International Circulation: Gene therapy has begun to emerge in the treatment of heart failure. Could you talk about its exciting achievements and corresponding results?

　　Dr Koch: Gene therapy is gaining momentum because in heart failure we don’t have drugs that are good enough to reverse the disease， so we are always looking for new therapies because heart failure is increasing in prevalence and is very problematic for the healthcare system. In heart failure， the heart as a pump is weakened so the goal of the gene therapies that are being experimented with right now are to make the heart muscles stronger. The reason it is gene therapy is because we are introducing new DNA into the heart cells themselves. More specifically， we are using a small virus called the adeno-associated virus， which brings in a DNA product that makes the heart beat stronger. We think that will be a novel way to improve the function of the heart. In animal models， it has been shown to strengthen the heart and reverse heart failure.

　　《国际循环》：近年来，基因治疗在心衰治疗领域开始崭露头角，请您介绍一下心衰基因治疗目前取得了哪些可喜的结果？

　　Dr. Koch：基因疗法正越来越热门，因为在心力衰竭领域我们没有足够逆转这一疾病的药物，鉴于心力衰竭发病率越来越高，且对卫生系统来说是一个重大问题，因此，我们一直在寻求一种新疗法。心力衰竭时，心脏泵血功能减弱，而目前正在尝试的基因疗法的目的是使心肌更强壮。之所以称为基因疗法是因为我们正将一种新DNA引入心脏细胞本身。更具体地说，我们正在应用一种叫“腺相关病毒”的小型病毒，这种病毒能制造一种使心脏跳动更强的DNA产物。我们认为这将是改善心脏功能的一种新方法。动物模型已显示这种疗法能使心脏强壮，逆转心力衰竭。

　　International Circulation: You have done many studies regarding GRK2 inhibition and heart failure. What do you think are the advantages of GRK2 inhibition in treating heart failure? And what are the feasible measures or methods that we can use clinically for GRK2 inhibition?

　　Dr Koch: We study G protein-coupled receptor kinase 2 (GRK2). It is an enzyme that is found throughout the body but it is highly expressed in the heart. In heart failure patients and other cardiovascular diseases like hypertension， it is increased. Our studies over the last twenty years have shown that when GRK2 is increased， there are negative consequences. For example， in heart failure， one of the classes of drugs that are being used and that have had some success is beta-adrenergic blockers. Beta-blockers are needed primarily because GRK2 is upregulated in heart failure. So GRK2 is the culprit behind this beta-adrenergic dysfunction. Almost twenty years ago， we found that if you inhibit GRK2 in the heart， you reverse this beta-adrenergic dysfunction and the heart improves in function and also in size (the heart actually gets smaller which is beneficial in heart failure). We have gone on to show that， not only is the beta-receptor system improved when you inhibit GRK2， but you also prevent cell death in the process of inhibiting GRK2. The only way we can inhibit GRK2 right now is with small peptides， which is why we are doing gene therapy. However， small molecule inhibitors that would actually be pharmacological drugs are emerging. We showed last year that a drug that is used to treat depression called paroxetine actually inhibits GRK2 as a side effect. We are getting ready to publish a big paper showing that if you treat animals with heart failure using paroxetine at a high enough dose， you can reverse heart failure.

　　《国际循环》：据我们所知，您开展了大量有关G蛋白偶联受体激酶2（GRK2）抑制与心力衰竭的研究。抑制GRK2治疗心衰的优势有哪些？目前，有临床应用前景的GRK2抑制方法有哪些？

　　Dr Koch：我们研究G蛋白偶联受体激酶2（GRK2）。GRK2是一种酶，在全身均可发现，但在心脏高度表达。心力衰竭和其他心血管疾病如高血压时，GRK2表达增加。我们过去近二十年的研究显示，GRK2增加时会有负面影响。例如，心力衰竭时，各种药物中正在被使用且已有一些成效的药物之一是β肾上腺素能受体阻滞剂。β受体阻滞剂之所以是基础用药，是因为心力衰竭时GRK2是上调的，而GRK2是β肾上腺素功能障碍的罪魁祸首。近二十年前，我们发现如果抑制心脏的GRK2，就会逆转β肾上腺素功能障碍，改善心脏功能和体积（心力衰竭时心脏变小通常是有利的）。我们的研究还显示，抑制GRK2不仅改善β受体系统，而且在抑制GRK2过程中还能防止细胞死亡。我们能抑制GRK2的唯一方法就是小分子肽，这就是我们为何进行基因疗法的原因。然而，实际上是药理学药物的小分子抑制剂不断涌现。去年我们发现一种用于治疗抑郁症的药物“帕罗西汀”的一个副作用实际上可抑制GRK2。我们正准备发表一篇高剂量帕罗西汀治疗心力衰竭动物能逆转心力衰竭的重要论文。

　　International Circulation: How do you evaluate the prospects of GRK2 inhibition in the treatment of heart failure?

　　Dr Koch: Inhibiting GRK2 will be a novel new class of drugs. It is a target that has not been utilized in any previous therapy. The animal model data are pretty strong that if you inhibit GRK2， you can improve the profile of the heart. I am quite excited. As gene therapy progresses or the small molecule therapy progresses over the next decade， we should expect to see benefits and new advances in the treatment of heart failure.

　　《国际循环》：您如何评价GRK2抑制在心衰治疗中的应用前景？

　　Dr Koch：抑制GRK2将成为药物治疗的一种新方法。GRK2是一个靶标，在过去任何治疗中从未被用过。动物模型数据相当有力，如果抑制GRK2，就能改善心脏轮廓。我非常兴奋。未来十年随着基因疗法或小分子治疗的进展，我们应该期待看到其在心力衰竭治疗中的获益或新进展。

　　International Circulation: What are your impressions of this Great Wall meeting?

　　Dr Koch: This is actually my third time at the Great Wall. There is a relationship between the American Heart Association and the Great Wall which we are always cultivating. This year we have twelve speakers from the American Heart Association in three separate sessions so we are growing each year. It is a great relationship. We have speakers from China that come to our big meeting on basic cardiovascular science in the United States in summer. It is a great relationship and I love coming to China.

　　《国际循环》：您对长城会有何印象？

　　Dr Koch：事实上这是我第三次参加长城会。美国心脏协会（AHA）和长城会关系良好，我们也一直在培养这种关系。每年来自AHA的讲者不断增加，今年有12位讲者来自AHA，他们在三个独立会节展开报告。夏天在美国举办的大型AHA会议上也有很多来自中国的讲者就基础心血管科学展开演讲。这是一个美好的关系。我喜欢来中国。