Sleep and Heart Disease Podcast with Kristen Knutson

Guest

In this show, I speak with Kristen Knutson, Associate Professor of Neurology and Preventive Medicine at the Feinberg School of Medicine at Northwestern University. Northwestern has long been a hub of excellent sleep research. Much of the Northwestern sleep research has been spearheaded by Professor Eve Van Cauter, whose careful laboratory experiments have shown that sleep restriction – limiting the numbers of hours people are allowed to sleep each night – tends to increase how much food people eat while concurrently worsening how well they regulate their blood sugar levels (1).

These studies have been very insightful, informing us precisely about the metabolic consequences of acute sleep loss. Like all studies, however, they have limitations: Such research is necessarily short-term, and participants are subjected to circumstances that differ substantially from their home environments. This means that we don’t necessarily know how applicable the results of these studies are to the outside world. As Professor Knutson points out, laboratory study participants are “very aware that their sleep is being monitored, so I really do think it’s going to affect their behavior”. Therefore, as an anthropologist, Kristen is particularly interested in better understanding the associations between sleep, circadian rhythms, and cardiometabolic diseases in people living in their usual habitats.

Professor Knutson’s Research on Sleep and Heart Disease

Kristen has made significant contributions to the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, which began more than three decades ago and was designed to clarify the determinants of cardiovascular disease risk in North America. This comprehensive study has unveiled race, sex, and socioeconomic disparities in sleep duration and quality. More recently, Kristen has built on this work by exploring whether similar findings are apparent in adults living in the Chicago area. The results have confirmed differences in metabolic disease risk between races too. So, could differences in sleep explain this variability in disease risk?

Much research has concentrated on how sleep duration and quality influence cardiometabolic function, but more and more studies are showing that sleep timing also affects disease risk. A prominent example of this is shift work, for night shift workers are predisposed to numerous cardiometabolic diseases (2). (Note that Greg discusses this at length in the humanOS circadian program that is available here.)

But does when non-shift workers engage in various behaviors also affect risk of cardiometabolic disease?

It seems so, and Kristen has published work since we spoke showing that evening types (night owls) are at higher risk of mortality from all causes, as reported in this hilarious Tweet by her co-author on the paper.

So, what about the future?

Might interventions to affect circadian timing be used to reduce cardiometabolic disease risk?

Intervening appropriately requires first understanding people’s circadian system timing and habitual sleep patterns, so how can we better measure these going forward?

Tune in below for answers to these questions and more!

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References

Contributions

Dan prepared for and conducted the interview, Greg wrote the first draft of this blog post, Dan edited the draft, and Dr. Knutson continues to do the hard work!

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Transcript

Kristen Knutson - 00:07: More recent evidence suggests that well maybe it does matter that even among day workers, going to bed a little bit later or eating a little bit later does seem to be associated with worse cardiovascular metabolic profiles.

Kendall Kendrick - 00:24: Human OS. Learn, master, achieve.

Dan Pardi - 00:34: Kristen Knutson, welcome to Human OS Radio.

Kristen Knutson - 00:36: Thank you for having me.

Dan Pardi - 00:37: So our mutual colleague, Greg Potter, who's been a guest on Human OS Radio and a collaborator with creating some courses for Human OS, put us in contact. So you guys met at a recent meeting I understand.

Kristen Knutson - 00:47: Yes, that's correct. We met in person, I follow him on Twitter, so I'm aware of Greg, and we met in the UK at a British Sleep Society Conference, and that's how we got in touch with you.

Dan Pardi - 00:57: Greg told me that you have an interesting story about how you got into sleep medicine. Would you mind sharing that with us?

Kristen Knutson - 01:03: Sure, so my Bachelor's degree is in English Literature, but after graduating from college, I wasn't really sure what I wanted to do, so I moved to Chicago and I ended up working at Northwestern University. And while I was there I took classes and ultimately decided that I wanted to go into biomedical anthropology, because my interest has been in human health. But I was interested in it from a, not just a biological perspective, but taking into account social and cultural factors.

01:29: But, while I was working at Northwestern University, my job was secretary to the Chair of the Neurobiology and Physiology Department. And at the time, that was Fred Turek. And if you don't know who he is, he is one of the leading people studying circadian rhythms in sleep in animal models, and so as a secretary I worked on grant applications, class slides, manuscripts, and learned a lot about sleep and circadian rhythms at that time.

01:54: Then I went off to graduate school in Albany in anthropology, but as many people may know, anthropology graduate school students are not well funded, so I came back to work for Fred one summer to make some extra money. And at the time, he asked me, "Well who in anthropology is studying sleep?" And I said, "Well, that's a great question," and it was really surprising to me that there were very few people in anthropology studying sleep per se, particularly given the fact that all humans sleep, and there are very few human universals but that's one of them.

02:21: And so, when I went back to Albany, I finished my Masters which was looking at pollutant levels, blood lead levels actually. I told my advisor, "Hey I wanna study sleep now," and I think at first he thought I might have been a little bit crazy but, in the end it worked out.

Dan Pardi - 02:36: That's a great trajectory of how you got to where you are. Tell us where you are now and the type of work that you do.

Kristen Knutson - 02:41: Right, so now I am Associate Professor in the Center for Circadian Sleep Medicine at Northwestern University, so I came back to Northwestern. Although now I'm at the Medical School Campus, downtown Chicago instead of up in Evanston. And my research focuses on, broadly speaking too many questions, as what is the role of sleep and circadian rhythms have in health, and often my focus has been on cardiovascular and metabolic health. But again, as an anthropologist, I'm also interested in socio-culture factors, and so have a bit interest in looking at whether sleep mediates health disparities between racial and ethnic groups, or socio-economic groups.

Dan Pardi - 03:17: We can talk about both of those today. Let's start with sleep and metabolism. That's where I first became aware of your work. That's area where I've done research myself, so I've read a lot of your papers. Tell me about some of the first studies that you got a part of, and then started to lead on your own.

Kristen Knutson - 03:31: As we know that, obesity has been on the increase for at least 40 years, rapidly so. Too rapidly to be explained by changes in our genetic makeup, and so a lot of people have been trying to understand what led to this obesity epidemic, because obesity is associated with a wide array of health problems. From diabetes, to heart disease, to cancer, to arthritis, and so it's really, we need to understand why obesity is so highly prevalent today. And I think the sleep field had started to identify associations between how much and how well someone sleeps, and obesity risk.

04:05: And so my early work, after I finished my PHD residency requirements at Albany, I joined the group led by Evan Cotter at the University of Chicago, who led some of the seminal work looking at experimental partial sleep restriction on cardiovascular and metabolic parameters. And that work is what led to an explosion of additional work looking at habitual sleep and cardio metabolic disease risk. So, that is where I started and why I started focusing a lot on the metabolic effects of sleep and health.

Dan Pardi - 04:37: And if you're listening to this podcast and you're not in the sleep field, it's good to understand that Chicago is like an epicenter for sleep and metabolism research. There's Evan Cotter, certainly a notable figure in there, but there is so much good research that, starts there and then spreads out, and goes to different institutions once people advance in their career.

Kristen Knutson - 04:54: Oh yeah, our trainees, we send them out into the world to expand the work. So, and Cotter's work has typically been experimental work. And her collaborators would bring typically healthy individuals into the lab and restrict time available for sleep, and look at the effects on cardiovascular metabolic measures. So for example they've seen that, you know restricting time in bed to only four or five hours per night, is associated with reductions in insulin sensitivity, and glucose tolerance, which if that was maintained on a chronic basis would increase their risk of diabetes.

05:25: But they've also seen that these experimental studies have led to alterations in appetite hormones, in a direction that would increase appetite. And indeed when they asked subjects, those research volunteers about their appetite, they did see appetite increase, especially for calorie dense foods like potato chips, cookies, candy, and so that led to concerns about, well maybe sleep is related to obesity risk. Other experimental studies that allowed the volunteers to eat what they wanted after sleep restriction did see in fact, that they did eat more after sleep restriction. But, you know these are experimental studies so they're short term by nature. They're a week or two at the most in the laboratory, and the question remained, well if they were to remain a short sleeper, maybe the body would adapt and it wouldn't really be associated with risk of obesity or diabetes in the long term.

06:11: And so that's where my work came in is, I wanted to take these research questions outside the laboratory, and look out in the real world and see, does habitual sleep pattern associate with cardiovascular, or diabetes, or obesity risk.

Dan Pardi - 06:24: We know that obesity is a major public health issue, and it's grown tremendously over the last 40 years, and it associates with 50 to almost 100 different co-morbidities. So it's a major public health issue. The association between less sleep, and the increased risk of obesity was noticed and these either happened concurrently or just before looking into, "Okay, well what if we restrict sleep in people in the lab, what kind of effects do we see?"

06:47: We see alterations in glucose metabolism, we see changes in hunger and even the type of food that they pursue the next day, it changes the eating behavior. And this is now led to you saying, "Okay, well here's another area of this that we can go a little further, so what are the risk of cardiovascular disease for people that generally get less sleep on average." Is that correct?

Kristen Knutson - 07:06: Exactly. Because experimental studies are obviously a very strong research design, but they're short term by nature, and if we're interested in chronic disease, we have to understand, or try to understand where long term associations between habitual, chronic sleep behavior and risk of disease. And there have been many large observational epidemiologic studies that have now looked at some measure of sleep, whether it's self reported sleep duration, or subjective sleep quality. And in general the results in these large observational studies are consistent with the experimental studies, and have found that people who sleep typically less than six hours per night, adults, who associate with increase in incident obesity, diabetes, coronary heart disease and stroke.

07:49: Poor sleep quality has also been associated with incident diabetes risk as well. Some of my early work with an epidemiologic study called Cardia, we added wrist actigraphy monitoring to try to get an objective estimate of sleep, because most prior observational studies relied on self reported measures and we wanted to try to obtain a more objective estimate. And if you're not familiar with wrist actigraphy, it's methodology's very similar to a Fitbit type of device that's based on wrist movements, but it has been validated against gold standard, polysomnography measures of sleep.

Dan Pardi - 08:22: Right, and that's easier to execute on that so instead of bringing somebody into the lab where they've got many hookups to measure sleep more intensely, actigraphy tracks decently well, at least in accordance to some measure, so it's easier to implement in the larger population or over longer periods of time.

Kristen Knutson - 08:38: I think that's important too, because you can do polysomnography in the home, and I do that as do others, but you can only do so many nights in a row, one, two, but even if you are, you're hooking up all these electrodes on these people's heads, and face, and arms. They're not gonna, after you hook them up, they're not gonna decide to run out to grab a beer, or go to a movie. You know they are covered in electrodes, and they're very aware that their sleep is being monitored, so I really do think it's gonna affect their behavior.

09:01: It's the only way we can get really well measures of sleep stages like Rem sleep or Slow Wave sleep, but if we really wanna understand habitual sleep patterns and behaviors, actigraphy is preferable. Because like you said, you can do multiple nights in a row, and people don't sleep the same amount, night, after night, after night. So you do need to capture multiple nights in order to get a more reliable average of what their sleep looks like.

Dan Pardi - 09:24: Let's look at the question of sleep quality versus just sleep time, and there does seem to be indications that changes or reductions in REM and Slow Wave sleep seem to be important for metabolism and eating behavior. Have you done any work in those areas specifically?

Kristen Knutson - 09:37: I have not, because most of our epidemiology studies have had actigraphy, so we haven't had sleep stages. I am doing a study now that has in home polysomnography, but I don't have any preliminary results to share at this point. Because I do think Slow Wave sleep and REM sleep, it's still important to try to capture what that looks like in the home, because how someone sleeps in the home is not necessarily how they sleep in my laboratory.

Dan Pardi - 10:00: Right.

Kristen Knutson - 10:00: But I think it's an important question based on some of the experimental studies that have looked at sleep, Slow Wave sleep suppression, and impairments in glucose metabolism. But, it's harder for larger epidemiology studies to collect this data. Some have, and there has been some evidence by others that Slow Wave sleep is still associated with some of these measures, based on home PSG.

Dan Pardi - 10:17: I'm fascinated by some of the new technologies to enhance Slow Wave sleep by phase locking sound to when the Slow Wave sleep is occurring, to amplify it and extend it, and it looks like there are multiple different groups that are working on something like that now, so I'm hopeful that, that will be a successful intervention that could be broadly used.

Kristen Knutson - 10:33: Yeah, and I'm fascinated too. I know a lot of people doing that right now are focusing I believe, on more cognitive outcomes but, from a cardio metabolic perspective is, Slow Wave sleep is pretty important for cardio metabolic function, then I hope some of these studies are also collecting that data as well.

Dan Pardi - 10:48: Yeah, perhaps clearing beta amyloid, perhaps proving memory and cognition, and also the metabolic parameters too. That needs to be addressed as well. Well, maybe we just thought of a study.

Kristen Knutson - 10:58: Okay, quick. Let's write a grant.

Dan Pardi - 10:58: Wonderful. Well tell us about the other path of your work is looking more at, is sleep playing a role in differential health outcomes among different populations?

Kristen Knutson - 11:06: Right, so my earlier work we started, as like I said we were interested in relationship between sleep and health, and in cardio we observed early on that there were these strong race/sex differences in sleep duration quality, based on actigraphy. Now Cardia was a study that started back in 1985, 1986 and they enrolled only whites and African Americans or blacks into that cohort. And when we first compared the sleep duration and then the sleep efficiency, which is the measure of sleep quality, the percentage of time in bed actually spent sleeping, we saw that black males had the lowest sleep duration and the lowest sleep quality, followed by black females, and then white males and white females on the other side. But we also saw socio-economic issues too. Higher income and higher education was associated with more sleep and better sleep quality.

11:53: And we thought once we did multi bier and adjustment that we would greatly diminish the race/sex differences, including adjusting for income, education, and employment status, which is the main three socio-economic indicators commonly used, as well as a variety of other behavioral or environmental factors, and still the race/sex differences persisted strongly. So this was really the first analysis, for me, that suggested that there may be these race/sex differences in sleep duration quality based on objective measures that aren't easily explained away, just by socio-economic indicators.

12:23: Now, as a caveat I should point out that these are broad indicators and certainly do not capture all the socio-economic, cultural, psycho social factors that differ between race ethnicity due to social differences in our country. So I do acknowledge that, but I think it's worth exploring, because I think it's worth exploring because if sleep's important for health, and minorities are not sleeping as well, then that is a pathway through which health disparities may arise.

12:45: And so that's what led me to another study that I was part of where Mercedes Carnethon at Northwestern led public Chicago area sleep study. In that study we had whites, blacks, and a group of Hispanics as well as a group of Asians. In that study again we saw that these differences between blacks and whites using objective actigraphy persisted. In that study we had an objective estimate of sleep disorder breathing so we could exclude that as a potential explanation for sleep differences between these groups. And we also saw that the Hispanics and the Asians also slept less than the whites. So again, it's a very common finding. Not just my group but other groups as well, so now we really wanna see, is sleep a mediator.

13:24: We've had two papers, one from Cardia, one from the Chicago area sleep study that suggest that sleep duration does at least partially explain differences in blood pressure between blacks and whites. There's more work to be done in this area, but these are some intriguing findings that suggest we need to understand better the role of sleep disparities in other health disparities.

Dan Pardi - 13:44: Did you mean that gender and race are mediators of sleep or am I misunderstanding?

Kristen Knutson - 13:48: For example, being African American or black is associated with higher blood pressure, or risk of hypertension. Is sleep partially explaining that difference in hypertension between blacks and whites?

Dan Pardi - 13:56: Right, okay.

Kristen Knutson - 13:57: So sleep is mediating the relationship between race and blood pressure, or diabetes or whichever outcome.

Dan Pardi - 14:02: You can see how you're really honing in on getting a true answer here. So is it just socio-economic, is it other factors, is it breathing, or is it the differences in sleep between gender and race that's leading to these outcomes. That's very, very interesting.

Kristen Knutson - 14:13: Yes.

Dan Pardi - 14:14: Are you currently enrolling and conducting the studies and, do you have plans for future studies as well?

Kristen Knutson - 14:18: Yes I have one ongoing study where I'm enrolling blacks and whites, and doing detailed measures of sleep in the home using actigraphy and polysomnography in their home, in their bedroom, as well as some circadian measures. So dim light melatonin onset to see if there's any circadian differences between blacks and whites as well because, in addition, if we talked about sleep duration, we talked about sleep quality, but I think timing of behaviors is another area, like sleep timing. That may be relevant for health as well, so just not to complicate the picture anymore than necessary, but now sleep is about duration, quality and timing, and so that's a whole new area that people are starting to look at with respect to cardio metabolic health.

Dan Pardi - 14:54: So when in your circadian phase are you actually getting the sleep, versus just how much sleep you're getting.

Kristen Knutson - 14:59: Speaking of timing, and we know shift workers, people who work at night shifts compared to day workers, 'cause for a long time we've known that shift workers have worse health on a variety of different health outcomes. But we also thought, "Well they're completely backwards in terms of when they're doing things. It's a very severe and extreme circadian disruption situation but the rest of us who are day workers, it doesn't matter." But, you know more recent evidence suggests that maybe it does matter, that even among day workers, going to bed a little bit later, or eating a little bit later, does seem to be associated with worse cardiovascular metabolic profiles. And so even given the same sleep duration to someone who goes to bed earlier, are they healthier, a better cardio metabolic function than people who go to bed a little bit later?

15:43: And those are the questions they're now trying to ask, 'cause even among those of us who aren't shift workers, is it still important what time you go to bed? And data so far suggests that it is, that people who do these things earlier in the day have better health profiles.

Dan Pardi - 15:54: You also have a study going on that looking at morning light treatment to improve glucose metabolism in people.

Kristen Knutson - 15:59: Right and this is following some of the circadian rhythm perspective on cardiovascular metabolic health. So in this study, yeah we're still enrolling. We want to see whether morning light treatment which is known to advance rhythms if it's at the correct time. It also, morning light is an alerting factor in and of itself. We wanna see whether that can lead to improvements in glucose metabolism in people at high risk of diabetes. So I don't have preliminary data for you yet, but that is in line with this interest in circadian rhythms and circadian disruption in relation to metabolic disease risk.

Dan Pardi - 16:31: There was a study that just came out in the ZLab saying that bright light exposure at night and in the morning seemed to be problematic for glucose control.

Kristen Knutson - 16:34: Yes, and they're actually right down the hall from me.

Dan Pardi - 16:34: I figured you did.

Kristen Knutson - 16:35: Right, so a bright light at night would be associated with a delay in your circadian rhythms, and that's gonna be bad. Bright light in the morning in and of itself, should advance your rhythms I think. Part of what matters is when you're getting that light relative to your internal clock, so you can't just tell everyone to have bright light at seven am without knowing what that clock time is, relative to what their internal clock time is, and so I think it gets complicated when you start looking at observational studies, because you need to take in account, is their internal clock relative to external stimuli? And so in that study I'm doing with the morning light, we are measuring their dim light melatonin onset to know where they are, on their internal clock relative to the external world.

Dan Pardi - 17:20: Know any consumer measures where somebody can assess their internal clock timing?

Kristen Knutson - 17:24: I wish. Yeah, that'd be the lot. I mean the short answer's no. I know there's some people trying to develop ways of assessing it. I think we'll have to stay tuned on that technology.

Dan Pardi - 17:35: If you could measure your melatonin night after night, if you had the means to do that, could give you an indication.

Kristen Knutson - 17:40: Yeah, if you had the means to do that, yeah absolutely. There's saliva, melatonin can be measured in saliva, so you didn't even have to prick your finger, and you'd have to get it assayed, and you have to have the conditions correct. It has to be dim light, so it can be a little bit more challenging. But it can be done, but I don't know if it can be done easily right now, and that's what I think we were probably waiting for. So it'll be a little while before you see it on your Apple iWatch I think.

Dan Pardi - 18:00: But it's coming. You know I've been a part of that movement for a long time, and it's been really interesting to see how it's really advancing. One opportunity that all of these applications or services, whether it's Fitbit or Apple, they're really paying attention to sleep now, and hopefully they can put some big dollars behind it, to bring in technology to make some of this identification of these biologically meaningful important measures helpful to then guide behavior to do the right thing. Get light at the right time. Go to bed at the right time, eat at the right time. All that.

Kristen Knutson - 18:25: Oh absolutely. And I've been waiting as an anthropologist, you know my work is field based, and I need good field based technologies to really estimate habitual sleep behaviors. And actigraphy has been great but, as you said, you can't get sleep stages from that. You can't get circadian phase from that, and so every conference, I always go through the booths to see what's coming out now, what's the next field based device I can use. And it is nice that bigger companies like Apple for example, or Google, or whoever, might be interested in these devices to drive the technology advancement, because up until then, it was really clinic based measures that where the money was to put it crudely, and so they were really more interested in developing technology to be used in the clinic, not necessarily in the field. And now we have the population who want to be able to monitor their own health and behavior, providing the demand and now maybe we have more companies interested in providing supply and advancing our technology.

Dan Pardi - 19:16: I'm interviewing the Founder and CEO of Oura Ring next week. Have you heard of them?

Kristen Knutson - 19:20: Yes, I have heard of that.

Dan Pardi - 19:21: Yeah so they're people from Polar which is one of the oldest self tracking companies in the world and they've broke off from there and started this company and they're just about to launch their Gen2. Pretty interesting so they're triangulate multiple different signals including movement, and heart rate, and temperature to then say, "Okay, we've got good samples of these different parameters, can we use that to give better prediction on sleep stages, and et cetera." So one cool example about how we're getting there.

Kristen Knutson - 19:44: Yeah, I think temperature, coming back to is there any way for us to figure out our own internal clock. You know we also have biological rhythms and temperatures so if the surface temperature measures can be validated well enough to reflect core body temperature rhythms, then that may be an easier way than have you take saliva or blood, if the technology can get us there, and that would be great.

Dan Pardi - 20:04: I gave a presentation at the University of Washington back in September about hunter, gatherer sleep, talking about how it's difficult to bring PSG into the field, even though it's gotten more portable, but PSG's great when you're really trying to identify markers of sleep pathology, but it's not good for measuring natural sleep. So the more powerful these devices become, and the less friction that they have in measuring sleep itself, then there's a lot more to discover about what natural sleep looks like.

Kristen Knutson - 20:28: Yeah, now and whether that's hunter, gatherer or just in Chicago, it's not easy, like I said earlier on, like the second you slap on a bunch of electrodes on somebody's head, you know you're gonna affect their behavior and it may not reflect what a normal night of sleep would look like for them. And yeah, I agree. If you can get the technology to a point to where it's less intrusive, it's gonna improve our measures.

20:48: And last thing I just wanna add is, we hear a lot about diet and exercises, the core of healthy lifestyle, but I want everyone to add sleep into that group and think about not just sleep duration, but quality and potentially timing as well for chronic disease prevention and a healthier lifestyle.

Dan Pardi - 21:03: I think that's a perfect summary of where we are. Thank you so much, Kristen.

Kristen Knutson - 21:07: All right, thanks Dan.

Kendall Kendrick - 21:10: Thanks for listening, and come visit us soon as humanos.me.