Gαs-Biased β2-Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart

Synchronizing abnormal contraction in the failing hearts permanently alters β2-adrenergic signaling, pointing to a new therapeutic approach. Salubrious Synchrony for the Heart Like rowers in a shell stroking in unison, the human heart works most efficiently when all sides contract simultaneously, sending blood to the body more effectively. In some patients with heart failure, a defective conduction system causes the ventricles to beat out of phase, further reducing the efficiency of an already damaged heart. An implanted pacemaker can resynchronize the ventricles, improving heart function, correcting some of the anatomical abnormalities of the weakened heart, and decreasing mortality. Hearts treated with resynchronization therapy are stronger and healthier. To find out why, Chakir et al. resynchronized the heartbeats of dogs with heart failure and discovered that their previously feeble response to β-adrenergic agonists (normal regulators of heartbeat) was restored to normal, a result of enhancement of two key regulators of G protein–coupled signaling—RGS2 and RGS3. The authors propose that drugs targeting this pathway may help people with all sorts of heart failure. Heart cells taken from dogs with failing hearts, whether they were beating dyssychronously or synchronously, showed depressed contractile responses to β2-adrenergic stimulation, but resynchronization therapy only improved function when applied to previously desynchronized tissue. Further dissection of β2-adrenergic control of the heart showed that resynchronization recoupled the β2-adrenergic receptor to the stimulatory Gαs G protein rather than the inhibitory Gαi G protein. This Gαs coupling resulted in more cyclic AMP generation and protein kinase A activity at the sarcoplasmic reticulum. Up-regulation of the pathway modulators RGS2 and RGS3 accounted for the effects of resynchronization. Finding the pathway responsible for the therapeutic effects of cardiac resynchronization therapy should, in theory, allow the development of drugs that mimic its resynchronizaton-induced up-regulation, for use more generally in heart failure. But the authors found another potential therapy that is easier to develop than new drugs: Forcing a period of dyssynchrony in dogs with synchronous heart failure restored normal β2-adrenergic signaling. Perhaps a bit of independence makes for better cooperation later. Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling (RGS2, RGS3), yielding Gαs-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum–localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.