"Sleep and Cardiovascular Disease" Reena Mehra, MD, MS (01/04/2023)

January 17, 2023

ID9378

To CiteDCA Citation Guide

00:00Seminar series for the spring semester.
00:02My name is Kritika Thapa and I'm an assistant
00:05professor at Yale School of Medicine.
00:07I'm pleased to be taking over from
00:09Doctor Janet Hilbert as course director
00:11for this weekly Sleep seminar at Yale,
00:13along with Doctor Clara Yagi. First,
00:15a brief few housekeeping announcements.
00:18Please take a moment to ensure
00:19that you are muted in order to
00:21receive CME credit for attendance.
00:23Please see the chat room for instructions,
00:25and if you have any questions or
00:27comments during the presentations,
00:28please use the chat room or take
00:30the opportunity to unmute yourself.
00:32At the end of the talk and ask questions,
00:34recorded versions of these lectures will
00:37be available online within two weeks at
00:39the link provided in the chat as well.
00:41Now I have the pleasure of introducing Dr.
00:43Reena Mehra.
00:44Today, Doctor Mehra received her
00:46medical degree from Northeastern Ohio
00:49University's College of Medicine.
00:50She completed her internal medicine
00:52residency from Loyola University Medical
00:54Center in Illinois and her pulmonary
00:56critical care and Sleep Medicine
00:58Fellowship from Cleveland Clinic,
01:00followed by an advanced training
01:01in Sleep Medicine.
01:02For biology and epidemiology by an I
01:06HT32 National Research Service award,
01:08acquiring a Master of Science in
01:10Clinical Epidemiology from Case
01:12Western Reserve University at Ohio.
01:14She's currently a professor of
01:16medicine at the Cleveland Clinic,
01:17Lerner College of Medicine of Case
01:19Western Reserve University and
01:21internationally recognized for expertise
01:23in sleep disorders and health outcomes,
01:25including cardio pulmonary disease.
01:27She holds joint appointments
01:29in the neurologic, respiratory,
01:31Heart and vascular.
01:32And Lerner Research Institute.
01:34She has also been the director of
01:36the Cleveland Clinic Sleep Disorders
01:38Research Program since 2013 and has led
01:41team based clinical and translational
01:43science initiatives and is best
01:45recognized for her work identifying
01:47the association between sleep apnea
01:49and nocturnal cardiac arrhythmias.
01:52She has received many awards as
01:54the recipient of several grants,
01:55including from the NIH,
01:57and has authored over 200 publications,
01:59including in the New England
02:01Journal of Medicine and JAMA Doctor.
02:03Mehra has also held leadership
02:05position in many national societies
02:07and is a strong advocate for women
02:10faculty in medicine.
02:11She has served on the editorial board
02:13of Chest as the author of the Up to
02:16date entry of Obstructive Sleep Apnea
02:17and Cardiovascular disease in adults.
02:19Thank you so much for being
02:21with us Doctor Mehra.
02:22And without further delay,
02:23I would like to hand it over to
02:25you to share your expertise on
02:26sleep and cardiovascular disease.
02:27And thank you again.
02:29Ohh well thank you so much.
02:31It's lovely introduction.
02:32I I really appreciate it and I I'm
02:36so I'm happy to to be here with all
02:39of you today and see the friendly
02:41faces who I know and and some who I
02:44don't and it's nice to meet everyone.
02:47Um, so, yes, I thanks for this
02:50invitation honored to to do this.
02:53I'll be discussing a bit about.
02:57Sleep disordered breathing mainly,
02:59but touching upon some other sleep
03:03disorders as well as it relates to.
03:06Cardiac arrhythmias,
03:07this is kind of been an interest of
03:11mine over the last 15 years or so.
03:14And and so we'll we'll kind of delve
03:17into the different aspects of this.
03:20I'll see here.
03:22And here's the requisite CME's
03:26disclosure and accreditation.
03:28So.
03:29It's, uh,
03:30there's your information for
03:31to obtain the CME credit.
03:36So you know what what we'll do is,
03:38is, is focus on, you know,
03:40some of the the mechanisms that tie sleep
03:44disorders with the focus on sleep disorder,
03:47breathing and cardiac arrhythmia.
03:49I think this is an area that's
03:52really interesting and there's
03:55actually quite a lot of you know,
03:58biologic experimental data to to
04:02lend credence to this association of.
04:07Of sleep apnea in particular and
04:09and cardiac arrhythmia and then
04:12we'll discuss a bit about you know
04:14the epidemiologic and clinic based
04:16studies that inform our current state
04:19of knowledge in this area and we'll
04:22talk a bit about clinical pathways,
04:26the role of mobile health technology.
04:29We'll touch upon that a little bit
04:31and then you know end with some of
04:33the you know interventional data
04:35and in the future directions.
04:37To address our existing knowledge gaps,
04:40so, so it's been recognized for
04:43several decades that there are
04:45diurnal variations of of cardiac
04:47cardiovascular events such that
04:49in general there is a morning
04:52predisposition to myocardial infarction,
04:54sudden cardiac death,
04:56ischemic stroke and there's you know of a
05:00variety of reasons why this may be the case.
05:03You know the predominance of REM sleep is
05:05during the latter part of the sleep cycle.
05:07So whether there should be some autonomic
05:10influences that are specific to you know,
05:12REM sleep which predominates during
05:14the latter part of the sleep cycle,
05:16blood pressure surges,
05:18increases in cortisol levels,
05:20even diurnal variation of various
05:22biomarkers of inflammation and and
05:25pro thrombosis such as plasminogen
05:28activator inhibitor 1.
05:29And there's also some molecular
05:32evidence as well that links a
05:35circadian rhythm specifically to
05:38the vulnerability of ventricular
05:40arrhythmias with KLF 15 deficiency,
05:43null and gain of function models that
05:47have various arrhythmogenic risk
05:49that has been associated with it,
05:51with QT prolongation noted with the KLF
05:5515 deficiency and gain of function of KALA.
05:5915 associated with some repolarization
06:02abnormalities that are similar to
06:05what is seen in Brugada syndrome,
06:07where there are fatal arrhythmias
06:09during sleep.
06:10So the circadian rhythm actually
06:12may also be tied to that.
06:15And in terms of these diurnal patterning
06:19of cardiovascular events, this is also?
06:23You know, been observed with sleep apnea,
06:25but more so, uh, you know,
06:28rather than the sleep period being,
06:31you know,
06:32cardioprotective as it is normally
06:34and again that's 6:00 to 9:00 AM
06:38morning period being the the time
06:40of predilection for cardiac events
06:42in sleep apnea.
06:44The we know that there are data
06:46showing that there's increased
06:48sudden nocturnal cardiac death
06:50that has been observed in those.
06:53Uh,
06:54with obstructive sleep apnea
06:56compared to those without and
06:58compared to the general population.
07:00And of course you know,
07:02we know that in the sleep Part
07:04health study data as well that
07:06there's these associations with
07:08increasing severity of sleep apnea
07:11and increase all cause mortality
07:13originally seemed to be perhaps
07:16more dominant in men and older men
07:19but as we have observed a certain
07:22sub cohorts age such as the.
07:24The Mesa study, we're seeing actually
07:27that cardiovascular risk predominate
07:29actually more so in women than men
07:31based upon some of the subcohort data
07:33and there are certain notable figures
07:36that have succumbed to you know,
07:40sleep apnea. As well.
07:43So we're aware it's, you know,
07:45obstructive sleep apnea is highly prevalent
07:48afflicting nearly 1 billion people worldwide,
07:50you know, still under diagnosed with
07:54about 85% of individuals estimated
07:57to be under diagnosed in, you know,
07:59going back to data in the sleep
08:01Heart health study and even more a
08:03bit more recently with the multi
08:05ethnic study of atherosclerosis.
08:06And this underdiagnosis appears to be more
08:11predominant in underrepresented minorities.
08:14Now having said that,
08:15these are population based studies
08:18and when looking at claims data you
08:21know that particular population
08:22we're seeing that you know the
08:25sleep apnea prevalence is increasing
08:28which is paralleling the increased
08:30use of diagnostic testing.
08:32With home sleep apnea testing,
08:34we're home sleep apnea testing
08:37doubled and polysomnography declined
08:39by 10% over over recent years
08:42and probably even more so.
08:44As of more recent years,
08:47so this is one of the first studies
08:50I had conducted as as a fellow
08:53during my T32 training in which
08:56Doctor Stroll and I were examining a
09:00cohort clinical cohort for adverse
09:04events during polysomnography.
09:06And there were about 16,000 patients
09:09and individuals in this particular study
09:12where we were looking at adverse events.
09:15And and and and one of those cases
09:18there was a 61 year old obese male
09:21with history of coronary disease
09:23and cardiomyopathy who came in for
09:26a split night study at a hospital
09:29based facility Sleep Lab and had some
09:32symptoms of snoring and with this
09:34apneas and had some ectopy during his
09:37study and some complex ventricular
09:39ectopy and and then at the end of
09:42his study had an an episode of
09:45polymorphic ventricular tachycardia.
09:47About 45 minutes and then 30 minutes
09:50prior to the end of this study and
09:52then at the end of his study had
09:55this particular event where you can
09:57also you can see some evidence of
10:00torsades there at the end of this
10:03epic and a code was called and
10:05unfortunately this patient did not
10:08survive despite the code team coming
10:12in pretty rapidly and conducting CPR.
10:15So this really brought to attention
10:18this whole notion of you know this this
10:21individual likely had long standing
10:23sleep apnea remained untreated and
10:25in and out you know came into the
10:28lab and was unfortunately succumbed
10:30to a lethal arrhythmia and and and
10:32sort of got us thinking about what
10:35are these relationships with sleep
10:37apnea and and cardiac arrhythmias.
10:39Uh, so we, you know,
10:41as has been postulated with
10:43many cardiovascular outcomes,
10:44can can postulate that, you know,
10:47there's the the intermittent hypoxia,
10:48hypercapnia,
10:49intrathoracic pressure swings and
10:51autonomic fluctuations that can have.
10:54These direct electrophysiologic
10:56effects on the effective refractory
10:59period QT prolongation triggered
11:02an abnormal automaticity.
11:04So in this electrophysiologic
11:06remodeling that can happen over time
11:10given these repetitive, you know,
11:13physiologic triggers from sleep disorder
11:15breathing and then also lead to structural
11:18remodeling of the heart as well,
11:21which also can predispose
11:23to to cardiac arrhythmia.
11:25And with involvement of some of
11:27these intermediate pathways as
11:29well with systemic inflammation,
11:31oxidative stress which is increased
11:33in vascular dysfunction and and so
11:35uh you know we have these immediate
11:37effects from sleep disorder breathing
11:39and then these acute and sub acute
11:41effects and then there's chronicity
11:43that leads to the remodeling of the
11:46heart and can increase arrhythmogenic
11:48city and and we'll we'll now get
11:50into some of the the experimental
11:52data and some of these studies.
11:55Reports on the effective refractory
11:58period of the Atria.
12:00And so this is basically a period of
12:03time where there's relative immunity
12:06during which the cells cannot be excited.
12:10And so as the atrial effective refractory
12:13period is reduced then there is more
12:17vulnerability or susceptibility
12:19to arrhythmic Genesis and and so
12:23one of the studies here looked at.
12:25Chronic intermittent hypoxia and then how
12:28that may lead to atrial arrhythmic genesis.
12:31And I'll just mention that you know
12:33a lot of the data that have been
12:36published in in terms of looking at
12:38mechanism have focused on autonomic
12:41dysfunction and perhaps you know
12:44lesser studies that have been looking
12:47at intermittent hypoxia or even
12:49hypercapnia and so in this model
12:52of of chronic intermittent hypoxia.
12:55And using this post electrical
12:58stimulation and burst pacing,
13:00it was identified that in this rat
13:04model that the arithmos Genesis was
13:07accentuated by carbachol Colon argic
13:10agent and abolished by atropine and and
13:15therefore these promoting effects of
13:19atrial fibrillation were dependent in
13:22response to chronic intermittent hypoxia.
13:24Where were.
13:25A dependent on parasympathetic activation.
13:29So there's this interplay of of,
13:32you know,
13:33parasympathetic activation with
13:35intermittent hypoxia that that is likely
13:38playing a role in atrial arrhythmia genesis.
13:41And also identified was a reduction in the
13:45atrial effective refractory period as well.
13:48So again more and more increased
13:50vulnerability to the cardiac arrhythmia and
13:53a higher level of the M2 receptor protein.
13:56Levels which can be indicative of
13:59some electrophysiologic changes
14:00that are happening to the heart.
14:03So also the repetitive upper airway
14:06occlusion that occurs with sleep apnea
14:09we know has direct impact on the on
14:13the mechanical impact on the heart as well.
14:17With increased left ventricular afterload,
14:20increased left ventricular transmural
14:22pressures and in particular can
14:25influence and impact the thin walled
14:28upper chambers the Atria and and be
14:31associated with atrial arrhythmic
14:33genesis and and then this particular
14:36study this was looked at in terms
14:40of application of negative tracheal
14:43pressure and how this influenced
14:46the atrial effective.
14:48Refractory period.
14:49So they basically in this animal model
14:54used 2 minutes of tracheal occlusion
14:56and then with negative tracheal
14:59pressure and then tracheal occlusion
15:01without negative tracheal pressure.
15:04And it was observed that with the
15:07application of the neck negative tracheal
15:09pressure there was a reduction in the
15:13atrial effective refractory
15:15period that was observed,
15:17which goes along the lines of.
15:19The kind of direct effects of the
15:22increasingly negative intrathoracic
15:24pressures and its mechanical influence
15:26on the heart and therefore influencing
15:29the atrial effective refractory period,
15:33and also with the autonomic
15:36function appearing to play a
15:39role with this pathway as well.
15:42And then with autonomic function,
15:44you know we're aware that there's
15:46with with sleep apnea and the apnic
15:49events are sympathetic activation
15:50that has been nicely shown in doctor
15:53Summers work with perineal micro
15:55neurography with increased amplitude
15:57and frequency of these sympathetic
15:59bursts that have been identified.
16:01And so in one of these studies
16:04in this canine model it was
16:06observed that prior to ablation.
16:10Of the right pulmonary
16:14arterial ganglionic plexus,
16:16there was apnea induced atrial
16:19fibrillation that was observed.
16:21However,
16:22after ablation of the right
16:24PA ganglion and Plexus,
16:26which has been houses both sympathetic
16:30and parasympathetic neurons,
16:32they're no longer was apnea induced atrial
16:36fibrillation as subsequent to this ablation.
16:39So this really points towards the.
16:42Role of the autonomic nervous system in
16:45terms of the generation of arrhythmia
16:49in response to apneic events.
16:52And there has been a couple other
16:55studies that have corroborated
16:56those findings as well.
16:59And in talking to some of my
17:01electrophysiology colleagues,
17:02some really believe that the,
17:05you know,
17:06increased systemic inflammation and
17:08oxidative stress that this actually
17:10may be the the the most potent driver.
17:12And common pathway that is is leading
17:15to increased cardiac arrhythmia
17:17Genesis and of course we know that
17:20there's many studies that have
17:22shown up regulation of inflammation
17:24in in sleep apnea and and some of
17:27these same biomarkers that have
17:29been implicated in that realm
17:31have also been identified to be.
17:36Implicated in the in the
17:38pathophysiology of atrial fibrillation
17:40in terms of atrial fibrillation,
17:42recurrence and longer duration
17:44of atrial fibrillation,
17:46recurrence of atrial fibrillation
17:48and so and so they,
17:51they may there may be the role of some
17:54of these biomarkers of inflammation
17:56and oxidative stress or you know,
18:00resulting in even direct alteration
18:03of that electrophysiologic substrate.
18:06And and structural substrate of the heart
18:09that that then increases a rhythm genesis.
18:13We've looked at some of this in in
18:16sleep apnea and and even as it relates
18:18to the amount of sleep that folks get
18:21with you know who have sleep apnea.
18:24And so we looked at polysomnographic total
18:27sleep time as well as habitual sleep time
18:31and sleep duration and interestingly
18:33found that there were differential.
18:36Relationships between polysomnographic
18:39versus more chronic sleep deficiency as it
18:44relates to myeloperoxidase and oxidized LDL.
18:48So, so it may be that there are different
18:51pathways of of inflammation that are
18:53increased with more acute versus
18:55more chronic curtailed sleep in the
18:57setting of obstructive sleep apnea.
18:59In terms of inflammation,
19:02we've also found that.
19:05Overall in this randomized control
19:07trial of individuals with moderate to
19:10severe sleep apnea who were randomized to
19:12CPAP versus sham CPAP that there were,
19:15you know,
19:15reductions as has been shown in other
19:18clinical trials and systolic and
19:20diastolic blood pressure also in some
19:22vascular measures of augmentation index.
19:25But overall in this particular trial
19:28we did not observe any oxidative
19:33stress measure improvement.
19:35There was an improvement in soluble aisle
19:406 receptor levels with CPAP versus sham CPAP.
19:45And interestingly when we delved
19:47further in post hoc analysis to
19:49look at sex specific differences,
19:51we identified that perhaps in women
19:53there was a a greater response to
19:56CPAP in terms of improvement and some
19:59of these oxidative stress markers
20:01and and and and and and markers of
20:04a systemic inflammation.
20:05Now these are post hoc analysis that
20:08that need to be further validated
20:10in terms of inflammation.
20:13We've also in the Safe Beat study.
20:15Um looked at individuals who have
20:19paroxysmal atrial fibrillation,
20:20uh who had and and also compared to
20:23these individuals to controls without
20:25atrial fibrillation who are masked,
20:28matched on age, sex, race,
20:30and body mass index and found that
20:34there were differences in proteomic
20:36profiles and those with proximal atrial
20:39fibrillation versus those without,
20:41and that some of these biomarkers
20:44were actually altered.
20:46With the treatment of that moderate
20:48to severe sleep apnea,
20:49so some of these differential
20:51biomarkers were actually on altered
20:52with treatment of CPAP.
20:54So these may be biomarkers that
20:57are implicated in the in the this
21:00inflammatory cascade that that
21:02that occurs with with sleep apnea.
21:05So taken together when putting
21:09together the experimental data that
21:12have been generated again there are.
21:16Are there's evidence of structural
21:18remodeling and I didn't share their there.
21:21There are data to show that overtime
21:23that there's actual changes to
21:25left atrial size that can occur
21:27increases in left ventricular mass.
21:30These autonomic nervous system
21:32alterations that that can directly lead
21:34to electrophysiologic changes in this
21:37electrical remodeling and and connection and.
21:42Some other biomarkers have been
21:44implicated in this in this biology as
21:47well and and reduction in this atrial
21:50refractoriness which can again increase
21:53that vulnerability to to atrial arrhythmia.
21:56So all of these different pathways are ones
22:01that can then contribute to development
22:05and progression of atrial fibrillation.
22:09So with atrial fibrillation,
22:11this is recognized to be in an
22:14ensuing epidemic with a fivefold
22:16increase in prevalence.
22:19By the year of 2050,
22:21uh from two more than two million
22:23now to more estimated more than
22:2510 million by the year 2050.
22:27And it was recognized in the Framingham
22:30Heart study that this was incompletely
22:33explained by the aging population alone
22:36and established risk factors such as
22:39male sex and again the increased age.
22:42And it is thought that unrecognized
22:44sleep apnea,
22:45as we had discussed earlier
22:48is estimated to be about.
22:5085% maybe partially contributing to this
22:53atrial fibrillation epidemic that's
22:56being observed and it's interesting
22:58to consider the risk factors.
23:01There are many shared risk factors
23:04of obstructive sleep apnea and
23:06atrial fibrillation.
23:07Increasing age,
23:09male predisposition and
23:12interestingly there are some data,
23:14you know,
23:15some pockets of data showing
23:18that sleep apnea.
23:19As defined by the apnea hypopnea index
23:22may be at increased risk for atrial
23:24fibrillation in African American
23:26patients versus the nocturnal hypoxia
23:28perhaps associated with increased
23:29risk of atrial fibrillation in Asians.
23:31So there there may be some race specific
23:36susceptibilities to to consider as well.
23:39And in this particular meta analysis
23:41as it's recognized that obesity of
23:43course is a risk for obstructive
23:44sleep apnea also is a strong risk for
23:47atrial fibrillation and and again.
23:49This is always the challenge and
23:51dissecting these pathways of obesity
23:54dependent and independent relationships,
23:56you know,
23:57this meta analysis you know may
23:59help shed a little bit light of
24:01light on that in terms of a stronger
24:04point estimate of of 2.18 versus
24:061.67 in terms of a relationship
24:09with atrial fibrillation of sleep
24:13apnea versus obesity respectively.
24:16And I think this,
24:18this interplay with obesity
24:21adiposity is one that likely you
24:24know needs some more attention.
24:27And so we've started to look at epicardial,
24:30adipose tissue and any
24:33synergies that you know we,
24:36you know that we can we can see
24:38even between the sleep apnea and
24:40obesity and in in panel B here
24:42you can see as an individual.
24:45With both obesity and severe obstructive
24:49sleep apnea compared to panel a,
24:52non obese with severe sleep apnea,
24:54panel D obese without sleep apnea,
24:57panel C without either obesity
25:01or nor a sleep apnea.
25:03So you know this is a small end
25:05and we're we're we're continuing to
25:08do just for you know feasibility
25:10data you know in terms of these
25:12cardiac MRI's to to generate this
25:14these epicardial adipose tissue.
25:16Volumes,
25:16but this may allow us to get a
25:19sense of the biology as you know
25:22local that's occurring locally
25:23at the level of the heart and how
25:26sleep apnea can intersect with that.
25:28And then I think also recognizing
25:30that atrial fibrillation occurs on
25:33a continuum where there's paroxysms
25:35of atrial fibrillation and then
25:37you know this can evolve into.
25:41Persistent atrial fibrillation
25:42and then chronic persistent atrial
25:44fibrillation at which point there's
25:46more remodeling of the heart that
25:48may be less likely to be reversible.
25:50So at what point in the spectrum are we
25:53likely to make the most difference in
25:56terms of treatment with of obstructive
25:59sleep apnea and intervening and I
26:01think that's that's an area that that
26:04warrants further attention as well.
26:06In terms of the epidemiologic data,
26:08you know this,
26:09these are you know older data.
26:11From a separate health study in which
26:14we examined those who presented for
26:19this population based study and
26:22examined the relationship of sleep
26:25disordered breathing with with the
26:28cardiac arrhythmias as identified on
26:30the polysomnogram during their sleep
26:33studies and found there to be a very
26:36strong association of anywhere from
26:38a two to five fold higher odds that.
26:42These arrhythmias as it relates
26:44to severe obstructive sleep apnea
26:47compared to those without even after
26:50accounting for a range of confounding
26:52factors and we had group matched
26:55and statistically adjusted for these
26:57factors of age, sex, race,
26:59BMI in addition to cardiovascular
27:00risk and cardio,
27:01other cardiovascular disease
27:05comorbidities as well.
27:08And in this study with the outcomes
27:10of sleep disorders in older men
27:12study as opposed to the sleep Heart
27:14Health study where we just looked
27:16at severe versus those without.
27:17We aimed to look at the spectrum of
27:21severity of sleep apnea as it relates
27:25to nocturnal cardiac arrhythmia
27:27and found there to be these graded
27:29relationships with increasing
27:31severity of sleep apnea and increasing
27:34burden of atrial fibrillation and
27:36also increasing burden of complex.
27:38Ventricular ectopy.
27:39And in this particular study where
27:41there were all male participants,
27:43we found the stronger relationship,
27:45interestingly,
27:46with obstructive sleep apnea and
27:48ventricular arrhythmia and central
27:51sleep apnea and atrial fibrillation.
27:53That was observed and we also have
27:56tried to better understand the
27:59temporal relationships of the discrete
28:01apnic and hypotonic events as it
28:04relates to the arrhythmic events.
28:07So in this case crossover study,
28:08which is commonly used in air pollution
28:12studies and lends itself to situations
28:14where you have a very short lived
28:17exposure and a short lived outcome,
28:19we identified a very strong association.
28:23Of these discrete nocturnal
28:25arrhythmias within 90 seconds
28:27following an apnea hypopnea.
28:30So we used a unidirectional design
28:31where there was an arrhythmic onset
28:33of either a discrete episode of non
28:36sustained ventricular tachycardia or
28:38a paroxysm of atrial fibrillation
28:40and proceeding only then looked at
28:42a hazard period of 90 seconds based
28:45upon estimated you know apnea related
28:48hypoxia and and autonomic fluctuations
28:50that are occurring and then also.
28:54And selected some normal sinus
28:56rhythm period control periods as
28:59reference and and and again found
29:01this strong relationship and this
29:03study was borne out of some
29:05observations as we were looking at
29:07the sleep studies from the sleep Heart
29:10Health study that you know some of
29:12these arrhythmic events appear to
29:14be aligned with when the respiratory
29:17events were occurring along with the
29:20hypoxia associated with these events.
29:23And and getting even further
29:25in the temporality,
29:27Dominic Langlands and his group have
29:31looked at the continuous monitoring of
29:35the respiratory events and also atrial
29:39fibrillation of paroxysms that occur
29:42over time and and found evidence that
29:46sleep disorder breathing and these events.
29:50Detected by this uh cardiac monitor
29:54uh were more associated direction in
29:57it from a directionality standpoint
29:59with subsequent atrial fibrillation
30:01suggesting sleep disorder breathing
30:04begets atrial fibrillation.
30:05However,
30:06the reverse did not appear to be true in
30:08terms of atrial fibrillation beginning sleep,
30:11disordered breathing.
30:12So I think the case crossover study
30:15we just reviewed and this study
30:18really point towards there being.
30:21You know a causal relationship,
30:23at least when considering the directionality
30:26of the respiratory events and the
30:30paroxysms of atrial fibrillation.
30:32We've also in the safety study
30:34when looking again at these.
30:37The the the patterning of atrial
30:40fibrillation as we had mainly focused
30:42on nocturnal cardiac arrhythmias
30:44identified from the sleep studies
30:46of the sleep Heart health study
30:49and the outcomes of sleep disorders
30:51and older men study.
30:52We in the safe beat trial had conducted
30:56continuous ECG monitoring along with
30:59overnight polysomnography as as well
31:02as actigraphy monitoring concordant
31:04with the continuous ECG monitoring.
31:08And and we're attempting to look
31:11at diurnal patterning of heart
31:14rate variability indices and how
31:17this related to severity of sleep
31:20apnea defined by the HIV and also
31:23as defined by hypoxia.
31:25And interestingly found that
31:28there were there was a significant
31:31interaction between sleep wake and
31:34HIV as well as the hypoxia.
31:39The level of hypoxia relative to
31:41these heart rate variability measures
31:44and there was a subset as well that
31:47underwent CPAP treatment and there was
31:50alterations in in these relationships
31:52also with with CPAP and so and and
31:56interestingly found that it was the
31:59the wakefulness that had stronger
32:02relationships of the HI and the the
32:06nocturnal HI and the HRV measures.
32:09Um,
32:10suggesting that there's some continued.
32:14You know,
32:15potential negative consequences of
32:17that sleep apnea that that maybe
32:20even more manifest during the
32:22day compared to the night,
32:25at least according to these
32:27data that we've generated.
32:29Other epidemiologic studies which
32:31have focused more on longitudinal
32:34relationships are the sleepout
32:36heart health study as well as the
32:38that Mister Ross Sleep study again.
32:40And in these studies,
32:42consistent findings were observed
32:44such that central apnea,
32:46more so than obstructive apnea,
32:49appeared to be as more associated
32:51with incident or new newly diagnosed
32:54atrial fibrillation over time.
32:57And so really, you know, very.
32:59Um, nearly identical findings in in,
33:02in these two independent cohorts and
33:05a similar magnitude of association
33:07with point estimates of two to three.
33:11And again after consideration of
33:15of confounding factors,
33:17subject characteristics,
33:19cardiovascular risk factors.
33:21A limitation of both of these
33:23cohorts is that we did not
33:25have echocardiographic data,
33:26so really couldn't in a
33:28very fine-tuned way adjust.
33:30For ejection fraction and cardiac
33:32function and so whether there could
33:34be some residual confounding there
33:36is is is something to to consider.
33:40We also have more recently leveraged
33:43some of the data from our our clinical
33:46registry that we have here at the
33:49Cleveland Clinic and examined and and
33:51and work led by Katie Heinz Singer
33:55examined again the relationship
33:58between sleep disorder breathing and
34:01an incident atrial fibrillation and
34:04in this work have found in particular
34:07that there is a strong relationship.
34:09Between the degree of hypoxia defined
34:12by the percentage of time spent
34:15below 90% as in relation to five
34:19year incident atrial fibrillation.
34:21And we also looked at minimum
34:24oxygen saturation,
34:25mean oxygen saturation and and found
34:28consistent findings across these different
34:31measures of hypoxic nocturnal hypoxia.
34:33And although the you know there,
34:37there there may have been,
34:39you know.
34:40An association with HIV,
34:41this was you know much less than in
34:45magnitude than what was seen with the
34:48hypoxia measures and we attempted
34:50to you know address confounding by
34:53underlying cardio pulmonary disease
34:55and smoking history as well as we had
34:59spirometry variables and a subset of
35:02these individuals and also adjusted
35:04for you know Fe V1 as well as a forced
35:08vital capacity and and the associations.
35:11The significant associations
35:12persisted Despite that adjustment.
35:15Interestingly,
35:17Dr.
35:17Heisinger has also looked at some of
35:20the sleep architectural disruption
35:23and incident atrial fibrillation.
35:25So there are some data from the Mesa
35:29study showing relationships with arousal
35:31index and some in the composition
35:35of of sleep as it relates to atrial
35:38fibrillation and a cross-sectional.
35:41A study in this study where we
35:44looked at more of the sleep
35:47architectural measures and incident
35:50atrial fibrillation overtime,
35:52we found that a reduction in sleep
35:56as well as reduction in sleep
35:59efficiency was associated with
36:02increased atrial fibrillation.
36:04And Doctor Patel from UPMC has
36:06actually also looked at this in
36:09his clinical cohort and.
36:11Has found,
36:12and these findings are somewhat similar,
36:14in finding that this reduction
36:17in sleep time is associated with
36:20incident atrial fibrillation.
36:22Ohh and and and these are Doctor
36:24Patel's data here.
36:25So you can see nicely that with the
36:28you know progressive reduction in
36:30sleep time of the the odds of atrial
36:34fibrillation had increased and and
36:37so these findings are are similar
36:40to the ones that we have identified
36:43in our again clinical registry.
36:45And this notion of post cardiac atrial
36:48fibrillation is also something to
36:50consider as this is associated with
36:52considerable morbidity after cardiac surgery.
36:54So Doctor Elsharif chose to examine this
36:58in our our cardiac surgery population
37:02and we found that those who were obese,
37:07you know,
37:08after dichotomizing on the median
37:10body mass index appeared to have
37:13a stronger relationship between.
37:15Severity of sleep apnea and post
37:19cardiac surgery atrial fibrillation and,
37:21and this is perhaps a bit of an
37:24understudied area in terms of trying
37:26to understand how intervening
37:28upon that sleep apnea may improve
37:31postoperative cardiac outcomes.
37:35In terms of you know interventions as well,
37:38in the heartbeat study we looked at
37:41measures of heart rate variability
37:44in this randomized control trial
37:46where individuals were randomized to
37:49receive CPAP versus a supplemental
37:52oxygen versus healthy lifestyle.
37:54So the objective,
37:55main objective of this study was to
37:58see if if using supplemental oxygen
38:00would would reduce mean arterial
38:02pressure collected by ambulatory.
38:04Blood pressure monitoring and it it.
38:07Essentially did not and CPAP you know
38:10did reduce mean arterial pressure as
38:12one would expect and so we elected
38:16to look at some measures of heart
38:18rate variability and and identified
38:21that there with oxygen versus CPAP.
38:24There were differences in in in
38:27the the Electrophysiologic heart
38:30rate variability measures in terms
38:33of the the alteration of these
38:35measures and it actually suggested.
38:38Um, you know that there's more of
38:42the the parasympathetic um influence
38:45of of supplemental oxygen in terms
38:48of that intervention and improving
38:51parasympathetic measures more so
38:53than than than sympathetic measures.
38:55And I think they're this data is
38:57is is similar to some data from
39:00Peter's doctor Systolic's group
39:01that they're they're looking at as
39:04well with heart rate variability.
39:06Doctor Rahman also looked at some of these
39:09heart rate variability measures in the Mr.
39:12Ross SLEEP study with the notion of
39:15of you know we we were able to collect
39:19ECG data in in this cohort and it's
39:23ECG is not something that's typically
39:27monitored with home sleep apnea testing.
39:29So the idea was to see well is
39:32there a utility in some of these
39:35signatures heart rate.
39:36Their ability wise in the ECG that would
39:41be informative in terms of of risk
39:44down the line and he identified that.
39:48LF and LF HF ratio in particular were
39:52predictive of incident atrial fibrillation.
39:55The the burden of premature atrial
39:58contractions was also related to
40:00incident atrial fibrillation and
40:01that burden of PAC has actually
40:04been shown in other studies as well.
40:06We were limited in in terms of
40:09looking at the SLEEP study ECG
40:11for this particular study.
40:13And also found there to be a significant
40:17interaction of the changes in her
40:20availability with obstructive sleep apnea.
40:23In terms of incident atrial fibrillation
40:26developed down the line and again
40:28these data seem to be pointing toward
40:31more of the vagal influences and
40:33pointing towards the more of this
40:36color energic atrial fibrillation
40:38that perhaps may be more of,
40:42you know related to to obstructive
40:44sleep apnea.
40:48We've recently been looking at sleep
40:52health disparities and cardiovascular
40:54outcomes and in this realm, Dr.
40:58Pena Orbea has leveraged our registry to
41:03to look at you know the the various major
41:08adverse cardiovascular outcomes and in
41:11this in this case showing the specific
41:14relationship with atrial fibrillation
41:16and so when looking at the area.
41:18Deprivation index which is an
41:22indicator of socioeconomic status.
41:24There was a significant relationship
41:28with a DI and the total time spent
41:34below 90% auction saturation as
41:37well as associated with you know
41:42atrial fibrillation as well.
41:44So atrial fibrillation was associated with.
41:49Both ADI as well as uh percent
41:52stat less than 90.
41:53So these this points towards
41:57disparities for potentially being
42:00exacerbated by you know at least
42:04nocturnal hypoxia in particular as as
42:07a as a risk for atrial fibrillation.
42:10We know that there are studies that
42:12have shown that after interventions
42:15such as cardioversion and ablation
42:17and and and looking at recurrence
42:20of atrial fibrillation and those
42:22with sleep apnea who are treated for
42:25that sleep apnea that there is a
42:28reduction in the recurrence of atrial
42:30fibrillation compared to those who are
42:33not treated for their sleep apnea.
42:35And there's these data also suggests
42:37that those who have recurrence
42:39of atrial fibrillation.
42:40Tend to have more um degree of hypoxia as
42:44well and so in in the untreated group.
42:48So again you know these recurrent
42:50themes of of hypoxia potentially
42:52you know playing a role here with
42:56recurrence of atrial fibrillation
42:58and that there may be some triggers
43:01you know outside of where you know
43:03at least with ablation that that
43:06are being targeted and and and could
43:09be the reason why there's.
43:10Continued the recurrence of
43:13atrial fibrillation.
43:14This was a you know just share
43:16with you some anecdotes.
43:18So this was a patient that presented
43:20to our lab for a split night study.
43:22She had moderate degree of sleep apnea
43:24and a very high degree of activity
43:26that was noted on the baseline
43:28diagnostic portion of her sleep study.
43:31And it was pretty striking that
43:33with the application of CPAP and
43:35resolution of her sleep apnea there
43:36was a bit of a dose dependent sort
43:39of relationship with increasing.
43:41Pressure and the ultimate resolution
43:43of her degree of activity and in
43:47another patient 53 year old gentleman
43:49with atrial fibrillation and dilated
43:52cardiomyopathy with known atrial
43:54fibrillation with the rate of heart
43:57rate of 100 to 1:20 at the baseline
44:00was found to have severe sleep apnea.
44:04And per this hypnogram,
44:06you can see that he was started on
44:09CPAP and there was a progressive
44:11improvement in his degree of sleep
44:14apnea and then he converted to
44:17a normal sinus rhythm during the
44:20application of CPAP.
44:22Now this could be happenstance,
44:24this is an anecdotal case,
44:26but again this temporally was a
44:29pretty striking in terms of the that
44:32that kind of conversion to normal.
44:34Sinus rhythm.
44:37So you know based upon our current knowledge,
44:41we attempted to survey cardiologists
44:45and electrophysiologists
44:46internationally to get a sense
44:49of clinical equipoise in terms of
44:52randomizing individuals to receive
44:54CPAP versus you know control
44:57whether that be sham CPAP or Umm,
45:00you know medical management of their
45:03underlying disease and and it was identified.
45:07Essentially that um,
45:09most cardiologists and Electrophysiologists
45:12responded with certainty that that
45:15there's benefit to treatment of sleep
45:17apnea in atrial fibrillation and and so
45:20that that I think is is interesting.
45:23So despite our our negative clinical
45:27trials such as SAVE and serve HF,
45:30they're at least in the from the
45:32standpoint of atrial fibrillation
45:34appears to be a general.
45:37Thinking that there is benefit to
45:40the treatment of of sleep apnea.
45:42So in one of the first randomized
45:45controlled trials to examine the
45:47impact of CPAP on atrial fibrillation
45:50recurrence is very you know small
45:53trial of 25 individuals after
45:55screening over 1700 individuals in
45:57clinical equipoise might have been
45:59playing a role in the ability to to
46:02recruit participants for this trial.
46:04Those with an HIV greater than five
46:07were were randomized and and post
46:11cardioversion followed in terms of.
46:13Atrial fibrillation recurrence and
46:15there was essentially in this small
46:18trial no difference between the two
46:20groups in terms of recurrence of
46:22atrial fibrillation in this trial,
46:24the A3 study the AF atrial fibrillation
46:27APTA airway pressure study this
46:30this was a randomized controlled
46:32trial of about 100 individuals with
46:34moderate to severe sleep apnea,
46:36mainly obstructive events,
46:38those who were not sleepy
46:41within upnorth significantly.
46:43Sleeping with an upward sleepiness
46:45scale score of less than 15,
46:47an ejection fraction of more than
46:4945% who were had a BMI of less than
46:52forty were eligible to participate in.
46:55They used a CPAP running period in
46:58an implantable loop recorder with
47:00the notion of looking at a three
47:03month atrial fibrillation a burden
47:05and those who were randomized to
47:07CPAP versus supportive care.
47:09And you know they did not see
47:12any differences between the two.
47:14Groups in terms of the atrial
47:17fibrillation burden but recognize
47:18that they may have been underpowered
47:20to observe that, you know,
47:22change and difference because of the
47:25lower than anticipated burden of
47:28atrial fibrillation that was observed.
47:33In terms of you know causal relationships,
47:36there's a a Mendelian randomization study
47:40that was conducted to further better
47:43understand the these causal relationships
47:47and it was identified that the risk for of
47:52atrial fibrillation based upon recognizing
47:54known genetic markers was genetically
47:57predicted obstructive sleep apnea.
47:59And and so there there are
48:01some data here to suggest.
48:03Um, you know, potential,
48:05you know, causal relationship.
48:09We also know that it is challenging
48:11to identify sleep apnea and those
48:14with cardiovascular disease,
48:16including atrial fibrillation.
48:18So Doctor May leverage some of the
48:23safety data to better identify if
48:26there are enhanced ways that we can
48:29screen for obstructive sleep apnea.
48:31So she looked at the upward sleepiness scale.
48:34Score. Stop.
48:35Bang, the Berlin and the Nosus and.
48:39And then um looked at some of the
48:43individual characteristics and
48:45symptoms and and found that the nabs.
48:48Including neck circumference, age,
48:51BMI may perform better than some
48:54of these other questionnaires in
48:57terms of screening for obstructive
48:59sleep apnea in this population with
49:02paroxysmal atrial fibrillation.
49:04So she compared this these the
49:07performance of these screeners
49:09in those with paroxysmal atrial
49:12fibrillation compared to controls.
49:14So when thinking about sleep apnea and
49:18atrial fibrillation and elements of of
49:22the clinical pathway and integrated care,
49:25certainly there are these sleep
49:28endophenotypes to be considered
49:31and what specific endophenotypes.
49:34And you know maybe most related to even
49:39atrial fibrillation and understanding
49:41the key physiologic stressors as
49:44we've we've reviewed a little bit
49:47with the with the experimental data
49:49the role of mobile health monitoring
49:52for for screening strategies you know
49:55to to monitor concomitantly these
49:58sleep and and and and ECG monitoring
50:01and and understanding better how
50:04this really impacts our outcomes.
50:07In terms of burden of atrial fibrillation
50:10and also patient reported outcomes,
50:12clinical outcomes in atrial fibrillation.
50:15And so the various you know paradigms
50:19have been proposed and I think
50:22technology is is advancing and
50:24this is an area I think that is
50:27of interest in terms of seeing,
50:30evaluating the the the merits of of
50:33conducting mobile you know using mobile.
50:36Technology to be to monitor ECG and
50:40and sleep data and also telehealth
50:43and in the management of obstructive
50:46sleep apnea and atrial fibrillation.
50:49And so you know the the role of
50:53apps for example in being able to
50:56screen for sleep apnea in those
50:58with atrial fibrillation.
50:59You know you know looking at some of these
51:02sleep physiologic variables you know
51:04home sleep apnea testing versus in lab.
51:06Only sonography you know better
51:09in an enhanced pathways to to use
51:12potentially cloud based platforms to
51:15communicate even feedback with the
51:17patient and in in in real time and
51:21again the ability to do more longer
51:24term monitoring to understand even
51:26how the the the impact of treatment
51:29to sleep disorder breathing on
51:31burden of atrial fibrillation.
51:34Um,
51:34there's a sleep app that has been
51:36developed by our group that we
51:39are currently integrating into
51:41our electronic medical record to
51:43screen for common sleep disorders,
51:45sleep apnea, insomnia,
51:46sleep duration and shift work.
51:48And this is something that may that
51:51we're using in our heart failure
51:54program and will be launching in
51:56our atrial fibrillation patient
51:58population as well as we have
52:01seen that sleep apnea and and.
52:04Curtailed sleep in particular may be
52:06playing a role in the pathophysiology
52:09of atrial fibrillation and and most
52:11of the the the work that has been
52:14done so far in terms of looking at
52:17interventions is focused on CPAP.
52:18But you know it would be of interest
52:21to know how other interventions such
52:23as hypoglossal nerve stimulation in
52:25this novel continuous negative external
52:28pressure you know and and other
52:31innovative treatments how those influence.
52:34Um atrial fibrillation outcomes and
52:37and would those interventions provide
52:40any benefit for the sake of time I'm
52:43going to skip over these slides.
52:46But you know I think there are opportunities
52:50to to look at you know sleep disruption,
52:54physiologic and symptom based biomarkers
52:56and some of the great work conducted by
53:00Doctor Zinchuk for example and in trying
53:03to understand the interrelationships.
53:05Between these these variables and how,
53:09how this can can help us in a more
53:12refined and better way predict outcomes.
53:16So we are right now working with IBM
53:19on a Discovery Accelerator grant to to
53:23leverage some of our clinical data.
53:27Uh,
53:27from our our registry to be able to to
53:31to see if we can come up with better
53:35ways even using you know these indices,
53:37just hypoxic sleep apnea,
53:39specific hypoxic burden and heart
53:41rate arousal responses that and and
53:44perhaps potentially these integrated
53:45measures to better predict outcomes.
53:48So in terms of our current state
53:50of knowledge,
53:51sleep apnea is associated with
53:53nocturnal incident atrial and
53:55ventricular arrhythmias the unexplained.
53:57Increasing atrial fibrillation epidemic
53:59is at least partially attributable,
54:02most likely to untreated sleep
54:04apnea and unrecognized sleep apnea.
54:06And accruing data really strongly
54:08implicate autonomic dysfunction
54:10as well as other mechanisms.
54:12In terms of culprits in the relationship
54:16between sleep apnea and arrhythmia,
54:19the epidemiologic data data really points
54:22towards the strong magnitude of association,
54:25monotonic relationships,
54:27temporal relationships.
54:30You know in terms of the the relationship
54:32of sleep apnea and atrial fibrillation
54:34and some data pointing more towards
54:36central versus obstructive apnea
54:38and other data also pointing towards
54:40sleep related hypoxia as it relates to
54:44increased incident atrial fibrillation.
54:46Certainly there are you know
54:49retrospective data,
54:50meta analysis of these retrospective
54:51data that suggests that sleep
54:53apnea treatment reduces recurrence
54:54of atrial fibrillation,
54:55findings that have not been borne out
54:58with these recent relatively small.
55:00Clinical trials.
55:02And uh,
55:03you know sleep apnea as we reviewed it,
55:06you know at the beginning is associated
55:08with sudden nocturnal cardiac death,
55:09the potential role for periodic limb
55:12movements during sleep with work done
55:14by Doctor May in in terms of and
55:16those associated with the arousals and
55:19that really you know being related
55:21to cardiac arrhythmia as well.
55:24So there are many you know knowledge
55:26gaps to be
55:27considered, you know, understanding
55:30better subgroups susceptibilities
55:31to specific physiologic triggers.
55:33Um, designing the clinical trials.
55:36Uh, you know, clinical equipoise
55:38being one area that you know to
55:41consider where on the trajectory of
55:44atrial fibrillation to intervene.
55:45How you know to consider those who
55:47are sleepy versus non sleepy, obese.
55:50Those are who are potentially more obese
55:53versus not better identifying prediction
55:56of arrhythmia development specific to
56:00sleep apnea development of collaborative.
56:04Clinical care models.
56:05So this is being such a sort of
56:09breathing is now recognized by
56:11various societies in terms of.
56:13Serving as a preventative risk
56:16for sleep apnea,
56:18the role of the autonomic function
56:21has been identified in this NIH
56:24workshop report and and with specific,
56:28you know,
56:29comment on sleep apnea in particular
56:32and a recent American Heart Association
56:36statement has also provided an
56:38overview of this and and are also some
56:41recommendations charting the way forward.
56:44And uh, a tentative sort of stepped
56:47care model that can be considered,
56:50uh, with the identification
56:52and treatment of sleep apnea.
56:55In, in, in those with cardiac,
56:57arrhythmia, atrial, ventricular, and.
57:01Conduction delay arrhythmias um
57:03so I will leave it at that and I I
57:07thank you so much for your time.
57:14Thank you Doctor Mehra for this
57:17excellent amazing talk and I would
57:19like to open the floor for questions.
57:21And I think we have a question here from SI.
57:24Is there heart problems such as CVD
57:27reversely lead to sleep disorder?
57:29I think there is just a reverse
57:32association between cardiovascular
57:33disease and sleep disorder.
57:36So, uh, meaning is there getting
57:40at the directionality in terms
57:42of is, is that the question?
57:44Yes, I think that's the question.
57:45Is there a hard problem such as CVD
57:48reversely leading to sleep disorder?
57:50Yeah, I mean I think,
57:51you know, there certainly.
57:55With what comes to mind is heart failure,
57:58right? I think with the compromise left
58:01ventricle pulmonary congestion, you know,
58:04central sleep disorder breathing, you know,
58:06so I think there are and, and you know,
58:08central sleep sort of breathing,
58:09then you know, leading to to
58:12negative influences on the heart.
58:14I think that comes to my mind
58:18at the forefront when looking
58:20at atrial fibrillation.
58:22At least you know, a couple of the studies.
58:25That we discussed seemed to
58:28suggest that it's more the,
58:31you know, apnic events,
58:33hypotonic events that are you know
58:37directionally leading directionality
58:38leading to to the arrhythmic events.
58:42You know in terms of the
58:44case crossover design.
58:45And then also in terms of the work
58:48with Doctor Linz and his continuous
58:51monitoring of respiratory monitoring
58:53looking obvious hypopneas as well as.
58:56Looking at the arrhythmic events now,
58:58how how well validated is that cardiac
59:00monitor and picking up the apneas hypopneas,
59:03I I don't know,
59:05but you know,
59:06the the data that we have in hand
59:08seems to suggest at least when it
59:10comes to atrial fibrillation that Umm,
59:12you know,
59:13sleep apnea seems to be the driver
59:15now there could be some reverse
59:18directionality there as well.
59:19And you know and I if I had to to guess,
59:22I would anticipate there would be some
59:24some reverse directionality as well.
59:27Thank you.
59:29I don't see any other questions.
59:30I have a question.
59:32So in terms of relation between the
59:34hypoxia and Afib that you mentioned,
59:36you know there are many measures for hypoxia,
59:39you know like means that oxygen saturations
59:43now their saturation the time below 90.
59:46Is there anyone that's more predictive
59:48you know like clinicians perhaps could
59:50talk to their patient about that,
59:52could you comment on that?
59:55Sure. I I think you know what we're seeing.
59:59Is. You know, in general with
01:00:02the epidemiologic work that
01:00:03has historically been done,
01:00:05percentage of sleep time spent below
01:00:0790% has been the measure that has
01:00:10been thought to be the one which is
01:00:13kind of getting at the maybe more
01:00:16cumulative burden of of that hypoxia.
01:00:19And now of course with the cutting edge
01:00:23work by Doctor Azar Barzan and others,
01:00:27you know, are showing that it's,
01:00:29you know, this sleep apnea.
01:00:31Specific hypoxic burden uh may be
01:00:33a more accurate and refined measure
01:00:37of that nocturnal hypoxia that's
01:00:40specific to sleep apnea in terms
01:00:43of getting at that area under the
01:00:45curve related to the discrete apnic
01:00:48and hypotonic events and maybe a
01:00:51more accurate measure of of that and
01:00:55but you're right how clinically?
01:00:59You know uh,
01:01:00can we can we pull that measure out
01:01:02and and be able to discuss that
01:01:04with our patients and you know it
01:01:06doesn't seem that we're there yet,
01:01:08but certainly there are very
01:01:10compelling data showing that this
01:01:12sleep apnea hypoxic burden is,
01:01:14is related to cardiovascular outcomes
01:01:17and and and and I think I imagine
01:01:21we are on the path towards you
01:01:23know being able to generate that
01:01:28measure clinically so that we can.
01:01:31Use that as a guide.
01:01:33Alright, thank you.
01:01:36Any other questions?
01:01:38In the interest of time
01:01:41if there's no questions.
01:01:44I would like to thank everyone
01:01:45and especially Doctor Mehra
01:01:47for this excellent talk.
01:01:48Learned a lot. Umm.
01:01:51A wonderful. Thank you so
01:01:52much for the invitation.
01:01:53It was lovely to see you all and
01:01:56done and I appreciate it and
01:01:58happy New Year to everybody.
01:02:01Thank you. Happy New Year everyone. Bye, bye.
01:02:04Bye, bye.