Characteristics of Chinese herbal medicine usage in ischemic heart disease patients among type 2 diabetes and their protection against hydrogen peroxide-mediated apoptosis in H9C2 cardiomyoblasts

Abstract

Evidence for long-term use of Chinese herbal medicine (CHM) as an adjuvant treatment in patients with type 2 diabetes (T2D) remains limited. This study aimed to assess the frequency of use, utilization patterns, and therapeutic effects of adjuvant CHM for ischemic heart disease (IHD) in patients with T2D in Taiwan. We identified 4620 IHD patients with T2D. After matching for age, gender, and insulin use, 988 subjects each were allocated to a CHM group and a non-CHM group. There were no differences in baseline characteristics except for comorbidities. The CHM group contained more cases with chronic obstructive pulmonary disease, hepatitis, ulcer disease, and hyperlipidemia. The cumulative survival probability was higher in CHM users than in matched non-CHM users aged 60 years or older (P < .0001, log rank test) regardless of gender (P = .0046 for men, P = .0010 for women, log rank test). Among the top 12 CHM combinations, Shu-Jing-Huo-Xue-Tang and Shao-Yao-Gan-Cao-Tang (13.6%) were the most common. This dual combination improved antiapoptotic activity in H2O2-exposed H9C2 cells by enhancing phosphorylation of glycogen synthase kinase-3β and p38 mitogen-activated protein kinase and could increase the survival of myocardial cells. Our study suggests that adjuvant CHM therapy may increase the survival probability and provides a comprehensive list for future investigations of the safety and efficacy of CHM for IHD patients with T2D.

Keywords: Chinese herbal medicine; cardiomyoblasts; ischemic heart disease; oxidative stress; type 2 diabetes.

Figure 1. Enrolment of IHD patients with type 2 diabetes

Abbreviation: CHM, Chinese herbal medicine; IHD, ischemic heart disease.

Figure 2. Cumulative probability of survival of IHD patients with type 2 diabetes according to use of CHM in each study group for A. total subject population, B. people younger than 60 years, C. people aged 60 years or older, and D. male patients and E. female patients

Abbreviation: CHM, Chinese herbal medicine.

Figure 3. Subgroup analysis for the endpoint of mortality

Use of CHM was associated with a protective effect when subjects were stratified by age, gender, and duration from diagnosis of DM to diagnosis of IHD. Abbreviations: CHM, Chinese herbal medicine; DM, diabetes mellitus; IHD, ischemic heart disease.

Figure 4. Effect of herbal formulas and single herbs most commonly used to reduce the mortality risk for IHD patients with type 2 diabetes

Abbreviations: CHM, Chinese herbal medicine; CI, confidence interval; HR, hazard ratio; IHD, ischemic heart disease.

Figure 5. Effect of the double CHM combinations most commonly used to reduce the mortality risk for IHD patients with type 2 diabetes

Abbreviations: CHM, Chinese herbal medicine; CI, confidence interval; HR, hazard ratio; IHD, ischemic heart disease.

Figure 6. Western blot analysis of the Shu-Jing-Huo-Xue-Tang and Shao-Yao-Gan-Cao-Tang (1 mg/mL each) or Bei-Mu and Jie-Geng (2.5 mg/mL each) in hydrogen peroxide-treated H9C2 cells

A. Western blot analysis of phospho-GSK-3β (Ser9), GSK-3β, phospho-p38 MAPK, and p38 MAPK expressions. B. The ratio of phospho-GSK-3β (Ser9) to GSK-3β in various groups [(phospho-GSK-3β (Ser9)/ GSK-3β)_group/(phospho-GSK-3β (Ser9)/ GSK-3β)_{cells only} × 100%]. C. The ratio of phospho-p38 MAPK to p38 MAPK in various groups [(phospho-p38 MAPK / p38 MAPK)_group/(phospho-p38 MAPK / p38 MAPK)_{cells only} × 100%]. The mean ± standard error values for at least three independent experiments are shown, along with representative Western blots.