iPSC-derived cardiomyocytes to model estrogen receptor modulation of stress cardiomyopathy and arrhythmic syndromes

人们早就知道，与男性相比，年轻女性相对不容易患心脏病。对于因心律失常引起的猝死，男性受影响的可能性要高出80%。这通常发生在突然或慢性压力之后，由肾上腺素触发。我们一直在研究一种新描述的综合征，在这种综合征中，突然的极端休克（事故、丧亲之痛）不会导致猝死，而是导致心脏功能暂时下降，然后逆转。患者来到医院时以为自己是心脏病发作，但在几天到几周内就恢复了正常的心脏功能。有趣的是，80-90%的患者是更年期前后的女性。我们在麻醉的大鼠模型中复制了这一过程，并表明单剂量的肾上腺素也能产生同样的效果。（事实上，注射一剂肾上腺素有时也会对人产生同样的效果）。我们发现非常高的肾上腺素可以通过对心脏细胞表面受体的影响，从兴奋剂转变为抑制剂。当我们试图阻止它对心脏功能的抑制作用时，我们诱发了心源性猝死。我们的想法是，高肾上腺素通过受体转换，从兴奋（但具有破坏性）变为抑制（但具有保护性），从而防止猝死。在这里，我们想知道为什么在雌激素下降的时候这种情况尤其发生在女性身上，以及这是否能让我们了解男女之间的差异。对于这些实验，我们希望从动物模型转向人类多能干细胞（hPSC）。我们知道hPSC可以可靠地转化为跳动的心脏细胞（hPSC- cm），并且它们可以显示出与患者相同的节律紊乱。与动物相比，它们的肾上腺素受体更像人类，肾上腺素在培养皿中产生的节律效应与在整个心脏中产生的节律效应相同。它们在培养中也非常持久，并且可以更容易地进行实验-例如关闭和打开特定的蛋白质。我们已经有方法来测量它们的跳动活动以及它们受损的容易程度。我们也有一些hPSC系，反映了人类群体中不同的自然基因变异。我们的目标是发现肾上腺素转换的机制，以及它是如何被女性荷尔蒙改变的。我们的理想目标是找到一种方法，在不造成心脏功能暂时丧失的情况下利用这种保护作用，并开发一种药物来利用这种机制。高效液相色谱- cm的另一个优点是它们可以大量生产并同时用于多个分析。现在，制药公司正在使用同样的细胞和方法来测试药物，这意味着我们的任何有希望的发现都可以更快地用于药物开发。

It has long been known that young women are relatively protected from heart disease compared to men. For sudden death arising from disrupted heart rhythm, men are 80% more likely to be affected. This often occurs after sudden or chronic stress, and is triggered by adrenaline. We have been studying a newly described syndrome in which a sudden extreme shock (accident, bereavement) produces not sudden death, but a temporary reduction in heart function which then reverses. Sufferers come in to hospital thinking they are having a heart attack, but recover within days to weeks to have normal heart function. Interestingly, 80-90% of sufferers are women around or after the menopause. We reproduced this in an anesthetised rat model, and showed that a single dose of adrenaline could give the same effect. (In fact one dose of adrenaline from an epi-pen can sometimes have the same result in people). We found that very high adrenaline could switch from being stimulant to depressant, through an effect on its receptors on the heart cell surface. When we tried to stop it being depressant on the heart function, we induced sudden cardiac death. Our idea is that high adrenaline goes from being stimulant (but damaging) to depressant (but protective) through a receptor switch, and that this protects against sudden death. Here we want to know why this happens particularly in women at a time when estrogen is dropping, and whether this can give us insights into male/female differences.For these experiments we want to move away from animal models to human pluripotent stem cells (hPSC). We know hPSC can reliably be turned into beating cardiac cells (hPSC-CM), and that they can show the same disrupted rhythm as a patient from which they came. They have adrenaline receptors more like human than are found in animal species, and adrenaline can produce the same kind of rhythm effects in the dish as in the whole heart. They are also very long-lasting in culture, and can be more easily experimented on - for example to turn off and on specific proteins. We already have ways to measure their beating activity and how easily they can be damaged. We also have a number of hPSC lines reflecting different natural gene variation in human populations. We aim to discover the mechanism of the adrenaline switch and how it can be changed by female hormones. The ideal goal for us would be to find a way to harness the protective effect without producing the temporary loss of heart function, and to develop a drug to use that mechanism. One other advantage of the hPSC-CM is that they can be produced in large quantities and used in multiple assays at the same time. The same cells and methods are being used now by pharmaceutical companies to test drugs, which means that any of our promising findings can go more quickly into drug development.