Sleep 2023.03.01 Kholdani

March 15, 2023

ID9672

To CiteDCA Citation Guide

00:00So without further ado,
00:02I want to introduce today's speaker
00:05and it's a really pleasure to
00:07introduce Doctor Cyrus Caldani,
00:09who's a former Yale Pomarico care
00:12and and Sleep Medicine Fellow.
00:15He is also an alma mater from Ohh.
00:18He's also a faculty at my former
00:20alma mater Beth Israel Deaconess
00:22Medical Center at Harvard now and
00:24just give you a few Nuggets about
00:27Cyrus who is an incredible physician.
00:30And educator.
00:31And so he was born in New York City,
00:33and then immediately after that
00:35he earned his Physiology degree
00:37at Georgetown before he got his
00:40training medical training at Drexel.
00:42He then moved to beautiful
00:44Charlottesville for his residency
00:46and training in internal medicine,
00:48and then moved on to Yale
00:50for pulmonary critical care,
00:51where he did research with doctor
00:55with our own doctor Mossanen,
00:58and had done some significant work
01:00on relationships in hypertension
01:02and sleep disorder breathing.
01:04And so he then moved on to do
01:07his pulmonary vascular disease
01:08fellowship at Stanford,
01:10where he then joined the faculty.
01:13And then in 2018,
01:15he moved to the Beth Israel
01:18Deaconess and now Leahy.
01:20Medical Center associate
01:22affiliated with Harvard,
01:23where he directs the Pulmonary
01:25Hypertension Center,
01:26and he's highly involved in teaching
01:28residents and fellows there.
01:29And so Cyrus,
01:30like me as a lover of Physiology,
01:33as evidenced by his publication
01:35record and his published work on
01:37the intersection of pulmonary
01:39arterial hypertension,
01:40pulmonary hypertension and
01:41sleep disorder breathing,
01:43addressing some mechanistic links
01:45and also clinical implications.
01:47And his recent work has actually
01:48focused on some different implication
01:50too for pulmonary circulation,
01:52including vascular pruning.
01:53It's a paper those recently
01:54published in chest.
01:56And so I am very excited to hear Cyrus's
02:00talk today on the intersection of
02:02the PD and sleep disorder breathing.
02:05So Cyrus,
02:05take it away.
02:06Welcome.
02:06Thank you so much, Andre.
02:08Glad to see your face, hear your voice.
02:11And then before this started,
02:13I was sort of running through
02:14a list of names with Debbie to
02:16find out who's still at Yale and.
02:17Would love to be back in grab a a
02:21Kati roll if those are still around.
02:24Uh, this is the same disclosure
02:27and accreditation slide,
02:28the outline of today's talk.
02:30We're gonna,
02:30I'll start with sort of recent changes
02:33in the diagnosis and definition of
02:35pulmonary vascular disease and then
02:37we'll jump right to sort of like
02:40how to use existing phenotypes to
02:42try and describe a relationship
02:45between pH and sleep apnea.
02:47Will highlight the unique
02:50relationship between pH and obesity
02:53hyperventilation syndrome over the
02:55course of the talk will be talking
02:57about the implications of CPAP
02:59and noninvasive positive pressure
03:01ventilation on those two conditions
03:03and probably vascular disease.
03:05And then if there is time,
03:06I I do have an interesting case
03:08to finish up with that I I hope
03:10you guys would find interesting.
03:12So just as a you know background,
03:15there was a seminal paper published in 2016.
03:18Using the VA card database,
03:20which is sort of a linking of all VM
03:24catheterization laboratories in the
03:27VA system that participated in the
03:29generation of a database and you know,
03:32an evaluation of almost 22,000
03:35very well characterized individuals
03:38that underwent catheterizations.
03:42Were able to demonstration very important
03:44findings that changed our concept of
03:47what pulmonary hypertension should be.
03:53And importantly, what we were able
03:56to establish is that the previous cut
03:59off of the main peer pressure of 25
04:02and above missed a significant amount
04:05of clinically significant disease.
04:06And it was based on this paper that
04:09we changed the criteria to mean
04:11peer pressure of 20 and above.
04:13And you can see here that we
04:16have 3 categories here.
04:18You know, your reference is sort of your,
04:21your, your previous.
04:23Um, criteria of 25 and the
04:27middle line here is,
04:29I mean you have person 1924 and then
04:31lastly is a normal OK pressures
04:34and you can see that even having a
04:36slightly elevated PA pressure results
04:38in a significant increase in risk
04:41and a reduction in the probability
04:43of survival and then also increases
04:46your chance of hospitalization.
04:47Importantly,
04:48it's sort of hard to see on here
04:50on this graph,
04:51but the hazard ratio that increased
04:55that happens between 20 and 2121
04:58and 22 all the way up to 25,
05:00each of those one millimeter mercury
05:03increments is of greater clinical
05:05significance than any one millimeter
05:08mercury increment that follows it.
05:10This study was also able to establish
05:13that the risk that comes along with
05:15having this mean pay pressure of
05:1720 and above occurs irrespective
05:18of what the PR is.
05:20So whether you're a low PVR
05:22patient or a high PVR patient,
05:24having a mean pay pressure that is
05:2720 or above increases your risk of
05:29mortality and your risk of hospitalization.
05:32Fast forward a couple years,
05:34there was a paper using similar data,
05:36same database,
05:37that was able to establish that
05:40the previous PVR definition for pH,
05:42which was three wood units and above,
05:44similarly was missing a lot
05:47of morbidity and mortality.
05:50The red lines here sort of reflect
05:52the density of patients that
05:54exist at any given PVR value,
05:57and the blue line here represents
06:00the increase in mortality.
06:02And you can see that.
06:04In individuals that have many pressures
06:07of 19 or above having a PVR that is above.
06:11Two, although this one really is 2.2,
06:14does confer significant
06:15increase in mortality and.
06:18As we mentioned before,
06:19this increase in mortality
06:21occurs both with subjects that
06:23have classic pH Physiology,
06:25which is to say I mean
06:27pressure that's you know,
06:2919 or above in the setting of a
06:31low wedge pressure or pulmonary
06:33venous hypertension Physiology.
06:34So if you're PR is over 2 and you
06:36have pulmonary venous hypertension,
06:38same thing,
06:39increased risk of mortality and
06:40increased risk of hospitalization.
06:44The sum total of all of these
06:47recommendations sort of came
06:49to a head in the fall of 2022,
06:51where the European Respiratory Society
06:54and European Society of Cardiology
06:56released their new set of guidelines.
06:58And define pulmonary hypertension
07:01and it's a subtypes as follows PH-20
07:05and above precapillary pH is sort of
07:08your your classic low wedge pressure
07:11but the PR cut off here is now too.
07:13And then we've isolated post
07:15capillary combined pre and post
07:16capillary and then exercise page also
07:18made it back into the definition.
07:21So now we're going to step back five
07:22years to the previous set of guidelines
07:24and instead of looking at the human
07:25dynamics as we know that changed,
07:27I want to just look at.
07:28Our Group 3 pH paradigm which
07:30was um pH in the setting of lung
07:33disease and or hypoxia,
07:34and then importantly both sleep
07:37disorder breathing and alveolar
07:39hypoventilation disorders were listed
07:41as causes of pH or Group 3 pH,
07:44specifically and.
07:50Group 2 PAH, which is P secondary
07:51left side of heart disease.
07:53They did recommend evaluating for
07:55sleep apnea syndrome and other
07:58commodities as well before any
08:00consideration of treatment of pH.
08:01So there's a little bit
08:02of a mixed picture here,
08:03but it's clear that sleep apnea appears
08:06in the guidelines Fast forward to.
08:09The new aesthetic guidelines
08:112022 and I quote the authors,
08:13instead of the general term
08:14sleep disorder breathing,
08:15the term hypoventilation syndrome should
08:16be used within Group 3 to describe
08:18conditions with increased risk of pH.
08:20Sole nocturnal obstructive sleep
08:22apnea is generally not a cause of pH,
08:24but pH is frequent in patients
08:27with hypoventilation syndromes
08:28causing daytime hypercapnia.
08:29OK, so.
08:31Great.
08:33Now the problem here is that there
08:35really isn't much else on sleep
08:36apnea in these guidelines at all,
08:38so it's sort of just subtracted.
08:41But we know based on our.
08:44You know, reality in our clinical
08:46experience that there's something there.
08:48So let's go back in time.
08:50This is before I was born,
08:51but there was a study in 1976 that looked
08:54at 12 subjects with severe sleep apnea.
08:56There's no way you get IRB
08:58approval for this again today,
08:59but these patients were all catheterized
09:02with radial and pulmonary arterial
09:04catheters and they were just
09:06allowed to sleep and have as many
09:09apneic episodes as they desired.
09:11You can see that during waking hours,
09:15there was probably a couple
09:16subjects that had mean pressures of,
09:18you know,
09:1920 or above.
09:20But importantly with sleep there was
09:23significant pulmonary hypertension
09:25that developed oftentimes in
09:27the setting of systolic and
09:30systemic hypertension as well.
09:31But nonetheless,
09:32this is a fact of sleep apnea.
09:34We know this is happening overnight.
09:37The exact prevalence is sort
09:39of difficult to ascertain.
09:41The studies that look for pH and OSA
09:45have non uniform diagnostic criteria for pH.
09:49PA pressures of mean pressures
09:51of 20 mean papers of 25.
09:53The modalities used to diagnose the
09:55pH echocardiogram or relocation buried
09:57in the patient populations were not
09:59particularly phenotyped at all,
10:01so there was a lot of variants and subjects.
10:04Some studies had a high fraction
10:07of subjects with significant COPD
10:10as others had not,
10:11but within all these limitations there
10:13is a prevalence range of between
10:1612 and 34% across a variety of studies.
10:20More recently,
10:21the group out of Cleveland Clinic looked
10:24at a cohort of almost 500 patients.
10:28That had right heart catheter relations
10:31done within two years of polysomnography.
10:34And they find some, you know,
10:37interesting findings,
10:39notably that the HIV doesn't seem to
10:43discriminate between developing pH,
10:46which is these three cohorts,
10:49or not having pH but having OSA.
10:53What did correlate,
10:54however,
10:55was your T-90 and then also your
10:59nature auction saturations,
11:00which they don't have listed on
11:02this table here as well.
11:05But the findings on the polysomnography
11:09that were predictive of pulmonary
11:11vascular disease didn't really
11:12do a good job of predicting,
11:14you know,
11:15whether you pulmonary venous
11:16hypertension or pulmonary arterial
11:18hypertension or something that's mixed.
11:20We just know that these desaturations
11:22were happening and they're associated
11:24with pulmonary vascular disease of some
11:27variety and that's sort of like you know
11:30clarified further here where it's the
11:32the T-90 that really differentiates.
11:35Between having pH and not having pH.
11:38But it doesn't discriminate
11:40between the types of pH.
11:42AI, like I mentioned earlier,
11:43does not predict whether you have pH or not.
11:48OK. So, so now what it's
11:51out of the guidelines.
11:52We know it exists.
11:53We know it's probably have some clinical
11:56significance just because we know that
11:58mild pH is of clinical significance.
12:00So what do we do?
12:02And so in a lot of ways this talk is more
12:06about my approach and a lot of credit
12:09should go to Doctor Mosimane because
12:11when I was a pulmonary fellow and we
12:15were working with that set of guidelines.
12:18I assume that OSA belonged in in Group 3,
12:21pH and he he was immediately doubtful of it.
12:26And thought it was much more related
12:29to the consequent diabetology.
12:32So there is a role I think for sort of
12:34trying to phenotype these patients and
12:36to that end in the Blue Journal 2014
12:39there was a consensus statement made by.
12:43A group of pH specialists who suggested.
12:50That within pH there should be an effort
12:53made to more adequately phenotype these
12:56patients just because there's a lot
12:58of diversity within that bucket of pH
13:01between congenital heart disease and
13:03HIV and portal pulmonary hypertension,
13:04a drug and toxin related pH,
13:06there are the underlying causes are myriad.
13:11To that end,
13:12the 2022 consent guidelines did actually
13:15sort of move the needle on this a little bit.
13:18And that was based on a cluster
13:20analysis that was done using one of
13:22the big pH registries in Europe,
13:24which is the compare registry.
13:26And it was an analysis of the
13:29compare registry that generated 3
13:33sort of main clusters.
13:38The classic idiopathic PAH cluster.
13:40So that's your, you know,
13:4230-40 year old woman.
13:46As opposed to a left heart
13:48phenotype or a cardio pulmonary
13:50phenotype which are often men,
13:52former smokers,
13:53low DL Co not particularly significant
13:56findings on CT scanning with risk
13:59factors left side of heart disease and
14:02these patients have well we the the
14:05classic idiopathic phenotype and these
14:08two phenotypes have fairly different
14:11responses to pH therapies both when it
14:14comes to improvement in functional status.
14:16Uh and then also sort of physiologic
14:19improvement on subsequent catheterization.
14:21Nonetheless in the guidelines
14:22they make a point to say that
14:24there are currently are still no
14:26evidence based rules for how best
14:27to determine the patients phenotype.
14:29We just know that there's something there.
14:32So what would an OSA pH phenotype look like?
14:36We know that there's some relationship,
14:40but how would we go about trying to do so?
14:42And so this is my approach.
14:45The guidelines do try and describe a
14:48phenotype for pulmonary hypertension
14:50secondary left side of heart disease
14:52and I'll draw your attention
14:54to a couple of these factors.
14:55And so patients that have
14:58a high likelihood of.
15:01PH second to left side of heart
15:02disease have a constellation of
15:04sort of the metabolic syndrome,
15:05obesity, hypertension and
15:07dyslipidemia glucose intolerance.
15:09They have no less side of heart disease
15:11or the risk factors for hypertension,
15:13diastolic dysfunction,
15:14coronary artery disease,
15:16clinical diagnosis of heart failure,
15:18much higher prevalence of atrial
15:20fibrillation and then echocardiographic
15:22findings that are suggested of
15:24a significant burning of left
15:25sided heart disease primarily with
15:27the left atrial dilatation and
15:29then echocardiographic signs of.
15:31Mythology I I should point
15:32out here that there is a,
15:34there is good data on insulin
15:36resistance in in pH but not
15:39necessarily frank diabetes.
15:41And so I sleep audience would look
15:44at this chart and say that's kind of
15:47familiar and we know that patients
15:49with OSA have a variety of associated
15:52commodities that are are shared with
15:56the pH left hand side of heart disease,
15:58phenotype, obesity,
16:00metabolic syndrome.
16:02Discology and atrial fibrillation
16:04to start the lease and so I I think
16:07a way to start this conversation
16:09is sort of just go through these
16:11to to to try and prove this point.
16:15I I will say there is you know
16:16maybe some data that would suggest
16:18that there is a little bit of
16:20bidirectionality between some
16:21of these findings and OSA.
16:23You know so for example patients
16:25with really bad heart failure
16:27might retain fluid overnight.
16:28Those fluid chest might sort of
16:31predisposed to worse obstructive
16:32symptoms since but you know by and
16:34large these are the communities
16:36we associate with OSA are driven
16:38that that lead to SA.
16:42So obesity alone can result
16:44in pulmonary vascular disease
16:45through a variety of mechanisms,
16:47prior use of anorexia,
16:49eens, frank cardiomyopathy,
16:50predisposition to thromboembolism and
16:53to fill this function and hyperuricemia.
16:58There is an interesting study that was done.
17:02Uh, in 2008, that looked at 76 consecutive
17:07autopsies of subjects with obesity.
17:10These are fairly high BMI.
17:1445 and above I believe and
17:16based on this autopsy study,
17:18there was a very high prevalence of
17:21pulmonary vascular changes that have
17:24implications for pulmonary hypertension,
17:27primarily pulmonary venous
17:29hypertensive changes but but
17:32also arterial changes as well.
17:36And then an increased fractures of Frank
17:39Hemosiderosis and findings that that look
17:42like pulmonary capillary Hemangioma.
17:44Business as well on biopsy here on
17:48autopsy you know here we've got sort of
17:52interstitial changes and then a lot of
17:55medial thickening and and pulmonary veins,
17:57tortuosity pulmonary veins,
18:00so in a non phenotyped.
18:04Cohort of OB subjects,
18:05we know that there are significant
18:08vascular changes happening in
18:10the lung and we know nothing
18:12about these patients besides that
18:15this is just sort of all comers.
18:18The other way to look at this is.
18:21Using cardiac Mr.
18:23Data and some of you might be
18:25familiar with the Mesa study,
18:28so the multi ethnic study for
18:30atherosclerosis trying to look at
18:33subclinical heart disease in a variety
18:35of subjects and communities in America.
18:39There was an ancillary study that was
18:41performed and 4127 subjects were obtained.
18:46Of those around 2/3 were overweight or
18:49obese compared to a lean population.
18:52And there was an obvious and
18:55linear trend with BMI and increased
18:59right ventricular mass,
19:01increased right ventricular diastolic
19:02volume and a decrease in the right
19:05ventricular ejection fraction even
19:07after adjustment for a variety at all
19:11democratic demographic factors and
19:13then also left ventricular function as well.
19:16And so we know at a vascular level and
19:19then now we know at a functional level.
19:22That obesity is associated with
19:24significant right ventricular changes
19:27and pulmonary vascular changes.
19:29Now going through the rest of
19:31those risk factors.
19:32The metabolic syndrome, like I said,
19:34is importantly it's a driver of.
19:39Both the development of pulmonary
19:41hypertension due to left side
19:43of heart disease,
19:43but there's some nascent data that
19:46would suggest that it also exacerbates
19:49and worsens that Physiology.
19:51We know that OS is associated
19:53with metabolic syndrome.
19:54And now I'm going to sort of like
19:56toggle between both the risk factor
19:58and then sort of the effect of
20:00CPAP on the risk factor and in this
20:02case the treat OSA Ms.
20:05study.
20:06This is pretty recent,
20:07I think came out at the end of 2022,
20:09looked at the effect of CPAP
20:10on the metabolic syndrome.
20:12And these aren't necessarily
20:13dramatic changes,
20:14but you can see that CPAP does
20:16seem to have a significant effect
20:18on a variety of parameters.
20:20In the metabolic syndrome where you
20:24had frank reversal of of some of these
20:28findings and very little development
20:30of of new findings over the course
20:33of six months of CPAP therapy.
20:35This is 100 subjects with moderate
20:38to severe OSA.
20:40So HI's are all 15 and above and.
20:45It was, um,
20:46placebo-controlled.
20:47So there's both CPAP and then I
20:50think they used the nasal dilator
20:52strip as the other group.
20:56Diastolic dysfunction,
20:57like I said earlier,
20:58is probably a big driver of pH Physiology.
21:01We know that you can develop diastolic
21:04dysfunction in OSA even in the
21:07absence of diurnal hypertension.
21:09This is a I'm showing you data here
21:12looking at 61 subjects with OSA
21:14who are being evaluated for ethyl
21:17pletal fragile plasty and there
21:19were compared to an equal number of
21:22normal tensive controls and based on
21:25echocardiographic findings of diastolic.
21:27Dysfunction um, even those with
21:30OSA with normal blood pressure,
21:34they had significant increases
21:35in left ventricular mass index
21:37to suggest The Isaacs function.
21:39We know that CPAP therapy,
21:41particularly in subjects that have
21:44clinically diagnosed heart failure,
21:46reduces LV after load and has a positive
21:49effect on parameters of diastolic function,
21:52both using echocardiographic
21:54data and then separately.
21:57Based on Cmdr Data as well.
22:00The Discology is sort of linked
22:04to another pertinent finding.
22:06If you guys will call from that first
22:09table that deals with left atrial
22:12structure and then in a sense function
22:16with progressive diastolic dysfunction,
22:18left atrial size will increase
22:21and that will predispose you to
22:24atrial fibrillation as well.
22:26Cpap therapy does definitely have an impact.
22:30On left atrial functions,
22:32so sort of left atrial contraction,
22:34um, it's less likely to actually
22:36cause a reduction in LA volume based
22:39on echocardiographic parameters.
22:41And I'm not sure if there's any data on Mr.
22:45The link here is towards a
22:48atrial fibrillation.
22:52And we know that OSA is a predictor
22:57of incident prevalent and worsening
23:00severity mitral fibrillation.
23:02We know that untreated sleep apnea
23:04reduces the efficacy of rhythm
23:07control interventions for the
23:09management of atrial fibrillation.
23:11More recently, the sleep AF trial
23:14that was published also I think at
23:16end of 2022 did demonstrate that
23:19CPAP therapy is associated with the
23:22reversal of HR modeling that happens
23:24along with the atrial fibrillation
23:27based on atrial mapping data.
23:29I've read this paper three times and I
23:32still really struggle with the methods,
23:35primarily because of sort of the,
23:37the technique of atrial mapping.
23:39There's a lot of vocabulary that you know.
23:41Is not familiar to a non electrophysiologist.
23:45But the data looked to be fairly convincing.
23:49It would also appear that CPAP therapy
23:52allows for improved efficacy over
23:54the control interventions as well.
23:59So what's the impact of OSA on pH?
24:06Well, the. Same things that impacted
24:10our ability to define the prevalence
24:14of pH and OSA sort of impact,
24:16our ability to define how much of an
24:19impact CPAP is happening on, on pH.
24:21And so the modalities that were used
24:24to determine how the pH was being
24:27surveilled was a catheter based,
24:28was a catheter based both
24:30pre and post intervention,
24:32was it echocardiogram based or was
24:33it based on different cut offs of
24:36pH systolic pressures or inferred
24:37mean pressures so on and so forth.
24:39Within those limitations,
24:40it would appear that CPAP therapy
24:43looking at completely on phenotype
24:45cohorts can have some effect on the
24:49calculator reduction in the mean PAP
24:51from nothing to a fairly mild to modest
24:55reduction of 6 millimeters mercury.
24:57Based on what we know about the risk that's
25:00conferred by elevations and key pressure,
25:02that's.
25:03Probably not insignificant, I I will say.
25:09Probably a liberty to speak about this
25:11because hopefully will be published soon,
25:12but but you know we will be showing
25:16momentarily that changes in the tricuspid
25:20regurgitation velocity jet which is used
25:23to calculate the estimated PA pressure on
25:26echocardiogram are clinically significant.
25:28So people that whose charge of
25:31velocity goes up even my small amounts
25:34are at increased risk risk for.
25:37Death.
25:38And we know that those whose TCRF velocity
25:42decreases over time for whatever reason.
25:45Do have a reduction in,
25:46in, in,
25:47in their mortality risk again
25:49in an all Comer population.
25:51And so I think that the the
25:54general take away from this is.
25:57The most legible way to try and define a
26:00OSA pH subject is using the paradigm that
26:03we're used for pulmonary hypertension
26:05due to left side of heart disease.
26:08And my approach in clinic and where
26:10you know occurs with the group to
26:12do is to sort of look through all
26:14of those risk factors that are
26:16shared in common between pH,
26:18LHD and OSA and sort of just
26:22have endpoints for all of them.
26:25Cpap and weight loss are the big inventions,
26:29obviously,
26:29because they'll have an outsize
26:31effect on all those subcategories,
26:34be it metabolic syndrome.
26:37Umm.
26:38And it's a associated manifestations
26:41but also with a noticeable impact on
26:45the frequency of the fibrillation
26:48which you know we seem to think in
26:53our practice has one of the higher
26:56correlations with the developing with
26:58having pH left side heart disease.
27:00So now I'm going to segue to the
27:03obesity Hyperventilation syndrome
27:04because this is a little bit.
27:07Some of the same,
27:09but some things are different.
27:11This is not the audience to
27:12sort of redefine the disease,
27:13but for those that are not providers,
27:16you know, obesity is defined as a
27:18BMI of greater than or 30 or more
27:21kilogram meter squared with the
27:23presence of daytime hypercapnia
27:25defined as a PCO two of greater than,
27:28equal to 49 millimeters mercury,
27:32without other causes of
27:33hypoventilation and with the known
27:35diagnosis of sleep disorder.
27:37Anything.
27:39It's oftentimes diagnosed during
27:41an acute on chronic episode
27:43of Hypercapnic grocery failure
27:45and with the presence of the
27:48classic constellation of symptoms
27:50and findings of sleep apnea.
27:53And then.
27:57In the case, I'll show this is
28:01an inpatient diagnosis as well.
28:03Ohh, just diagnosis are costly.
28:05They're delayed,
28:06they're oftentimes made fairly late and.
28:10Probably in the, you know,
28:12in the same age structure as OSA,
28:15but during that period of time
28:17patients with OHS will use a lot
28:21of healthcare resources compared to
28:23comparably obese you catnic subjects.
28:28The Physiology would be city sort
28:31of like well delineated here.
28:33The impacts on you know,
28:34pulmonary mechanics on airway
28:37diameter are are fairly obvious.
28:42The big difference is that in
28:45addition to all the sort of burns
28:47that we talked about before,
28:50the metabolic syndrome,
28:52diastolic dysfunction, atrial fibrillation,
28:54echocardiographic findings,
28:55there is the added burden of hypercapnia.
28:59We oftentimes talk about the
29:01impact of hypercapnia on,
29:02on on the pulmonary vasculature.
29:04The the the data on it is is good,
29:07but there's less human based data
29:08that's high quality than you would like.
29:10So a lot of it comes from animal based.
29:12Um studies,
29:13but in the setting of hypercapnia,
29:18oftentimes with concurrent hypoxia as well,
29:22the impact of hypercapnia on right
29:24ventricular size relative to left
29:26ventricular size and then also right
29:29ventricular size relative to the body
29:31weight in general is significant and.
29:36We know is a driver of increased
29:39pulmonary vascular tone and
29:41right for circular afterload.
29:43Based on cartographic data,
29:45we think the prevalence of
29:47pH and OHS is almost 70%.
29:50At the higher end and on
29:53prospective observational data,
29:54we know that patients with OHS are highly
29:59at risk for diastolic dysfunction,
30:01even the absence of their OSA
30:03being particularly severe.
30:09This is a study based on 18 subjects
30:11that had OHSU without any risk factors
30:14for precapillary pulmonary arteriopathy
30:16that we would associate with pH.
30:18So no HIV, no portal pulmonary,
30:21no portal hypertension.
30:24Um, no anorexigenic use and so on.
30:27And and you can see that there's a decent
30:32correlation between BMI and me and keep
30:35pressure on right heart catheterization.
30:39And then also on the degree of hypercapnia,
30:44in this case nocturnal hypercapnia
30:46and the mean PA pressure as well.
30:50In these subjects.
30:53They underwent 3 months of titrated Bipap
30:57therapy with a follow-up right heart
31:00catheterization and they were able to
31:03demonstrate a significant reduction in
31:05the mean PA pressure from a mean of 49 to 31,
31:09which is fairly dramatic,
31:11a significant reduction in the
31:13PVR from 491 dines to 292.
31:16And so this is roughly, you know.
31:19Between 5:00 and six wood units,
31:21all the way down to between
31:22three and four good units,
31:24so fairly significant.
31:27And not necessarily a particularly huge
31:30difference in in in the cardiac index.
31:37But that's still a significant
31:39reduction in the PR. Um, these?
31:41This intervention was also
31:43associated with significant
31:45improvements in functional status,
31:47with improvement 6 minute walk distance.
31:50And functionality based on CPET
31:51study and then lastly on a you know
31:54commonly obtained parameter for the
31:56management of heart failure which
31:58is your anti probie NP as well.
32:00So dramatic reduction from 2500 down to
32:04377 in this case is there was probably
32:07diuresis that was happening as well.
32:12Which is a bit of a.
32:14Confounder, but I think the the sort of.
32:19Very strong data for what Bipap can
32:22can do in this patient population.
32:26More recently, I'm sure you guys are
32:29familiar with the Pickwick project.
32:31So the Pickwick study was a multi
32:33center randomized control trial.
32:34They looked at just over 220 subjects.
32:38It was done in the late aughts
32:40to the mid 2000 tens and to
32:42compare the efficacy of CPAP,
32:43non invasive ventilation,
32:46lifestyle modifications on symptoms
32:49and polysomnographic parameters.
32:51The lifestyle modification was
32:53primarily entailed a low calorie diet.
32:56With a good sleep hygiene
32:59and then appropriately used
33:01supplemental oxygen as well.
33:04The study was designed to sort of
33:07determine the comparative efficacy
33:08of non invasive ventilation and
33:10cpap and lifestyle modification.
33:13And uh,
33:14there was an initial two-month
33:16follow up with the baseline and.
33:20Subsequent echocardiograms and then
33:22there was a subsequent long term
33:25study which I'll get to momentarily.
33:27Umm.
33:30There was a significant improvement
33:33in Echocardiographic systolic
33:34PA pressure estimates and then
33:38also significant improvement in.
33:416 minute walk distance using
33:43non invasive positive pressure
33:45ventilation in these subjects.
33:47So the main results we can summarize is
33:50more than half the patients that had OHS.
33:53First off they had echocardiographic
33:55evidence of of pH,
33:56they had echocardiographic evidence
33:58of diastolic dysfunction and the non
34:01invasive ventilation was more effective
34:03in improving the LV hypertrophy
34:05parameters compared to control.
34:07Maybe CPAP was was decent at it.
34:11That but it was only the non
34:13invasive ventilation that led to
34:15a significant reduction in in this
34:17peer pressure estimate and the
34:19significant improvement in the
34:20six minute walk distance as well.
34:23So,
34:23so big impacts of of of non invasive
34:26positive pressure ventilation
34:28on structural parameters but
34:30also on estimated peer pressures
34:32and and functionality.
34:37The Pickwick Project was continued
34:39over three years with the evaluations
34:42done during that period of time.
34:45And the results were sort
34:49of like further compelling.
34:52Here we see both CPAP and noninvasive
34:55ventilation having a significant impact
34:57on the estimated PA pressure over time.
35:00You got the, it seemed like there were
35:02still big returns happening at one year,
35:04but beyond one year,
35:05there wasn't really much in the
35:07way of significant reductions in
35:09for the reductions in pressure.
35:11And so in all likelihood,
35:12the study by hell that looked at
35:13those initial 18 subjects phase
35:14the cutoff of three months,
35:16there's probably more benefit to be had
35:19with additional time on therapy and then.
35:24Parameters of reticular function also
35:27were significantly improved as well,
35:29with both noninvasive ventilation
35:32and CPAP therapy.
35:34Again, if there was improvement to be had,
35:35it was usually happening by one year.
35:39And then these are parameters
35:41of diastolic function.
35:43And again,
35:44same thing.
35:45Whatever improvement was to be
35:47had seemed to happen in one year
35:49on both of these parameters and
35:52there was less of an impact on
35:54actual left atrial morphology,
35:56but but maybe a little bit of a signal
36:00here as well at one year's time.
36:03And so to sort of illustrate this,
36:06I'm going to go through a case that.
36:09I came across just a couple years ago.
36:12He was a 67 year old female.
36:13She had a medical history
36:16for OSA that was not treated.
36:18Her chart set.
36:20She had COPD.
36:21She had his own hypertension,
36:24diabetes mellitus,
36:24and then a history of a Tia as well.
36:28She presented to the hospital
36:30with progressive waking,
36:31hypoxemic failure,
36:32and concern for right ventricular failure.
36:36At the time of presentation,
36:38vital signs were not typically worrisome
36:40except for the degree of hypoxemia that
36:43she had reporting 15 liters of oxidizer,
36:45no Earth or cytosis.
36:47Renal function was
36:49probably largely preserved,
36:50but notably had a significant and chronically
36:55elevated PCO 2 on blood gas analysis,
36:59chest X-ray,
37:00nothing shocking here,
37:02a little bit of pulmonary vascular
37:04congestion and cephalization,
37:05lung volumes not.
37:09Too high, not too low.
37:10And echocardiography,
37:11here's a picture of a TR jet,
37:15you know, high value.
37:16So estimates in the low 60s, high,
37:19low 70s without the addition
37:21of the right atrial pressure.
37:23And then an echocardiography,
37:24we've got our apical 4 chamber view.
37:28We've got a very large right atrium.
37:29We've got a very large right ventricle
37:32that exceeds the size of left ventricle.
37:35With signs of right for truly dysfunction.
37:37So probably a moderately enlarged
37:39right ventricle to say at least,
37:41maybe like 5 centimeters with I would
37:44say moderate dysfunction as well.
37:46Her clinical evaluation looked
37:49for secondary causes of PAH.
37:53Her antibody panels were strictly negative.
37:56There was no evidence of portal
37:57hypertension based on ultrasonic optic data.
37:59She had no history of stimulant
38:01use and orexigen use.
38:03And then lastly on a spirometry
38:05didn't have any evidence of
38:06actual obstruction as well,
38:08just a suggestion of a
38:09restrictive ventilatory defect.
38:12She had to write her catheterization.
38:15Notably our subject was £317.00,
38:18pretty high PSA as you can see here.
38:20This is our PA pressure tracing.
38:23I reported here as a papers of
38:2684 or 34 of the mean of 53.
38:28And then importantly, her wedge
38:30pressure wasn't all that impressive.
38:32This is again after a little bit of diuresis.
38:35But. If you were to sort of
38:39calculate this out and if I were
38:40to sort of like hide this data,
38:43this would look very much like a subject that
38:46had frank pulmonary arterial hypertension.
38:49And here you can see her
38:51peer pressure tracing.
38:51So you can probably if you
38:53can try and commit to memory.
38:54This is a fairly broad.
38:57About pulmonary artery pulse pressure,
38:59you know, 50 points.
39:01With the.
39:06Index of 2.51 so just at the
39:09very lower end of a normal.
39:12Her diagnostic polysomnogram was
39:15significant for a fairly high HIV
39:18using the 3% criteria and then notably
39:22significant amount of nocturnal
39:25hypoxemia with the nature of a 58%
39:28and then I can't quite figure out
39:30how this got calculated, but I am.
39:33I am not a sleep doctor.
39:35I just guessed that sometimes T88 can
39:38get above 100% with and then lastly.
39:42I think here we have some transcutaneous
39:45carbon dioxide monitoring as well.
39:47So definitely has pretty significant
39:50sleep apnea with both hypercapnia
39:53suggested by the transcutaneous
39:55monitoring and hypoxemia as well.
39:58So we got to Sleep Medicine consultation,
40:01she was put on Bipap therapy.
40:03Everybody that saw those hemodynamics
40:06thought I was committing a mild form
40:09of malpractice by not treating her
40:11pH with a basic dilator therapy.
40:13Her outpatients Bipap was a ultimately
40:16titrated up to 20 / 16 and then we
40:20subsequently got a blood gas that.
40:23Sort of the,
40:23the best one we got had a PCO two of a 46.
40:29Her subsequent echocardiogram,
40:30this is her new TR jet.
40:32So you can see that they were
40:35divining the envelope around here,
40:37honestly not the worst placement.
40:40So just not a very good
40:42quality TR jet to work with.
40:44But you can see that echocardiogram is,
40:46is, is dramatically improved and
40:48this was strictly with BIPAP therapy
40:50alone and maintenance of her
40:52diuretic therapy when she had that
40:54catheterization that was a diuretic
40:56therapy that that she went home on.
40:58And so you can see an improvement
41:00in right atrial size,
41:00you can see an improvement in right
41:03ventricular size and then also
41:05right ventricular function as well.
41:07We repeated the catheterization,
41:08a lot of weight reduction and happened right.
41:11She was over 300 pounds the first time.
41:14But we've seen improvement in
41:17significant improvement or pressure.
41:19Oops.
41:21Umm.
41:23Countermine value of 31 and you
41:25can see that that PA pulse pressure
41:28went from 50 to 20 and she did have
41:31a little bit of an improvement
41:33in her cardiac index as well.
41:34The clinical significance of
41:37this is that your.
41:40Pulmonary compliance is going to
41:42be determined by your PA pulse
41:44pressure and your stroke volume.
41:46And so it's going to be pulse
41:49pressure divided by stroke volume
41:50is going to be the the determinant
41:53of your pulmonary compliance.
41:54And so in this case we have a PA
41:56compliant all special that went
41:58from 50 down to 30 or 20 rather and
42:01her stroke volume increase given
42:03this increase in cardiac index.
42:05And so this is a dramatic improvement
42:08in take compliance which is again best.
42:10Explained by a change in vascular
42:13tone and possibly a change in Frank
42:17Arteriopathy and Venography as well.
42:21Um.
42:21And so one of the better examples
42:23I have of just how significant
42:26an impact BIPAP therapy by itself
42:28can have on patients with OHS and
42:31this really does differentiate the
42:33OHS phenotype from this? Umm.
42:38O SAPH phenotype as well.
42:42And so summary points,
42:44you know the the current rubric we
42:46have for pH phenotypes does lack
42:49a clear space for for OSA.
42:51But based on what we know about pH
42:54and secondary left side of heart disease,
42:56I think we can use that to sort
42:58of create a phenotype for for for
43:01pH OS and to guide therapeutic
43:03approaches for those patients.
43:05And then lastly CPAP and non
43:08invasive positive pressure therapy
43:10can have significant if not.
43:12Dramatic positive impacts on
43:14pulmonary hemodynamics and I would
43:16suspect outcomes as well in subjects
43:19with a variety of sleep disorder
43:21breathing conditions.
43:22So I ran through that pretty quickly.
43:26But there is plenty of time
43:28for questions and I'm happy
43:30to chat about any of this.
43:35Hey, Sarah, it's very good.
43:36Thank you so much. A great talk.
43:39So everybody, please feel free to
43:42leave your questions in the chat
43:44or if you want to be unmuted,
43:47raise your hand and I'll be happy to oblige.
43:51Doctor mossanen.
43:51All right, here we go.
43:57Hello, Cyrus. Good to see you likewise
44:02and I was glad that you brought some
44:05clarity to this confusing areas and
44:07I was somewhat disappointed by the
44:10latest 2022 International Conference
44:13on H2 Remove sleep apnea or sleep
44:18disordered breathing and it only
44:20include the the OS and as as you know
44:24there are several case studies that
44:27showed sleep apnea without necessarily.
44:30Having hypercapnia during the daytime
44:33they had the hypertension either
44:36a pre capillary type pulmonary
44:39hypertension or or post or mixed.
44:43I think what they're not considering
44:46is the phenotypic expression,
44:48or rather the individual
44:51susceptibility to sleep disorder,
44:54breathing consequences,
44:55hypoxia plus or minus hypercapnia,
44:58plus their own perhaps genetic component
45:02that will set the reactions to a
45:06remodeling of the pulmonary vasculature.
45:09The data on hyper responsiveness,
45:12so high altitude hypoxia size is
45:14really telling that there are some
45:17subset of individuals at high altitude
45:19they develop on their hypertension
45:21and others don't with therefore
45:23they're given exposure to hypoxia.
45:25So if you just lump everything
45:28into an OHSU is going to eliminate
45:31lots of folks that they may have a
45:34lingering pH through sleep disorder
45:36breathing undiagnosed or or or not.
45:40Consider it to be a worthwhile
45:42to investigate either by doing
45:44an echo or or follow up actually
45:47with the echocardiography.
45:49So would you in your practice continue
45:52perhaps to look more carefully into
45:55the presence or absence of pH in
45:59those individuals that they may have
46:02non hypercapnic during the daytime
46:06hypoxia and they may have actually
46:09hypercapnia during the night?
46:10But not during the daytime and and
46:13pursue whether they may have pH.
46:16Yeah. So. So great points
46:18and then great question.
46:20So just the first part you said about
46:24the the ERS and ESC conferences in 2022,
46:27I went to ER S and you know there really was.
46:33No mention of it at all except for
46:36one comment that Marius Hooper made
46:39and one comment that that that Mark
46:42Huber made during one of the sessions
46:44about just it being removed because
46:45it wasn't a factor separately on
46:47the side of the Marius would would
46:49agree that there is something there.
46:50It's just it's such a difficult
46:53thing to study. Definitively,
46:54you know, So what we would need to
46:57really create a link in order to
47:00sort of phenotype these patients.
47:03Would be a complicated site that
47:05would require a lot of people,
47:08and it would be a fairly big
47:10diversion from routine clinical care.
47:12Now to your point about how well are we
47:16surveilling these subjects that we're
47:19getting during routine clinical care,
47:21one of the challenges that I have is that.
47:25Monitoring for nocturnal hypercapnia is not
47:29particularly straightforward in our practice.
47:32Those sleep studies get delayed because
47:35there's only one site that does them.
47:38And a lot of times I'm more compelled
47:41to just get a sleep study and establish
47:45somebody with a sleep doctor and
47:47and sort of have them make sure
47:49that the therapy is most tailored
47:51for them as opposed to.
47:53Getting that additional layer of
47:55information that I think would
47:57be really useful to know to
47:59actually properly phenotype them.
48:03You know, I have a colleague here
48:05that has a a lot of interest in in
48:08diastolic dysfunction, you know,
48:09through the cardiology practice
48:12who you know would be interested in
48:14trying to tease this out a little bit.
48:16It would just be.
48:18Difficult to do using routine clinical care.
48:23Uh. And I I don't foresee any.
48:30I'm not aware of any.
48:33Developing or ongoing studies that
48:35are trying to tease us out at all,
48:37but that is the goal to to to be able to
48:43sort of establish a clear phenotype of of.
48:48Hypoxic and hypercapnic intermittently.
48:50Hypoxic intermittently hypercapnic OSA
48:53patient and seeing what the risk is for pH.
48:59Great. Thank you. Thank you, Cyrus.
49:01Claudia, you have the next question.
49:03Thank you, Andre. Cyrus,
49:04it's so good to see you.
49:05Thank you for an excellent and
49:08very thoughtful presentation.
49:12SO22 questions, two comments, one is.
49:16We in the field of Sleep Medicine too,
49:18we are starting to better phenotype
49:21our patients both with respect to
49:23the physiologic sequelae of sleep
49:26apnea and better understanding more
49:28precise measures that may impact
49:30adverse health outcomes and for
49:32the development of sleep apnea.
49:34And so one of those measures that
49:36has risen to the top with respect
49:38to the physiologic sequels as a
49:41metric called the hypoxic burden.
49:43So unlike the frequency or the T-90 this is.
49:46A measure of hypoxia that is very specific
49:50to that related to apnic events and.
49:57There have been a number of publications
49:59now showing that this is a much
50:01better measure of cardiovascular risk.
50:03I was curious if one is it to your
50:05knowledge as it's been looked at
50:07or is this at play in the field
50:10of pulmonary hypertension?
50:13Not to my knowledge.
50:14So you know I I think the the
50:17long term pick study is the best
50:20one of late that's. You know.
50:24Tried to tease this out and I don't
50:26think I've come across anything,
50:28at least up until the end of 2022 when I
50:31was doing my last searches that looked at.
50:34Predictive.
50:34Parameters that are predictive of pH in OSA,
50:39apart from the study that I showed that
50:41looked at the Cleveland Clinic cohort
50:4390 and the exactly, exactly so.
50:48Uh, but but a really good point now, is this
50:53a parameter that is derived or measured?
50:57It is both.
50:58It requires some sophistication and
51:00there's not ready for for prime time.
51:03It's not something we can automatically
51:05download on our clinical studies.
51:07So we can get proxy of that.
51:09But it's something actually the Harvard
51:11group has developed and looked at
51:13it in a number of cohorts including
51:16the Maza cohorts and some other sort
51:19of national cardiovascular cohorts.
51:20It'd be interesting to examine that in the
51:24context of pH because I think you know.
51:27Measures like the AI and T-90 may
51:31not be deriving some of the risk
51:33and we obviously hypoxemia is
51:36a maybe a central driver here.
51:38Yeah, yeah, absolutely have potential.
51:40The other comment question is that
51:42one of the things that our group has
51:45been interested in more recently.
51:47And and we've started to establish
51:49this link by the way,
51:51diabetology is my new favorite word.
51:54I haven't heard for your present day
51:56is it diabetology or diastole apathy?
51:58I use diabetology just
52:00and I it's now a reflex.
52:02So I try not to do it when
52:05I'm in you know informally,
52:07but it's yeah. Anyway
52:10love the word and but one of the
52:13mechanisms that we've been looking at
52:15and this link between sleep disorder.
52:18Breathing and die.
52:20Astrology or diastole apathy is
52:23through coronary microvascular
52:25dysfunction and which is something
52:28we can look at now with pet imaging
52:33or at least proxies of that.
52:36And so beyond just the left
52:38atrial enlargement and atrial
52:40fibrillation that you were measuring,
52:42this could be another plausible
52:45mechanistic way between sleep apnea and.
52:49And diastolic.
52:49Yeah, that I'm more familiar with.
52:53There's sort of like a, you know,
52:54there's a just like there's a
52:56fractal pattern that we see
52:58in the pulmonary circulation,
52:59there's a fractal pattern in the
53:01myocardial circulation that gets
53:02obliterated in certain disease states.
53:04And I wouldn't be surprised if that
53:07happened in in the in the setting of
53:10OSA like you're implying that it does.
53:12Sounds good. Great talk.
53:13Thank you.
53:15Yeah, this is, this is great.
53:16Thanks for the good questions Clark.
53:18So I might I wanted to ask a
53:20question you know are are there
53:22physiological studies looking at
53:23people with pH and sleep apnea and
53:25what happens to them when they're on,
53:27when they get pap like in the lab with a
53:29catheter in place that you're aware of?
53:33Umm. And I I've looked so.
53:39And I would love to that would be great.
53:42But the that one in the 70s
53:45I I wish they had applied.
53:47Yeah at the time like that. Well
53:49you know because we do have a new
53:52biobehavioral lab that Clare Clare
53:54has has Co leading and so this might
53:57be a nice nice way to actually have
54:00some some you know our pulmonary
54:01hypertension group folks right
54:04that's low hanging fruit
54:04if you guys can do that.
54:06Yeah. And and so it might be a
54:08a very interesting mechanistic
54:10study to look at because.
54:12You know, there's nothing,
54:14nothing better than looking
54:16at what happens in real time
54:18for these physiological
54:19studies, especially if you're
54:20getting a relatively clean
54:22patient that doesn't have a lot
54:23of combat conditions that are,
54:25you know, have frankly developed.
54:28Um, that'd be fantastic.
54:30But it it would just be it.
54:32It'd be, you know.
54:36I mean, yeah, go ahead.
54:38I mean even even for those with
54:40diastolic dysfunction or, you know,
54:41have that, for example, you know,
54:43you have an acute change in.
54:45Absolutely. And and treatment and
54:47so that that's just one thought.
54:49I was wondering whether that's
54:50happened before and so and also for
54:52the case that you presented kudos for
54:54for sticking to your guns and not.
54:58Now get back to phase dilator therapy.
55:02That it's a it's interesting I
55:04mean it's sort of hard you may not
55:05for a lot of these patients. I
55:06wonder if we may not be
55:08able to dissect you know
55:09how much of this is sleep apnea how
55:12much of this is you know obesity and
55:15diastolic and have death type situation
55:16because oftentimes I mean they they
55:19just comes this together right.
55:21Yeah you know in that case what I was
55:24able to do with risk calculators for pH
55:26and I was able to demonstrate that her,
55:28her risk wasn't dramatically high
55:30and you know with her functional.
55:33At us being what it was. Yeah.
55:35People felt comfortable discharged
55:36because I was a consultant, right.
55:38Like they they I wasn't making the
55:40call on her leaving the medical ward.
55:43But I think people saw her walking around and
55:47lots of very good and they said OK you know,
55:49as long as she's got follow up and uses the
55:52mask and it's on you then then go right
55:54ahead. So. So all right, sounds good.
55:57And so here's a clinical question unless
56:00let's see are there any questions
56:02down in the chat? Not quite yet.
56:04And so I guess the clinical
56:05question is when you see patients
56:07with pH who are at risk for OSA,
56:09do you send them to sleep docs in
56:11hopes of improving their pH or you
56:13just send them to sleep docs because
56:14they should see a sleep period?
56:18Mostly the latter. I mean, I just,
56:20you know, I care most about. Uh.
56:25The data would suggest that the big
56:27drivers are the nocturnal hypoxemia
56:29and so as long as that gets addressed,
56:32I feel good. But there's no way that.
56:37Apnic and obstructive episodes
56:39are good, and so I.
56:44I sent them for for for both reasons.
56:48And I feel fairly comfortable
56:50reading them the riot act.
56:52And if they, you know,
56:53trust you when it comes to managing their pH,
56:55then they'll, they'll listen to you.
56:56When it comes to sort of the
56:58consequences of untreated OSA,
56:59I do have a handful of patients that
57:02just can't tolerate PAP therapy,
57:03but they've all made an effort.
57:09And I I I hold the record for a for.
57:12The highest fraction of patients
57:14referred to the Sleep Lab with
57:16BMI is less than 30 because of.
57:21Very good, very good.
57:22Alright, well, thank you so much.
57:24Great talk, very important area and.
57:29Good discussion.
57:29Good to see you everybody.
57:31And we are gonna,
57:32most of us are going to head
57:34over to the pulmonary critical
57:35care and sleep messing around.
57:37And so we'll see you next week everyone.
57:38Thanks very much for participating.
57:40Take care.