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?
Further reduction in left ventricular function by adding beta3-agonists to beta1-blockade
Based on in vitro data this is a possibility and you might get a temporary decrease in left ventricular function because we have clearly shown that the beta3 in isolated muscle preparation induces a negative inotropic effect. But in the long-term it may be beneficial just because it prevents excessive activation of contractility and calcium which we know is toxic in the long-term. We anticipate that the combined beta1-blockade and the beta3-agonist might produce the same type of effects that people have seen with pure beta1-blockers in late stage heart failure patients， which is a temporary decrease in left ventricular function but followed by long-term benefit.
β3受体的作用
目前仅发现了β3受体在心脏中的作用，研发针对这一受体的特定活性药物仍然是一种尚未成熟的理念。然而，来自不同研究的有力证据表明，阻断β1受体时紧接着激活β3受体可能是有益的。治疗领域仅有的证据来自于应用一些特殊的β阻断剂，它们不仅阻断β1受体，同时也有激活β3受体的额外特性。我们以前发表的证据表明，这类β阻断剂对β1和β3受体具有双重活性。近期我们在JACC上发表的研究表明，在小鼠心肌梗死（MI）模型中，双重β受体阻断剂（β1受体阻断和β3受体激活）优于传统单一β1受体阻断剂，有额外获益。
β3受体激动剂与β1受体阻滞剂谁为优先选择
需要强调的一点是，任何β3受体激动剂都基于β1受体阻断。何时、何种患者应给予β3受体激动剂治疗，仍是尚待商榷的问题，其解决的唯一方法是，首先通过长期HF动物模型确定加用β3受体激动剂的准确时间窗，一旦明确，然后设计不同阶段HF患者的临床试验。我们常规选择中度HF患者，即 NYHA 分级Ⅰ/Ⅱ级患者，若结果满意，再进一步选择更严重、分级更高的HF患者。目前需明确的首要问题是，β1阻断和β3激活的联合治疗是否为必需？
β1受体阻滞剂联合β3受体激动剂进一步改善左室功能
体外研究数据表明，β1受体阻滞剂加用β3受体激动剂可能改善左室功能，因为β3受体能抑制过度收缩和钙离子通道，在分离出的肌肉标本中产生负性肌力作用，长期效应可能是有益的。我们预计，在终末期HF患者中联合β1受体阻滞剂和β3受体激动剂可能产生与单独β1受体阻断剂同样的效应，即暂时性左室功能下降，但长期获益。
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