All right, welcome everyone. Thanks for being here. So, we're excited to talk about sleep in the context of cardiovascular disease. And I have a fantastic panel. We have Dr. Castriata, who is going to give us some fascinating insight into the role hypertension plays. We have Dr. Mehra, who's a leader in the field. She has worked with AHA and multiple groups to fill in what we already don't know. Unfortunately, Dr. Javahiri couldn't be here because of a recent illness. He's doing okay, but Dr. Castriata has graciously agreed to step in for him. So, I will move on. I work at UT in Houston, McGovern Medical School. I have nothing to disclose. All right, so jumping right into normal sleep. Sleep is good for us. I think we're all on the same page there. It's been a bit difficult to convince the population and the consultants that we work with, but I think we're moving in the right direction is what the signals are indicating. So, this is data from, I don't know, 30, 40 years back, several decades ago, that looked, again, these are normal patients, subjects looking at MI. And this is, can you see my pointer? I guess not. So, looking at MI and sudden cardiac death, the nadir for events is when we sleep. So, between midnight and 6 a.m. So, that's when the nadir for bad events, cardiovascular events occur, and the peak is in the morning between 6 a.m. and noon. And so, let me just go over, for the non-sleep physicians in the group, let me just go over the physiologic changes that we see in sleep, moving from awake, drowsy, different stages of non-REM sleep, and finally, REM sleep. They're different. Even through stages of non-REM sleep, the significant difference is between the states, between non-REM and REM, and between different stages of N1. You see the spindles and the Ks here with N2, nice delta, but also look at how similar awake and REM looks, and that's important to keep in mind. So, moving into the respiratory and cardiovascular differences between the two states, non-REM is where we have a heightened parasympathetic tone, and our heart rate is lower, blood pressure drops. These are all good things. That's what it's supposed to do, and breathing is more stable, with lower ventilatory responses to hypercapnia and hypoxemia than awake, but gets worse in REM sleep. So, breathing's more unstable during REM sleep. Heart rate and blood pressure increase because of a sympathetic surge that sets upon the existing parasympathetic tone that occurs in majority of sleep. This is some fascinating data by Dr. Summers' group, again, from three decades back. It's highly replicated in fellow education talks and everything on the slide decks when we are teaching fellows. We'll look at the difference between wake and then moving on to different stages of sleep. This was the older staging where we did stage four, and REM, heightened sympathetic activity in REM sleep higher than in wake. Also seen with, going back one more, where with K-complexes, which indicates arousal, there is a spike. Seen better here, higher sympathetic activity during arousals. And so, to tie this conversation into the circadian angle to cardiovascular disease, it's important to go over a couple of things. Our cortisol peaks at nine in the morning. We have higher sympathetic activity during the day. It's a pretty steep rise. Higher coagulation parameters in the morning. Again, platelet aggregation peaks at nine. And so, with this, it's a little easier to understand why we have that peak in cardiovascular disease, bad events during that, when the ambulances are all running in the general population. Again, the beneficial effects of melatonin cycles off at the onset of dawn. And we have just come out of REM sleep, which is very heavy in the second half of our nocturnal sleep period. So, again, I think we talked about all of this. So, sleep is, every aspect of sleep that we look at, pretty much every diagnosis that includes obstructive and central sleep apnea, sleep deprivation, shift work, insomnia, PLMs even, they are all somehow linked to cardiovascular, poor cardiovascular outcomes. Of course, the bulk of the data that we have is on obstructive sleep apnea and sleep deprivation. We are seeing fascinating data with shift work and the circadian misalignment as well. So, we'll briefly go over some of them. So, whatever I showed you in the first slide, it is flipped in sleep apnea patients. Their peak for sudden cardiac death is now in the nocturnal sleep period. And it's easy, for those of us who treat sleep apnea, it's easy to understand why the periodic, profound hypoxemia that occurs, especially in the severe sleep apnea population. It's not just the nature of hypoxemia or the hypoxemic burden, it's also the generation of radical oxygen species that is detrimental to the body. The arousals, the sympathetic surge that comes from that, changes in the intrathoracic pressure that comes with the big negative in effort that generates the negative pressure, which can increase LV transmural pressures. All of that plays into the sympathetic activity, increased inflammation, metabolic dysregulation, which ends up causing disease that we know or say to be associated with. There is no doubt about the fact that we see a whole lot of cardiovascular disease in patients with obstructive sleep apnea. There's been very nicely done prospective observational studies that indicate that sleep apnea is independently associated with various cardiovascular outcomes, including all-cause mortality. But I think where we are stuck right now is the lack of randomized control trials that indicate the benefit of treatment with CPAP. Again, there's cross-sectional data as well as prospective observational studies that show improved outcomes with PAP. And highly-evaded randomized control trials have failed to show an improvement in outcomes, except when you look at the population by adherence, when they looked at patients in the postdoc analysis who used PAP better, they saw improved cardiovascular outcomes in this population that were adherent to PAP. But there's a few other things as well. Sleepy patients were excluded in pretty much most of them, and that's a hard one, because, well, how do you let go of an upwards of 18 and let them drive and do bad things at work and not treat them? So that's a hard study to design. And then also, the hypoxemia, the ones with significant hypoxemia were excluded, for example, in the SAVE trial. So these are challenges. So designing future randomized control trials will need to address this. I've just listed a few. This one's a tricky one. Like I said, what do you do with these sleepy patients? But there's other things that can be done, such as improving adherence and utilizing existing resources to improve adherence and factor that into the design of the trials. And Dr. Mehra was involved in some of the studies and a write-up that looked at, looking at different metrics, for example. Maybe we traditionally would have looked at the HI, but maybe the hypoxic burden or the number of arousals. I mean, those, looking at sleep apnea from a different angle might help as well. Again, challenging, but we're sort of stuck there, and that patient, young patient with a BMI of 50 and a HI of 60 and a satinator of 52, I give him an impassioned speech about the need for treatment, but we like evidence. We like to let evidence lead us, and at this point, we are lacking that. Quickly on periodic limb movements. That has been a consistent association between PLMs and cardiovascular disease. It's not a causality. It's more of an association. So, you know, with the PLMs, with or without arousals, there is an increase in the heart rate, sympathetic tone, and an increased inflammation as well. Not so much with restless leg syndrome. And, well, even if it did, maybe the hypothesis is that it does it mostly through the periodic limb movement. So the data on this, there's been several positive studies, but also several negative studies. This has been a bit inconsistent. Insomnia is another big one. Again, it is highly prevalent. They have heightened cortisol throughout the night, and the phenotype they're worried about is the short sleep duration. Shift work, again, it's hard to summarize all of this in less than a minute, but shift work is another big one with a significant misalignment between our internal rhythm and the external light-dark cycle. But then there's other factors as well. They are notorious for sleeping a lot less, and there's association with significant cardiovascular outcomes. Sleep duration, it is a bit more nuanced because there's also that relationship, the U-shaped relationship between sleep duration. Long sleep specifically is what I'm alluding to, and mortality, but it's a bit more nuanced conversation to have. Snoring, well, the sleep partner complains about it. It is a marker for sleep apnea. We look at that before as part of our screening, but we don't look at it as disease, and a majority of Americans snore, men more than women. Snoring is associated with carotid atherosclerosis, and when they used, in the Lee study, they used the femoral artery as control. The heavy snorers had significantly higher risk for carotid atherosclerosis, and this might be important for when we're looking at stroke risk. There's some signal that the evening chronotypes and the social jet lag that the lay media is exploiting with some write-ups about that. I mean, there's some signal that it might be leading into the cardiovascular disease intermediate mechanisms, but I think we gotta wait a little bit on that. I thought I was cooler being the evening chronotype, but apparently I'm at higher risk being the evening chronotype. All right, and let me stop with this, but the fact that the AHA included sleep in the cycle of life, if you will, because we didn't factor here. Sleep medicine did not factor in the previous public health campaign that AHA had released, but this is progress. I think we're moving in the right direction. All right, with that, let me ask Dr. Castriata to move to the next talk. All right. Well, good afternoon, everybody. Today, I hope to make this visit worthwhile. I hope to change everything that you thought you knew about blood pressure. I have nothing to disclose, no conflicts of interest, and right now I would like to help you identify sleep blood pressure as really the major risk factor for cardiovascular outcomes for the population at large and also for those with obstructive sleep apnea. There is a circadian rhythm for everything. I don't think that's showing up, but if you look at the lower, at the right-hand column, the circadian rhythm in process C. Yeah, but it's not showing up. Is it? Oh, it is, okay. So you can see that there's a circadian rhythm of everything, and for blood pressure, it's higher at night and down in the morning. If you look down in the lower left-hand corner, you see that temperature does the same thing. It turns out the temperature and blood pressure are really intimately connected, and we're supposed to have a higher blood pressure during the day and a lower pressure at night. During non-REM sleep, there should be a 10 to 20% reduction in blood pressure from wakefulness. We call this a normal dipping pattern. If you don't have that normal dipping pattern, there's hell to pay. There's a lower systemic vascular resistance, a reduced heart rate and cardiac output, reduced sympathetic activity. This is the normal resting state in non-REM sleep. REM sleep, of course, is a whole different thing because it's a challenge and has really bursts of blood pressure going up and down, and heart rate as well, but we'll talk about that later. There's a daytime blood pressure peak a couple of hours after awakening and in the early evening, and an eight or around three in the afternoon. Our normal blood pressures for sleep, however, you'll have to get adjusted to. Now, we look at 120 over 80 as the normal blood pressure when you're taking the blood pressure in your office. I'm gonna hopefully convince you that those blood pressure readings are meaningless and useless. But during sleep, the mean blood pressure for wakefulness is 130 over 85 for men, 125 over 80 for women, I mean, during wakefulness. This is for ambulatory blood pressure monitoring, so over a 24-hour period, and it's lower in sleep, and a difference between men and women. The 24-hour mean is also different, a little higher in sleep, and the mean is also different, a little higher in men than in women. I'm gonna give you the results of a few studies that I don't think you're familiar with, but are supremely important. The first one is the MAPEC study, both of these were done in Spain, which was a prospective study looking at hypertensive patients randomized to get treatment of their medication, either at bedtime or during normal times, with ambulatory blood pressure monitoring and actigraphy for 48 hours at baseline, annually in a termination. Primary outcomes were all-cause mortality, cardiovascular morbidity, defined as myocardial infarction, angina, coronary vascularization, heart failure, lower extremity acute arterial occlusion, stroke, or TIA. And there was a Cox regression survival analysis done, which was adjusted for each individual parameter for sex, age, diabetes, renal function, and hypertension treatment. The results of this study show that only sleep systolic blood pressure was a significant predictor of cardiovascular events, that the office blood pressure and the mean wake blood pressure did not independently predict cardiovascular morbidity or mortality when adjusted by sleep blood pressure. And the best Cox regression fully adjusted model included only sleep blood pressure and the sleep time relative sleep blood pressure decline, or the dipping index. And when the wake blood pressure was adjusted by the sleep blood pressure, only the sleep blood pressure significantly predicted cardiovascular outcomes, so the hazard risk for the general population of 1.67. It's illustrated in this slide, and what you can see is that it doesn't matter what your waking blood pressure is, it only matters what your sleep blood pressure is. So if your sleep blood pressure is high, you have an increased risk of cardiovascular events, as you can see from this. But if your sleep blood pressure is normal, then you have no increased risk, even if you have high blood pressure during the day. The difference between these two slides, this is the top slide is the mean wake blood pressure by ABP, and the bottom one is the waking blood pressure by office blood pressure, but same difference. So cardiovascular disease risk is jointly associated with an elevated mean sleep blood pressure, regardless of the office blood pressure or the wake blood pressure, and a non-dipping pattern, regardless of the mean sleep blood pressure. That's illustrated here. Highest risk is for a high sleep blood pressure with a non-dipping pattern, but also a high risk for a normal sleep blood pressure and a non-dipping pattern, and higher risk for that would be a normal wake blood pressure, but a high sleep blood pressure. So dipping makes a big difference, no matter what. Oops. It also showed that progressive attenuation of the mean sleep blood pressure was significantly associated with a diminished cardiovascular risk, but progressively lowering the wake blood pressure was not, so that if you lowered the wake blood pressure, it didn't make any difference, but if you lowered the sleep blood pressure, you lowered the risk of cardiovascular disease and mortality. Cardiovascular risk was lowest with an achieved mean blood pressure of 100.3, and the wake blood pressure had shown no significant relationship with adjusted hazard risk, as you can see here. So the top is the sleep blood pressure, the bottom is the wake blood pressure, and once again, you lower your sleep blood pressure, the lower the risk, and you can do the same with the wake blood pressure, but it has no effect. So the only blood pressure that's important in cardiovascular disease and treatment is the sleep blood pressure. Ambulatory blood pressure monitoring, therefore, should be the gold standard for diagnosis and treatment of hypertension. Antihypertensive treatment should be given at bedtime when it also lowers the blood pressure at night more, and this encouraged the U.S. Preventive Services Task Force to recommend ambulatory blood pressure monitoring to confirm any office blood pressure. The second study is a much bigger one, and this was the HyGaEA Project, and here, once again, primary outcomes were cardiovascular morbidity, mortality, reduction of cardiovascular risk from specific ambulatory blood pressure-derived treatment. The outcomes, cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke, either ischemic or hemorrhagic. This HyGaEA Project was a network of 40 primary care sites in Spain established to evaluate ambulatory blood pressure monitoring and response to treatment. There were over, now, over 20,000 subjects, at this time, over 19,000 when this data was done, fulfilled all the study requirements, and minimum follow-up, and then there was a recent subset of 2,000 subjects with sleep apnea that we looked at, and so, once again, from this study, this was a long-term prospective study, and it shows basically the same things, only the significance even more so, where the hazard risk is increased if you have a high sleep blood pressure, but if you have a normal sleep blood pressure, you do not have a high risk of cardiovascular events, even if you have a high wake blood pressure, so it doesn't matter what the waking blood pressure is, it's only the sleeping blood pressure, and if it's done by ambulatory monitoring or by office blood pressure, it's the same results. The sleep blood pressure holds no meaning, the wake blood pressure holds no meaning, the sleep blood pressure is the only one that's important, and this, again, the same kind of data for waking above and sleep on the bottom, that if you lower the blood pressure during sleep, you lower the hazard risk for cardiovascular disease, and if you increase the difference between wake and sleep blood pressure, so that BP dipping index, the more you do that, the more you lower the blood pressure, but the wake blood pressure doesn't do anything. There were, within this group, 2,000 patients who had polysomnography in lab with an AHI over 10, mean age of 61, and they were mostly 80% men, and once again, it showed the sleep histolic blood pressure was the most significant indicator of adverse cardiovascular events in these sleep apnea patients. Hazard ratio even higher, 1.72, and the sleep time relative blood pressure decline or blood pressure dipping index was the most protective parameter, hazard risk 0.6. That's illustrated in these slides. The top data is non-adjusted, and the bottom data is adjusted for all those parameters, and it shows, once again, doesn't matter what your sleep, your wake blood pressure is, but your, excuse me, wait, but that your sleep blood pressure determines your hazard risk, even when adjusted for all the other risk factors, and also the amount of blood pressure decline, so whether you're a dipper or non-dipper is important. And this is the overall results in adjusted hazard ratio. So as you can see, office blood pressure and awake mean blood pressure have no significant input into the risk for cardiovascular disease. It's only the sleep. So we conclude ambulatory blood pressure monitoring should be done and treatment adjusted to normalize sleep blood pressure and assure blood pressure during dipping during sleep is a marker of effective blood pressure control and effective sleep apnea treatment. Masked normal intensive patients, that is patients with high wake blood pressure, but a normal sleep pressure, blood pressure, or white coat hypertensives can be unnecessarily treated when they don't need to be. And masked hypertensive patients that have a normal daytime pressure, but elevated sleep pressure may not receive the requisite treatment. So here we have the final conclusion. Sleep blood pressure is the most significant risk factor for cardiovascular diseases, including sleep apnea patients. Hazard risk 1.29 for everybody and 1.72 for sleep apnea patients. The decrease in sleep blood pressure, the dipping effect is the most significant marker for event-free survival. Hazard risk of 0.75 for everybody and 0.6 for sleep apnea patients. And only the decrease in sleep blood pressure and the increase in sleep time relative blood pressure decline are significantly associated with reduced cardiovascular risk. Well, we think about this. Non-REM sleep is a period of rest and protection for the heart. Sleep onset coincides with an increase in distal to proximal skin temperature gradient, which effectively measures the level of the blood flow into the arteriovenous anastomosis. And this is the best predictor of sleep onset. This is how we fall asleep. We open up those vessels, we disperse our heat, we lower our core body temperature, and we fall asleep. The increased DPG results in a distal heat dispersal, reduced body core temperature, but also a reduction in peripheral vascular resistance and systemic blood pressure. It's all interconnected. When we fall asleep, we have to cool our core body temperature. We do this to cool our core body temperature, and as a result, we lower our blood pressure. This is the resting and restorative state of non-REM sleep. So during the day, we have to have a high blood pressure sometimes. You don't raise your blood pressure during exercise, you're in trouble, you can't do it. So maybe the resting body doesn't tolerate this. This may be a mechanism by which the nocturnal rise in blood pressure resulting from obstructive sleep apnea contributes to the cardiovascular and cerebrovascular morbidity of obstructive sleep apnea. And ABPM should be done on sleep apnea patients and evening blood pressure medications adjusted to normalize the sleep blood pressure and assure this BP dipping as an effective mark of treatment. So thank you. Good afternoon, everyone. It's great to be here. And I want to thank Dr. Matthew for organizing this great session. It's great to be here with Dr. Castriata as well. I enjoyed his lecture. And so today, for my talk, I'll be focusing on sleep disorder, breathing, and cardiac arrhythmia and kind of where we are now with our current state of knowledge. Some of the work I'll be presenting has been funded by the NIH, American Heart Association, American Academy of Sleep Medicine. And I've received royalties from up to date in terms of disclosures. So the way the talk is structured is, you know, there's a lot to cover in 10 minutes. So I thought I'd kind of give you a flavor of mechanism, a flavor of epidemiology, of the relationship of sleep apnea and cardiac arrhythmia. And then some of the work, more recent work in terms of interventional studies, what is the impact of treatment of sleep apnea on cardiac arrhythmia outcomes. And then we'll kind of summarize things together. Along the way, we'll be presenting some newer data that's actually in press as well as it relates to these relationships. So, you know, as was discussed, there are, you know, many mechanisms at play with sleep disorder breathing in terms of the intermittent hypoxia, the autonomic nervous system fluctuations, and the elevations in CO2 even, and so forth that can actually directly affect our cardiac electrophysiology. There are data to show in particular alterations in the atrial effective refractory period, but also other aspects of cardiac electrophysiology. And over time, as can be shown here, over time with increasing age, we know that increasing age is a risk for sleep apnea, increasing age is a risk for atrial fibrillation in particular. And then with these repetitive physiologic, overnight physiologic stressors of sleep disorder breathing that are sustained into daytime as well, this can result in not only structural remodeling of the heart, but also electrophysiologic remodeling of the heart. And we'll be reviewing some of the data, some of the, in particular the mechanistic data I think are really interesting in sort of, in terms of biological plausibility, you know, really supporting that notion of sleep disorder breathing being a risk for arrhythmogenesis. So, you know, just again briefly touching on some of the mechanistic data, which I think is really fascinating. So this is a model of chronic intermittent hypoxia in a ROT model. And they found that in this model of chronic intermittent hypoxia, that there was enhanced atrial fibrillation vulnerability when they used this post-electrical stimulation model. That was accentuated by carbacol and abolished by atropine. And these, so therefore supporting the notion that these atrial fibrillation promoting effects of chronic intermittent hypoxia are principally being mediated by the parasympathetic activation. And again, there was direct effects on this atrial effective refractory period. So that's the time where, when that is reduced and there's increased vulnerability to atrial arrhythmogenesis. And there was also higher M2 receptor protein levels. So, and you can see the increased inducibility of atrial fibrillation in the chronic intermittent hypoxic exposed rats. So there's some, again, biological plausibility that, okay, sleep apnea, its ramifications are leading to increased arrhythmogenesis. Also with the application of negative tracheal pressure. So in this particular study, they actually applied negative tracheal pressure with, so tracheal occlusion with increasingly negative tracheal pressure and then without the negative tracheal pressure. And you can see when negative tracheal pressure was applied, there was reduction in this atrial effective refractory period. And again, when this is reduced, that increases the vulnerability for atrial arrhythmogenesis. And in this study as well, they seem to implicate the autonomic nervous system as being a mechanism that is mediating these relationships. In this study, it was one of the first studies where they focused on the autonomic system in this canine model. And so what they did was, they looked at apnea induced atrial fibrillation before and after ablation of the right pulmonary arterial ganglionated plexus. So before the ablation, there was apnea induced atrial fibrillation as shown in panel A. And then after ablation, there was no longer apnea induced atrial fibrillation. So this is really again, pointing towards the autonomic nervous system really playing a key role in terms of sleep apnea and in terms of mechanism with cardiac arrhythmogenesis. And then of course, we have upregulation of systemic inflammation, oxidative stress. And we know that sleep apnea has been shown in several studies to be associated with elevated cytokines, increased prothrombotic potential and prothrombotic markers have also been implicated in atrial fibrillation, oxidative stress. We've in particular shown that it's the morning levels of some of these biomarkers that seem to be increased related to that overnight physiologic stress of sleep apnea. And then we know in atrial fibrillation, a state of upregulated systemic inflammation can really increase atrial arrhythmias and in particular be related to more prolonged duration of atrial fibrillation, the development of atrial fibrillation and the progression of atrial fibrillation. So these, even at the local milieu, these markers of inflammation, even the adiposity, the visceral adipose tissue itself can be a generator of some risk there. And the intermittent hypoxia and other mechanisms of sleep apnea are likely operating through a variety of these mechanisms to increase the cardiac arrhythmia. We've looked at a little bit of this in terms of biomarkers and proteomic biomarkers in particular in the SAFE-BEAT study, which is an NIH funded study where we looked at those with proxysmal atrial fibrillation compared to those without. And here in this volcano plot, you can see that there's certain biomarkers, proteomic biomarkers that are related in, that are kind of differentially expressed in those with AFib shown in red versus those without AFib shown in blue. And some of these biomarkers that were increased in atrial fibrillation when we applied CPAP and gave CPAP pressure for three months were actually shown to change with the intervention of CPAP. So these may be some candidate biomarkers complement shown in one, which is related to the J and K pathway, matrix myeloproteinase three. So these may be some candidate biomarkers that potentially are targetable proteomic biomarkers in terms of even treatment. So taken together, there's a lot of great, again, mechanistic data that is showing us that there, over time, with sleep apnea, structural remodeling, increase in left atrial size, increase in left ventricular mass. We just heard about, you know, nicely about high blood pressure as well, and we know that's also a risk for atrial fibrillation, in part because of alterations in the left ventricle. Autonomic nervous system alterations, we've seen a bit of data supporting that. And then electrical remodeling. So direct changes have been shown in terms of atrial refractoriness, diffuse after depolarizations, and even some biomarkers, such as connexin, which is responsible for fibrosis in the myocardium as it relates to sleep apnea. And here you can see in the study, in the top, this is the individual with sleep apnea, in the bottom, without, and the areas in red are the areas of electrical silence. And so this is more dominant in the individuals with sleep apnea, indicating that kind of fibrosis that occurs. So atrial fibrillation is, you know, an ensuing epidemic. The number of Americans afflicted by atrial fibrillation is estimated to increase more than five-fold, so two million to five million by the year 2050. And it was recognized initially that this is unexplained by established risk factors, such as increasing age, male gender, and so forth. And in those older studies, they weren't really taking into consideration sleep apnea. And we know sleep apnea is underdiagnosed, as it is, and so this unrecognized sleep apnea, which is estimated to be at 85%, is likely at least partially contributing to this atrial fibrillation epidemic, so really something that we should be, you know, paying mind to. And I think also important to remember is that there's a progression of atrial fibrillation. So we have paroxysmal atrial fibrillation, persistent, and then longstanding persistent atrial fibrillation. And as, you know, over the course of time, you know, changes in body mass index, increased, you know, genetic susceptibilities, and then just with the atrial electrophysiology of that atrial fibrillation and the remodeling of the heart as it occurs over time really sets people up for, you know, poorer clinical outcomes as well. So it's important to kind of keep this in mind, especially as we think about even optimal timing for treatment of sleep apnea along this continuum. And as we think about this too, also adiposity. So we know obesity is a risk for sleep apnea. We know obesity is a risk for atrial fibrillation. So what are the synergies there? And in this particular study, we looked at the epicardial adipose tissue. Now this is a small sample size, but I think pretty striking. So you can see an individual who has sleep apnea in the top right, an individual with both sleep apnea and obesity here, obesity, and then an individual without either. And the individual with obstructive sleep apnea and obesity you can see has a much higher, even by visual inspection, you can see a higher volume in terms of that visceral adipose tissue, which in of itself can be, you know, a risk for atrial arrhythmogenesis. And again, so taking into consideration, obesity is important, even as we think about those who may be more vulnerable to sleep apnea specific stresses and atrial arrhythmogenesis and also over time as well. So one of those first studies we did to look at these relationships was in the sleep heart health study. And we found in those with severe sleep apnea compared to those without sleep apnea, even after adjusting for confounding factors, including established cardiovascular disease and cardiovascular risk factors, that there was anywhere from a two to five fold higher odds of having atrial and ventricular arrhythmias in those with severe sleep apnea compared to those without. And then in the outcomes of sleep disorders in older men study, this was a cohort of about 3000 older men. We found that there were these dose response relationships such that with increasing severity of sleep apnea, there was increasing atrial fibrillation, increasing complex ventricular ectopy. In this study, we found also that central apnea appeared to be more closely tied to atrial fibrillation and obstructive apnea more closely tied to ventricular arrhythmias. And again, this was an all male cohort, so the findings are generalizable as such involving about 3000 individuals. And in terms of temporality, when we were looking at the data, we found these interesting relationships such that with the discrete apneas and hypopneas, we noted that there was some discrete arrhythmic events. So we decided to apply this case crossover design, which is oftentimes used in pollution studies, where you're looking at a fleeting predictor and a fleeting outcome. And we found that there was a very strong relationships between the timing of when these apneic and hypopneic, mostly hypopneic events actually in this study as it relates to discrete episodes of atrial fibrillation and also discrete episodes of non-sustained ventricular tachycardia. And now some hot of the press data where we've kind of looked at these relationships also in our clinical registry, the STARLET registry at the Cleveland Clinic, which has housed over 200,000 sleep studies. So in this study, Dr. Heinzinger, one of our early career scientists and T32 scholars, decided to look at the relationship of sleep apnea and atrial fibrillation in about 40,000 of our patients in this clinical cohort. And what she found was that more so than the apnea-hypopnea index, it was really the degree of hypoxia that seemed to be even internally consistently identified as a risk for new incident atrial fibrillation development over time, even after consideration of confounding factors. And this is in press, in the Journal of the American Heart Association. And also data I don't show here is she even accounted for underlying pulmonary physiology. We had spirometric values of FEV1 to FEC ratio and even lung volumes on a subset of these individuals. And even after accounting for those alterations in physiology, there persisted these pretty strong relationships as well. And she's also now doing some cluster analyses to better understand the clustering of the sleep-specific phenotypes as it relates to this risk as well. So what about treatment? So we know that there have been several studies that have shown, mainly retrospectively, that treatment of sleep apnea after cardioversion and ablation appears to reduce recurrence of atrial fibrillation. And so this is one of the first studies that was done where you can nicely see that after cardioversion in about 118 individuals, those that actually were treated for sleep apnea, as shown here in beige, had a reduction in that recurrence of atrial fibrillation compared to those without and compared to controls. And hypoxia, again, rears its head in terms of those that were more hypoxic appear to be more vulnerable to this recurrence of atrial fibrillation as well. And here I thought I'd share a case of a patient who presented to our sleep lab, a 53-year-old male with atrial fibrillation dilated cardiomyopathy, heart rate of actually 100 to 120 during the baseline portion of his study. And you can see snoring, and there was profound degrees of apneas and hypoxia that was occurring during the baseline portion of the study. So here you can see the hypnogram, so sleep stages, oxygen saturation, arousals and subtypes of arousals. Here are the baseline, here are the pap titration, oxygen saturation is here. And you can see when the goal pressure was achieved, there was actually conversion to a normal sinus rhythm that you can see here in the heart rate data, which is pretty striking and the reason why we decided to write it up. Now, this is one case, it's anecdotal, but I think it's very interesting to conceive of the idea that institution of positive airway pressure may have some benefits there. So as we think about clinical trials, and we'll share some of those results as well, but one of the things we did in the International Collaboration of Sleep Apnea Cardiovascular Trialist Study, we conducted a study across different countries and tried to get a sense from cardiologists and electrophysiologists about their clinical equipoise of conducting a clinical trial, given the knowledge that we have so far. And it turns out that there was no clinical equipoise, that most of the cardiologists and electrophysiologists actually felt that treatment of sleep apnea has benefit in terms of atrial fibrillation and those outcomes. So this is really important to keep in mind as we're designing our clinical trials and the ethical aspects of clinical trials as well. So there have been a couple clinical trials, so I'll focus on the most recent one that's been published in the Blue Journal. So this was the A3 study where they randomized about 100 individuals with moderate to severe sleep disorder breathing who are not sleepy, ejection fraction of greater than or equal to 40%, BMI of less than 40, and without a significant degree of hypoxia. So they actually used a CPAP run-in period in this interventional trial, and these individuals had implantable loop recorders, and they found that there was no difference in three-month atrial fibrillation burden in those randomized to CPAP versus supportive care. So as always, I mean, there are always limitations with these clinical trials, and one of the points to just kind of keep in mind is that the burden of atrial fibrillation observed in this clinical trial was far less than what they had initially powered the clinical trial to detect. So that's something just to kind of keep in mind. And as we think about sleep apnea and atrial fibrillation, there's a lot of opportunities, right? We're in this era of mobile devices and telehealth, and so there are opportunities that we highlighted here in this statement in terms of even sleep apnea and looking at arrhythmia burden and in terms of being able to manage our sleep apnea in terms of adherence with treatment and how that impacts even the burden of arrhythmia. And in this statement, which is the first dedicated American Heart Association statement that kind of highlights sleep disorder, breathing, and cardiac arrhythmias, I was honored to co-chair. We actually have included here a stepped care model in terms of the different arrhythmia subtypes, not only atrial fibrillation, but also conduction delay arrhythmias, ventricular arrhythmias, in terms of how we should be screening to the best of our knowledge, right? In terms of the data that we have in hand and how we should be treating our patients in this stepped care model. So overall, we have unexplained increasing atrial fibrillation epidemic that's partially attributable to sleep apnea. Sleep apnea is associated with sudden nocturnal cardiac death. We didn't go over that data. We didn't have time, but it was nicely shown by Dr. Matthew. There's accruing data implicating in particular the autonomic dysfunction in these relationships of sleep apnea and arrhythmia. And it is associated, sleep apnea is associated with incident nocturnal, atrial, and ventricular cardiac arrhythmias. There's support for causality in that there's high magnitudes of associations. There's dose response relationships. There's temporal relationships as we saw in the case crossover design. There's some data to show that there's this relationship with central apnea in particular, and development of atrial fibrillation over time. Mobile monitoring presents a key opportunity in this area as well. And there's retrospective data that suggests there's benefit in treatment of sleep apnea in the setting of cardioversion and ablation, but we need, you know, bigger, better clinical trials and being able to include those that are in particular going to be responsive to treatment. So I'll leave it at that, and I thank you for your attention. Thank you. There's one topic that is loaded with frustration and controversy with regard to the heart and sleep. It's central sleep apnea and complex sleep apnea. And this is one tool which at one point we thought was the solution to that problem, and then somebody put a bomb on it, and we wondered, what are we going to do? So I'd next like to update the treatment of sleep-disordered breathing in heart disease and review adaptive cerebral ventilation as a treatment for central sleep apnea, Jane Stokes breathing, and complex sleep apnea. Again, nothing to disclose, and here, in particular, I want to say that I've got no support from RestMed, Philips, Respironics, or Vyneman, which are the three manufacturers of the ASV models that I will be discussing. So first of all, what is it? What is ASV? It's an attempt to allow computer-controlled management of breathing with variable ventilation, pressure support, and positive airway pressure. And what's it good for? Well, it's good for some forms of sleep-disordered breathing that don't resolve with CPAP, continuous positive airway pressure, BPAP, bilevel positive airway pressure, or APAP, autotitrating positive airway pressure. Jane Stokes breathing, central sleep apnea, complex sleep apnea, it was not designed for hypoventilation problems. So it really was invented to treat Jane Stokes breathing. It provides ventilation which is intercyclic to the patient's own respiratory drive periodicity. So in the hyperventilatory phase, it gives minimal support, but not enough to worsen the hypocapnia. In the hypoventilatory phase, or the apneic phase, it increases the ventilation. So it dampens the oscillations in the patient's own respiratory drive that would otherwise result in this pattern of periodic breathing and central apnea. It's got its origins back in 1992 with the first development of autotitrating positive airway pressure. The first use of real ASV was actually in Germany using ventilators in the ICU. Unfortunately, this proved to be a failure with too many deaths. We never saw these machines in this country. But the ASV as we know it as a non-invasive tool was first patented in 1999. And first used for chain stokes breathing and heart failure in 2001. And the paper that shows this where you have typical chain stokes breathing with periods of central apnea in between. And then with the ASV on the bottom, you can see that everything is balanced out and you have continuous breathing. So it worked very well to treat chain stokes breathing. That's what it was designed for. And then later other manufacturers developed other models. And there was an adaptation with an auto-EPAP algorithm placed in a couple of different other models. And in 2009, this was shown to be effective to treat complex sleep apnea, not just central sleep apnea. This are some slides from an exposition at the European Sleep Society in 2009 by Sharak Javaharian. This is an important little exhibition. So just pay attention. So these are people with complex sleep apnea, which is of course the combination of central sleep apnea and obstructive sleep apnea in the same sleep study. And in this case, the furthest left column of PSG just is these patients without treatment. The second column are these patients treated with CPAP. And the last two columns is ASV with and without the auto-EPAP algorithm. So these are both ASV. And this is central apnea index. And you can see that it works really well in treating central apnea. This is the obstructive apnea index. This is the same group of patients, no change. And you see CPAP works even better at treating the obstructive sleep apnea. This is the important slide. This is the hypotenia index. Same group of patients, complex sleep apnea. And what we see here is that most of these hypotenias must have been central. Because they didn't go away with CPAP, but they went away with the ASV. And this is one of our conundrums, because we still don't have a good way of distinguishing central from obstructive apneas. We still have a lot of people who push PAP upwards when they're looking at hypotenias, thinking they're obstructive and making things worse. Wait. Okay. Boy, that's... Okay. Touchy. So, going on with the historical development of this machine, this is still going too far. Wait a minute. Okay. This is also important. In 2008, there were studies, two studies done using ASV. This is just VPAP-ADAPT-SV was the model currently used. It's a RestMed model. To use complex, to treat complex sleep apnea secondary to opioids. And it was successfully used when the end-expiratory pressure was adjusted, but unsuccessful with a fixed end-expiratory pressure and rate. This is important later when we look at the CIRV-HF trial and what happened. Now, and just to clarify, end-expiratory pressure and EPAP and positive airway pressure are the same thing. The manufacturers use the different terminology. So, EPAP and EPAP are the same. But this is important because now later we're gonna find there's a big difference. These are both the same machine. It worked when the EPAP was adjusted. It didn't work when the EPAP was fixed. And now we get to some really important data because here we're using, this is the German model that we do not have in this country, but it's a good model with auto-IPAP and auto-EPAP. And here, using this machine and treating complex sleep apnea, we see that there's an actual improvement in New York Heart Association functional class. And VO2max has improved. This is really solid, important information. This is not flimsy questionnaire data. So, on cardiopulmonary exercise testing, the anaerobic threshold improved and the work capacity, the actual peak oxygen consumption improved, cardiac function improved, the heart improved. Oh gosh, okay, this is really touchy. Why is it doing that? With a lot of this data, it was so impressive and everybody welcomed this. Boy, we all started using it. The American Academy of Sleep Medicine actually endorsed ASV for the treatment of central sleep apnea and heart failure. And there was a favorable meta-analysis done that same year in 2012, showing that it was better than CPAP, BPAP, oxygen, sham ASV, or no treatment at all, in both, in not just reducing the AHI, but improving cardiac function, improving ejection fraction, and increasing exercise capacity. And that's shown here. This is from the meta-analysis. This is the left ventricular ejection fraction. And there's a significant improvement in heart function with the ASV. And then, Chirag Jevehary published this in 2015. If you just take this machine with the auto, this BiPAP auto ASV advanced, was the respironics model with the auto-EPAP algorithm, it's sort of like what we do with APAP. You can take it out of the box and set it up and it works without doing any adjustments. It takes care of itself. Works just fine. That's why we tell our techs when they're doing an ASV titration, don't fiddle with it, try to leave it alone. And in my lab, my old lab in Houston, we did a study where we took a group of patients that had been treated with ASV. These are all complex sleep apnea patients, either primary, primary complex sleep apnea is the combination of obstructive and central apnea de novo when you first study them without any intervention. Secondary complex sleep apnea or treatment emergent central sleep apnea, TEXA, is when you do something. And that can be anything. It could be PAP, it could be surgery. And we took these, half of them were primary and half of them secondary complex sleep apnea. They're treated for an average of four and a half years. We brought them back into the sleep lab and we had to look at them and all but one of them, the central apnea had disappeared and all they had was obstructive apnea. The one patient that still had central apnea had tight aortic stenosis and worsening non-ischemic cardiomyopathy. So it looked like, you know, you treat. My theory for this is that what happened is by treating the sleep apnea, the obstructive sleep apnea as well as the central, we made the heart better. And making the heart better resulted in better cardiac output. And that's where the central apnea went away. The obstructive apnea on the other hand is, it's got anatomic and physiologic properties that don't change so readily and so it stayed. So what could be wrong? Everything looked hunky-dory until this safety notice came out saying there's an increased risk of death if you use this machine, so stop using it. FDA said black warning, anybody with an ejection fraction under 45% which is most of the patients, stop using it. And this is the CERV-HF trial. So the CERV-HF trial was a trial that was sponsored by RestMed and their aim was to prove that ASV reduced mortality. So they deliberately enrolled a lot of patients they thought had a high risk of dying. You had to have an ejection fraction less than 45% to get into the study and they thought they were gonna get a good thing but they used this old first generation machine with fixed EPAP, that's one of the big problems. And they didn't have pure central apnea. All you had to do was have more than 50% of the AHI central and that didn't take into account the unknown hypotenuse whether they were central or obstructive and at least 20% of the patients had a significant obstructive component. But what it showed was a 10% mortality in the ASV arm and a seven and a half percent mortality without ASV. It's already a very high mortality rate and the difference is not very good. They didn't have a significant difference in their primary endpoint of all-cause mortality. The other thing was all the deaths occurred in subjects with an EF of 30%, less than 30%. So all these patients started off with just barely enough function to be alive. All were sudden death during the day. There were no deaths at night. So all sudden death during the day presumably arrhythmic deaths. The device was this first generation machine that's no longer used by any manufacturer with only fixed expiratory positive airway pressure. More subjects in the ASV arm were on antiarrhythmic drugs to start off with so they would be more susceptible to arrhythmias. The other thing was that the sleep disordered breathing wasn't really well controlled. Residual AHIs vary from zero to 72 during the treatment. And then there was an intention to treat analysis. I've always had a problem with intention to treat analysis but statisticians love it. But it may have generated faulty conclusions because 87 of the controls and 85 of the ASV subjects withdrew from the study. 21 of the ASV subjects never received their machine but they're still counted on in the statistics and 168 of the ASV subjects stopped using it. I think that that may have hurt. So people stopped and they said, well, what can be wrong? Maybe it's wrong to treat central sleep apnea. Maybe central sleep apnea is an adaptive mechanism and it helps us. There's actually, and if we have time at the end, I'll show you, there's actually a study that supports this but only at high altitude, 5,000 meters in the Himalayas. And that's completely, among normal healthy people. So that's completely different from the heart failure patients. And this is definitely negated by the CANPAP trial data which I'll show you in just a minute. So what really could be wrong? Well, the first is excess positive interthoracic pressures caused by these older machines could have had adverse consequences by reducing the cardiac output. The fixed EPAP may have been inadequate to treat the sleep apnea. So remember, you had residual high AHIs and residual oxygen desaturation from the untreated sleep apnea. And then there could have been a reverse problem with low IPAP and EPAP. The mean was less than six centimeters of water at baseline. It could have caused an increase in the PCO2 and generated a sustained metabolic alkalosis during the night. And then during the day, of course, the kidneys can't adapt like the lungs do. So you would have a combined metabolic and respiratory alkalosis and arrhythmias and sudden death. Remember that more subjects in the ASV arm were on antiarrhythmic drugs. And so they were at greater risk. And then there could have been excessive ventilation or excessive pressures. The device didn't allow for pressure support less than three. So there would have been impaired venous return, a lower ventricular preload and a reduced cardiac output. What about what happened after that trial? Well, there's one more trial, the ADVENT-HF trial, which started while the CIRV-HF trial was going on and just finished. We hoped we would have complete revelation of that now. But the results, although the study is finished, the paper is written and been accepted, it's not been published yet. So they're still prohibited from actually giving what's in the, everything that's in the paper. That'll come out soon. This was a study using a Philips respironic device funded by Philips and the Canadian Institute of Health Research. Again, it was a similar kind of study. You had to be an EF less than 45% in heart failure to get into the study. And what we now know is that in this study, because they had continuous, because of the CIRV-HF results, they had continuous examination for years during the study. And the people that kept looking kept saying, it's okay, keep enrolling patients, it's okay. No adverse effects from the ASV. And if you look at the 200 patients, there were only 200 that actually had central sleep apnea. There was actually a 22% reduction in mortality in the patients that had central sleep apnea. Those final results should be out soon. Do we need ASV for anything? Well, most secondary complex sleep apnea, or TEXA, resolves over time with just CPAP treatment or the underlying OSA. You treat the obstructive apnea and you wait. But you can't do it in the sleep lab. It doesn't go away right away. It takes months. We don't know how long it takes, but it takes a long time for that to happen. Do central sleep apneas need to be treated at all? Well, we think they do. And the reason I think that Reena's given some examples and Reba, Reena and Reba have both given some examples of why it causes increased arousals in disturbed sleep, causes increased sympathetic activity, recurrent hypoxemia, an increased amount of arrhythmia is associated with central sleep apnea. And it's associated with increased mortality in and of itself. So the higher the AHI in these heart failure patients with central sleep apnea, the worse the mortality. So the answer is, do these people have to be treated? I think yes. I think that's the answer. And the famous CANPAP trial. Why can't we just use CPAP? Well, this was a trial looking at central apnea and heart failure patients and trying to treat with CPAP. Sounds like a good idea. It turns out that CPAP can hurt or harm, depending upon how you looked at it. The beginning results looked like it was harmful. The end results looked like it was beneficial. Turns out it depends on whether or not the obstructive apneas went away and the central apneas went away. So if people responded to CPAP with an AHI less than 15, they had a significant improvement in their mortality. Look at that, they just stopped dying. But in those people that received the CPAP in the same trial where the sleep apnea didn't go away, AHI over 15, they actually had a worse outcome with a higher mortality. So if you give CPAP and it doesn't work, you can kill your patient. So it's risky. And this Javahari hypothesis about excess CPAP was first published in 2006 where he said, CPAP can increase enterostatic pressure, decrease venous return to the right ventricle, lower the cardiac output and kill people if you have the wrong pressure in a heart failure patient. It's like PEEP in our ICU on patients on a ventilator. You put the PEEP up too high, you'll lower the blood pressure because you lower the cardiac output. So what do we know? Severe heart disease patients with central sleep apnea treated with an older obsolete RestMed ASV device with fixed EPAP had a higher cardiovascular mortality in a flawed CIRV-HF trial. Prior studies showed improved heart function with ASV. There are no adverse consequences and maybe a lower mortality in this more recent ADVENT-HF study with the Philips Respironics ASV device with auto-EPAP algorithm. Current models of the ASV devices with all three manufacturers have the auto-EPAP in them. And you can put that on all of your patients. And CPAP may cause a higher mortality in CHF if your HI remains over 15, but it improves survival if your HI residual is less than 15. So ASV eliminates sleep disordered breathing and complex sleep apnea, central sleep apnea and chain stokes respiration. Most secondary complex sleep apnea, or TEXA, eventually resolves with enough CPAP to eliminate the obstructive apnea, but this persists on the CPAP titration night. It may take weeks to months to resolve. We don't know how long. And it may increase mortality if it persists. And central sleep apnea may resolve completely in most patients who are on ASV. So what do we do? Who gets ASV right away? Maybe central sleep apnea at baseline without any intervention, pure central sleep apnea. Primary complex sleep apnea without any intervention. Or very mild obstructive sleep apnea, very bad central sleep apnea. Who gets a trial of CPAP first, treating the obstructive apnea and leaving some persisting central? Maybe the very severe sleep apnea patient that has severe obstructive apnea and just mild TEXA. And how long do we wait? Who knows? We really don't know. So we have a lot of unanswered questions, all of which I will answer during the question and answer period. Okay? Thank you.

sleep

cardiovascular disease

hypertension

cardiovascular events

blood pressure

heart rate

sleep disorders

sleep apnea

continuous positive airway pressure

adaptive servo ventilation

CIRV-HF trial