<International Circulation>: How common is vasospastic angina in patients with chest pain?

　　《国际循环》：在胸痛患者中，血管痉挛性心绞痛占多大比例？

　　Dr. Beltrame: This is difficult to quantitate because routinely people don’t do spasm testing in people undergoing angiography. We think this should be done more frequently. In Japan， for example， where there is a high prevalence of vasospastic angina， in many institutions vasospastic angina testing in terms of provocative coronary spasm testing is regularly undertaken in any patient who has a normal angiogram. In Europe， Australia and the United States， coronary artery spasm testing is less frequently performed and that is why it is difficult to work out its actual prevalence. But in Japan and a few institutions in Korea as well， this is more routinely done which gives us a better idea of how prevalent it is. In relation to China， it would be interesting to see if vasospastic spasm is particularly prevalent in the Chinese population as it is more prevalent in Japan than the Western countries.

　　Beltrame：这很难测定，因为常规情况下做血管造影的患者不会做痉挛测试。我们认为这应该更常做。例如在日本，血管痉挛性心绞痛高发，很多医院将血管痉挛性心绞痛测试作为冠脉痉挛激发试验的一部分，对常规进行正常冠脉造影的患者施行。在欧洲、澳大利亚和美国，冠脉痉挛测试不常进行，所以很难计算实际发生率。但是在日本和韩国少数医院，该测试较为常规，也可以帮助我们了解血管痉挛性心绞痛的流行性。中国的血管痉挛发生是否像日本一样比西方国家更流行，这也很值得关注。

　　<International Circulation>: What is the reason for the difference between Asian and Caucasian populations in this respect?

　　《国际循环》：亚洲人群和高加索人群血管痉挛性心绞痛发生率不同是什么原因导致的？

　　Dr. Beltrame: We don’t know， is the basic answer. What we know is that it could be genetic in origin but it could also be environmental. It has been well documented that atherosclerotic coronary artery disease is less prevalent amongst Japanese/Chinese/Korean people than in European/Australian/American populations. But vasospasm may be more prevalent in the Asian population.

　　Beltrame：我们不知道，这是基本的答案。目前只知道这可能与遗传相关，但也可能由环境因素导致。已经确定的是，动脉粥样硬化性冠脉疾病在日本/中国/韩国发病率更低，而欧洲/澳大利亚/美国人群发病更高。但血管痉挛可能在亚洲人群中更常见。

　　<International Circulation>: Vasospastic angina is also more common in females than males. What is the reason for that?

　　《国际循环》：血管痉挛性心绞痛在女性中更常见？这一现象如何解释？

　　Dr. Beltrame: That is not quite correct. Where we have patients who have chest pain and a normal angiogram， the chest pain could be cardiac or it could be due to large vessel coronary artery spasm and in those cases there is an equal representation in males and females. However， microvascular dysfunction (the vessels we don’t see on the angiogram) is more prevalent amongst women. Again， the reason for this is complex and we really don’t know. One of my colleagues who has presented work we have done at our institution showed that there is a difference between male and female blood vessels. She was able to take internal mammary arteries from people who had undergone coronary bypass surgery， put them into an organ bath and subjected them to various vasospasm agents to show that females exhibited more sensitivity to vasoconstrictors than males. This occurred particularly with alpha-agonist phenylephrine and also serotonin indicating that women’s blood vessels are more sensitive than men’s and this is perhaps why we see more microvascular angina in females.

　　Beltrame：这不太准确。胸痛但血管造影片正常的患者往往胸痛是心源性的，或者可能由大血管冠脉痉挛引起，这在男性和女性中发病率相当。然而，小血管功能紊乱在女性中更常见。再者，男女性发病率之间的差异很复杂，原因尚未阐明。我的一个同事发现男性和女性血管有所差异。她从接受冠脉旁路移植术患者身上取得内如动脉样本，放入组织培养液中并用不同血管痉挛药物刺激，发现女性的血管对血管收缩剂更敏感。这种现象尤其在α受体拮抗剂苯肾上腺素以及血清素刺激下更明显，再次证实女性血管比男性更敏感，这也是我们需要更关注女性小血管的原因。

　　<International Circulation>: Coronary microvascular dysfunction is an important factor in vasospastic angina. Could you explain the mechanism in a little more detail especially for unstable angina?

　　《国际循环》：冠脉小血管功能紊乱是血管痉挛性心绞痛的重要因素。能否详细解释一下具体机制，尤其是对不稳定性心绞痛？

　　Dr. Beltrame: Microvascular angina is a complex disease entity because there are many causes. There have been four syndromes characterized and I think there are probably many more. The first classical one is syndrome X. This is where people have a positive exercise test as evidence of myocardial ischemia and have a normal angiogram， so the ischemia must be due to microvascular dysfunction. You would also be spasm testing to exclude large vessel coronary artery spasm. So syndrome X is more common in women than men. The second type is often called microvascular angina where the problem is that the actual microvessels fail to dilate so these patients have a reduced coronary flow reserve which is what distinguishes this syndrome. Only about 30% of these patients will have an abnormal stress test. The next group is the coronary slow flow phenomenon. This is where patients have an angiogram and the dye progresses very slowly on the angiogram or has TIMI 2 flow. In these patients， when we look back， most of them undergo angiography because they presented with an acute coronary syndrome. So these patients are often more likely to be males and are more often smokers so are different from the syndrome X microvascular angina patients. The Japanese have described another group that have microvascular spasms. These are patients who are undergoing provocation testing with acetylcholine and they get chest pain with ECG changes but no evidence of spasm， again implicating the microvessels.

　　Beltrame：微血管性心绞痛是复杂的独立病种，因其由多种原因导致。以4种综合征为特点，或者更多。首先是X综合征，患者运动测试阳性作为心肌缺血的证据，血管造影正常，缺血症状源于微血管功能紊乱。患者也进行痉挛测试以除外大血管冠状动脉痉挛。所以X综合征在女性中更常见。第二类常称为微血管性心绞痛，病因为微血管扩张障碍，这类患者冠脉血流储备低，可作为鉴别标准。这类患者中仅有30%压力测试异常。还有一类是冠脉慢血流，血管造影显示血液染色剂移动缓慢或TIMI 2血流。在这些患者中，大部分接受血管造影是因为他们有急性冠脉综合征。因此这些患者大部分为男性，吸烟者更多，与X综合征和微血管性心绞痛不同。日本人群分出另一类微血管痉挛亚群，这些患者用乙酰胆碱做激发试验并引发胸痛，心电图改变，但没有痉挛证据，依然可能与微血管有关。

　　<International Circulation>: Regarding coronary slow flow， how do we correct the flow rate?

　　《国际循环》：对冠脉慢血流患者，如何矫正血流速率？

　　Dr. Beltrame: On angiogram studies we have shown that if you give dipyridamole， which is a small vessel vasodilator， the flow improves. There is also a drug we used many years ago called mibefradil which is no longer available which is a type of calcium channel blocker， and this agent also sped the flow up in patients with slow flow. The important point is that in a randomized clinical trial where we were looking at angina， we showed that mibefradil reduced the frequency of angina by over 50%， and severe episodes by over 70%. So this was a very effective agent， but unfortunately is no longer available because the drug blocked cytochrome 3A4 and so had problems with drug interactions and was taken off the market. We still need to find an agent that is effective for the coronary slow flow phenomenon.

　　Beltrame：在血管造影研究方面，我们发现如果服用小血管扩张剂双嘧达莫，血流会改善。也有一种用了多年的钙拮抗剂咪拉地尔，现在已经不再使用，这种药也可以提高血流速度。重要的是咪拉地尔可降低心绞痛发生率50%，严重发作减少70%以上，所以这是一种很有效的药物，但该药能阻断细胞色素3A4，而且有药物相互作用，于是撤出市场。我们依然需要研发对冠脉慢血流有效的药物。

　　<International Circulation>: With regards to treatment for vasospastic angina， apart from the classical therapies of nitrates and calcium channel blockers， are there any new promising treatments on the horizon?

　　《国际循环》：对血管痉挛的治疗方面，除硝酸盐类、钙拮抗剂等经典治疗外，是否有新的疗法即将出现？

　　Dr. Beltrame: Firstly， the nitrates and calcium channel blockers are very effective in vasospastic angina， whereas in microvascular angina， nitrates are not so useful and calcium channel blockers can be useful. Calcium channel blockers are particularly important because what was shown many years ago is that not using calcium channel blockers in someone with vasospastic angina is a predictor of cardiac events. If somebody has vasospastic angina， they should really be on a calcium channel blocker. If you have nitrates and calcium channel blockers and the patient is still getting chest pain， then this is a difficult population to treat. One thing that has been shown to be of benefit in the Japanese cohort was statins. It was shown that patients not responding to nitrates and calcium channel blockers， the addition of statins will reduce the angina frequency. Another drug which is not widely availableis the Rho-kinase inhibitors. This is a new group of drugs. Fasudil is available in Japan but certainly not available in Australia， the US or Europe. This is an agent that works via a different mechanism and would have additional beneficial effects to the calcium channel blockers. I think this is a potential future treatment for vasospastic angina.

　　Beltrame：首先，硝酸盐类和钙拮抗剂对血管痉挛性心绞痛非常有效，但是对微血管性心绞痛，硝酸盐不如钙拮抗剂有效。钙拮抗剂非常重要，因为多年试验证实，微血管性心绞痛患者不用钙拮抗剂将导致心血管事件。如果患有血管痉挛性心绞痛，患者应该服用钙拮抗剂。如果服用硝酸盐类和钙拮抗剂后，患者胸痛症状依然没有缓解，就归为难治性。日本相关队列研究发现，他汀类可使这类患者获益，患者对硝酸盐类和钙拮抗剂无应答时，他汀作为替代药物可减少心绞痛发生频率。另一个药物目前没有广泛应用，为Rho激酶拮抗剂。这是一类新药。法舒地尔已在日本上市，但还未能在澳大利亚、美国和欧洲应用。这类药通过不同的机制起作用，对钙拮抗剂有补充获益。我认为这可能成为血管痉挛性心绞痛的潜在未来疗法。

　　<International Circulation>: What about future therapies for microvascular angina?

　　《国际循环》：对微血管性心绞痛来说，未来有哪些疗法？

　　Dr. Beltrame: We still have a long way to go with microvascular angina because it is more difficult to diagnose because we have different techniques. A group of us called Covartis， which is the Coronary Vasomotion Assessment International Study group， is trying to work out the nomenclature for this complex heterogeneous disorder. Once we have done that， we can do more formalized studies to look at treatments for microvascular angina. It is a heterogeneous disorder so it is difficult to isolate one particular drug， but of the treatments that are currently recognized， nitrates are not so useful. Beta-blockers can be useful. Calcium channel blockers can be useful. There have been studies to show that ranolazine could be useful in this group. Then some of the more uncommon anti-angina drugs have been suggested to be of benefit in this disorder such as nicorandil.

　　Beltrame：对微血管性心绞痛来说，我们还有很长的路要走。首先它非常难确诊，因为诊断技术不同。我们成立了国际冠脉血管收舒评估工作组，旨在解决这种异质性疾病的命名。一旦完成命名方法，就能进行更多正规研究来寻找微血管性血管痉挛的治疗方法。这种疾病是多病因导致的，所以很难独立出特定药物，但近来发展的治疗方法中，硝酸盐类作用不大。β受体阻滞剂可能有效。钙拮抗剂可能有效。已有多项研究证实雷诺嗪对这类患者有效。随后，一些不常见抗心绞痛药物也被发现对这种疾病有效，如尼可地尔。

　　<International Circulation>: There are also reports of using stenting to treat these anginas.

　　《国际循环》：也有研究报道用支架可以治疗这些心绞痛。

　　Dr. Beltrame: Stenting is of no use in microvascular angina because we can’t stent the microvessels. In terms of vasospastic large vessel angina， if those patients are refractory to medical therapy， there have been a few case reports where if one particular area can be identified where spasms occur， it might be stented. There are significant concerns with this type of practice because other studies have shown that if you stent the area， the adjacent area then causes the spasm so the problem persists. I think for this approach， we still need a more generalized treatment of the artery such as medication rather than stenting. I think there would be very few cases where you would need stenting for vasospastic angina.

　　Beltrame：支架对微血管性心绞痛无效，因为我们不能微血管中置入支架。在大血管痉挛性心绞痛方面，如果这些患者属于药物难治性，有少数病例报道发现如果能鉴别患者血管痉挛发生的确切位置，就可以进行支架。这种临床实践备受关注，因为其他研究发现如果在特定区域置入支架，会引发临近区域痉挛而症状持续。我认为还需要对动脉进行更大范围的治疗，应该用药物而非支架。我认为很少血管痉挛性心绞痛患者会需要支架治疗。