The changes of VPCs in a 24-h ambulatory ECG were observed at baseline and after 12 weeks of treatment; the parameters are summarized in Table 2. Compared with the placebo group, the total number of VPCs in 24 h at the week 12 visit was significantly lower in the SSYX group (1538 ± 2187 vs. 2746 ± 3889, P < 0.05) and the mean reduction value of VPCs was much higher in the SSYX group (ΔVPCs −2145 ± 2848 vs. −841 ± 3411, P < 0.05). Calculated with the formula (week 12 value − baseline value)/baseline value, the SSYX group had a higher reduction rate at −0.51 ± 0.59 versus −0.22 ± 0.82 in the placebo group (P < 0.05). To evaluate the favorable effects of SSYX administration with a powerful method, the patients at four different VPCs reduction percentage levels were analyzed. According to Table 2, the number of patients at reduction percentages of 90%, 70%, 50%, and 30% was significantly higher in the SSYX group than in the placebo group (P < 0.05).
Figure 2 summarizes the results of the echocardiogram analysis. At baseline, patients in the two groups demonstrated no significant difference in the LVEF and LVEDD. At the 12 weeks visit, the SSYX group had more improvement in cardiac function with a higher mean change in LVEF (ΔLVEF 4.75 ± 7.13 vs. 3.30 ± 6.53, P < 0.05) as compared with the placebo group. However, there was no significant decrease in the LVEDD in both groups.
After 12 weeks of treatment, the plasma NT-proBNP changed in both groups showed a significant decrease in the NT-proBNP level, which were 208 (Q1, Q3: 56, 839) versus 399 (Q1, Q3: 144, 1705) in the SSYX group (P < 0.05) and 287 (Q1, Q3: 67, 1182) versus 418 (Q1, Q3: 147, 1346) in the placebo group (P < 0.05). Because there is a consensus on the accuracy of NT-proBNP for heart failure (HF) at a cutoff value of 125 pg/ml, the subgroup analysis was performed in the patients with NT-proBNP ≥125 pg/ml before and after the treatment. There were 174 patients in the SSYX group and 177 patients in the placebo group with no difference in the value of NT-proBNP at baseline; 12 weeks of SSYX treatment resulted in a significant larger reduction in NT-proBNP as compared to the placebo (−122 [Q1, Q3: −524, 0] vs. −75 [Q1, Q3: −245, 0], P < 0.05).
The NYHA class was evaluated at baseline and each visit of the 4th, 8th, and 12th weeks of treatment. The following three categories were used to assess changes in the symptoms of HF: improvement, no change, and deterioration. Improvement was defined as the NYHA class improving at least one grade, and deterioration was defined as the NYHA class worsening at least one grade. As shown in Figure 2, there were no significant differences in the NYHA functional class between the two groups at baseline and at the 4th week visit. At the 8th and 12th week visits, the percentage of patients in NYHA Classes I, II, and III was significantly different in the two groups; the SSYX group had superior improvements, with improvement percentages of 32.6% and 40.5% in the SSYX group versus 21.8% and 25.7% in placebo group (P < 0.05, respectively).
The 6MWD test was performed at baseline and at the 12th week visit. There was no difference between the two groups at baseline; compared with the placebo group, patients receiving SSYX treatment had a greater increase in the 6MWD at week 12 (Δ6MWD 35.1 ± 38.6 vs. 17.2 ± 45.6, P < 0.05).
The MLHFQ was completed at each visit. There was a gradual improvement in the quality of life during the entire treatment period, and SSYX compared to placebo resulted in greater changes in the scores at the 4th, 8th, and 12th week visits (ΔMLHFQ −4.24 ± 6.15 vs. −2.31 ± 6.96, −8.19 ± 8.41 vs. −3.25 ± 9.40, −10.60 ± 9.41 vs. −4.83 ± 11.23, all P < 0.05).
The assessments of safety and tolerability were based on spontaneous reports of adverse events, vital signs, and laboratory measurements. CCEs were defined as death, cardiac arrest with resuscitation, readmission for HF, worsening HF with an intravenous pharmacological agent for more than 4 h, stroke or cases in which the patient ceased active treatments because of worsening HF. Overall, 2.2% and 3.5% of patients in the SSYX and placebo groups experienced CCEs (P = 0.403). One patient died and four patients were readmitted to the hospital for HF in the SSYX group. In the placebo group, one patient died, six patients were readmitted to the hospital for HF, and one patient received implantable cardioverter defibrillator treatment for worsening HF. The total number of adverse events was 39 in the SSYX group versus 52 in the placebo group (P = 0.134). The analysis of drug-induced adverse events revealed no differences between the two groups. There was no report of any serious adverse events related to the study drugs.
In the present study of CHF patients with frequent VPCs, we demonstrated that, combination with usual care and therapy for CHF, 12 weeks of SSYX treatment had more significant suppression of VPCs and improvement of cardiac function. These results suggest that SSYX might benefit CHF patients by improving ventricular electrostability and reversing ventricular remodeling.
Frequent VPCs are commonly encountered in patients with CHF, and they always produce a less efficient ventricular contraction in aggravating ventricular dysfunction. On the other hand, as the cardiac function worsens, the frequency of VPCs and complexity of ventricular dysrhythmias increase. Therefore, the therapy that is given to break the vicious cycle is considered to be crucial. VPCs provide an arrhythmogenic substrate with a ventricular electrical instability that is the potential cause of malignant arrhythmia and cardiovascular mortality. Therefore, many studies have been conducted to suppress frequent VPCs by either AADs or catheter ablation. Unfortunately, in spite of substantial effort focusing on drug development, few AADs are available for clinical use because the benefits of VPCs suppression in CHF patients are usually counteracted by the negative inotropic and proarrhythmic effects of AADs, which also failed to improve survival. At present, among the Class IA, IB, IC, II, III, and IV AADs, only amiodarone seems to improve the ventricular function as well as has an antiarrhythmic effect in CHF patients with VPCs without increasing the mortality rate. However, the extracardiac side effects of amiodarone, including effects on the thyroid, lungs, and liver, have hampered its clinical utility. β-blockers are a cornerstone of pharmacotherapy for CHF; however, the VPCs response to β-blockers changes to a variable extent, and they are rarely completely suppressed in CHF patients. Therefore, the pharmacological treatment options in CHF patients with frequent VPCs are limited.
The recorded description that palpitation was diagnosed as symptomatic premature beats around 600 BC with pulse palpation from the early Chinese physicians. Chinese medicinal herbs have been used over the past centuries in China for treating arrhythmia and increased in popularity as complementary and alternative therapeutic agents used worldwide. However, few have been subjected to the rigorous evaluation processes. SSYX is a well-known compound with antiarrhythmic effects described in the Chinese Materia Medica textbook. According to the method of ultra-fast liquid chromatography combined with quadrupole time-of-flight mass spectrometry, the 12 herb materials of SSYX that were definitely identified or tentatively characterized could be classified into seven fractions, including saponins, phenolic acids, tanshinones, lignans, terpenoids, alkaloids, and flavonoids. The characteristic behaviors were investigated, and 11 representative compounds were found. Previous pharmacological studies revealed that SSYX suppresses arrhythmias that are induced by toxic chemical compounds or ischemia-reperfusion injury in animal models. SSYX was found to block multiple ion channels in isolated ventricular myocytes, inhibiting the sodium current, L-type calcium current, transient outward potassium current, delayed rectifier current, and inward rectifier potassium current. In a randomized, double-blind, controlled multicenter trial conducted in patients with or without organic heart disease, SSYX compared with placebo or mexiletine had a significant therapeutic efficacy in reducing VPCs and alleviating VPCs-related symptoms. Another randomized controlled trial of SSYX combined with routine pharmacotherapy in chronic HF revealed that SSYX further normalizes the heart rate variability (HRV) and heart rate turbulence (HRT) as well as reduces the incidences of VT and AF compared with the routine pharmacotherapy for HF alone.
Although the exactly active ingredients and the clearly mechanism of SSYX on VPCs and CHF remain unknown, some researches of part of the compositions involved in SSYX may explain part of the underlying pharmacodynamic profiles. Ginseng, the emperor herb in SSYX, has been revealed a number of beneficial properties in cardiac protection as protecting the ischemia-reperfusion injury, attenuating myocardial hypertrophy, and blunting the remodeling and HF processes. Tanshinones from the S. miltiorrhiza in SSYX were demonstrated to suppress ischemic arrhythmias as well as prevent cardiac injury, hypertrophy, and atherogenesis. Downregulation of miR-1 and consequent recovery of Kir2.1, activation of KCNQ1/KCNE1 potassium channels may account partially for the efficacy of tanshinone IIA in arrhythmia suppression. Since SSYX is a complicated herbal composition, larger validation studies are needed to provide further evidence for its active ingredients and mechanisms.
In our study, 24-h ECG was used to evaluate the situation of VPCs. However, the frequency of VPCs is also subjected to daily or periodic variations, so prolonged period up to 72 h or even 7 days ECG is proposed to be more convincing. Since 12-week period in our study is a short time point, a larger scale and a longer term as 12 months of a rigorous designed clinical trial should be carried out for a more comprehensive analysis of SSYX in CHF patients with VPCs.
On a background of routine pharmacotherapy in CHF patients with frequent VPCs, SSYX treatment showed more significant VPCs suppression and further cardiac functional improvement. The bidirectional benefits of the mutual promotion of SSYX in mechanical and electrical functions are derived from the comprehensive modulations of neurohormonal, structural, and electrical remodeling. A rigorous clinical trial that evaluates the long-term outcomes, including all-cause or cardiovascular mortality, is needed to validate that SSYX provides clinical benefits to CHF patients with frequent VPCs following this study.
Financial support and sponsorship
The study was supported by a grant from the 973 Program of China (No.2012CN518606).
Conflicts of interest
Shijiazhuang Yiling Pharmaceutical Co., Ltd., (Shijiazhuang, China) provided the Shensong Yangxin capsules.
The authors gratefully acknowledge the contribution of the following sites (and staffs): The First Affiliated Hospital of Zhengzhou University (Chun-Guang Qiu, Zheng-Bin Wang); Chongqing Zhongshan Hospital (Xia Mei, Xiang-Qing Zheng, and Yong-Mei Li); Dongfeng General Hospital (Han-Dong Yang, Xin-Wen Min, and Ji-Shun Chen); Nanjing Drum Tower Hospital, Nanjing University Medical School (Wei Xu, Rong-Fang Lan, and Ning Zhang); The People's Hospital of Liaoning Province (Ying Liu and Xing-Ke Qiao); The First Hospital of Hebei Medical University (Yue Xia, Guo-Qing Qi, and Qing-Wen Zhang); Jiangxi Provincial People's Hospital (Guo-Tai Sheng and Yu Tang); The First College of Clinical Medical Science, China Three Gorges University (Jun Yang, Song Li, and Jia-Wang Ding); First Affiliated Hospital of Guangxi Medical University (Wei-Feng Wu, Yu-Ming Chen, and Xian-Zeng Xu); The Central Hospital of Enshi Autonomous Prefecture (Yuan-Hong Li, Xin Ji, and Chang-Jiang Zhang); Jinzhou Central Hospital (Shan Jiang, Chun-Hong Qu, and Bo Zhang); West China Hospital of Sichuan University (De-Jia Huang, Hong-De Hu); Xiangyang Central Hospital (Wen-Wei Liu, Bin Li, and Rui Zhu); Jingzhou Central Hospital (Xin Li, Gang Hu, and Li Zhang); Suizhou Central Hospital (Jin Qian, Wei Yao, and Neng Wang); The First Affiliated Hospital of Nanchang University (Ze-Qi Zheng and Yuan Wen); Ruijin Hospital, Shanghai Jiao Tong University (Li-Qun Wu, Rong Tao, and Yu-Cai Xie); Wuhan Asia Heart Hospital (Yang-Yang Dai, Xin-Hui Yang, and Jun Yin); Shanghai First People's Hospital (Fang Wang, Ying Wu, and Wei-Chun Xi); Chongqing the Fourth Hospital (Rui-Hua Yue and Ying Zhang); Beijing Anzhen Hospital, Capital Medical University (Chang-Sheng Ma, Qiang Lyu, and Tai-Yang Luo); The General Hospital of Shenyang Military Region (Zu-Lu Wang and Jing Liu); China-Japan Friendship Hospital (Yong Wang, Hong Jiang, and Ying Zhou); Zhongshan Hospital of Fudan University (Juan Peng, Ji Zhao, and Yuan Zhang); People's Liberation Army 252 Hospital (Xue-Bin Cao, Zhao-Chuan Liu, and Hong-Tao Liu); Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine (Ying Wang and Fang Liu); Wuxi No. 2 People's Hospital (Yan Jin, Wen-Chao Quan, and Zheng-Jie Yang); Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine (De-Yu Fu, Ming-Tai Gui, and Lei Yao); and Shandong Jiaotong Hospital (Tian Wang and Hai-Yan Meng).
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Edited by: Li-Min Chen
Keywords:© 2017 Chinese Medical Association
Congestive Heart Failure; Randomized Controlled Trial; Shensong Yangxin Capsules; Ventricular Premature Complexes