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Heart failure: genetic mutation alters response to beta-blockers

Drugs known as beta blockers help slow nerve impulses traveling through the heart in order to reduce the heart's workload. This effect is achieved via their action on beta-adrenergic receptors present in cardiac cells.
As such, beta blockers have become a mainstay of the treatment regimen for chronic heart failure. However, doctors have remained puzzled by the variable responses to some beta blockers among heart failure patients.

In a study published in the Journal of Clinical Investigation, Stefan Engelhardt and colleagues from the University of Würzburg, Germany, explain why some heart failure patients may respond better than others to certain beta blockers. The secret lies in a single amino acid change in the beta1-adrenergic receptor, that may differ from person to person, which alters the receptor's conformation and in doing so may alter the receptor's response to a given beta blocker.

Engelhardt and colleagues examined variant beta1-adrenergic receptors in which the amino acid at position 389 had been replaced by either an arginine or a glycine residue. The authors were able to directly assess, in real time, the effects of 3 different beta1-adrenergic receptor antagonists – Bisoprolol ( Zebeta ), Metoprolol ( Lopressor ), and Carvedilol ( Coreg ) – on the Arg389 and Gly389 variant beta1-adrenergic receptors in rat cardiac cells. They found that while each of these drugs caused a conformational change in the receptors, the effect of Bisoprolol and Metoprolol was minor and did not noticeably differ between the Arg389 and Gly389 receptor variants. In contrast, Carvedilol treatment induced a response from the Arg389 variant that was 2.5-fold that of the Gly389 variant. This was attributed to Carvedilol's ability to induce a more extreme conformational change in the Arg389 variant of the receptor, resulting in significantly dampened cAMP signaling in cardiac cells.

In an accompanying commentary, Brent DeGeorge and Walter Koch from Thomas Jefferson University comment that " 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." Furthermore, " It has been reported.. [ that ].. the Arg389 variant is 20% less common in black patients compared with non-black patients, and this may partially explain the poorer response to beta1-adrenergic receptor antagonists seen in blacks compared with that of the rest of the population."

Future work to characterize the effect of genetic mutations in these receptors and the role such mutations play in the receptor's (and hence a patient's) response to these drugs, may eventually lead to a situation in which doctors could prescribe drug treatment that is adapted according to each patient's own genetic makeup, bringing new meaning to the idea of personalized medicine for the treatment of heart failure and other cardiac disorders.

Source: Journal of Clinical Investigation, 2007