The role of the beta3 receptor
　　We are just discovering what the beta3-receptor is doing in the heart so the development of drugs with specific activity at this receptor in the heart is a concept that is still in its infancy. Nevertheless， there is now strong evidence coming from different groups over the years showing that activation of this receptor on top of beta1-blockade may be beneficial. The only proof that we have for that in the therapeutic area is the use of specific beta-blockers that not only block beta1 but have ancillary properties that activate the beta3 at the same time. We have published previous evidence for such beta-blockers to have dual activity at the beta1 and at the beta3. Very recently we published a paper in the Journal of the American College of Cardiology showing that in the mouse model of myocardial infarction， there is an additional benefit of these dual beta-blockers (i.e. beta1-blocker and beta3-agonist) over a classic and pure beta1-blocker， thereby lending more credence to the concept that the additional activation of the beta3 may be beneficial. Now the pharmaceutical industry is putting efforts into developing new agonists of the beta3-receptor but not in the cardiovascular field. They develop these drugs mostly for the field of depression and bladder instability but they come up with new molecules that are reasonably specific for the beta3 and without toxicity. With these drugs emerging from Phase III trials and beyond， then we will have tools in our hands to systematically test these drugs on top of classic beta1-blockade and confirm the concept in human heart failure.
　　Is there a preference for beta1- blockers or beta3-agonists in certain subsets of patients?
　　It is too early to say and again， we want to emphasize that any beta3-agonist needs to be on top of a beta1-blockade. Beta1-blockers should still be used because there is ample proof of their clinical efficacy. As to when and which patients should be treated with the beta3-agonist on top of the beta1-blocker is something that needs to be determined. The only way to do that is to first undertake studies in animal models of long-term heart failure to try to determine the exact window of time at which beta3-agonists should be added and once this is known， then design clinical trials with patients in heart failure at different stages. Classically we would go for moderate heart failure with NYHA class I-II and if this is promising， we would go to more severe heart failure patients at later stages. All of this needs to be done in future work but what is clear at present is that the combination of therapies， beta1-blockade and beta3-agonist， will be required?