Effects of Angiotensin Receptor-Neprilysin Inhibitor (Arni) with Supervised Exercise Therapy on Mitochondrial Function and Immune Regulation of Lymphocytes in Patients with Heart Failure

Heart failure (HF) is the terminal stage of many cardiovascular disorders, often accompanied by other comorbidities, resulting in extremely high rates of rehospitalization and mortality. HF causes sympathetic activation and elevates oxidative stress, which aggravates myocardial deterioration and impairs immune function. The infection caused by immune dysfunction is an important factor that causes death in HF patients. Clinical investigations demonstrated that HF patients frequently present abnormal distribution of leukocytes in blood. The number or relative proportion of lymphocytes in blood showed a negative correlation with the severity of the disease. Therefore, the number and function of lymphocytes in blood may be used as the biosignature for the HF progression. Exercise training improves the regulations of nervous, endocrine and immune systems. The exercise benefits may either counteract the development of decompensation or reduce the risk of non-cardiac comorbidities (eg, infection) in patients with HF. High-intensity interval exercise training (HIIT) had better improvements of aerobic capacity and circulatory function than moderate-intensity continuous exercise training (MICT) in HF patients. Moreover, HIIT also alleviated hypoxia-induced autophagic suppression and apoptotic activation in lymphocytes. However, what kind of exercise prescription should be performed for eliciting the best immune adaptation in HF patients, which is still unclear. According to the latest guidelines for the management of HF medication, angiotensin receptor-neprilysin inhibitors (ARNI) have the dual pharmacological effects of angiotensin receptor blocker (ARB) with neprilysin inhibitor (eg, vasodilation, lowering blood pressure and diuretic effects) can effectively reduce the rates of rehospitalization and mortality in HF patients. Studies in the HF have also found that the benefits of HIIT for cardiac remodeling and cardiomyocyte function were similar to those of the ARB-losartan. The immune functionality is associated with mitochondrial bioenergtics in lymphocytes; while the bioenergy characteristics of mitochondria depend on the electron transport chain operation, fusion and fission equilibrium, biosynthesis and apoptosis/autophagy of this organelle. However, there is currently no research to investigate the effects of ARNI combined with supervised exercise therapy on the mitochondrial quality, biosynthesis and signaling pathways, and immune function of lymphocytes in patients with HF. This series of study projects will be completed in three years: the first year of the program is to compare the lymphocyte immunomodulatory markers (eg, phenotypic switching, activation, homing, and proliferation/differentiation) and mitochondrial bioenergetic characteristics (eg, electron transport chain, oxidative phosphorylation, membrane potential, oxidative stress, fusion/fission, biosynthesis and apoptosis/autophagy) among various functional stages (as defined by NYHA) in HF patients. The second year of the program was to evaluate the effects of ARNI drug therapy and/or three-month supervised exercise training on lymphocyte immunomodulatory markers and mitochondrial bioenergetic characteristics in HF patients. The third year of the project was followed by a one-year follow-up of the ARNI drug-integrated exercise; lymphocyte mitochondrial and immune functions, disease progression, and quality of life were analyzed following various interventions. The goal of this study is to develop a safe and effective strategy for drug-integrated exercise therapy to comprehensively improve the aerobic fitness, immune function and quality of life in patients with HF.

Project ID:PC10901-1372
External Project ID:MOST108-2314-B182-039-MY3