Beta-Blocker in Heart Rate Control and Cardio Protection: The Role of ADRB1 Variants and HCN4 Regulation – A Systematic Review

Beta-blockers exert cardioprotective effects against heart failure. However, variability in therapeutic responses is associated with ADRB1 variants. ADRB1 variants contribute to rate control and autonomic dysfunction. Persistent hyperadrenergic stimulation contributes to the impairment of the pacemaker (SA node). HCN4 significantly influenced the regulation of heart rate in the pacemaker. Exploring the effect of beta-blockers on pacemaker cells is expanding the view of their cardioprotective effects in heart failure. The objectives of this review were to identify ADRB1 variants affecting heart rate response in heart failure patients receiving beta-blocker treatment and to explore the effect of beta-blockers on HCN4/SA node. A systematic review was performed using three databases (Scopus, PubMed, and Science Direct). The inclusion criteria were English language and original manuscripts with relevant topics. The exclusion criteria were duplication and inaccessibility to the full text. Quality assessment tools were classified based on the use of research subjects and study designs, including NOS (cohort), SYRCLE (animal studies), and SciRAP (in vitro studies). Eight of 668 manuscripts were selected. This review found that ADRB1 variants (A145G(Ser49Gly) and C1165G(Arg389Gly)) can affect heart rate response in beta-blocker-treated heart failure. The percentage of patients with Ser49Ser-Gly389X (67) who achieved the heart rate target was higher than that of the other haplotypes (48-52). Among the responders, Arg389Arg required larger carvedilol equivalent daily doses of beta-blockers to reach the identical heart rate target than those with Gly389X (>50 (>25mg) versus ≤50 of the guideline-directed medical therapy (GDMT) target dose (≤25mg), respectively). In addition, this review found that beta-blockers demonstrated beneficial effects in regulating heart rate by inhibiting HCN-gated channels and improving channel regulation in the SA node. In general, this review provides important insights into beta-blockers in treating heart failure, specifically concerning the genetic variability of ADRB1 and the effect of beta-blockers on SA node/HCN4. © 2024 by Indonesian Journal of Pharmacy (IJP).