Thank you for that kind introduction, and again, it's great to see many friendly faces in the audience, colleagues in industry. And this is actually a tough topic, so I didn't quite know what to put in as cases. But I thought really what would also set the stage for the discussion is to really, again, state the problem. We may be completely off on this one statistic, but when you look at the challenge faced by the field of cardiac electrophysiology, it's amazing. Twenty-two people die every minute in this world. So to all of you in this room, to all of us, the challenge really is to have low-cost globally applicable therapeutics. And the reason I put this up is because we spend most of our lives in this image. What you're seeing here is the entire population at risk for dying suddenly. Heart failure is a subpopulation of people who have heart disease, which is typically seen in patients over here, but sort of significant ventricular dysfunction, which is the group that we've studied a lot. But we now know that heart failure as a syndrome even extends to people not just with a classic systolic where in the toilet analogy where the squeezing function of the heart is reduced, but also filling problems even with a normal sort of systolic function, you can have heart failure. And of course, if you look at patients who don't have any word or heart disease that we can pick up. So this little sort of pie that we've cut across all these population groups is really the people who are dying suddenly in the world. Of course, if you look at the people with very severe heart disease as a slice of this, there are more people dying suddenly within that group, just numerated denominator. But if you look at absolute numbers of people dying, there are more people dying with minimal or no heart disease. So if you were to look at it from the perspective of an industry, that is a potential market. That is really how you have to be really thinking about the entire world. And sure enough, dealing with this virus, we quickly realize how quick and how much the world is linked. So the overview and the scope of the problem is right there, it's massive. And just in the United States alone, when you look at these numbers and extrapolate them to global, it's about 12 million deaths suddenly. Heart failure affects 5 million people in the U.S. today. And up to 60% of these patients die suddenly. So throughout this conference, the theme that's going to emerge is any case that I present. It's now been established, thanks to the support of the NIH and various industry sponsors, that we actually have incredibly good evidence for life-saving therapies, especially implanted devices. And the reason why that is so is shown over here. And the group of patients who have been studied the very best are the patients who have significant heart failure, the problem which I said, the squeezing function of the heart. So when you look at systolic function, and really this is the mortality, it's pretty dismal. And it turns out we've not had a very, very big impact on this. We've been able to change the kurtosis of this a little bit, but not dramatically. So we need really completely new therapeutic strategies to deal with this. We can also sub-classify these patients, and this is, of course, an often-repeated slide that comes from multiple studies. Using heart function, you can sub-stratify people who are at risk for dying suddenly. So the worse your heart function, the more likely you are to die. And really, that set the stage for implanting all these big devices. But in pathophysiologic mechanisms, it's worth going back to what causes heart disease. So when you look at origins of heart disease, atherosclerosis, a common player, or it could be even inflammation of any sorts these days, the ultimate reason why you get heart failure and the biggest pathophysiologic mechanism is the heart sending signals to the other parts of the nervous system, which completely sets the stage, a vicious cycle where the heart communicates to the brain, the nervous system, and the brain now sends out all these signals to the periphery, and it causes release of norepinephrine, which is the neurotransmitter that activates what is called the renin-angiotensin system, and, of course, the heart swells up, and you get this whole syndrome of heart failure. And hand-in-hand, arrhythmias are driven by the exact same pathophysiologic process. So the whole field of heart failure thus far has been trying to tackle one problem or the other. We try to treat heart failure by trying to block all these chemicals that the body releases in response to injury, and which is the beta blockers, and you'll see drug therapy is established, and in fact, the most effective treatments that we have for heart disease today are drugs that block the adrenergic signaling mechanisms in the body. And of course, the other approach for arrhythmias, what we are able to do, and in fact, the only treatment we've been able to offer our patients is to give them a small, portable EMS in your chest, which is your ICD. Unfortunately, at least we have in the past two decades very good studies that have told us how and when and who to treat and implant devices, and still there are some subgroups of patients in whom we need to pick and choose. But then it's a very big ticket item, and of course, it is a measurable percentage of the entire budget of Medicare. And that's not sustainable long-term, and all of you know this better than us in industry that outside a handful of rich nations, it almost has no global applicability. So that is a problem. Drugs on the other hand, many of them have become generic, have actually helped, and these are guidelines. And if you look across all professional society guidelines, we are able to treat the two bad outcomes of heart failure, arrhythmias and worsening heart failure, by giving medications that target the nervous system shown over here, ACE inhibitors, beta blockers, angiotensin receptor blockers, well-established, very, very good studies have been done. And this is a great example of public-private partnership for getting these studies published. But then what about devices? And this is where we'll talk about a couple of cases. First thing, here's a case, and I think this is an interesting case. The most physicians in the audience will now realize that this is actually a fairly sick patient who has an ICDN, is on appropriate medical treatment, the QRS is not wide so they don't need a cardiac resynchronization device. And we typically face this type of a question in the clinic, what would you do for this patient? The patient had an ICD implant, was not really in heart failure, but now has worsening heart failure, and the EF has actually gone, it's gone the opposite way. So this patient has worsened, and we've given a defibrillator in this condition purely to prevent a, more or less like a parachute. If something really bad happens, the device could actually get them back. So what do you do in this kind of a setting, right? So it's a fascinating point to keep in mind. The first thing we learn over here is what not to do with devices. So here's an example where this patient was treated simply by reprogramming the device and have the device completely as a backup. So what was happening, the details of this particular case is, the device was programmed to DDD, which is a form of pacing, and some of you in the pacing industry know this, don't unnecessarily pace the heart. Because we now know, thanks to a very good study that was published in the literature, again, supported by industry, where patients were randomized to two types of programming, right? So the first rule of medicine is knowing what not to do. And of course, in this particular trial, two groups of patients, one was programmed to standard programming, simply because it was a nice programming number to use. It was not driven by great science. But the other group was a patient in whom we decided, okay, the device should only be there to shock if you have a bad rhythm, but it should not pace unnecessarily. And look at what happened. The outcome was dramatic. Unnecessary pacing can kill you. So this is a pretty distressing finding. And of course, this resulted in more lives being saved, because you're implanting a device to prevent or protect the patient if they have a serious rhythm. But when the device was not treating a serious rhythm, there was no reason for it to pace. And this is a beautiful example of pathophysiology at work. Because this pacing, this unnecessary signals, electrical pacing of the heart, actually activated all the bad stuff that I showed you in the previous slide, neuroendocrine activation. So this is physiology at work for you. It turns out that this is traditional devices. These are non-CRT devices. What about catheter ablation? That, of course, has a very big role, because we can actually prevent heart failure using catheter ablation. We know that if people have extra heartbeats, we can discuss this, of course, in the conference and further discussions, that if you have extra beats, PBCs, you can actually develop heart failure and cardiomyopathy. And this is one of those huge success stories of the world of technology and catheter ablation, because we can prevent patients developing heart failure in the first place simply by zapping these extra beats. And there's also another area where there's a cooperation between the two. What if you have these extra beats, and you've implanted a CRT device, and these extra beats are interfering with how the device works? You could actually use catheter ablation to make the implanted device work better so that you don't get these interfering beats that mess up cardiac resynchronization therapy. So we are now getting into a more sophisticated way of how we monitor and deal with devices. And I'll probably conclude with one case, we'll nicely segue to the next part, because I'm coming to the very end of my presentation. Here's a 74-year-old female with hypertension, diabetes, severe aortic stenosis, underwent aortic valve replacement, septal myectomy, because a region of the heart that actually has a left bundle has been removed. Patient had complete heart block, post-operative resolve, had residual left bundle, had a very wide QRS, and of course, six-month data trend, the EF was continuously dropping and the patient was getting worse and worse in terms of heart failure. All medications were given. What do you do? This is a classic indication for a cardiac resynchronization device. And what we ended up doing for this particular patient actually was to map the his bundle, and we found that the hedge means was very long, and we put in a his bundle pacing lead. And this patient actually had a phenomenal response, the QRS narrowed, and when you looked at the outcome, you know, pre- and post-pacing, significant increase in EF, and this is one of those types of smart use of pre-existing, already available devices. And this is having a very fascinating, good impact, and we really discovered these technologies yet again, and I tell the device people that they've made pacing interesting again, so. So there you go, and this is, of course, another thing that may come up for discussion in terms of, you know, what could be novel studies that we could do without actually having going through a very huge process of doing completely new PMA studies, right? So a better use of pre-existing technology, well-established technology would be one of the points for discussion in the world of heart failure. And again, the details of some of these patients and the studies is something that we can talk a lot more. There is a lot of promise to say that his bundle pacing perhaps is going to be as exciting, if not more, than even CRT patients are properly chosen. So that's going to be a fascinating question, and perhaps at this point, I'll stop, thank my colleagues in the team, stay on time, and hand it over to Dr. Passman. Thank you.

heart failure

therapeutic strategies

arrhythmias

device reprogramming

his bundle pacing