International Circulation：Beta-Blockers are standard therapy for patients with heart failure（HF）. The effects of chronic monotherapy with different beta blockers may be different. In your institute， evidence show that in HF dogs， chronic therapy with atenolol does not elicit the same left ventricle（LV） function and remodeling benefits as those achieved with metoprolol. What do you think about this result?

《国际循环》：β受体阻滞剂是心力衰竭（心衰）患者的一线用药，但是不同的β受体阻滞剂在疗效上可能存在一定差异。您的中心在犬心衰模型研究中发现，美托洛尔较阿替洛尔在改善左室功能及防治左室重构方面疗效更好，您如何看待这一结果？

Prof. Hani N. Sabbah: The reason we did the study is to try to find out whether it’s effective， because many physicians treat heart failure with atenolol instead of metoprolol， carvedilol or other drugs that are approved for treatment of heart failure. Nobody has ever done a trial in patients showing that atenolol is effective in heart failure. So we wanted to ask the question， “is atenolol as effective as metoprolol in treating heart failure?” But since we can not do that in patients which requires millions of dollars trial， we decided to do that in animals with heart failure. What we found is atenolol is not as good as metoprolol for treating heart failure. The reasons are not very clear to us yet， but all we can say is left ventricle function， ejection fraction or the size of the left ventricle does not improve as well with atenolol as with metoprolol， even though we have accounted for the differences in the dose that we used. So， at the same treatment of the same dose， atenolol does not work as good as metoprolol at least in animals with heart failure. So what we like to encourage physicians to do is to treat with drugs that have been proved by evidence， by clinical trials to work in patients with heart failure， and not to use a generic drug that has never been shown to work at heart failure.

Sabbah教授：我们做这个研究的目的是确定阿替洛尔是否有效，因为目前有很多医生采用阿替洛尔治疗心衰患者，而不是用其他已证实对心衰有效的药物，如美托洛尔、卡维地洛等。尚无临床试验证实阿替洛尔对心衰患者有效。所以我们要问，阿替洛尔在治疗心衰方面是不是跟美托洛尔一样有效？但因为在患者中开展临床试验花费甚大，所以我们选择了动物心衰模型。我们的研究结果表明，阿替洛尔治疗心衰的效果不如美托洛尔，其原因目前尚不清楚，但我们能够确定的是，即便考虑了剂量差异的影响，阿替洛尔在改善左室功能、射血分数以及左室大小方面仍不如美托洛尔。因此，在同样剂量下进行同样的治疗，阿替洛尔的效果要比美托洛尔差，至少在心衰动物模型上如此。所以我们要鼓励医生采用有临床试验证据证实有效的药物来治疗心衰患者，而不是采用没有经过证实对心衰有效的药物。

International Circulation：So you suggest to use clinically effective drugs?

《国际循环》：所以您建议要采用临床有效的药物？

Prof. Hani N. Sabbah：At Henry Ford hospitals and many hospitals in the United States， we practice what is called evidence-based medicine， in other words， you have to show that the drug works in clinical trials with patients who have heart failure in order to use that drug for that indication. You can not be switching drugs just because they belong to the same class. So atenolol is a beta-blocker but it’s a different kind of beta-blocker than the one that we used in the clinical trial. By the way， the same company can make both atenolol and metoprolol， so it has nothing to do with the company， but has to do with why use a drug that has never been shown to work. So you have to use the one that we know for sure that is the drug to use. And that is what we tried to show in this article that just because it’s a beta blocker， it does not mean it’s will do the same thing. Not all beta blockers are clinically equal. Just because it’s a beta blocker， it doesn’t mean it will work in heart failure. I will give you an example. There is a beta blocker called bucindolol. bucindolol is a beta-blocker that was trialed in a clinical trial called BEST， and in that trial Bucindolol， when given to the general population of patients with heart failure， did not work as good as metoprolol， carvedilol or bisoprolol. 

Sabbah教授：在美国像Henry Ford医院等很多医院都是依照循证医学来行医的，也就是说你必须在临床试验中证明该药物对心衰有效才可以用。不能因为他们同属一类药物就随意替换。阿替洛尔虽然是β受体阻滞剂，但不是我们在临床试验中所证实过的β受体阻滞剂。另外，因阿替洛尔和美托洛尔可由同一家公司生产，所以这与公司无关，重点在于为什么我们要用一种未证实有效的药物呢？正如我们文章中所显示，我们应使用已确定有效的药物，不能因为同属于β受体阻滞剂就断定作用相同。并不是所有β受体阻滞剂的临床效果都是一样的。并不是因为它是β受体阻滞剂，就一定对心衰有效。我举个例子，BEST临床试验对β受体阻滞剂布新洛尔进行了研究，发现对于心衰人群，布新洛尔不如美托洛尔、卡维地洛、比索洛尔有效。

International Circulation：In your recently study， you and your colleagues found that ranolazine combined with enalapril or metoprolol could prevent progressive LV dysfunction and remodeling in dogs with moderate heart failure. Would you like to introduce the possible reaction mechanism?

《国际循环》：您和同事在近期研究中发现，在犬中度心衰模型中雷诺嗪与伊那普利或美托洛尔联合应用可以延缓心衰进展，您认为可能的机理是什么?

Prof. Hani N. Sabbah：When we started to work with ranolazine， we showed that when you use ranolazine by intravenous( iv)， ranolazine will in fact improve LV function in heart failure. What we then did is to look at ranolazine alone， and then ranolazine combined with enalapril， and then ranolazine combined with a beta blocker， with metoprolol， in animals with heart failure. And we showed that when combined ranolazine with either enalapril or with a beta blocker， it gets a better improvement in LV function than with ranolazine alone. The ranolazine works by blocking what is called delayed inward sodium current. In heart failure， you have a condition that is called calcium overload， there is too much calcium in the muscle cell. And part of this calcium comes through delayed inward sodium current， what ranolazine does is to block that current and therefore limits the entry of calcium into the cell. And when you do that， you reduce calcium overload and the cell begins to function better， and function of the heart improves. So when you add it on ACE inhibitor， you get the benefit of ACE inhibitor from remodeling， and then you get the benefit of ranolazine which reduces calcium overload， and the two combine together. Combined function better than each one alone.

Sabbah教授：我们研究雷诺嗪时发现，静注雷诺嗪可以改善心衰患者的左室功能。之后我们研究了单用雷诺嗪、雷诺嗪联合依那普利及雷诺嗪联合β受体阻滞剂美托洛尔对动物心衰模型的效果。结果发现，雷诺嗪联合依那普利或β受体阻滞剂的效果较单用雷诺嗪更好。雷诺嗪的作用机制是阻断迟发性钠离子内流。心衰患者存在钙超载现象，即肌细胞中的钙离子过多。部分钙离子是通过迟发性钠离子内流进入，而雷诺嗪的作用就是阻断这种内流，限制钙离子进入细胞，从而降低钙超载，改善细胞功能和心脏功能。在ACEI的基础上加用雷诺嗪，不仅可以通过ACEI改善心肌重构，还可通过雷诺嗪降低钙超载。联合用药的效果优于这两种药物单用。

International Circulation：While Keep looking for drugs to treat heart failure， evidence has shown that statins might be beneficial as a