β1-Adrenoceptor Genetic Polymorphisms and Other Predictors of the Tolerability and Response to β-Blockers in Patients with Heart Failure in Taiwan.

Background: The tolerated doses of β-blockers in Chinese heart failure (HF) patients were substantially lower than those wildly used in the Western countries, and the therapeutic response was heterogeneous. Although the mechanism responsible for the various tolerability and response was often attributed to β1-adrenoceptor (β1-AR) genetic polymorphisms at codon 49 and 389, their allele distribution was similar between Chinese and Caucasian, and β1-AR genetic full length sequencing has not been performed in Asian population.

Objective: This study aimed to examine whether there are novel polymorphic loci in the β1-AR gene responsible for the difference in tolerability to β-blockers between Chinese and Caucasian HF patients, and to assess for other clinical predictors of tolerability and therapeutic response to β-blockers in Chinese population.

Methods: We performed full length sequencing for β1-AR in 69 patients who had the diagnosis of chronic HF and were using, or have used, one of the three β-blockers carvedilol, metoprolol succinate, and bisoprolol. Clinical parameters including comorbidities, HF etiology, concurrent medication, left ventricular ejection fraction (LVEF) before the initiation and at the stable dose of β-blocker were retrieved from the medical records or inquiries into the patients.


Results: Tolerated carvedilol stable dose was significantly different by HF etiology (p = 0.047). The stable dose of carvedilol for patients with dilated cardiomyopathy (DCMP) as the etiology of HF was higher than that of valvular heart disease (VHD) patients (14.589 ± 8.882 and 5.357 ± 7.594 mg/day, respectively, p = 0.018), and also tended to be higher than that of coronary artery disease (CAD) patients (9.544 ± 5.558 mg/day for CAD, p = 0.054). Multiple stepwise regression revealed that DCMP (B = 4.852, p = 0.007) was the only significant predictor of stable carvedilol dose; DCMP (B = 9.015, p = 0.011) and baseline LVEF (B = - 0.503, p < 0.001) appeared to be the significant predictors of LVEF improvement. In a subgroup analysis of 26 patients with CAD or DCMP (baseline LVEF≦35%), low-dose carvedilol (12.464 ± 7.977 mg / day) produced a significant improvement in LVEF (13.49 ± 16.66 %, p < 0.001). Neither novel variants other than the reported codon 49 and codon 389 within the coding region, nor correlation between β1-AR gene diplotypes and tolerability or response was found. The allele distributions of codon 49 and 389 were similar to those reported previously in the Chinese and Caucasian populations.

Conclusion: Low-dose β-blocker therapy improved left ventricular function in Chinese patients with HF. Moreover, DCMP patients tolerated better to β-blocker, and those with DCMP as the etiology of HF or those had lower LVEF at baseline gained a greater improvement. For the β1-AR gene polymorphism, neither novel variant within the coding region, nor a different distribution pattern of alleles at codon 49 and codon 389 was noted.