The role of ß-adrenergic receptors and p38MAPK signaling pathways in physiological processes of cardiosphere-derived cells.

The effects of ß adrenergic receptors (ß-ARs) and p38 mitogen-activated protein kinases (MAPK) pathways on cardiosphere-derived cells (CDCs) are largely unknown. This study aimed to investigate the roles of ß-ARs and p38MAPK pathways on the proliferation, apoptosis, and differentiation capacity of CDCs. The CDCs were treated with ß1-AR blocker (Met group), ß2-AR antagonist (ICI group), and p38MAPK inhibitor (SB group), non-selective ß-AR blocker (PRO group), and ß-AR agonist (ISO group). The viability, apoptotic rate and differentiation status of CDCs were determined by MST-1 assay, flow cytometery, and Western blot, respectively. The CDCs viability significantly reduced in ICI group (all P < 0.05), and SB group had a significant high viability after 48 h treatment (P < 0.05). Compared with control group, all treated groups had a low apoptotic rate. After treatment for 72 h, ISO treatment elevated the expression of Nkx2.5, and could partially or fully attenuate the inhibitory effects of ß-AR antagonists and/or p38MAPK inhibitor. A similar overall trend of protein expression levels among all groups could be observed between protein pairs of cTnT and ß1-AR as well as c-Kit and ß2-AR, respectively. These results suggested that ß-ARs and p38MAPK signaling pathways play crucial roles in the proliferation and differentiation of CDCs. Our findings should be helpful for better understanding the molecular mechanism underlying the physiological processes of CDCs.

Genotype-Guided Warfarin Dosing in Patients With Mechanical Valves: A Randomized Controlled Trial.

BACKGROUND: The clinical utility of genotype-guided warfarin dosing remains controversial. The objective of this trial was to evaluate the efficacy and safety of genotype-guided warfarin dosing in East Asians. METHODS: A double-blind, randomized control trial was performed to compare a genotype-guided dosing algorithm (CYP2C9, VKORC1, and CYP4F2) with a clinical-guided one in the initiation treatment for patients with mechanical heart valves. The primary outcomes included the time to reach a stable dose and the percentage of time in the therapeutic range (TTR). RESULTS: Two hundred one patients were randomly assigned to treatment, 101 to control and 100 to study. The major bleeding and thromboembolic event-free rate in the study group was 97.0% (95% confidence interval: 90.9% to 99.2%). Compared with the control group, the study group shortened the time to reach a stable dose (mean: 42.09 ± 23.655 days versus 33.52 ± 20.044 days, p = 0.009). The TTRs were 47.257% and 47.461% in the control and study group (p = 0.941), respectively. Patients with the CYP2C9 *1/*3 genotype had higher international normalized ratio (INR) variability than patients with the CYP2C9 *1/*1 genotype (p = 0.024). Compared with normal and sensitive responders, the highly sensitive responders were at increased risk of an INR of 4.0 or greater (p < 0.05). CONCLUSIONS: The genotype-guided warfarin dosing was safe and might be more efficient for the time to reach a stable dose. Pharmacogenomic testing might be beneficial to identify the patients with the CYP2C9 *1/*3 genotype and the highly sensitive responders, who were in the high-risk subgroup of patients with mechanical heart valves. An appropriately powered study is needed to further confirm these findings.