Würzburg, Germany - Data from a small genetic study has helped shed light on the variable response to beta-blocker therapy in heart-failure patients, with investigators showing that a polymorphism of the 1-adrenergic receptor resulted in a specific and marked inverse agonist effect when treated with the beta blocker carvedilol [1].

"The present data show, for what we believe is the first time, real-time measurements of 1-adrenergic receptor activation in living cells and provide evidence for the supersensitivity of the frequent ARG389 variant of the 1-adrenergic receptor toward carvedilol," write lead investigator Dr Francesca Rochais (University of Würzburg, Germany) and colleagues in the January 2007 issue of the Journal of Clinical Investigation. "It will be interesting to investigate whether patients carrying the ARG389 polymorphism may benefit from treatment with carvedilol as opposed to other beta blockers."

As previously reported by heartwire, a common polymorphism of the 1-adrenergic receptor is the substitution of arginine (ARG) or glycine (GLY) at position 389. The frequency has been shown to differ by ethnic group, with the ARG389 allele more common in persons with a European background and less common in African Americans.

Researchers have been particularly interested in -adrenergic receptor polymorphisms, as the beneficial effects of blocking the receptor in heart-failure patients appears to differ by ethnicity, leading to speculation that genetic heterogeneity with respect to 1-adrenergic receptors might account for the lack of benefit in some patients. In 2004, for example, in a DNA substudy analysis from the Beta-Blocker Evaluation of Survival Trial (BEST) trial, a study of 1040 patients with moderate to severe HF, previously reported by heartwire, treatment with bucindolol in patients with the ARG389 variant resulted in improved survival and lower combined death and hospitalizations, whereas those with another variant showed no response to treatment in survival or death/hospitalizations with bucindolol.

Still, despite those findings, data from clinical studies analyzing the association between various polymorphisms and beta-blocker treatment is conflicting, making it difficult to reach conclusions about the importance of these polymorphisms with respect to treatment outcomes.

In the present study, investigators sought to determine whether the ARG-GLY polymorphism at position 389 determines sensitivity of the response to beta-blocker treatment by using a fluorescent resonance energy transfer (FRET) technology to record directly and in real time any conformational changes of the receptor protein that led to its activation. Based on the resonance energy transfer between fluorescent molecules, the FRET approach allows for the measurement of interactions between proteins, as well as dynamic changes within the proteins.

In comparing the activation characteristics of the two polymorphisms, investigators report differences in the response of the receptor variants to different beta blockers. To varying degrees, metoprolol, bisoprolol, and carvedilol were all able to actively switch off the GLY389 variant of the 1-adrenergic receptor in rat cardiac cells. Metoprolol and bisoprolol each caused a conformational change in the ARG389 and GLY389 receptors, but the effect was small and did not differ between the ARG389 and GLY389 receptor variants.

In contrast, carvedilol treatment induced strong inverse agonism with regard to both variants, but the ARG389 variant exhibited a 2.5-fold increase in the FRET ratio compared with GLY389, which signifies a greater change in the receptor conformation upon binding of the beta blocker. This resulted in downstream receptor inactivation, as shown by a marked reduction in cyclic AMP levels. These results were confirmed phenotypically in neonatal rat myocytes, as carvedilol significantly decreased heart-rate contractility significantly more in the ARG389 variant.

"This study identified a unique property of carvedilol, which is likely to become clinically relevant," Rochais and colleagues write.

In an editorial accompanying the study, Drs Brent DeGeorge and Walter Koch (Thomas Jefferson University, Philadelphia, PA) write that the study represents the first "direct assessment" of the G-protein-coupled receptor (GPCR), the family to which the 1-adrenergic receptor belongs [2]. "The implications of these findings are of potentially profound clinical importance when considering the interindividual and ethnic variation that occurs in response to beta-adrenergic receptor therapy in the treatment of heart failure," they write.

DeGeorge and Koch note the ARG389 allele is 20% less common in African American patients than non-African American patients, and this might explain the poorer response to 1-adrenergic receptor antagonists. In the BEST study, for example, there was a lack of benefit in African American patients treated with bucindolol compared with other patients.

The editorialists also note that carvedilol, unlike metoprolol or bisoprolol, is a nonselective beta blocker and can act on other receptors in the GCPR family. Because of this, say DeGeorge and Koch, there might be other effects of these receptors on cardiac rate control. Still, they write that this study lends credence to the viability of pharmacologic intervention adapted to an individual's genetic makeup, and the "realization of personalized medicine for the treatment of cardiovascular disorders such as heart failure."