture, and calcification that lead to a variety of fatal pathologic consequences (Arbab-Zadeh and Fuster, 2015; Otsuka et al., 2014). Chronic inflammation and lipid metabolism disorder have been widely studied as two major pathogenesis of

The effect of H2 on CHD

In recent years, many fundamental and clinical studies have illustrated that H2 is a potent anti-inflammatory, antioxidant and antiapoptotic molecule with a protective effect on metabolic heart diseases, such as CHD. H2 has discovered to reduce atherosclerotic lesions and infarct size in CHD, although the mechanisms remain unclear. Here, the applications of hydrogen in CHD are systematically described and the possible mechanisms are expounded.

Conclusion

Conventional drugs for the treatment of CHD are mostly limited due to side effects. Metoprolol may induce bradycardia and affect the nervous system and digestive system. Aspirin may cause severe allergic reactions. However, no significant side effects of H2 have been found thus far. In addition, CHD is more prevalent in elderly individuals with low sensitivity to pain, leading to inconspicuous symptoms that are easily ignored and misdiagnosed. Complicated conditions accompanied by hypertension, 

CRediT authorship contribution statement

Yunxi Chen: Writing – original draft, Visualization, Validation, Software, Data curation, Conceptualization. Youzhen Wei: Validation, Investigation, Funding acquisition, Conceptualization. Wenjie Tang: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study was funded by Small and Micro Science and Technology Project of National Health Commission of the People’s Republic of China (Grant No. 20004), and Key Discipline Construction Project of Shanghai Pudong New Area Health Commission (Grant No. PWZxk 2022-20).