The prevalence of certain comorbidities is higher in people with narcolepsy compared with matched controls—both at diagnosis and at prolonged follow up.
Comorbidities that are more prevalent in patients with narcolepsy include psychiatric and sleep conditions, as well as cardiovascular and cardiometabolic conditions.
Hypocretin (orexin) dysfunction in patients with narcolepsy may partially explain the increased risk of certain comorbidities in these patients.
An increased prevalence of cardiovascular and cardiometabolic conditions, such as hypertension, obesity, diabetes, and hypercholesterolemia have been reported in people with narcolepsy compared with matched controls. One interview study of 320 patients with narcolepsy and 1,464 age-matched individuals from the general population identified that the odds of heart disease in patients with narcolepsy (5.9%) were twice that compared to the age-matched general population (2.9%) (AOR, 2.07 [95% CI, 1.22 to 3.51]). By an average age of 38 (mean age during study), an increased incidence of cardiovascular comorbidities has been observed among patients with narcolepsy compared with matched non-narcolepsy controls.
In episode 4, listen as Sleep Review’s Sree Roy and cardiologist-sleep specialist-intensivist Younghoon Kwon, MD, MS, FACC, discuss:
- Narcolepsy is linked with multiple cardiovascular risk factors and comorbidities. Can you inform our audience to any of the specifics of the cardiovascular burden among patients with narcolepsy?
- Why is it that patients with narcolepsy commonly present with cardiovascular comorbidities? Is there a potential mechanistic link between narcolepsy and these conditions?
- Does sleep disruption itself impact cardiovascular risk? If so, what is the evidence for the connection between sleep disruption that’s a hallmark of narcolepsy and increased cardiovascular risk?
- How do you balance narcolepsy management with the management of cardiovascular health factors, both in terms of lifestyle and pharmacotherapy?
- Are there any published studies about narcolepsy and cardiovascular risk that you’d recommend for additional information?
Hello and welcome. I’m Sree Roy with Sleep Review, and I’m thrilled to be here with Younghoon Kwon, MD, MS, FACC, who is board certified in cardiovascular disease, sleep medicine, and critical care medicine. He is an associate professor in the division of cardiology at UW. He completed a sleep medicine fellowship at Hennepin County Medical Center.
This episode is sponsored by Jazz Pharmaceuticals.
Today, we are chatting about reducing the risk of cardiovascular comorbidities in patients with narcolepsy. Narcolepsy is linked with multiple cardiovascular risk factors and comorbidities. Can you inform our audience to any of the specifics of the cardiovascular burden among patients with narcolepsy?
Thank you so much for letting me discuss this topic. Maybe perhaps I can start off by saying that this is clearly an underappreciated topic by cardiology field for sure, and even perhaps by professionals or clinicians in the sleep field as well, and partly because narcolepsy itself is not the most common health condition, as you might agree with me. Of course, we, as sleep physicians, are biased because we see patients coming through the referral system. But at a population level, the prevalence and incidence of narcolepsy is relatively low compared to other more common conditions, including sleep apnea and insomnia, and those conditions that we often see in our clinical space.
Yes, so your question about what might be the burden of cardiovascular risk factors or disease in narcolepsy. I think there have been some anecdotal reports about this for many years, whether patients with narcolepsy may be at higher risk of cardiovascular disease. But I would say the anecdotal experience mostly related to the medications that were prescribed to patients with narcolepsy. Because oftentimes, the older-generation medications—and we still use them quite often—are classified as sympathomimetics, which in essence stimulates one’s cardiovascular system, specifically heart. And so, oftentimes the questions have been raised whether patients who are chronically on these type of medications may be vulnerable to heart disease, because their heart is constantly being stimulated. So for example, their blood pressure might be higher because they may be on methylphenidate, that kind of stimulant medication.
But then, I think the science is slowly uncovering potentially more important mechanism, which is that the pathophysiology of narcolepsy itself may be linked to higher cardiovascular disease. So now, we are talking about the condition itself may be an important mediator of cardiovascular disease.
So, they’re having some number of studies. But I think one study, the retrospective study called the BOND study, I think that was published not too long ago, several years ago, in sleep medicine. But what they looked at was retrospectively they looked at the common comorbidity that are often found in patients with narcolepsy. This is a study, where they looked at the claim data set where they looked at the ICD code narcolepsy in adult subjects, and then trying to link that ICD code with comorbid conditions. So, this was a fairly large study. They looked at about, I think about 10,000 subjects with narcolepsy. And then, they of course had some control groups just to see what association might be present.
In this study, basically they looked at various conditions and there were lots of conditions that had the narcolepsy patients had a much higher risk. For example, like mental illness or even digestive system, all this various health conditions. Actually, narcolepsy patients had higher risk for many of all this conditions, including cardiovascular disease. This is when we realize as an expert in this field or as professionals in this field open up our eyes and saying maybe the narcolepsy itself is an important risk for a cardiovascular disease.
Why is it that patients with narcolepsy commonly present with cardiovascular comorbidities? Is there a potential mechanistic link between narcolepsy and these conditions?
Yeah, so that’s a good question. I should say, I think that this is still work in progress area. I don’t think we have a greatest understanding about the potential link. But as I mentioned, this kind of an epidemiological association that was found between narcolepsy and cardiovascular disease, from this claim data…In fact, I think this cardiovascular study, the Burden of Narcolepsy, so-called the CV-BOND study, came out pretty recently. But there was definitely an association.
And then, you have dietary intake of sodium. So, that can easily increase the risk of sodium intake. I mean the likelihood of high sodium intake. And that will put you at a higher risk of high blood pressure. And as you know, high blood pressure is one of the most fundamental and well understood risk factors for cardiovascular disease. So, that is one potential mechanism that we can easily think of.
Narcolepsy is a condition where an individual is inherently experiencing sleepiness, daytime sleepiness, and also disruptive sleep at night. So, it’s not just about daytime sleepiness, but also disruptive sleep at night. And narcolepsy obviously is more of an interim condition. There could be an acquired narcolepsy. But primarily when we refer to narcolepsy, we were talking about the inborn narcolepsy. Although, the onset of narcolepsy is typically until late teens or in the twenties, young adulthood.
Going back to the pathophysiology of narcolepsy. So symptoms, as I mentioned, is characterized by sleepiness as well as interrupted or disruptive sleep. Before I go into more of a molecular level of pathophysiology, the symptoms alone here are a well-perceived factors that are adverse to our health in general, but also in terms of cardiovascular health. We know that disruptive sleep, for example, could be a mediator of cardiovascular disease.
So if somebody sleeps poorly because they wake up frequently at night and their sleep is inadequate in terms of quantity and quality, that alone confers a high risk of cardiovascular disease. Now, there are lots of studies out there that link poor sleep or disruptive sleep with cardiovascular disease, so I don’t have to reinvent that concept.
But again, the narcolepsy, the essential traits of narcolepsy, which is excessive daytime sleepiness as well as disruptive sleep, points to the fact that they may be inadvertently exposed to very high risk of cardiovascular disease, and I think I skipped about this topic of daytime sleepiness.
Excessive daytime sleepiness is another important phenotype that links many sleep conditions with adverse health conditions. So for example, sleep clinicians are well aware of that condition like obstructive sleep apnea, which is very common in the community, is associated with increased cardiovascular risk.
However, we have found that not everyone with sleep apnea appeared to have increased risk of cardiovascular disease. Secondly, people with sleep apnea… Not every people with sleep apnea appeared to take advantage of sleep apnea treatment, such as using CPAP in terms of cardiovascular benefits.
Many studies, and these are mostly secondary, post-hoc analysis, so sometimes it’s not always definite, but many secondary analysis studies have suggested that it’s often people with daytime sleepiness. So people with sleep apnea—so common denominator is sleep apnea—but it’s when you have excessive daytime sleepiness that you have actually higher risk of cardiovascular disease.
In a similar token, people who exhibit excessive daytime sleepiness in people with sleep apnea are the one who appear to benefit from CPAP therapy or treatment of sleep apnea. That alludes to the fact that the phenotype of sleep is very important in any sleep disorders.
So daytime sleepiness again, and as well as disruptive sleep at night, these are highly phenotyped sleep risks that are linked to cardiovascular disease, and narcolepsy has all of these. So at that level, we can certainly assume that naturally, the patients with narcolepsy may be at higher risk of cardiovascular disease.
Now, often times, the studies around this area have been very challenging because a lot of patients with narcolepsy are relatively young. These are young patients. These are not, often times, patients that are included in the study or in clinic space. They’re young people. They’re people in their 20s, 30s, 40s.
We don’t really see a lot of patients with narcolepsy in their 60s and 70s. It may be a selection bias, but it’s just that they’re not as common, partly because they’ve either never been diagnosed or they’ve been diagnosed but they got lost. So because of that nature, and as you know, youth is one of the protection factor for cardiovascular disease, so their manifestation of cardiovascular disease may not be as obvious.
And that’s one of the logistical challenge in showing all these links. However, as I said, accumulating evidence, not a lot right now, might suggest that this link is real and then that more studies are necessary to uncouple the mechanism. I want to just briefly touch on a pathophysiological link between narcolepsy and cardiovascular disease in terms of more of a biochemical and molecular level.
Narcolepsy is a condition that’s characterized, especially type one (type two is a little bit more complex, and I think the definition of narcolepsy type two is still evolving to some extent), but type one is the most well-established subtype of narcolepsy, and it’s essentially a disease or disorder where the hypocretin is deficient.
So hypocretin or orexin is an important neuropeptide that has an important role in keeping us alert and awake. And so deficiency of that element, that biochemical, the neuropeptide, namely hypocretin, is likely the underlying…the etiology of all the symptoms that patients may experience. some studies have suggested that hypocretin plays an important role in autonomic regulation, which is a very important factor in blood pressure control and regulation, which in turn is an important risk for cardiovascular disease.
So the hypocretin and some of these… the autonomic, the sympathetic, parasympathetic regulation have been studied in animal studies. The findings, I would say, in my opinion, are not always consistent, but I think there is suggestion that the lack of hypocretin itself can cause autonomic dysregulation, which can, in turn, lead to a blood pressure regulation dysfunction, and then cardiovascular disease.
Now, some studies have also tried to look at the endothelial function, another important potential mechanism that can link narcolepsy or any other conditions to cardiovascular disease. The endothelial dysfunction in narcolepsy type one has been described, but again, the findings have not been consistent. So I think jury is still out there as to what is really the biochemical underpinning of how narcolepsy might confer increased risk of cardiovascular disease.
Does sleep disruption itself impact cardiovascular risk? If so, what is the evidence for the connection between sleep disruption that’s a hallmark of narcolepsy and increased cardiovascular risk?
Actually, there’s a couple of meta-analysis that have been… where they show that poor sleep, poor quality of sleep… Now, when we say poor quality of sleep, often times, it encompasses quantity as well. Not all studies distinguish the two necessarily. But this encompasses lack of sleep, so for example, short sleep or subjectively perceived poor quality of sleep.
Now, of course, what is the definition of disruptive sleep? It’s arguable as to what that might be. But from narcolepsy perspective, we know that independent of subjective perception of their sleep quality, which typically is very poor, patients with narcolepsy, not all, but a lot of patients with narcolepsy would complain some degree of sleep difficulty at night.
So there is a subjective component of that as well. But objectively, a number of studies have shown that the sleep state transition is more common, and also the arousal may be more common in individuals with narcolepsy. So this is objectively characterized sleep traits, either using polysomnography or a tool like an actigraphy where they track the continuity of sleep or sleep architecture, so to speak, and that individuals with narcolepsy exhibit more disruptive sleep.
Now said that, how is that going to increase the risk of cardiovascular disease? Again, going back to meta-analysis that I mentioned, the studies have shown that either subjectively perceived poor quality of sleep or objectively assessed poor quality of sleep, again, it includes some of these phenotype that I talked about that characterized narcolepsy, whether you call that disruptive sleep or frequent arousals or sleep state shifts, frequent sleep state shifts, or poorly consolidated sleep architecture.
These may all belong to this type of studies, but have clearly been linked to increased risk of cardiovascular disease. Now, even though we are talking about cardiovascular disease as a whole, usually, this extends to overall outcomes as well. I think as we might understand, things that are not good for your heart or a risk to your heart typically would be a risk to other health conditions such as, for example, neurocognition or cardiometabolic conditions. Some people may even link this to risk of cancer, aging, or even mortality. I think a lot of things needs to be studied here, but there is some hint that narcolepsy patients have higher risk of mortality as a whole. So again, this may not be just cardiovascular risk, but the overall health risks.
We’ll be right back with Dr. Kwon after the short break.
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How do you balance narcolepsy management with the management of cardiovascular health factors, both in terms of lifestyle and pharmacotherapy? For example, smoking, physical activity, sleep hygiene, dietary sodium intake.
Yeah, that’s a good question, because what we can do to reduce their potential cardiovascular risks, of course that is the most important question that we should raise for our patients. So first we can talk about more of a general recommendation as to how we can keep our cardiovascular system healthy. And answers to that, I don’t probably have to explain that or go over that with you in a lengthy manner by any means, because to some extent we all know that very well. This is lifestyle. There’s lifestyle modifications that we can work on. These are modifiable things that we can do, such as exercise. We all know exercise is important. This is not limited to patients with narcolepsy. We know what good diets are. I know and you know. It’s often not the knowledge gap that we have, but it’s often the action that is missing, whether that’s because of individual factors or issues that are beyond your control.
But going back to the lifestyle factors, so we talked about exercise, diet, what else? Of course, the sleep, which has become one of the eight components that AHA designated as an important lifestyle (a factor for healthy heart), sleep is important.
Now of course this is a little bit more complex in this patient population because it’s not that they do not want to have good sleep or enough sleep, but it’s often because of their condition that they are not able to achieve good sleep. So we can talk about that a little bit separately. But yeah, the healthy diet, exercise, and reducing stress in general, these are all very important things that we can work on. Of course, avoiding stress or addressing stress in a healthy manner is a little bit more difficult to some extent, but something that we can all be more conscious of.
The other things that we can also do is things like smoking that are obvious that are not good for your heart health. We can avoid those things, or excessive alcohol intake, those we all know that are linked to adverse health outcomes. We all know that. And tied with all that is also maintaining healthy weight, body weight. So weight management, of course this is all linked together. Healthy diet, exercise, these are all associated with your weight, but some may have to go take medications, or some people have to go through bariatric surgery and that’s beyond this discussion. But obesity itself is also a major risk for cardiovascular disease.
So if we can address these potentially modifiable lifestyle factors, I believe that the cardiovascular risks can be curtailed. And again, this applies to everyone, but this also applies to patients with narcolepsy.
Now, specifically more pertinent to patients with narcolepsy, and we can, I guess, divide this discussion into two topics. One is, how do we mitigate their sleep difficulty if that is part of their condition? And I just mentioned that healthy sleep is very important in maintaining cardiovascular health.So going to the first aspect, how do we achieve better sleep? Of course, number-one and number-two agenda are very interrelated because sometimes it’s a pharmacotherapy that will improve their sleep.
Now, narcolepsy, we are often naive to believe that narcolepsy defines their sleep 100%. But I have learned, and perhaps you or other clinicians, colleagues of mine have experienced, is that that is not true. Of course, narcolepsy, the pathophysiology of narcolepsy itself probably explains majority or large portion of sleep problems that they experience, but again, it’s not 100%.
Just like everyone or like us or people with other sleep disorders, they are vulnerable to poor sleep because of other factors, not just because their hypocretin level is low, but perhaps they have a poor sleep hygiene. Maybe they’re looking at their smartphone too long, late at night, or perhaps they… Again, a lot of patients with narcolepsy are susceptible to falling asleep during the daytime. That’s just part of the pathophysiology of narcolepsy. But I’ve seen some patients take less control of that and take naps kind of irregular basis. They take naps here and there and here and there, which will only make their night sleep more challenging. Some strategic napping can be helpful, but we know that narcolepsy, that may not be actually as helpful.
So some of those behavioral factors needs to be also considered. So coaching is necessary. The usual “10 commandments” that we give as part of sleep hygiene still applies to this patient population, let alone environmental factors. When you are sleeping, you really want to have an optimal sleep environment. You do not want to sleep in an environment where there’s high level of noises around or just that there’s just no well-established geographic location. So for example, some people are not good at making their place where they sleep as peaceful as possible. These are often underappreciated logistics. So for example, having a blind or dark curtain is very important. And I personally have experienced this myself. Seemingly, that is very small minor factor, but in some patients and some individuals, those small things make a lot of difference. Again, this also applies to patients with narcolepsy
Are there any published studies about narcolepsy and cardiovascular risk that you’d recommend for additional information?
Yeah, so there is this BOND study where they looked at the… I think this study is good because they looked at the large size population, again, using claim dataset. The original dataset, the BOND, looked at various health conditions. But the subsequent study, I think that was published not too long ago, the one that was published in Neurology, it’s presented in the form of abstract. It’s called the CV-BOND, Cardiovascular Burden of Narcolepsy Disease, and titled a Real-World Evidence Study. This abstract looked at a large number of adults in the claim database and they looked at the association, and here they looked at various cardiovascular conditions such as stroke, heart failure, and things like that. And strikingly, they showed higher risk of these conditions.
Well, thanks so much for chatting with us about reducing the risk of cardiovascular comorbidities in patients with narcolepsy. You can find Sleep Review at sleepreviewmag.com. Thank you so much for tuning in to this episode.
To dive even deeper:
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- Black J, Reaven NL, Funk SE, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13-8.
- Cohen A, Mandrekar J, St Louis EK, et al. Comorbidities in a community sample of narcolepsy. Sleep Med. 2018;43:14-8.
- Jennum P, Ibsen R, Knudsen S, Kjellberg J. Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Sleep. 2013;36(6):835-40.
- Ben-Joseph RH, Saad R, et al. Cardio-Vascular Burden of Narcolepsy Disease (CV-BOND): a Real-World Evidence Study. Presented at: SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies. Virtual Meeting, June 10-13, 2021. Abstract 503.
- Jennum PJ, Plazzi G, Silvani A, et al. Cardiovascular disorders in narcolepsy: review of associations and determinants. Sleep Med Rev. 2021;58:101440.
- McAlpine CS, Kiss MG, Rattik S, et al. Sleep modulates haematopoiesis and protects against atherosclerosis. Nature. 2019;566(7744):383-87.
- Dauvilliers Y, Jaussent I, Krams B, et al. Non-dipping blood pressure profile in narcolepsy with cataplexy. PLoS One. 2012;7(6):e38977.
- Grimaldi D, Calandra-Buonaura G, Provini F, et al. Abnormal sleep-cardiovascular system interaction in narcolepsy with cataplexy: effects of hypocretin deficiency in humans. Sleep. 2012 Apr 1;35(4):519-28.
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