Time-related accurate investigation of multicomponent drug interventions in heart failure

Chronic heart failure (CHF) is one of the most common disabling, painful, and deadly syndromes. As a syndrome, heart failure (HF) has been divided into more specific processes, and these processes may occur at the same time or have a precedence. In addition, drug intervention in the process of HF has the most appropriate time point, which means that it is not always the best time to intervene with this drug during the entire course of HF. Traditional Chinese medicine (TCM) Dengzhan Shengmai capsule (DZSMC), a TCM formula, is known as a multitarget complementary medicine that is widely used clinically to treat HF in Asian countries. However, because the mechanism by which DZSMCs treat HF has not been demonstrated comprehensively, the uncertainty of the occasion of drug use makes the precise intervention of DZSMCs a challenge. In this article, for precise research on the time point of DZSMC intervention during the process of HF, we applied the time-related proteomics data we measured combined with proteomics data reported and online database to perform a precise prediction to learn DZSMC intervention in specific progression and time points of HF. Then the precise prediction was validation in rats after ligation of left anterior descending coronary artery. We demonstrate that DZSMC can improve the cardiac function of myocardial infarction (MI) rats by raising the cardiac ejection fraction (EF) and slowing down the thinning of the anterior wall of the left ventricle. In addition, we found that the appropriate time point for DZSMC intervention is when the serum level of voltage-dependent calcium channel subunit alpha-2/delta-2 (Cacna2d2) increases and that DZSMCs play their role in delaying HF mainly by reducing the myocardial load through decreasing Cacna2d2. In this study, we used a multidimensional data integration strategy by combining the proteomics data and bioinformatic tools to explore the suitable time points for DZSMC intervention in HF induced by MI on a rat model. We verified the efficiency of DZSMC in treating HF and found that DZSMC can improve HF by increasing the cardiac EF, FS and retarding the thinning of the anterior wall of the left ventricle by echocardiography. Futhermore, the upregulated Cacna2d2 in 3 weeks post MI could be a potential signal for DZSMC intervention and DZSMC can downregulate the abnormal decrease of Cacna2d2 in 4weeks post MI. This study provides a practical and feasible method for determining a suitable time point for TCM intervention, and this is the first report of DZSMCs decreasing the serum level of Cacna2d2 to improve cardiac function.