 So I'm going to talk today, as was mentioned, about the life course of cardiovascular health, which has been really the major area of focus for myself and many in my research team for the last 12 years, since we first got a formal definition of what cardiovascular health looks like. And we're going to go through some of the outcomes that have been associated with that formal definition, but also mechanisms, correlates and determinants. And I have no relationships with industry. So many of you know, obviously sort of second nature that we've understood what the cardiovascular risk factors are since really the 1960s or 1970s. And Framingham and a number of other investigators really led the way in helping us understand what those sort of core traditional risk factors are. But led by one of my mentors here at Northwestern, Dr. Jeremiah Stamler, really since 2000 or so, we've tried to look at it from a different perspective, turning that risk paradigm on its head and trying to focus on those people who actually have maintained optimal levels of all of those traditional risk factors later into life to understand, one, what the outcomes are that are associated with that very favorable profile. And two, how can we get more people into middle age preserving that very favorable profile? And a major step forward happened in 2010 when the American Heart Association actually published that formal definition of cardiovascular health. So this was the report that I was really very fortunate to lead as chair of a writing group of just superstar individuals. AHA really does pull together the very best people to do these kinds of big projects. And as we thought through how we were gonna define this new construct of cardiovascular health, we had a couple of kind of guiding principles. First and importantly, I think we all understand that health is more than just the absence of disease. So sure, that's part of it, but we wanted to find something more that could be something that people could strive for to either achieve or maintain better health. So of course we needed an evidence base. So we went to the literature to look for things that were associated with greater longevity, certainly free of cardiovascular disease, but also with better quality of life and better, as I say, better healthy longevity. We wanted it to be things that were accessible and modifiable that people could take control of on their own. And of course, importantly, it had to be measurable, monitorable over time and modifiable so that the AHA and its partners could actually try to improve the cardiovascular health of the population and of individual patients. So when we went to the literature to look for what was the evidence to suggest what cardiovascular health might look like, we started with the founding chair of my department, Dr. Jeremiah Stamler, who I just mentioned a moment ago. Now, I noticed that you are celebrating your 60th anniversary at the Texas Heart Institute. Congratulations, that's really wonderful. This year we're actually celebrating the 50th anniversary of the founding of my department by Dr. Stamler in 1972. And if you don't know about Jerry Stamler, it's worth reading about him. He actually just passed away two months ago on January 26th at the age of 102. And if anyone really embodied the principles, but also the lifestyle of cardiovascular health, it was Jerry. Jerry discovered the Mediterranean eating pattern when he was in his 40s and really pursued it for more than 75 years of his life. And it clearly paid off because literally three days before he passed away, he was working on a manuscript with one of our faculty and he was actually planning the renewal of his R01 grant. Yes, he had an R01 at the age of 102. So clearly something was going right and Dr. Stamler had kind of found the fountain of youth. But unfortunately we did lose him recently. But one of the seminal studies that he really performed that pointed us in the right direction here was with his cardiovascular, excuse me, Chicago Heart Association Detection Project and Industry or CHA cohort. And also he was the lead investigator of the Mr. Fit trial. So he had access to decades of follow-up data on, as you can see, hundreds of thousands of individuals. And he wanted to look at, again, those people who made it to midlife with optimal levels of all those risk factors. So very low cholesterol, optimal blood pressure, not currently smoking, no history of diabetes and no history of prior cardiovascular disease. And when he looked in more detail at these people, what he saw was really remarkably lower rates of cardiovascular disease mortality, even also lower rates of all cause mortality and a substantially greater life expectancy among all sorts of different groups. So that was sort of a first clue for us that maybe there is a package here that if you're maintaining all the traditional risk factors at optimal levels, that might be one part of defining cardiovascular health. And when I was working at Framingham, we actually started this project and we showed that in fact, if you look at this from a lifetime risk perspective, this really does play out in a very strong way. So notice here we looked at all the people in the Framingham Heart Study as they passed through their 50th birthday. And we took their risk factor levels on the dates closest to that 50th birthday. So notice if you were a man at age 50 and had two or more major risk factors, it's about a 70% chance you would have a major atherosclerotic event before you died of something else. And if you were a woman with two or more major risk factors, about a 50% chance that you would have a major atherosclerotic event. But notice in the green lines, even if you had just one risk factor at not quite optimal levels, you still had about a 30% lifetime risk for a major cardiovascular event. So not really optimal levels. That's still a pretty high lifetime risk. But what was really interesting was this special group of individuals in the blue line who made it to age 50 with truly all optimal risk factors. Similarly defined as Dr. Stamler did. And so notice while there weren't very many of these people in the absence of cardiovascular disease risk factors with truly optimal levels, they essentially abolished their remaining lifetime risk for getting a cardiovascular event. So what this suggested to us was if you can get more people to age 50, we might see dramatically lower burden of cardiovascular disease in the population. Now at the same time, Dr. Mayer Stamfer, a different person at Harvard, said, okay, that's what happens with the risk factors. What about lifestyles? So he published some data from the US Nurses Health Study which as you can see, tens of thousands of women nurses followed for almost 14 years. And he defined a package of five healthy lifestyles, not smoking, pursuing moderate to vigorous activity per guidelines, keeping a lean body mass index, eating a healthy diet consistent with the dash diet pattern. And here's the good news, half a glass of wine or more per day. So he just did a simple count of how many healthy lifestyles these women were following in middle age. And then he looked at their coronary heart disease outcomes over 14 years. And what he found was that those women following three healthy behaviors had about a 57% lower risk for coronary heart disease, four healthy behaviors, two thirds lower risk and five healthy behaviors. If you had all five, 83% lower risk for coronary heart disease during the 14 years of follow up. So pretty striking. So that suggested to us that maybe if we melded the data from these two studies and a number of other studies, defining a package of all optimal risk factors and lifestyles could really get to a powerful statement about what ideal cardiovascular health looks like. And so that's what we did for this statement. What you see here is what's now called life's simple seven, the seven factors of lifestyle and measured physiologic factors that define ideal cardiovascular health as you see here. But we also understood that it can't just be about ideal cardiovascular health because that remains relatively rare in the population. So we wanted to define the entire spectrum of cardiovascular health in that document in 2010. And that looks something like this. So across the seven metrics, the life's simple seven metrics we defined poor levels, intermediate levels and ideal levels. I'm not gonna walk you through each individual definition but this really covers the life course so that you can have a definition of what ideal or intermediate or poor cardiovascular health looks like at any point in life. And of course, the goal here is that we want people to go from poor to intermediate to improve whatever metrics they need to or if there are intermediate levels, try to get to ideal. Now the way this has been summarized in now the couple thousand papers that have used this metric to understand how it plays out in patients and in the population is we often summarize the cardiovascular health as a score either on a range of zero to seven just simply counting how many of those metrics are at ideal levels. Or more commonly now people use a 14 point score where we assign zero points for anything that is poor of the seven, one point for anything that's intermediate and two points for anything that's ideal. So you can get a score that ranges from zero to 14. So during the remainder of my talk you'll see me referring to these zero to seven or zero to 14 point scores as we look at some of the outcomes and some of the mechanisms that are associated with cardiovascular health. Okay, so just to give you the headline cardiovascular health has been associated with lots of favorable outcomes. Higher cardiovascular health scores mean much better outcomes both in terms of total mortality all of the different types of cardiovascular events that we've looked at. Interestingly, better cardiovascular health maybe not surprisingly also associated with lower risk of cancer, lower risk of kidney disease, atrial fibrillation, lower risk of subclinical measures even as early as childhood around ages 10 through 12. Interesting relationship with cognition. So the better your cardiovascular health the less cognitive decline that you suffer as you go through adulthood to middle age. Associations with depression, quality of life and we're gonna focus a little bit later on this concept of compression of morbidity and also healthcare costs. So lots of favorable outcomes. This is a short list of all the things that have been associated with this package that identifies better cardiovascular health. So let's look at a little bit more detail at some of the outcomes that have been associated with cardiovascular health. And I'm gonna start with older individuals and look at their outcomes and then we're gonna move progressively back through the life course to understand just how early does it matter that you have high cardiovascular health. So this is kind of our working model that we think cardiovascular health in middle age is really kind of an important milestone that you want to achieve. But we wanna understand how that cardiovascular health plays out downstream in terms of subsequent events and death but also how do you get there? What are the upstream factors that influence your likelihood of maintaining optimal cardiovascular health into midlife? Is it young adult behaviors and lifestyles? Is it even earlier with childhood exposures or even in utero exposures and genetics that really determine the likelihood that we can maintain higher levels of cardiovascular health? So I'm gonna walk you through this whole model. You'll see this diagram a couple of times to kind of help you understand the way we've tried to unpack in our research understanding the true life course of cardiovascular health. Okay, so starting with older age individuals from the multi-ethnic study of atherosclerosis, what you can see here just very simply is that across that zero to 14 point score of cardiovascular health, this is really good cardiovascular health. This is really lousy cardiovascular health if your score is zero. You can see there's a log linear relationship. The higher your cardiovascular health, the lower your risk for cardiovascular events. Makes sense, right? But nice to kind of validate that that's true in an older population. Now moving upstream a little bit to the atherosclerosis risk and community study. This is middle-aged individuals who are 45 to 64 and enrollment followed them for 20 years. And they had measured all the factors that were needed to calculate the cardiovascular health score. Here's our zero to seven point score on this slide. And notice if people with zero points are at the highest risk, just having one ideal cardiovascular health metric didn't matter which one, but just having one compared to zero, 36% lower risk for cardiovascular events in the next 20 years. And then a nice kind of dose response or stepwise reduction in risk. And then these couple hundred participants, not very many, but a couple hundred participants who had a perfect score of seven had zero cardiovascular events over the next 20 years. So people with an average age of 55 with ideal cardiovascular health truly ideal had zero cardiovascular events in the next 20 years. A pretty remarkable statement. I don't know very many groups of middle-aged people who have zero cardiovascular events going from 55 to 75. So pretty special group. And this research paper actually went a step further to say, well, is it more about those health behaviors in the seven factors or is it more about the health factors, those things we measure that represent physiology? And the answer was yes, it was about all of the above. So notice that people who had six or seven ideal factors had very, very low rates of cardiovascular disease. But with each one worse factor or each one worse behavior, there's a stepwise increase in that risk so that people again with zero points were at the very highest risk. But it didn't seem to matter whether people were improving on one of the behaviors or one of the factors, you got a pretty similar difference in risk. Okay, let's move back a little bit further or earlier in the life course. And here you see the CARDIA study which is actually 18 to 30 year old young adults where again we had measured the kinds of things we needed to calculate their cardiovascular health score. And now on that 14 point health score, people we defined just arbitrarily with 12 to 14 points as high cardiovascular health. And notice among these very young adults, 18 to 30, extremely low event rates over the next 30 years. So these would all have been premature cardiovascular events because again, they're starting so young but very low event rates of premature cardiovascular disease if they also had high cardiovascular health scores, more if they had moderate cardiovascular health scores. And of course the highest rates if they had poor cardiovascular health scores. And when we looked at this in terms of hazards ratios, you can see really dramatically low hazards ratios around 0.15 for individuals with high cardiovascular health compared to poor cardiovascular health. And that explains somewhere between about 55 and 75% of all those premature cardiovascular events. So we could get rid of a lot of even premature events if we got people to have more and better cardiovascular health even by young adulthood. So here's a recent study from Korea where they actually were able to measure the metrics in 3.5 million young adults that were part of a large health system there. And they categorized it at the ages of 20 to 39. So a mean age of 31 years with the baseline cardiovascular health assessment. And then interestingly, most of them were seen again within about two to five years. So they were able to look at a second cardiovascular health assessments. They could look at the score at baseline and two to five years later. And then they had about 16 years of follow-up. What they found was that the baseline score as you can see here was strongly associated with event rates for cardiovascular disease. So those with a poor score of zero had the highest risk. Those with a high score of six out of seven have the lowest risk as we would have expected. And you see that similar kind of dose response across the zero to seven point score. But what's really interesting about this paper is the change data, right? Remember they had two assessments of cardiovascular health. So notice that for people who had a very high point score of five to six at baseline and also had a five to six score two to five years later, they had a dramatically lower 85% lower risk for cardiovascular disease over the next 16 years. But what about the people whose cardiovascular health score changed? Well, here are people who had lower scores at the baseline and better or higher scores at follow-up. And notice all of them had hazardous ratios of 0.68 down to 0.17. So if you improved your cardiovascular health score in those two to five years, significantly lower risks of subsequent cardiovascular events. But here's what's also interesting. Even those people who had very good baseline scores but then lost some cardiovascular health, they maintained some protection over the next 16 years. So it was important to have high cardiovascular health earlier even if you subsequently lost it, you still maintain some protection. So I think that's a very important finding in this study as well is that as early as possible if we can get better cardiovascular health, even if we're subsequently gonna lose a little bit of it, we're still gonna be better protected. Okay, so now let's move even further back or earlier in the life course. And these are data that we took, we had a number of different child cohorts that have measured many of the metrics of cardiovascular health. And we also have a number of young adult cohorts like Cardia, we were able to create what we call a synthetic cohort to knit together the experience of cardiovascular health scores from age eight to age 55. And here you see in these lines, the trajectories of cardiovascular health scores among that group of individuals. And there were basically five different types of people each represented in one of these lines. So there was a group that had relatively high cardiovascular health early at age eight and it stayed pretty high. So we call that a high with late decline pattern. There were other groups that had a high at baseline but had a moderate decline shown in the blue or high at baseline and a more rapid decline shown in this sort of brown color. Then there was a group that had more intermediate cardiovascular health and that had a late decline as well, that orange curve. But finally noticed that even at age eight we could detect kids who had much lower cardiovascular health in this sort of baseline and it dropped quite rapidly into middle age. So that we called an intermediate early decline phase. So notice even by age eight, we're already seeing some stratification in how these individuals are gonna live out their cardiovascular health destiny. And it mattered because on average, these cohorts then measured carotid IMTs at around age 30. And what we found was that there were significant differences in the carotid IMT thickness at age 30 based on which cardiovascular health trajectory these individuals were in. So really interesting and notice this range of 0.64 to 0.72, that's associated with markedly higher event rates once people get into their 50s to 60s. So that 0.08 millimeter difference really is very important especially as early as age 30 where we're demonstrating these differences. But again, I wanna call your attention to this age eight already seeing people have stratified themselves into different cardiovascular health trajectories. So it suggests we need to move perhaps even further upstream to understand when do we need to capture and try to improve cardiovascular health so that everyone has the chance for optimal cardiovascular health across their lifespan. Okay, that's about as far back as we've taken it at the moment, although we have a current AHA funded center that's actually looking at cardiovascular health and trying to define it in young kids really from birth out to age 12. So we can overlap the curves you see on this slide and try to really define the true full life course of cardiovascular health trajectories. So stay tuned for those data coming in the future. Okay, so let's kind of think about what we just saw. Remember that cardiovascular health status at any age was associated with dramatically different types of outcomes, high cardiovascular health at any age, much lower rates of cardiovascular disease and total mortality, poor cardiovascular health at any age, high rates of cardiovascular disease and total mortality. So let's take that information to the population and figure out what does that mean for population health. So I mentioned I was gonna talk to you about this construct of compression of morbidity. So we use data from Dr. Stamler's Chicago Heart Association study to look at how people compress their morbidity based on their cardiovascular health status. So this is about 40,000 men and women enrolled in roughly 1970. And we've been able to follow them routinely with contact for questionnaires but also linkage to the National Death Index and also to Medicare. So as soon as these middle-aged individuals who are mostly about in their 40s at baseline, as soon as they hit Medicare eligibility, we're able to start tracking what their utilization is of healthcare services and what the healthcare costs are that are associated with that. Okay, so what you see here are Medicare-based utilization data that tell us when someone develops heart disease, stroke, heart failure, other cardiovascular outcomes. But we've classified people based on what they looked like back at about age 40 in this study. So here's the group that had two or more major risk factors at age 40 in the top bar. And here's the group that had essentially ideal cardiovascular health back at age 40 in the bottom bar. And what these bars represent is the total lifespan after age 65, so your Medicare lifespan, if you will. But within each bar, the green part is what we call your health span. How long do you live without any cardiovascular comorbidities on average, okay? Then the yellow part means how long on average do people spend with at least one cardiovascular comorbidity? Orange is two or more, red is three or more, okay? So total lifespan and then average amount of time healthy or with one, two or three or more cardiovascular conditions. So what you see here is that for those people who back at age 40 had two or more major risk factors, on average, they lived at age 76 before developing a cardiovascular event or condition. And total, they lived at age 84. So what that says is they spent 8.3 years of their Medicare lifespan with some form of cardiovascular disease or 43% of that part of their life. But down here, notice the health span is much longer, 83 years before on average they developed any cardiovascular conditions and they lived on average stage 88. So that's about 20% of their Medicare lifespan. But that means is that we're seeing compression of morbidity. These people are living longer but they're pushing the date of their diagnosis of cardiovascular disease much closer to the end of life. They're compressing that morbidity which is a desirable outcome because it means they have so many years longer of healthy life. So the difference between these two groups as you see is four years longer average lifespan but seven years longer of average health span. And that we think is where patients are really interested in. When we looked actually beyond that because it's not only about cardiovascular disease, right? It's about cancer, it's about dementia, it's about COPD, it's about debilitating degenerative joint disease, all sorts of different things. We looked at all cause morbidity, we also see compression of morbidity based on what your cardiovascular health score looked like back at age 40. So these folks in terms of all cause morbidity, again, four year longer lifespan, four and a half year longer health span. Again, that's the difference between dancing at your grandchild's wedding and not being able to dance at your grandchild's wedding. Okay, so I know what you're saying. Well, these people are living longer. Yeah, they're healthier for part of it but they're living longer. Are we gonna spend more money on them? And the answer is no. If you look here in this graph across that total Medicare lifespan, what you see is that people with all favorable risk factors back at age 40, so essentially ideal cardiovascular health, we spend on average about $75,000 less per person during their Medicare lifespan compared to the folks who have two or more major risk factors back at age 40. So this would go a long way to helping with our obviously runaway healthcare expenditures in this country too, but it means we need to get more people into middle age with optimal cardiovascular health. Okay, other population implications. So these are some data from one of our former fellows, Josh Bundy, who used our lifetime risk pooling project to say, okay, well, what if we could magically snap our fingers and make a certain proportion of the population have ideal cardiovascular health compared to what the current state is? Well, what he estimated was that if we could do that, if we could take 100% of adults and magically to give them ideal cardiovascular health, we would actually avoid 2 million cardiovascular events each year, 2 million events each year in the United States alone. If we could magically snap our fingers and give everybody ideal cardiovascular health. Pretty tall order admittedly. So what if we could get 50% of people to ideal cardiovascular health? We'd avoid about 900,000 events each year, still a pretty good payback. So we need to get more adults living better lifestyles so that they get better cardiovascular health into middle age. So clearly we all know this. If you have prevalent risk factors we need to treat those patients aggressively to reduce the risk that's associated with those risk factors. But what I'm suggesting to you is that it's even more important not to let the risk factors develop in the first place. And this is a construct which many of you are now familiar with called primordial prevention. I think I saw Dr. Kohn's on the list and he's written a lot about this. Very important construct, starting early in life and don't let people develop hypertension, diabetes, start smoking, develop dyslipidemia. Don't let those things happen in the first place. And particularly don't let them start gaining weight in the first place since that drives so many of those other things. Okay, so that's primordial prevention. That's maybe our way forward to improve cardiovascular health in the population and achieve those great outcomes. But I know you're asking, so why does it work? Is it just the absence of risk factors that's making these people live longer and live healthier longer? And the answer is sure, of course it is but there's actually a lot more to it than that. So some of our research, I think has given some nice insights into this. So when we looked in the, again, the multi-ethnic study of atherosclerosis older adults and we stratified people based on their cardiovascular health score, of course those people with higher cardiovascular health were less likely to have coronary artery calcium. They, if they had coronary artery calcium they had less of it overall. Their carotid IMTs were thinner, not normal, but thinner than people who had low cardiovascular health. And they had lower left ventricular mass index. Again, makes sense, but nice demonstration that there's less burden of the subclinical disease as well as clinical events subsequently. And we've done some research here using black blood MRI techniques to look at, can we actually dive down and look at the vessels of people based on their cardiovascular health status. So this is from one of our studies called the Charisma Study where we looked at people, same CHA cohort. We knew what they looked like back at age 40 but we saw them a number of years later to look at their vessels based on what their cardiovascular health status had been in this case, 40 years earlier in this gentleman. So we're looking at cross sections of their coronary arteries using MRI. And here you see this gentleman's left main coronary artery. So he had elevated risk factors 40 years ago. Notice the lumen of his left main is fairly small relative to the thickness of the wall and the wall is kind of irregular and there's this low attenuation area which represents typically lipid-rich plaque. Also you see again that smaller lumen compared to wall thickness in the LAD, kind of ratty looking RCA. So this guy who's had risk factors for now four decades has evidence of atherosclerosis. Here's a similar gentleman, he's 70. His 40 years ago, his cardiovascular health status was optimal, truly optimal 40 years ago. Notice much bigger lumen relative to the wall thickness. Still a little bit shaggy but overall much better looking, much less total burden of atherosclerosis. Same here in the LAD, same here in the RCA. Although again, not perfect but clearly better than the other gentleman. And when you kind of look across all of our data in about 430 people, what you see is that that maximum wall thickness is actually kind of similar between people with low risk or high cardiovascular health and people with poorer cardiovascular health. It's not normal though. Truly healthy young adults have wall thicknesses of about a millimeter. And this is almost twice that. So that says, okay, these people are actually developing atherosclerosis even if they have ideal cardiovascular health. So is there something qualitatively different about the atherosclerosis that develops in people who have high cardiovascular health for much of their life? And the answer is it looks like maybe there is that while it's present, the wall is thickened, there's remodeling of the coronaries. It looks more like it's sclerosis and less like athero. So it's a more benign form of atherosclerosis than happens to people with frankly elevated risk factors. We're continuing to look at this with MR angiography studies and with contrast enhanced 3D carotid ultrasound. So lots more to know. But again, there seems to be a qualitative difference in the aging of their vessels for those people with high cardiovascular health compared with lower cardiovascular health, but not absence of atherosclerosis, which is really interesting. The other thing to note is that from the Framingham study as well as, sorry about that, from the Framingham study as well as again from Mesa, if we look at the relationship between the cardiovascular health score and the cardiovascular event outcomes, there's a clear relationship as I've shown you. But what if we adjust for the things that happen in the middle? If we adjust for subclinical disease like carotid IMT like coronary calcium burden like left ventricular mass index, should that abolish this relationship between cardiovascular health and cardiovascular events? And the answer is you might expect that to be true. We think cardiovascular health has to work through subclinical disease to get all the way to a clinical event. But the answer is it doesn't actually abolish all of the relationship. So if you look down here that people with high cardiovascular health are at, in this case, 67% lower hazards for cardiovascular events. And when we adjust for things like coronary calcium left ventricular mass index, carotid IMT, we only attenuate part of that. They're still at 50% lower risk. So there's something special about cardiovascular health above and beyond what we're measuring in the pathways related to subclinical cardiovascular disease. So the way we think about this is it may be a little bit more than the sum of the parts. There are probably associated extra lifestyle factors that are favorable that protect these people as well. And there are probably some other things that we haven't measured at all that also protect these people. Okay. So now you all wanna know, well, how can I achieve ideal cardiovascular health or how can I maintain it if I've already achieved it? And so we've started to ask these questions, I think in a number of different, from a number of different angles. First thing to know is in this country, we don't do a very good job of achieving or maintaining our cardiovascular health. What you see here is that by ages 12 to 19, so adolescents, only about 40% of US adolescents actually have even five of the seven metrics at ideal levels. So we've already lost a lot of cardiovascular health that presumably was better as we were younger. And then across, as we age, you can see 20 to 39, 40 to 59, by age 60, very few people have even five of those seven metrics at ideal levels. So it makes you ask the question, is this programs to happen? Do our genetics make it that we're gonna lose cardiovascular health as we age? Does it have to be that way? Or is it something in our control? So as we've said, it seems like we're all born with high or high-ish cardiovascular health, but clearly as I've shown you, we lose it. So is that genetically programmed or could we modify it with health behaviors? So the first question was, is it related to genes and heritability? Went back to my friends at the Framingham Heart Study and they have three generations of individuals who have been phenotyped for cardiovascular health across the years. So again, three generations of related individuals and we know their cardiovascular health status in middle age. So what we found was that the heritability, the proportion of cardiovascular health variants that could be explained by relatedness of these individuals was only about 15%. So it's real, but it suggests that about 85% of the variants in your cardiovascular health in middle age is not determined by who you're related to. It's determined by what you've been exposed to in your environment and what your behaviors have been during your early life course. So really interesting, indirect data, but very interesting. So let's ask the question a little bit more directly. Could it be that young adult behaviors and lifestyles actually also help determine your likelihood of having ideal cardiovascular health in middle age? Went back to our Cardia Study, remember these are the young adults we first met at ages 18 to 30. And the answer is, among these 5,150 black and white men and women, we characterized them based on the five healthy lifestyles that we looked at earlier, right? Lean BMI, not smoking, no or low alcohol intake, dash type eating pattern and participating in physical activity. Simple count of how many healthy lifestyles they were following. And what we saw was that when we looked at them again at age 50, mean age at the start was age 25, when we characterized their cardiovascular health status at age 50, the number of healthy lifestyles they followed mattered a lot. So regardless of who they were, if they'd only followed zero or one healthy lifestyle, about 2% of those people made it to middle age with ideal cardiovascular health. But if they followed all five healthy lifestyles, somewhere between 50 and 70% made it to middle age with ideal cardiovascular health. More direct evidence than the heritability that in fact this is within our control that following healthy lifestyles from early adulthood can actually help us achieve and maintain cardiovascular health and win the game, right? Achieve that sort of fountain of youth effect. Okay. Now these are some data that just came out last month really kind of interesting and exciting and they're from your neighbors. This is from a group at UT Houston and they took data from the atherosclerosis risking community study, we've seen it before. And they had whole genome sequencing on 8,600 participants in this study. So they said, okay, let's apply the UK Biobank polygenic risk score and characterize people as either low risk based on their genes, intermediate or high risk based on their genes. And at the same time, we're going to characterize their cardiovascular health score on that zero to 14 point score. So they called them poor, intermediate or ideal. And what they found was that the polygenic risk score as you would expect stratified risk over a number of years of follow-up. This is the lifetime risk estimates based on polygenic risk. And the life simple seven score the cardiovascular health score also stratified risk. So things are kind of playing out as you would have expected, but now they did the right thing. They said, what if we consider both of these things at the same time? So what you see here is again, one of these compression of morbidity graphs, the length of the bar is the total lifespan. The black part is the health span and the gray part is the average time spent with coronary heart disease in each of these groups. Up here, you see low polygenic risk. Here's the group with high polygenic risk. And then that's all stratified by whether they have poor intermediate or ideal cardiovascular health. So let's look at the extremes. These are people with low polygenic risk in this bar. So good genes, but lousy lifestyle, poor lifestyle, good genes, okay? We're gonna compare them to people with terrible genes, very high polygenic risk, but pursuing an ideal lifestyle. Notice what happens for people down here with bad genes, but good lifestyle, 11 years longer lifespan, 18 years longer health span and on average, seven years less with coronary heart disease. So this tells you that lifestyle can indeed trump a bad playing hand of genetic risk. Really, I think important data to empower our patients, give them hope that sure, you may have a strong family history, but if you follow a healthy lifestyle, we can actually trump a lot of that family history. We may need some help from medications, of course, along the way, patients with FH, absolutely. But this is really a more general population, not FHers that we're talking about, where healthy lifestyle seems to be making a very big difference in their compression of morbidity and their total longevity as well. Really compelling data, I think, and again, empowering for our patients. Okay, so clearly ideal cardiovascular health status is a key indicator of healthy longevity on multiple axes, as we said. It is heritable, but only pretty modestly so. It's modifiable and we definitely wanna achieve and maintain cardiovascular health as early as possible, but I think it's also clear it's never too late to change, right? Change was always making a difference. So really, really important and obviously high cardiovascular health seems to be able to trump adverse genetics as well. So we wanna go early in life as possible to achieve optimal weight and really maximize the lifestyle so that people maintain higher cardiovascular health. Okay, how about even a little bit earlier? And this is some of the preliminary data from our AHA center I mentioned earlier. So now we're gonna focus way upstream, particularly focusing on the intrauterine environments. So this is another of our cohort studies, the hyperglycemia and average pregnancy outcome study, the HAPO study, where we actually had studied these women a number of years ago and collected data that allowed us to look at their cardiovascular health status at about 28 weeks gestation. So during pregnancy, what did their cardiovascular health look like? And then not only do we have the birth outcomes in those women, we actually saw them back with their children 10 to 14 years later. So we were able to measure mom's cardiovascular health status 10 to 14 years later and the baby's cardiovascular health status now that they were young kids. And not surprisingly, mom's cardiovascular health status at 28 weeks gestation was associated with a number of different adverse pregnancy outcomes. So worse cardiovascular health status, more likelihood of preeclampsia, unplanned C-section, large for gestational age, high birth weight, more thicker skin fold, so heavier, fatter babies and more insulin resistance in the babies of moms who had poorer cardiovascular health during pregnancy. But what about 10 to 14 years later? Well, to summarize those data, women with poor gestational C-VH, that's our reference group, women who had high gestational C-VH were eight times more likely to have a kid 10 to 14 years later, who also had high cardiovascular health. Not causal data, but very strong correlation between mom's gestational cardiovascular health and baby's, well, kids 10 to 14 years later. Really interesting. So I've already told you that genes don't seem to be playing a huge role here. So if it's not genetics, what could it be? In the last couple of minutes, we're gonna focus on the epigenome. And obviously many of you know what this is. It's not our fixed DNA code, those four base pairs that match up to create the DNA code. It's actually alterations that occur on top of the DNA strand. Typically something like methylation at the cytosine residues across the genome. And those methylation groups are interesting because they happen in response to health behaviors and also environmental exposures. And in some places across the genome, they can happen at predictable rates as we age. So they can form sort of a biological clock. But what's important to know is that when there's a methyl group sitting on the DNA, it alters our ability to express the gene. So you might have a favorable gene or an adverse gene, but if you can't express it, it may not matter for that cell. If there's methylation at a certain point, it might disrupt your ability to translate that gene or just transcribe that gene, excuse me. So this is really the decorations on the Christmas tree if you will, as a nice analogy. And as I mentioned, there are epigenetic clocks that represent biological aging. So we can look at the pace or the burden of methylation and regress that on your chronological age to understand are you epigenetically older or are you epigenetically younger than your chronological age? And when we've done that, what we found was that cardiovascular health status in our young adults in Cardia was associated with your genetic, excuse me, your epigenetic age to the point where one point higher in your cardiovascular health score meant eight months younger epigenetic age. So that's not nothing, right? One point higher cardiovascular health through young adulthood meant you were eight months younger on your biological clock. Kind of interesting. And this may be one of the mechanisms, perhaps through which cardiovascular health is really inferring some of these great benefits. When we actually look at the arrays of DNA methylation, we find that there are sort of some hot spots in the genome where cardiovascular health is associated with differential methylation in these individuals. And in fact, those sites seem to explain at least statistically some of the variants in things like coronary calcium and lefentricular mass. So here you see three genes, oops, sorry, let me go back, sorry about that. Three genes with differential methylation seem to explain about 20% of the variants in coronary artery calcium in these Cardia participants. Really interesting. And these genes have biologic plausibility for the relationship of coronary calcium. We looked at lefentricular mass, two of the three genes here are by the way of the same, but again, three genes and their methylation status seemed to explain almost 30% of the variants in lefentricular mass. So really interesting and compelling to say that maybe that intra-unit environment, maybe our health behaviors and our environmental exposures across early life are really determining our ability to be in different cardiovascular health trajectories, which we saw earlier. Okay, last thought, thrown a lot of data at you. Hopefully convince you that cardiovascular health is an important phenotype to be looking at in your patients. What can we do actually to help our patients improve their cardiovascular health? Well, many of us in the audience are obviously physicians and no question, we need to get more aggressive controlling risk factors with primary and secondary prevention when those risk factors exist. But also I think it's important to help our patients manage and understand their cardiovascular health so that they can actually perhaps pursue primordial prevention. So the AHA has the my life check or the life simple seven tool. You Google either of those phrases, you'll go right there. They can enter a few questions, answers to questions, get their cardiovascular health score. They'll get a red, yellow or green assessment on each of the seven metrics and they can click through to understand, how can I lose weight? What's a healthy diet? What types of physical activity will help me improve my cardiovascular health? So lots of great content and I'd really recommend this site for all of you. But I also wanna remind you that as physicians we have a very powerful voice as advocates in our communities, in our states, yes, even with the federal government. So if you wanna become an advocate through the American Heart Association you can go to this website, you'rethecure.org, sign up. And when there are important legislative or policy things happening, you'll get a ping and with just three little clicks you can actually send a letter to your congressperson, your state representative, maybe the FDA, now that our friend Dr. Kaliff is in charge there so that we can actually improve the health through policies, through legislation to try to get to better cardiovascular health for our families and friends. Okay, so to summarize what I threw at you here, thinking about flipping the risk paradigm on its head means, again, looking at those people who are aging healthily and maintaining cardiovascular health deep into the life course. It does seem to be a little bit more than the sum of the parts, right? But if we can maintain cardiovascular health in the middle age, it does seem to optimize our health span, improve that compression of morbidity concept and lower healthcare costs. And I think very much of this is in our control. Lifestyle factors seem to matter more than genetics for this phenotype of cardiovascular health. And there's some interesting thoughts about mechanisms, more benign atherosclerosis, epigenetics may be an important mediator of maintaining cardiovascular health. But I hope I've given you the sense that we do have lots of tools in our toolbox and this is something that we need to focus on more and more. So thank you so much for your attention. It's great to be with you even if virtually and I hope to have some time to answer some questions for you. Thanks so much.