247 ‒ Preventing cardiovascular disease: the latest in imaging, blood pressure & metabolic health

hey everyone welcome to the drive podcast I'm your host Peter attia all right Ethan thanks so much for uh for making time to sit down again this is this is round two although I kind of don't remember when round one was I think it was 2019 but it might have been 2018 right I think it was 18 I think it was 18. uh which is just a function of the fact that neither of us can remember it tells us how long ago it was yeah yeah well that time we spoke in person and we sat in your office at UCSF um but you're sitting in a new office today and we're not in person but more importantly where are you sitting today and uh there's been a bit of a change in your life in the past year huh yeah so I did uh it's been an evolutionary change over the past couple of years but I did uh I have sort of a midlife crisis decided that I I didn't envision myself doing the same thing I'd been doing for the prior 25 years for the next 25 years if I should be lucky enough to be around in 25 years and uh I was given the opportunity to get involved with the local group of investors who create biotech companies and they asked me to help them conceive and eventually uh start a new biotech company so I closed my lab and have become a volunteer clinical faculty at UCSF and see patients infrequently and spend most of my time over here working to to build this new company that I could at least tell you a little bit about later on yeah well I know we're gonna talk about some of the science that the company is interested in because it factors in directly to what we wanted to talk about today so there will be a chance to talk about that for sure um but in some ways this podcast is really just a compilation of our email exchanges over the past couple of years uh and and so I think at some point we said we should just do another podcast because we keep emailing each other about these things and I I suspect is as often the case um there's value in Sharing what it is that we we talk about with others so um let's just start with a quick recap of what a calcium score is and uh and then we'll follow that up by what a CT angiogram is because I think those two need to be understood to understand much of what we'll talk about in the next uh God knows how long yeah uh so you know we talked about this the last time I think I do remember that we spent a lot of time talking about the distinction between calcium calcium scanning and CTN geography and as we discussed last time Cal I think you know you've used the analogy before the calcium scan to sort of demonstrates a side of a prior injury uh what we know is that quantitatively the amount of calcium that is in the distribution of the coronary arteries is uh correlated significantly with adverse outcomes so the more calcium you have in your arteries the worse you do the higher the risk of both cardiovascular and all cause problems uh and the reason we suspect is that that calcium represents a healed plaque and then so the amount of calcium you have in your arteries is is really strongly related to the amount of plaque they have neural arteries we know that the amount of plaque Avenue arteries is related to your your risk of having heart attacks and dying from heart attacks so calcium scans are great ways to kind of uh the way the analogy I use for my patients is that it's a you know sort of a satellite image of your of your heart and gives you a sense of has there been damage there over over your lifetime uh and what and then also gives you a nice adjunct indicator of your overall risk of dying for heart attack which people like to know and one of the nice things about a calcium score is it's very very low in radiation I mean it's really you know even ctas are now low we'll talk about that but but the calcium scan is a really low radiation and a very inexpensive tool as well um there are you know places that are doing these scans for a couple hundred dollars uh now that's right so not all places no and that's the that speaks to the problem in U.S Healthcare where you'll still find some places charging two thousand while some will do the exact same scan for literally 200. um but it needn't be an expensive procedure it's a low risk procedure it doesn't require dye so it's effectively a zero risk low-cost procedure that at least at the population level as you say has really great Insight especially the first time it's done right absolutely and I think we talked about this the last time but I'll just say it again for those who weren't around back then that I did a full 180 on these you know when I first started practicing as an independent cardiologist back in early 2000s I would get patients showing up with these calcium scans and I really sort of wanted to make them go away I thought they were annoying and I didn't know what to do with them and it really has been a full 180 I do find Value obviously there's epidemiologic value and understanding the risk of different populations but I do find that there is value in in many contexts and even in individual patients and we can talk about which context I think are most valuable certainly not everybody I think you know a calcium scan and a 25 year old is probably not worth anything it's just not worth doing uh so yeah I think I've I've come around now to seeing the value of calcium scanning as a tool that I use regularly yeah and I and I know we did talk about this but again I I've learned that one of the things that makes podcasting difficult is it's very difficult for people to go back and listen to them there's just too much volume so we should never apologize for repeating stuff that we talked about more than four years ago um and the way that I kind of explain it to patients as well is that if you have a two by two of sort of you know young versus old and Zero versus non-zero as the calcification you know there are two areas where the scan provides insight and there are two areas where the scan doesn't really provide insight and so one of them as you said you know if a 40 year old shows up has a calcium scan of zero I haven't really learned a lot and if a calcium scan of zero in a 40 year old is accompanied by other risk factors I would not be dissuaded from aggressively treating those risk factors and similarly when an 80 year old with lots of risk factors shows up and has a zero calcium scan we'll talk about the false negative right there all things equal you might be less inclined to push for aggressive measures would you would you agree with that framework I do yeah I think there's a uh a group of very committed uh whatever you want to call them calcium scanographers who believe in the power of zero and believe that a calcium score of zero is Meaningful no matter where it comes but I just think that defies logic right you shouldn't have any if you shouldn't have any calcium when you're 25 uh I'm not sure what you learned there there may be edge cases where you know one and several million people will have some calcium but I just think mostly the two two cases you described are are where I find the most value well this gets to something that I think I've learned a little bit more about both through personal experience and and also just kind of spending more time in the literature on this is that a calcium scan is is a relatively imprecise measure so the the thickness of the slices that are used in that scan are significantly greater than the CT the slices that are used in the CTN geography and I'll I'll give you a stark example of how I learned this in my own life and I think I shared at least part of this story last time although clearly not all of it because I just learned more recently so in 2008 or 2009 when I was in my mid-30s I had my first calcium scan now at the time my doctor thought this was a crazy idea I was 35 I was exercising at least 24 hours a week um there's no seemingly relevant reason for me to waste insurance money and do this but I had a horrible family history um and it didn't seem to make sense it wasn't like everyone in my family was smoking or anything like that so anyway had the calcium scan and it showed that I had a score of six so I had a a single Foci of calcium in the proximal lad um and interestingly despite being in my mid-30s with that calcium score of six nobody really seemed to care either that was viewed as well I mean look your lipids are really not that bad my LDL cholesterol was about 120 110 to 120 milligrams per deciliter so nobody took that terribly seriously of course it changed my life and it changed my interest in this field forever fast forward to 2016. so call it six seven years later I went and had a CT angiogram and a calcium scan and the calcium scan had a score of zero the CT angiogram which now is at much finer resolution indeed found a tiny Speck of calcium in the proximal lad no other finding uh Bob Peters who is the remarkable radiologist that now sees a lot of our patients explain to me not uncommon at all like that little speck that you had six years ago uh can easily be missed if you had five calcium scans half of them would miss it because it's just too small but now in the CTA we can see it so we repeated the CTA now I'm just kind of partially interested in progression more of soft plaque I had it repeated very recently so call it 2022 this time the calcium score came out as two and the CT angiogram was identical to what it was in 2016 six years earlier so you could certainly believe that if I had a CTA in 2008 or 2009 it would have looked similar and you would argue that for basically the same lesion the score was 6 and 2 and 0. in the SRA 6 and 0 and 2 in that order um have you seen this yourself in patients where you've had the luxury of both longitudinal assessment and simultaneous CAC and CTA you know I can't off the top of my head I can't think of anybody but I would ask you and this may be a leading question but what were the percentiles of those I mean I would imagine that's calcium score of six when you were 35 was 99th percentile it was 75th to 90th percentile at that age that's right yep yeah but there's a big difference even between six and two and a huge difference between six and zero yes exactly yeah so uh I haven't seen it but yeah exactly my guess is at a low enough calcium score that's not that's not uncommon of course that then got me into the literature and I realized that 15 of people who have a zero calcium score have a finding on CTA that is either as mine was meaning a calcification that was not picked up or a soft plaque furthermore two percent or maybe it's one and a half percent of those people who are deemed with a negative attack have an unstable plaque on CTA so it's not just the 15 that have something but like 10 of those people have something that's would be deemed relevant if we saw it on the CTA and just back to our uh prior discussion on unserved age and utility of this of the scan I would imagine I don't know that not very familiar with the David I would imagine that that that 15 is largely represented in younger people or is that not the case I'd have to go back and look it's a great question I'd have to go back and look at the study because it's been probably about six months since I I looked at it um um but yeah so we'll we'll find it and we'll link to it on the show notes so that it's unambiguous and we'll include the the table that that summarizes all this which would hopefully include age and if not it'll be in the fine print and then the other question I have for you Peter is over the course of the whatever it was 15 16 17 years since your first calcium scan what's your average apob been yeah so that's the point it's been lower and lower and lower right so I immediately you know that's that's about the time I met Tom Dayspring and you know began to learn I didn't know what APO B was at the time at first I was just sort of bombarding ldlc and then that turned into really now targeting APO B and so my target APO B is between 30 and 40 milligrams per deciliter that's sort of where I aim to be uh day in and day out and obviously that requires you know pharmacological intervention now again I never really had a particularly High APO B but in some ways that actually gave me more concern Ethan because I didn't have the obvious risk factors right I'm normotensive I don't smoke and my APO B at the time was probably about 85 to 90 milligrams per deciliter I mean very few doctors would get phosphorylated over that APO B in someone in their late 30s or mid-30s at the time but again I'd watched countless men in my family die some of them as young as in their late 40s from heart attacks and you start to realize hey this is probably quite polygenic and B there's something going on here that's not just standard Plug and Play risk factor stuff yeah which of course is your practice right I mean you get these really tough cases where it's not just oh you know the LDL is too high yeah it's it is my practice and unfortunately at least for now the the only tool set of tools that we have are aimed at well I should say independent blood pressure which is a different conversation we'll have later but the tools we have now are focused really on lowering the apob through any number of different means I think we all expect that there's something else there there was clearly something else there in you it wasn't I mean again I don't think it's hard to make the argument that you are sort of a ticking time bomb with a Widowmaker that you were going to drop dead of a heart attack you you had a tiny of you know minuscule lesion the question would have been what happened to you over the next 15 or 20 years had you not taken the intervention that you did pharmacologically yeah as I approach 50 now I do find it interesting to play the thought experiment of had I been on a different path in life had I never looked at that 15 years ago had I never cared what would what would it look like today what would that CTA look like today how significant would that lesion be would there be others um yeah and my belief is that because you know and we should obviously talk about this I think that the epidemiology the clinical trial data and the mendelian randomization to my reading of this literature and I don't think there's anything I pay closer attention to truthfully is that APO B is a necessary but not sufficient criteria for atherosclerosis and as such removing it removes atherosclerosis and so my best guess as to why there has likely been no progression of this disease in 15 years at least to the level that it can be detected by a CT angiogram is that we've basically taken away the causal agent yeah I think I mostly agree with you I think it's absolutely necessary I think the data really do suggest that if it's bottomed out absent some really bizarre probably monogenic things that we don't see very often that you can't get atherosclerosis I think that's demonstrated not just in humans but across many other animal species the the one place where I might quibble a little bit is that I do think it's probably sufficient in some cases right that interesting that in FH for example uh it's probably sufficient in other words I don't think you have to have something else uh to get out through in in cases where the B is Sky High the sufficiency is complicated right I uh I I mean I suppose there are people with FH that don't go on to develop ascvd yeah a lot yeah I mean that's sort of the argument that the sort of and I don't know if we're going to get into this or if I ever want to talk about this ever again but this lean mass hyper nonsense uh that this that's the argument that they make that it's not that having a high apob is not sufficient and um and it's definitely true that there are some people with FH who don't go on to have asuvd it's interesting I mean obviously suggest some other genetic modifier or something else that protects them yeah I mean I I so I think that one could could argue that that apoby is not sufficient but is necessary which is is how I feel and still take it very seriously because let's look at another obvious example which is smoking right um and again is smoking even I would argue smoking is even weaker right smoking is neither necessary nor sufficient for the development of let's just pick lung cancer let's just pick the most smoking Associated cancer so small cell lung cancer smoking is neither necessary nor sufficient but there's nobody in their right mind that would argue that not smoking if in our analogy that's the equivalent to reducing APO B does not improve risk absolutely yeah so so I just think that you know to point to people with elevated apob as an example of why it's is safe has never made sense to me and I'll tell you another reason it's ever made sense I know I'm not going to get an argument out of you but I'm I'm hoping we can try to formulate some argument here is um there are other ways to treat apob besides diet and so I feel like if part of the argument for I need to have this APO B high is because the diet that's making it high is producing other benefits that's sort of not necessary right one can consume a diet that if it needs to be in a certain way and produce a high APO B you could still continue to consume that diet and just pharmacologically address the apob problem yeah it's it's the sort of mind-numbing uh in in congruity of this whole discussion and again it makes makes my um my skin sort of want to fall off uh but uh yeah no I I think you made a great point about smoking and and frankly any other risk factor for any other disease you know you can use smoking replace smoking for corn energy with smoking for cancer we all have lots of stories of people who smoked four packs of cigarettes a day or even emphysema right you know it's that where the toxicity is much more direct yeah it's part of the nature of the heterogeneity of response right that this penetrance in this case of a of an of an environmental factor is not 100 percent yeah I guess there are some that are right cyanide probably is uh but most of the things that we encounter in our environment don't have that level of penetrance in terms of causing risk it's certainly not the ones that we encounter frequently right yeah yeah so so yeah cyanide's a great example 100 penetrants carbon monoxide at a certain concentration 100 penetrants yeah um okay so let's go back to our discussion and now um contrast the the calcium scan with the CTA and then especially we'll use this to now explain these other variations of ctas that have shown up where they're uh more like software additions to CTA sure I mean look in uh what I tell patients is that what you get from a CTA is uh is Clarity and more information which in most cases is really really good and that comes at a small cost uh in terms of increased radiation uh and I guess you know some potential risk of the of the contrast although it's relatively small the biggest cost and the biggest reason that I don't use it uh in all of my patients in whom I'm thinking about these kinds of things is is that it's hard to get it paid for so it is actually in this case more expensive if you pay for it yourself out of pocket which almost all of the calcium scans that I order end up getting paid for out of pocket almost none of them as of today at least are reimbursed by by insurance but as you said that's calcium scans you mean and ctas they're both just out of pocket these days no no calcium scans are are almost exclusively out of pot I would say 90 plus percent of them are paid for by patients themselves but again as you said but it's so inexpensive it's a couple hundred bucks and almost everybody can make that leap and sort of uh convince themselves that it's worth a you know whatever it is 10 Starbucks so uh but for CT angiograms the cost is much higher you know and again I don't know and this is one of the problems with our health care System I don't want to get distracted in that but it's transparent to me what the cost is to my patients unless they go and do some digging and what's really annoying is that it's often not clear to them what they're going to pay for until after they already have it and so the the cost of a CT angiogram is much higher it depends on the insurance that you have and even if you pay out of pocket so even if it's not covered the negotiated rate is going to be different based on whatever carrier you have so I would say much fewer than uh 50 of my patients uh have coverage we could talk about what would justify coverage for a CT angiogram and I've sort of gotten I think a little bit more sophisticated in trying to be able to get around some of what I think are these sort of absurd blockers for for coverage but then obviously depending on the patient spending anywhere from let's just say 700 to two or three thousand dollars on a scan may be more or less of an issue and in some patients it's enough of an issue that they don't get it so I think that's just worth pointing out that it in a world in which they were covered universally and we could have access to the data that in my opinion at least it provides so much more information than a calcium scan that I'd probably just go straight there and especially because in a lot of these cases we're talking about like like you and and your 35 year old self these are cases where we just don't have a lot of data and the calcium itself is just not going to add that much so yeah yeah I agree um and and we kind of have that discussion with our patients as well which is that look the um the IV contrast is virtually a non-risk outside of a handful of settings which are clearly well understood and can be you know you know we know how to handle those pretty well the radiation these days is so low it's really in the neighborhood of two millisieverts for a person our size so you know that's four percent of your annual allotment of radiation uh but you're right the cost I mean we sort of assume 2000 to 2500 is pretty standard for that test yeah when it's paid for out of pocket it is uh I would say that's probably average but there are some for whatever reason I don't understand Insurance in this country at all but for whatever reason some insurance carriers are able to negotiate a lower rate for their for their members and so I've seen some people get and it's very different institution to institution right so you could go to UCSF and it would be 700 you might go to Stanford it'd be 1500 or the other way around and so I do advise people when it comes to these decisions if the money's an issue which it is for almost everybody because it's you know significant amount of money to shop around a little bit and then you know the question of sort of all right well what do I get for my money and uh we know that right there are different scanners in different places and those different scanners provide different information in terms of resolution but they also provide differences in terms of how much radiation exposure so uh that's another variable that we kind of have begun to address a little bit and those are the two things we always sort of say I mean we have places we send people that we because we know the answers to those questions but if it's not convenient for them we're sort of saying you've got to ask what the radiation version and it's actually it can be a 10x difference I've seen scanners out there that are at 20 millisieverts so now you're up to 40 percent of your annual allotment of radiation for one uh screening scan which you know personally I think is too much I just don't think it's worth it even if you're saving a bit of money I agree I I I I agree and it's just another layer of complexity and sort of uh how you think about applying these different tests and getting this information it's just really important to to make sure not to forget about it so every time I've had these CTA scans you know we get these beautiful images and they're 3D reconstructed uh and then their 2D sectioned and you know we're looking at the Lumen right the the tube of the artery in both cases that little speck of calcium shows up in the wall uh of the artery um and then we're also looking for sort of soft plaque as well and fortunately there hasn't been any but that's you know soft plaque doesn't show up anywhere in the calcium score so you can have a significant burden of cardiovascular disease without any calcium I think that's the thing that maybe gets missed a lot and that shows up in that 15 of people who have a zero calcium score a lot of them still have a significant burden of disease as you mentioned earlier I mean it could be that that calcification uh where it's actually placed is not problematic it's just that it's a harbinger of whatever it took to get there do you look at patients with a high burden of soft plaque and no calcification is even higher risk uh I don't really just because I don't think I buy that their data suggests that I think a high burden of plaque period is a problem uh do I believe that a high burden of calcified black might be less risky because it's more stable I guess in theory but it's super I get really nervous about sort of trying to impute plausibility and things like that to drive clinical decision making I think the reality is a lot of plaque is bad I mean we know that people who have a calcium score of 4 000 which by definition means they've got a shitload of calcium that that's a high risk and even if they don't have any soft plaque the risk is still high so I I don't pay too much attention it's part of the reason why I actually if again if everything else is equal I prefer the information I get out of a CTA of course I'm you know I'm greedy I want more and I feel like we just get so much more information and don't have to make that distinction between soft and hard black and frankly I'm not sure we're at a point in in this field yet where we can make a compelling argument about black characteristics it's been a field that I think has evolved now since the early days right since the 70s probably when the Pathologists were doing autopsies on people who died of sudden cardiac death and you know we've been trying to understand the vulnerable plaque and different plaque characteristics and what confers what confers risk of rupture and ultimately of an event I just don't think at least in my estimation and I'm certainly no expert it's not we're not there yet so I don't I don't use it anything other than as a sort of how much plaque is there um tool yeah it's really interesting that we don't yet have a better tool to explain what vulnerability means or to predict what vulnerability is right I mean I think um do you think that in the research setting things like intravenous ultrasound uh or intravascular ultrasound where they can actually look and measure the the thickness of the cap on the atheroma do you think that in a theoretical sense those things are any better even if they're impractical from a clinical perspective I guess but ultimately as a lot of things in biology this is just so stochastic that it I think we we might convince ourselves that it means something that it doesn't so I think you know we've learned a lot that you know again from the early days of trying of even understanding that ruptured plaque leads to a thrombosis on over the over the surface of the rupture plaque and that's what causes a heart attack that was a debate until 1979. or even maybe even a few years after that it really wasn't settled until Isis 2 was published in the late 1980s that showed that if you gave streptocin as harassment that you could reduce the risk I think um I think we learned early on that it didn't necessarily it wasn't necessarily that 75 or 80 or even 90 plaque that led to the big one that oftentimes the plaques that ruptured and led to sudden cardiac death were the smaller plaque the 30 plaques which kind of makes sense in in the context of how we think about you know we'll all hear these stories and I'm sure you get patients coming to you after somebody prominent dies uh and I will I'll mention the name just because I think this is an example and I I don't know Cheryl but when Cheryl sandberg's husband died on a treadmill a few years ago I mean I had probably 25 people call me that week to want to come in and get a risk assessment that happens a lot I don't know anything about his case and I don't know anything about the pathology but my guess is in younger people who die of heart attacks suddenly that oftentimes it's a sort of relatively mild plaque that wouldn't trigger any discussion of revascularization um and you know wouldn't make anybody nervous at all that those are the plaques that end up causing problems and and we can begin to weave together reasons why that might be right that that maybe in a person who's got more plaque burden that there's more chance for ischemic preconditioning and therefore the the chance of an arithmic sort of malignant arythmic response to the ischemia is lessened because of that um but I think my point is I don't think we have an understanding of to me at least that's satisfactorily would allow me to change the way I practiced clinically based on the characteristics characteristics of the plaque even the volume of the plaque and so for that reason I treat people with plaques you know any plaque 30 plaque pretty much the same way that I treat people with extensive plaque and and I treat them maximally with sort of the best optimal medical therapy I can I can offer yeah so boy we we feel so similarly about this Ethan that we're gonna have a hard time coming up with with some some something to really Clash about here because um you know this is basically the same discussion we have with our patients which is I don't I mean I'm treating the causative risks not the end stage problems like if the goal is I need to wait until you have a 30 stenosis or a calcium score of 200 to start acting that's insane it goes back to the smoking analogy right I want to tell someone that Sarah I want to tell somebody the second they pick up a cigarette to put it down not until I see that the pulmonary function tests are problematic or they've been smoking for 20 years and their risk is significant yeah and this is the sort of eye bleeding experience that I have with insurance companies talking about adding pcsk9 Inhibitors to what you know sort of statins and whatever else they're on and uh and often they'll say well they need to have an event first and I'm and you know I'm so I'm thinking to myself so backwards you're you're gonna ask me to let my patient have a heart attack so that I can prescribe the drug that's going to prevent them from having a heart attack I mean it's really incredible and uh hopefully we won't practice that way down the line I the the problem of course is that and I don't want to get distracted but all these trials are so incredibly expensive to do that the information that we're going to get from sort of the most rigorous randomized clinical trials is going to be limited just because we're not going to be you know all the questions that I want to ask and answer I'm sure all the ones you want to ask and answer are just not going to be feasible to do because they're going to be overwhelmingly expensive so we have to find a way to be able to make decisions to treat patients independent of this gold standard level of evidence and hopefully the insurance companies come around yeah I've kind of accepted the fact Ethan we're never going to have the gold standard evidence that we need in the most important demographic which is the demographic for whom we have the most Runway to effect change so in other words there will never be the study done in 40 year olds that says what is the 30-year risk of ascvd in a cohort of 40 year olds one group whose apob is reduced to 30 because we've used a pcsk9 inhibitor plus or minus whatever other agent we need versus the group that's managed with standard of care or some Placebo or something else and I mean again I I feel more convinced of the outcome of that theoretical trial than I do virtually any other theoretical trial I could ever muster up in my brain and yet it'll never be done and therefore there will never be an evidence-based case for True prevention of ascvd uh I say something very bold in my upcoming book which is that ascbd should basically be an orphan disease there's actually no reason it needs to be the leading cause of death it really doesn't even need to be in the top ten it's that preventable if you start early enough and if you're maximally aggressive and really at that point I think it just becomes a question of working through the challenges of tolerating side effects in patients who are sensitive and I think there are going to be patients who are going to be challenging but um with a long enough Runway this disease is sort of irrelevant let's let's talk a little bit about these flavors of ctas that keep showing up so um I guess we'll start with the this the CTA ffr because we did speak about it briefly we don't have to go back into all of the detail of and I'm blanking on the name of the trial there were two trials that looked at ffr in angiography Fame and fame too I think that's right yeah Fame and fame too um I guess give the give the the short version of what those trials looked at what the technology was and then we can talk about the CT side of it well I mean the original ffr that was performed that is still now performed in a cath lab is uh is basically a way to detect a pressure gradient across a stenosis right so the simplest thing I used to explain to patients is if you take a guard nose and squeeze it that there's a gradient of pressure right that there's going to be pressure proximal to this your finger your finger squeezing the garden hose and the pressure on the other end is going to be lower and that what they'd effectively do is to put a wire with a uh with a pressure sensor on one on one end of The Wire on the other end of the blockage and they put one on the near end of the blockage and they can measure the Delta and that using a mathematical formula that I've you'll know the name of it I I'm blanking on it you can impute you can impute the diameter of the of the artery relative to the diameter of the unobstructed artery or the garden hose in this case and so that kind of gives you a way to uh to get at the severity of the of the blockage and I guess what this stems from is is a 40-year Odyssey to try to take a very qualitative measure which happens in a in a Catholic catheterization laboratory which is to sort of measure the percent stenosis which is done if you've ever seen it it's done very much sort of by like uh Gestalt and the people who are good at it are pretty good at it but if you watch it you you understand that the difference between 30 and 50 is probably not that meaningful when they're severe blockages or stenosis you can sort of all agree that it's really high grade so I think you know I think of things in sort of the sort of high grade modest and low um so this has been one of a number of tools that have been developed to try to supplement the information you get from that sort of very qualitative assessment of visually how bad does that lesion look and many of these things have happened over the year you know I have as you mentioned earlier is one of them there have been a you know quantitative coronary angiography where they actually try and take a cursor and electronically draw around the the diameter of the of the vessel um Mike Gibson you know back in the old days used to do this um blush thing I can't remember what it was called but basically it would he'd count the number of frames it takes for the for the contrast die to leave The myocardium and that was sort of another indication of how severe the um the lesions were ffr evolved as a sort of hemodynamic way to be able to impute the severity of the stenosis and so I think Fame was the first of these studies and it showed that if you had a significant pressure drop If the ratio of the pressure and the sort of Upstream sensor was was much you know higher than the uh Downstream Center that that conveyed that there was a bad lesion and that it conveyed worse outcomes in people uh who didn't get stented I can't even remember the design of sales but basically I think the idea was basically look there's no ambiguity in two subsets of people who should be standard right so somebody who's actively having an MI they show up in the Ed with chest pain enzymes are leaking I mean we just go to the cath lab there's no need to putts around right um or I mean what's the algorithm on uh um uh clot uh dissolve versus stent in the active mi in the ER oh in the modern era if there's a cath lab within whatever it is I think you know I don't know what the exact number is and they're the latest guidelines but it might be like 90 miles it's really the amount of time you have to calculate the amount of time it takes to get transported to a place where there's a cath lab that does stenting primary PCI so primary PCI is the standard of care I think uh thrombolytics are used sparingly in this country and only in remote places where there's no accident where they can't get to a cath lab okay so it's the elevation am I it's primary PCI is the standard of care class one the whole deal and as quickly as you can get there and then the other indication in the non-mi setting is is symptomatic right if you have a person who is who for example on a stress if someone if someone has a stress test and on the on the stress test you see St changes does that is that an indication for a PCI as well so we'll back up so uh stemmy's St elevation Mis where there's a complete in the physiology of pathophysiology is a complete obstruction of blood flow SD segments go up you go in there's no blood beyond the blockage that's clear and everyone understands what we're now calling ACS which we used to call unstable engine or non-est elevation Mi which is not it's same pathophysiology right ruptured plaque a thrombus sitting on the plaque but it doesn't completely obstruct blood flow I think there's General consensus even among some of the more conservative groups out there that those people benefit from going to the cath lab early and having a stent to uh to fix that blockage I would say it's generally accepted on the order if I had to guess of 85 or 90 of people had practiced that way and what I mean early I mean within the first 24 hours so it's not a sort of code level emergency where you you know now most hospitals have these stemi teams where they'll automatically the emergency department will page the pager and everybody comes in from the technicians in the cath lab to the Interventional cardiologists to the fellows and everybody else they all just assemble there to get there as quickly as possible that doesn't happen there's no stemi activation for a non-stemi or a ACS event but I think there's still General consensus that that disease is treated best with early intervention and the only distinction between those people even the only distinction is the St change on the EKG when they present that's right yeah I mean that's the that is the distinction uh and of course that is sensitive but not 100 sensitive there are certain uh lesions that are obscured right where you would you know for example a posterior Mi you'd have to do posterior leads to be able to see that so but mostly it's stemi is a is a emergency go go straight to the cath lab done pass go uh non-stemi or ACS is is urgent and generally people end up in the cath lab and it wouldn't be a bad thing to have them go there you know relatively quickly depending on how unstable they are obviously if anybody has unstable symptoms no matter what they have in other words if their blood pressure was labile or if they had heart failure um or ongoing chest pain that was refractory to medical management then that would also become a sort of don't pass go go straight to the cath lab so I would say those things generally end up getting stented the the and this is a this is my opinion my read of the literature but over the past 15 years um what has changed is people with plaque but without symptoms generally don't get stented even the most aggressive Interventional cardiologists I won't mention names would probably agree that people who have a lot of plaque maybe with the exception of the proximal idea of left main there might be still some people who would think gosh even without symptoms I've got to put I'm going to put a stent in this person but generally people with with plaque no matter how bad the plaque looks angiographically those people are treated medically if they don't have symptoms where things have gotten interesting is in these cases for symptoms right because I think most I'm sorry when you say symptoms Ethan you mean symptoms in day-to-day life or do you mean under stress and provocation yeah so no so rest symptoms is unstable symptoms and that falls into that first category and those people would be should be hospitalized and they would go in that first 24-hour window so any symptoms at rest without doing anything uh we can debate about what what is like what happens if you have an argument with your wife and you get chest pain is that unstable or stable you know but mostly it's the sort of non-classic exertional angina where you're walking up a hill and you get chest pressure get chest tightness or rarely pain you stop it gets better or you take a nitroglycer and it gets better classic stable angina just people have plaque but do not have stable or unstable symptoms at all in general these days are treated medically with some exceptions um it's the people who have this classic stable angina stable symptoms so they go out and walk up a hill they get chest tightness you know feels like somebody's tightening a belt around their chest they stop it gets better it's those people who I think are kind of the most interesting today in the Contemporary practice setting and those are the people I think that require the most thought and I think you know we we hadn't put it on our list of things to discuss I don't remember if we discussed you know these trials the last time around but but obviously courage was the trial that sort of taught us that it's okay to have a lot of plaque and not necessarily intervene on it there have now been several other trials to get at that question of is is and this is part of the reason why Fame is to me like not that interesting because we've kind of already answered the question in all comers that stenting people without symptoms even if they have some significant lesions doesn't offer a benefit over optimal medical therapy there's uh there's now I think some discussion around even patients with symptoms whether they and the range of opinion I think goes from anybody with symptoms should be stented or revascularized you know in edge cases with bypass uh some people think you know medical therapy in all cases and then I think there's sort of this nuanced in between people who think give a trial of medical therapy and see if you can get the symptoms better it's not an automatic take to the cath lab but try to optimize medical therapy and if you can make the symptoms go away then there's no need to go instant that artery and that's probably where I land right now is I don't I still use Interventional Cardiology I certainly don't use it as much as I did in the past but I do use it for people who do have what I would consider to be refractory symptoms and then obviously for the unstable sort of emergency acute settings that's a different story and if you had a patient with a really high calcium burden so they're north of a thousand um and they never experience symptoms which and they're young they're you know in their 50s or something like that would you put them on a treadmill and push them as hard as you could possibly go and assume that like hey they're not necessarily exercising that hard every day I want to really see if they have any St changes or while motion abnormality when I make them you know go to 15 Mets I don't but um because because like I said I sort of land in that camp of even if you had symptoms medically yeah probably I would still try to optimize medicines now if somebody came in and was on great medicines and was still having symptoms then obviously it's a different story but yeah I don't routinely do anything to people who have high calcium in fact if you have a high calcium score whatever it is a thousand it to me it triggers a response and it's the same I don't think you need a CTA in that case send it back to CTA might might not be very useful because there may be so much calcium that kind of obscures the ability to be able to see yeah into and Beneath The Vessel so uh and it's to me I don't automatically do stress testing in something like that I often will see patients who've been completely freaked out by the result and that and they'll have had a big workup including potentially stress testing and and a CT angiogram but but I don't do that and and I likewise don't do any routine stress testing anymore as a way to follow coronary disease right that was something we used to do in the old days when somebody had a lesion you knew they had a lesion you'd kind of exercise them over you know once a year or something to see how they progress that I don't do that anymore either okay so in light of that Fame if I recall basically said or sought to answer the question if you took a bunch of asymptomatic people and you did this ffr on them you measured the fractional flow Reserve if you took the people who had a pressure drop of I think it was either 30 or more I think it was a 0.7 P2 to P1 maybe 0.7 yeah something like that it was either a 20 or 30 percent drop if those people automatically got stented and the others did not and these are both asymptomatic would we see better outcomes in the more aggressive stenting strategy isn't that effectively what the trial that was the design and that was the result and and so therefore that became standard of care in a cath lab in most cath Labs that in fact we were doing ffr in a lot of patients where yeah initially ffr was there for these edge cases where you weren't sure is this significant or not should we extend it should we not stent it I think it's it went through a period I think it's now come back but I think it went through a period where it was being used a lot based on Fame with the sort of assumption that you're impacting people's outcome hard outcomes based on your decision making and that there were certain groups of people who benefited tremendously from getting stented and our job was just to identify who they were on the surface that's not an absurdity right that's definitely a possibility but I think uh you know after however many years now of understanding the data I think the consensus is it's just not necessary I think really mostly it comes from the sort of line of evidence that we've had through you know courage ischemia orbit all these different trials showing really that the take home is that optimal medical therapy even in a mildly symptomatic person patient is is quite effective so all of this basically is Prelude to um a CT based version of this study which of course can't do the intervention but it can identify people who are getting ctas which are far more than the people who are getting traditional angiography um to say hey maybe you do need an intervention uh so again in theory the idea here is well you had a CTA I see a stenosis there it's a 50 stenosis is it significant or not I can't tell I don't have a pressure transducer in there that I can measure but I can run this algorithm on it and the algorithm will tell me what the pressure drop is so of course question one is how successful is that algorithm I I'm I don't know myself um I assume that there was a head-to-head that was done where you had a whole bunch of people that actually had cath that actually had pressure transduction and then concurrently had CTA and then they could actually see how predictive they were I I have to believe that was done right yeah there was a trial uh I don't remember the details of it uh I guess the questions are in my mind so does the physics and I don't understand the physics but does it make sense can you actually really make this calculation in a meaningful and reproducible way and these people uh I imagine back in the day when the method was being validated that there was some comparison the FDA required some comparison to be able to say that this is just as they probably required something to clear the ffr catheters themselves they probably required something it probably was close enough I don't have any knowledge that the the thing is a random number generator uh to me that that's a distraction I think there are plenty of people who who go down that path to me the question remains what are we doing and really in the way I practice do we need to identify asymptomatic people who are at higher risk is there something about is there a group of these people who are special and might show something that no other Group Patient has ever shown in the history of Interventional Cardiology which is a benefit from stenting and I I know that my Interventional Cardiology colleagues are going to hate what I just said um but we've been doing this for a long time now and we've been looking for any group of people who would benefit from outside of the key to my setting which we've talked about any group of people who would benefit from a stent being placed in their artery and we've had a hard time doing that and it's not for lack of trying it's been I mean again courage which sort of was the beginning of the end of this in somewhat sense that was a trial that was conceived of and executed by a group of Interventional heart cardiologists who wanted to demonstrate the superiority of stenting over medical therapy it was designed that way and all the bias you know sort of was was weighted towards getting that outcome it did not get that outcome and and frankly there have been you know however many dozens of studies since then and at least from my point of view there's nothing that screams at me that hey look our job as you know our private preventive cardiologists or you know thoughtful internists should be to go looking for people who who might benefit from a stent in the absence of symptoms and that that's where I'm left today is that I just can't I don't see any evidence yet that there's something magical about some group of people where they derive that much more benefit from a stent Beyond truly optimal medical therapy and I think as you said earlier if everybody got truly optimal medical therapy like if we could didn't have barriers to using all these tools and everybody I think this disease would largely be controlled now I do believe there's something else going on that's residual and you're an example I think potentially uh but uh but yes if if you know I think the quality of the medical therapy we have today is so good that it's going to be really hard to demonstrate the value of stenting people that assumes that stenting doesn't do something harmful right that and and again I think that's a open question why if you have a very high grade lesion okay even you know before there was great PCS get animators right they were just you know Zocor or something why wouldn't opening that artery lead to improved outcomes outside of the Akita my setting and that's a question that always plagued maybe even as a Cardiology fellow I was like well this doesn't make any sense it should right you're opening up an artery that that's severely blocked and we're storing blood flow back to the heart and there are lots of explanations for why that might be I don't think we have a good one but you could imagine that in going in there and put it blowing up a balloon inside that artery and put and deploying a stent that you're elaborating the contents of that plaque Downstream and much like what happens when you break up a beaver dam in a in a stream it's just going Downstream and causing its own set of problems I I don't that's just me speculating and making it up but to me it's an interesting question why why it wouldn't be has the has the study been done for example where they take a group of individuals who were asymptomatic at the time of being stented or they weren't being stented in an acute uh stemi um who then go on to have subsequent events what the location is of the uh plaque in other words when a person gets stented in the mid LAD and they go and have another event is that other event more do we can we identify a pattern so for example is it distal in the lad is it you know in a part of the heart where you could say you know maybe there was some mechanical change that took place as a result of that stent or maybe it was hey you know what the reason it doesn't work is you're playing whack-a-mole and this person had lots of disease you just happened to pick the one that had the most stenosis although stenosis by itself is actually a really crappy predictor of future events so you weren't more likely to do anything here you know maybe if you stented the entire maybe if you you know stunted the entire vasculature you would have but of course you can't do that so it really comes down to how lousy is plain up stenosis as a predictor of subsequent events well I think it's it's a good predictor that but as we discussed earlier these plaques that end up leading to bad things often are not the blacks that we would get stinted anyway so I think there's that and that's my point right which is yeah because another explanation which I think you had a good one is if you have a 90 stenosis and you haven't experienced symptoms as a result of that yet that's probably telling that if you throw a clot there you're going to survive it that's right because there's collateralization and we know that right from seeing these you know you can see that uh and that's probably the mechanism right that this ischemic preconditioning leads to this growth of collaterals and basically it's like if there's an accident on the freeway it's still I could tell my patients that you get off on the side streets and you wind your way through it takes a lot longer and it's not great when there's like a lot of traffic but if there's no traffic and it's relatively Light Flow you do fine right but that 30 lesion hasn't been tested yet no so you don't really know how it's going to work because you would never spent a 30 lesion yeah yeah so there's that and then the other thing I think is that if if you look at and now with the Advent of sort of high sensitivity troponins and other more sensitive measures if you look at say troponin or ck elevations after a long intervention they most certainly go up not in all cases but they they do go up and so the question is are you doing are you basically creating a little MI in the process of putting the stint in and does that then cause Downstream risk in the form of you know arrhythmias or other issues you know later on in life um that to me is sort of an interesting thing to think about it obviously there's you know no great data at this point but I think there are data at least observational data looking at the the area under the curve of the troponin elevations post PCI as a predictor of outcomes I think obviously the more Chipotle you have the worse you do as you'd expect okay so there was this study that I don't think is published yet but I think you and I saw it and emailed each other about was it was is it the precise trial that was that we saw the abstract for remind me this is the one that did the I think this is the one that did the ffr and it found no difference in all cause mortality no difference in mace but a reduction in the need for catheterization right yeah yeah so this has now become the sort of um value add of doing these non-invasive adjuncts to CT and geography and right it's the reason that we at UCSF now do ctffr on not all of it most of the ctas that we do is that in theory you've reduced the number of people who go to the lab you only reduce the number of people go to lab if you send people to the lab right it if you're not sending people to the lab you're not reducing number of people so again to me it comes back to the primary issue which is that people with plaque probably you know in the absence of symptoms people with plaque should probably be optimally medically treated and left alone and that taken in the cath lab is of very little value and obviously if they get to the cath lab the chance of them getting extended goes up astronomically once they're there so yes you do theoretically prevent unnecessary unnecessary stents with CT ffr but you can do that without the ffr you don't need the ffr yeah I think that's really well said right because to me I don't get hung up when a study like that doesn't find a difference in ACM because I think that's a short time Horizon but I do get a bit alarmed when there's absolutely no difference in mace right when you see no difference in anything related to cardiac pathology and the only difference is an algorithmic difference that to your point you can make on your own again I think we should maybe Reserve judgment until the final study is published I mean so we'll wait for that I don't know when that's coming out but I found myself very underwhelmed by this and it didn't change my thinking which is that at this time I'm struggling for the use case of ffr and as such we really don't employ it with our patients um it's I mean I I think that the issue is sort of you have all these levers you can pull and so your job is to kind of figure out which levels am I going to pull and I think sometimes people over complicate it right that you know they're going to be relatively low-risk people whom you could get away with Statin or maybe Statin in a very low dose of zedia I mean you know in my opinion if you have plaque significant a plaque you know they say a 30 plaque or greater in an artery in your coronary vasculature I'm pulling all the levers like that I don't need any other information like I don't need more and that's a pretty good intervention pulling all those levers by the way to your point earlier let's just assume there's something in me that's off I think the fact that the moment I had a six score ditzel every lever got pulled that's probably why 15 laters 15 years later it looks like a ditzel still nothing's changed which means if we just pulled all the levers all the time we could kind of take this disease off the table for virtually entire population this is the mission statement of my friend said Catherine reasons company verb right I mean this is they want to crispr out pcsk9 not necessarily initially in everybody but they you know he believes that if you did that you'd eradicate this disease I don't totally agree with him actually uh we disagree a little bit on sort of some of these things but in general I think he's probably right the question is do you need to go to that extreme to be able to to solve for this problem and could you apply that solution to everybody you know feasibly and worldwide that's his problem to think about not mine that's it that's it's a very and I mean yeah I I I'd love to have Seth on to talk about many of these things um okay so let's talk about two other things before we leave CTA um there's the fat attenuation index Fai what is what is that exactly I actually I'm going to be totally honest I have no idea I've seen it I assume it's been maybe presented I guess I sort of have learned in now doing this for as long as I have right I mean so I graduated from medical school in 1996 and did my residency for two years and then started my Cardiology Fellowship here 25 years ago so I've sort of learned to tune out like put blinders on and um to some of this stuff just because it it's something new every like few weeks it's been that way like consistently uh so I'm sorry I'm not like completely up to speed on this latest and greatest fat attenuation index I imagine some CT based way to look at the characteristics of the plaque and to see if it's potentially vulnerable is that the that the idea uh no it looks um and I'm not an expert in this I was hoping you were so so it basically it is a CTA bolt-on just like the ffr is yeah but it looks at the characteristics of the fat around the plaque um yeah so it's not trying to predict vulnerability per se it's actually trying to predict how much inflammation is even if I hope I'm getting this right but I think it's looking for how much inflammation is around the plaque I see that that's interesting uh that's interesting I I don't I'm not familiar I am familiar with PET CT you know we the uh the amount of it you can measure using ftg pet you can measure the amount of inflammation in a plaque that can be done quantitatively there's a group of people who've been doing that for years and I think certain pharmaceutical and biotech companies have used that as a way to kind of gauge efficacy in evaluating new molecules to see if they if they can have an impact there uh that I don't think has been being used now clinically at least to my knowledge and routinely uh I'm not familiar with the fat attenuation index it kind of makes sense so it's epicardial fat not that's right yeah okay yeah I mean it's an interesting idea right I mean epicardial fat is visceral fat and there's uh it probably does impact risk in some way again what are you going to do with that information [Music] you're already pulling all the levers I guess maybe you'd focus a little bit more on metabolic stuff yeah I guess which which we'll come back to okay yeah let's now let's pivot to another topic that seems to come up from time to time um online I guess which is are there subsets of people who in whom an elevated CAC is not a predictor of risk so there's been some confusion about this I think it's maybe worth clarifying this for folks so James O'Keefe has commented on um the fact that certain athletes you know who exercise a lot so very high degrees of cardiorespiratory Fitness might have a higher frequency of coronary calcification so let's first talk about that what how robust are those data and more importantly what does it mean yeah well I think it's plausible I mean we know that's a sort of increasing sheer forces occur you know across an endothelial surface can certainly lead to damage and that would potentially increase calcification we know that in state patients are the bicuspid aortic valve that people who exercise at extreme levels do it appear to have an increased rate of calcification of that valve and I say appear to because none of these studies are controlled but it does seem that that's the case and it makes sense and as plausible as dangerous as that word is I think the same thing could be true in in a coronary uh artery vascular bed the increasing Shear as you would expect to by increasing flow as you would during extreme exercise could potentially uh lead to some damage and therefore calcification so I do think it's plausible uh I guess I don't I still don't think and sorry I do think there is this one example where there is a disconnect between the amount of calcification the artery the amount of risk and that is within people taking statins and that's a very difficult concept for people to grasp and frankly it's a difficult concept for me to explain and uh I do find myself getting tied up and trying to explain it and I can make up explanations like you know what you're doing is healing the plaque and stabilizing the plaque which we think statins are doing and that that's a good thing and not a bad thing but I think it's incontrovertible that stedens probably to increase the risk of calcification despite lowering the risk of events so there is this one example so is it possible that exercise could be similar to that maybe but we don't have the flip side right we don't have the you know 40 Years of of really rigorous randomized trials showing that some exercises versus some version of placebo does that would I say don't exercise absolutely not would I tell some patients not to exercise to that extreme level I don't know I'm on the fence there and and the question is what's the so so each let's just assume that it is the case that high high amounts of cardiorespiratory Fitness come at the expense of some endothelial damage again I don't know if it's true but I agree with you right um there's certainly mechanistic plausibility there the question is if a person goes from call it I don't know 50 met hours per week of exercise to a hundred met hours per week of exercise and let's assume that doing that increases their calcification a is that with or without more risk let's assume it is with more risk but is that risk more or less than the benefit that they gain going from the 25 or 50 to the 100 met hours a week of exercise in other words this is what makes exercise a bit more complicated here which is most of the other things that are increasing the burden of calcification are net negative right obviously smoking more having higher blood pressure having worse lipids but the correction of that moves in the same direction as the correction of the calcification works in the same direction as the calcification of as works in the same direction as the Improvement of the risk modifier which I said it's not the same um what's I think unambiguous though and we were talking about this earlier more exercise is better than less and more calcium is worse than less that's right I've yet to see an exception to that rule that in terms I yeah I agree with you and I think that discordance is only mimicked by the Statin story right where we need more statins are are better and and also lead to more calcium look here's the thing if you put it back into sort of the terms in the context of a patient comes to me and says hey I got this calcium score or whatever let's call it 800 I don't know whatever you want to call it 500 300 200 100 uh but I I don't think it means anything because I exercise a lot like that's the question right that's the question that gets presented to us sort of at an individual level and I guess what I'm saying is I'm not yet comfortable saying oh don't worry about that whereas I am comfortable saying don't worry about that if it's because they're on Statin and so what I would say to that patient is we have to assume that that calcium is representative of plaques in the arteries and that having plastic arteries is a bad thing and that we should treat you accordingly even though you exercise a lot and if you want to be sure then we could do a CT angiogram to kind of see how much plaque you actually have uh because you know I don't know any evidence that this calcification is not plaque related that it's somehow extravascular calcification or beyond the it's in the intimate or something uh or media I guess but that's how I would approach it today is I just can't tell you I can't give you a free pass on the calcium uh because you exercise a lot exercising is great keep exercising don't stop exercising but I think the burden of proves on us to show that that is not risky and if we did a CT Andrew garment it showed you didn't have any plaque and all the calcium has sort of extra vascular somewhere else then sure I'd be okay with that but that if we do it and we see plaque I'm not I'm not aware of any data that would say let's not treat you which is sort of the subtle but important difference between the Statin star because the people on stands are already by definition on the third on the risk reducing therapy that's been shown to save lives so like it's uh it's not like what are you gonna do to that person because their calcium score is higher you know would you be more aggressive I guess is one question people might ask but I think it's a little bit of that's the difference is that there's that lever still to pull and the exercise person you step by you so what percentage of your patients take statins I mean it's a completely our uh biased group of people because it's awesome of course of course that's right yeah yeah 90. I'm guessing and is the implication that the five to ten percent who don't um have have some side effect that they aren't able to tolerate uh there there's those for sure although I think that's less frequent now because would you say Statin or any other like or pcsk9 inhibitor because I do have a few people I would just say Statin to start because what I want to sort of explore for a moment is what what are the real world implications of the use of these drugs what are the real world side effects what are the real world um conditions that prevent people from being maximally uh medically treated small number of patients to mine who don't take them because of true side effects a equally maybe even slightly large group of patients who don't take them because they're afraid of them and uh and I I don't mean that to be pejorative I think there's been a tremendous campaign a propaganda campaign to demonize statins that's been going on for a long time 25 or 30 years and it's been very successful and people are terrified of statins and uh you know I mean there have been documentaries made on house dents or poison and they're killing people and while not everybody or even maybe most people are aware of that plenty of people who spend any amount of time online are and so that is I do spend a lot of time with patients who come to see me because I have some openness to at least having that conversation with them and I'm not going to force them I have a patient of mine who came to see me with a tremendous amount of skepticism had every risk factor was probably having Angela when he first came to see me and I recommended that you start taking a Statin that first day and he was afraid to because of stuff that he'd read about how dangerous they were he ended up needless to say a few months later in the ER with an Akita Mai and uh fortunately the outcome was good he ended up with a stand he stayed on a Statin ever since then so that sort of was enough of an experience for him to change his mind but I have a number of people who just fled out either won't or it takes me years to convince them to years I mean some some people I've seen for years I've had the same conversation year after year after year after year and some people never changed their mind some people change their minds because of other things happening like this patient having an MI and some people change their minds because finally they are convinced but I never force it what's the what's the core belief that's at the root of the of the fear you think I mean again and I say this just acknowledging that yeah probably about five percent of patients are going to experience Muscle side effects that are going to Warrant not taking a Statin because it's going to impede in their quality of life and that you know but so if you just acknowledge unemotionally that there are side effects you're going to see transaminase elevations that are just too much especially if mixed with Zetia um but if you if you acknowledge all of those things there's there's obviously some deeper seated fear in something that can't be seen or measured or Quantified where do you think that comes from and why don't we see that with with other classes of drugs to the same extent I think we do I just think this happens to be you know one of the most prescribed classes of drugs in the history of of humankind and so it's just the denominator is bigger I think this is sort of the same thing that gets at a lot of skepticism around science and big Pharma and you know I mean there's a whole world of people out there with these like vast conspiracy theories about about the development of statins and you know about how Rory Collins is an evil you know person you know he's engineered this whole conspiracy to try to get the whole world on these poisons and I mean there are people out there who really believe that and look if you hear something enough and you aren't an expert and don't have access to all the data that we have access to it can be compelling and I've watched some of these documentaries they're terrifying just as I'm sure you know the documentaries were made after the Wakefield experience in the late 90s were terrifying to Young mothers who were worried about giving their kids MMR vaccines or whatever you know any other I think it's very easy to convince people to be scared of something it's a lot harder to make people unscared of something and this is just an example I think where there's a group of people out there who just don't believe in this whole Enterprise there for whatever reason very skeptical of of big science and big Pharma and don't let get me wrong obviously there are plenty of things that big Pharma has done wrong and we can go through the examples of that this happens not to be one of them you know that the sad thing about how demonized statins have been is that it's one of the most profoundly important interventions that we have in modern medicine and it's it's astonishing to me that like this is being compared effectively to to smoking right to cigarette companies I haven't heard that comparison but certainly people will quickly point to Purdue in the opioid crisis has proof positive that the Pharma entities are evil and um uh it's again it's uh there's no question that Purdue Pharma is indeed evil and again I've said this before on the podcast I think it's really difficult for for us as a species to think dialectically and to hold seemingly contradictory truth simultaneously that Pharma companies can do good things and bad things and uh you know that that seems to be true across the board that seems to be true of every person as well right any given individual can do something good and something bad the exceptions would be those that are universally good or universally bad as people right so yeah yeah I mean I think you know there are people out there who just are clearly bad and yeah and there are people who are probably clearly always good and yeah again I'm not either of those I'd like them I'd like to meet them yeah um okay let's let's talk about blood pressure because I I think this is one of those areas that I've personally become more and more interested in over the past year um and it's actually become more of a concern to Me Maybe over the past two years through the lens of the kidney so we have this organ that just doesn't get much attention I'm trying to think outside of my podcast with Chris Sonnen day where we talked about kidney and liver transplantation I don't think I've got a single podcast that deals with the kidney um and it's a really special organ and I sort of explained to my patients that in our bootstrapping approach to living an extra few years on this planet a lot of it requires a phase shift in time right so if you're 50 years old you really need to be held to the standard of a healthy 40 year old if you want to live an extra 10 years that's the way you want to think about it you want to think about that in terms of your mind you want to think about that in terms of your body you want to think about that in terms of your coronary arteries I want to think about it in terms of your bone density but you got to think about it in terms of your kidneys and so when we look at a person and estimate their glomerular filtration rate which we use you know sistatin C to measure that we've largely abandoned a creatinine um it's really tempting to say well you know this guy's 55 years old is egfr is 70 mils per minute that's good enough but in reality it's not actually it's far from good enough and the kidney is not uniquely but exquisitely sensitive to high blood pressure again I'm not a nephrologist and I never really I don't think I remember much from Nephrology but I certainly remember that something about its vasculature is incredibly sensitive right it probably has to do with the fact that it's such a tiny organ that takes such a high amount of our cardiac output um and I suspect just like the heart and the Brain it's very sensitive to pressure um and so that really is the lens through which I think about this first and foremost with with the meaning even the slightest amount of elevation in in blood pressure is going to interfere with long-term Kidney Health and also with heart and brain health so so really there's a win across the board if we just normalize blood pressure so I'll posit that and and have you just kind of explain from the um ascbd perspective the importance of blood pressure and how it Stacks up with smoking APO B and some of the other heavy hitting risk factors yeah so I I guess I just want to acknowledge how strongly I agree with you about the neglect how much we neglect the kidney is an organ and Nephrology as a sub-specialty of medicine uh I actually used to give a lecture on hypertension to the first year medical students at UCSF and I did that in conjunction with a kidney pathologist who interestingly was uh had been at Hopkins when I was a medical student was my advisor very interesting woman has now retired named Gene Olson and she she and I co-gave the lecture she gave the pathology part and I gave the clinical part and I learned so much about the importance of the kidney and regulating blood pressure in that you know in giving that lecture with her for however many years it was 10 years um so it's it's uh it's both an important cause of blood pressure and in fact I think if you go back and look at um you know Rick lifton who's sort of one of the Premier human geneticists in in you know history remember the National Academy had it some probably should win a Nobel Prize he characterized all of the single gene mutations that lead to extreme increases or decreases in blood pressure uh you know I think at the time and this was 20 years ago they were they were like you know 10 each 10 10 Single gene mutations that led to people who had really really low blood pressure had to constantly supplement salt and do things like that and then 10 that led to extremely high blood pressure and I think like nine or whatever it is 19 out of 20 of these things were located in the same location in the uh in the proximal collecting doctor in the tubule it was it was like you couldn't have picked a place that was more important evolutionarily for how we handle volume and uh and salt and solute so it's an incredibly important organ both as a cause of high blood pressure and also as a consequence and those experiments you know Gene showed these beautiful slides that I'll send along sometime you know pictures of what happens too your kidney after it's exposed to low increased levels of blood pressure over time so um it was interesting because I was giving this lecture as a cardiologist during the kidney block it always felt I fell out of place so most people kind of know that when they go to their doctor and they get their blood pressure checked normal is about 120 over 80 millimeters of mercury um what do we know about how much that changes in a healthy person across the course of the day uh so when they're sleeping when they're ambulatory and walking around but not under stress I.E not exercising when they are exercising vigorously when they're you know under stress physiologic stress psychological stress all of these different things that we do every single day surely our blood pressure must change and yet most of us myself included have virtually no idea of how our blood pressure is changing under those situations even if under perfect optimal conditions I.E sitting down legs uncrossed for five minutes it reads 120 over 80. so what do we know about the rest of the time so I guess it's it we don't I don't want to get too distracted but I think it's fascinating I've thought about this a lot and the question of what's normal is and you know we'll assume 120 over 80 is normal if you look at blood pressures across different animal species it's mostly in that range there are some that are outliers obviously a giraffe is is the best example of an outlier species with much higher blood pressure that it needs to have to be able to pump blood up to that very hit that head that's sitting way up high it is weird to me from an evolutionary evolutionary perspective why we would have the same blood pressure as a mouse right it's a little tiny creature who walks around on four legs why should we have the same blood pressure it speaks I think to the conservation of the sort of vascular system that we have I think most people when I was a medical student I'm sure you were the same we're taught that 120 over 80 is normal but that's just normal whether you're uh you know 7 17 or 75. I don't think we have a good understanding of well we have an understanding of what is epidemiologically normal as we age and so we know that blood pressure does go up with each decade of life if I had access to that lecture I used to give I could show you what happens but but certainly with each decade of Life your blood pressure goes up on average if you're looking at a population of people is that normal is that part of normal healthy aging or is that just a function of pathology is it a function of something going wrong over time to your point is it's something about decreased kidney function or maybe as an increased vascular stiffness over over time I think all those things are possible and probably probably probable so for a long time it was assumed that a blood pressure that was normal for somebody in their 20s and 30s was probably too low and not normal for somebody who was in their 60s 70s and 80s and so we let had sort of had this permissive hypertension in elderly people because we thought well gosh they required it's just part of the aging process and it really hasn't been until the past really 10 plus years that we've begun to ask specifically in really well-designed clinical trials is that the case and is it the case when it comes to looking at an important clinical outcomes and I think uh you know my take on this now is different than it was 15 years ago and that is that 120 over 80 is normal no matter where you are in life and that anything above that is abnormal and you know just to kind of get to the punch line what I tell patients is that my aspiration is that we can get you as close to 120 over 80 as we can without harming you because there are certainly potential harms that are associated with treating people to these low numbers they can be in the form of side effects or impacts on lifestyle they can be in the form of real toxicity you know hyperkalemia have risk of death I mean there's all kinds of potential issues that it's not just a simple intervention like treating LDL or apob lower and lower lower there's really no consequence at all there is a consequence of lowering blood pressure too low in this case so that's my overall kind of philosophy of how to think about blood pressure is I do think there's now evidence from good clinical trials that 120 over 80 is normal and that we should try to get there as best we can without making a mess so through that lens basically we're saying that the amount of float that we see in blood pressure again we're all we're talking about blood pressure in a very narrow instance which is seated resting Etc oh yeah yeah we'll come back to the other point but just to build off that that when that drifts up to 125 130 135 140 in an aging population we're actually calling that pathologic in the same way that I think we would all agree that the reduction in glomerular filtration rate the reduction in ejection fraction the reduction in pulmonary function okay yes that occurs with aging but that doesn't mean that it's not part of an aging process and therefore part of something we want to minimize correct that's right we lose muscle mass as we age is that something we want to accept and that's normal or do we want to try to do it we can to preserve the muscle mass that we had it younger in life and again I think here the the crutch that we fall back on and is good high quality well done clinical trials and in this case we have now have them and it's not just sort of an opinion based thing that says oh we'll really get closer to 120 over 80 we actually have evidence that being closer to 120 over 80 impacts mortality and uh and that permitting people to run higher to a level that we used to consider to be just basically pre-hypertension or just normal even an older person 140 over 90 that leads to a significant increase in risk of dying so to me I think uh we've learned a lot and I don't I don't consider it to be a normal function of Aging I think there may be a process there's obviously a process that goes along with aging that there's a decrease in function of a lot of different things that combines to lead to this increase in blood pressure but I don't leave it alone okay uh I think that makes sense to me as well um let's let's ask this second question now which is the one that vexes me the most um which is how much of a given day let's assume I sit down three times a day for five minutes relax don't look at my phone don't drink coffee don't cross my legs I'm perfectly Zen I put the cuff on my arm I measure the blood pressure it's 120 over 80. let's assume I do that three times a day and I get that number how reflective is that of what my blood pressure is when I'm sleeping let's say I'm sleeping eight hours when I'm exercising let's say I'm exercising for an hour 90 minutes a day and when I'm sitting at my desk stressing out over email how how much variation am I getting tons so you know the first time I ever was in the cath lab it was really amazing to me to see the variation in blood pressure just in a patient lying on a table based on before they were sedated and after they were sedated or I mean like you know there are all kinds of things so there's no doubt that there's a huge amount of variation from second to Second minute to minute hour to hour day to day and Beyond in blood pressure and I think it's very easy to get distracted by that and and I do all the time and obviously when I'm sitting in traffic my blood pressure is not 120 over 80. when my kid you know spills coffee all over the computer it's not 120 over 80 right that when I'm exercising it's not 120 over there's physiology and there's pathophysiology so physiologically our blood pressure does go up and it's meant to go up during some of these cases it's it's a function of increased cardiac output which is one of the components of of blood pressure so uh I think it's understandable the question then is what do you do about that relative and sort of how best do you measure blood pressure and so again and this is a broken record I'll just keep doing this but I fall back on the clinical trials and just as you know we try to practice as best we can with some sort of fidelity to the way the trials are done I go back to sort of how are they measuring blood pressure in these trials and therefore how are the decisions made to adjust medications and how did that influence the you know the practice of the trial and therefore how should that influence our practice because those are the outcomes that we look at so this got a lot of attention when Sprint was first published which was I think 2014 or 15 I can't remember the exact date but it got a huge amount of attention there was all kinds of pushback from almost every angle you could think of there were a lot of people out there who felt like this is just yet another example of medicine trying to do too much the less is more crowd hated it right that this is just over medicalizing normal aging right there was a significant amount of attention paid on how they actually measured the blood pressure because it wasn't the way that we typically measure blood pressure and it was the way that we probably ought to measure blood pressure but it certainly wasn't the way that we typically measure blood pressure so if you go back and you look at the data if you look at the methods what they did was they had people in a quiet room they had an automated cuff one of the sort of standard you know sort of uh Best in Class at that time automated cuff they put the cuff on the person they had them seated and relaxed in a quiet room by themselves and they had the blood pressure measured three times five minutes in between right so total of once five minute break one more five minute break and once more and they took the average of those blood pressures and that's obviously much different than having somebody rush in after parking their car and run into the office in a sweat and show up and somebody slaps a cuff on them and measures their blood pressure but my point is that that optimal way of measuring blood pressure even if it ends up yielding numbers that are lower that are what we typically get that led to the result in that trial which was so spectacular that the trellis stopped early and this is not to all the you know conspiracy theorists out there this was not a farm response sponsored trial this is an nih-sponsored trial the government-sponsored trial and was agnostic to different agents right I mean it was not about the the Physicians who enrolled patients in the trial had had access to almost any therapy during that trial so this was not about sort of proving the benefit of one drug over another this is purely about testing the hypothesis that getting as close to 120 over 80 rather than letting people sort of float up to 140 over 90 was better or not and it turned out that it was with caveats so let's let's talk about that methodology and then let's talk about the algorithm agents and then the the potential downsides so um I have started testing my blood pressure six months ago and the reason for it so I shouldn't say that I have always checked my blood pressure because both my parents have hypertension I'd always attributed to the fact that I had low blood pressure to the fact that I was super healthy and did all these other things but I realized look there's genetics to this as well so I'm just going to start checking my blood pressure every couple of days and I did and so for a couple of years I just checked my blood pressure three four times a week just when I'm sitting at the desk working never attempting to relax or rest or do anything and it was pretty low you know probably averaged 110 over 70. was sort of a typical reading of while I was sitting there working um and then something happened in August it was consistently a little bit higher than that not a lot higher but it was 125 to 130. and it was you know more or less 80 in the denominator this made me get a little more serious I got another cuff and now I started doing the full sip protocol three times a day with both the Omron cuff and the Withings cuff and what I realized were two things the first is I can always breathe my blood pressure down to normal in other words there's never been a five minute window when if I don't sit there and really focus on breathing I can't get that blood pressure to come to normal but most often than not that first reading the second I sit down especially in August it got better in October and September was kind of a transition month it's kind of normalized now but it was not uncommon for that first one to be as high as 140 over 90. if I just you know was literally doing something not exercising but if I was you know doing something active and then I went and sat down like the equivalent of the guy who shows up from the parking garage you know just parked the car had to walk up one flight of stairs sits down 140 over 90. five minutes later it's you know it's 117 over 74. and you know I've been in sort of a back and forth discussion with my doctor and with my colleagues about is this something I need to care about because now if you look at my spreadsheet and all of my phone data my blood pressure works perfectly normal for the last six months I've averaged below 120 over 80. but I kind of feel like I'm cheating Ethan because to guarantee that it's low I have to take five minutes of being calm which then makes me wonder I know that that's in line with how the Sprint study was done and you could argue well Peter You're simply you're actually doing something that's less extreme than what they did because they did three measurements over 10 minutes but I think but deep down I know my blood pressure is not 120 over 80 when I'm sitting at my computer you know writing because when I check that blood pressure straight away it's it's above that so I hear your point that it's okay I mean what I think I'm hearing you say is based on the way the trial was done we have to assume that the other people when they first sat down might have been higher as well yeah so here's what I would say is I think uh sounds like something changed in you and yeah a book deadline is definitely what changed in August so there's no question that well so if that's the case then that's understandable and that's that's okay I think uh in your case it sounds like what I was going to say was if it was truly a change and there was no explanation for it like a lot of things in medicine uh then I probably uh would have paid more attention to it even though it was going from what was normal to normal right that you just it sounded like something did change but in this case it sounds like there is an explanation in that you had this stress in your life from the book so I guess the cheating thing reminds me of my daughter I think I told you before is uh my younger daughter is legally blind and she plays basketball and we were discussing a potential uh this is such a crazy little aside but I thought I'd tell this story because it's kind of cute she we were discussing a potential procedure she could have to improve her vision uh because part of her decrement of visual Acuity is that she has pretty bad nystagmus lateral nystagmus and the opthamologist was saying that if you can sort of make that better understandably he'll improve her visual Acuity and that they somebody stumbled onto the idea that if you cut the optic the extraocular muscles and just to reattach them don't do anything else but just sever them and reattach them that nystagmus can go away and that people's visual Acuity can improve a lot so we thought well gosh that sounds really interesting we should do that it's fascinating how that might happen but uh she said she didn't want to do it because she was like that's cheating there's a kid who runs around with a visual Acuity of 20 over 200 and she was like that's cheating so we haven't been able to convince her to do it yet we'll see if she changes her mind someday but I don't think you're cheating uh what you're doing is optimizing the measurement I think what you could do if you want to and maybe you've already done it if you really want to get a sense and it would be great to have this over time serially is to do a 24-hour inventory blood pressure monitor to really get a sense of what what is the average blood pressure you're seeing over a 24-hour period because there is a difference when you're sleeping your blood pressure should be low right that's physiology yeah when you're out and about and doing things it's going to be higher so what is the you know survive and they can quantify all the spikes and it's actually a really nice tool that I'll use and Peep especially in people who have some degree of what's you know commonly termed white code hypertension which is kind of what I mean white could hypertension is real life right why could hypertension is living in the real world uh so so how does it how does an ambulatory uh BP cuff work um it's it's presumably a cuff that sits on the arm and then it straps to a device like a halter would I actually it's funny I don't think I've ever seen the device uh I've ordered a bunch uh it's a cuff so it's really old school right it's not like this is new technology where they can measure blood pressure without doing the old finger manometer so it's a cuff it's I think got a self-incl I would imagine it's got some you know Hardware attached to it that tells it to inflate and measure blood pressure just as you would a with a one that you have in your office and it does that once a minute or whatever it is over the course of 24 hours so it's constantly inflating deflating over the course of the of a day patients who have mine who've worn them say that after a while you get used to it and just you can ignore it it seems to me like it would be really annoying to have this thing like inflating and deflating all the time but that's what it is what it does though is it buys it buys you sort of an a distraction from real life it buys you sort of when you're not thinking about things when you're clearly not stressed or you shouldn't be stressed are you when you're sleeping um what is your blood pressure and we know that blood pressure that hypertension during sleep is abnormal it's the it should really be a time when your blood pressure is the lowest so it's just another tool that we have to kind of get at that question it is always interesting to me that we measure blood pressure not just once up you know 10 or 30 second interval in a 24-hour day but then we do that you know on average you know once or twice a year that we assume that this very variable number is actually meaningful and it's remarkable to me that it has been even meaningful the way that we've been measuring it because it is such a poor sample I mean we we in our patients will will ask them to do twice a day checks at home same method that I'm using for at least two weeks once a year and you know if we have reason to believe that that suspect will do it more and yet so even though that's much more than they would be asked to do normally it still feels woefully inadequate and I've tried a bunch of devices that's supposed to measure you know supposedly measuring blood pressure like little wrist based devices yeah I've never found them to work is there anything on the horizon that's that's uh that's closing the gap on that you'd think so uh you know there was a period of time where people were using a cell phone camera and you could press your finger on the camera and that it could basically detect the pulsation it could almost calculate a uh you know a pulse wave and it could give you a sort of imputed systolic and diastolic blood pressure that never made it obviously we don't we're not seeing those around we're not seeing any other devices that people can wear that can accurately measure blood pressure so I do think it's a interesting question you'd have to think that at some point even if it's an intravascular device that you could put a miniature device you know much like you know we're now using uh I don't know how much you use them but I use them a lot these uh uh implantable event monitors these Loop recorders we use them to detect a rhythmias it sounds bad right when you think about it but it's really not that big of a deal there has to be a way to get a pressure transducer into a into an artery safely that you could leave there for some period of time it feels like that's gonna come but I haven't seen it and then non-invasively would be amazing but I just again haven't seen it so yeah it's it you know I I as you know I find CGM to be kind of a remarkable tool I would think this is even more important because glucose in many ways is less variable than blood pressure or at least its variability is more predictable um in other words you could I think much more easily get by with just spot checks of glucose than you can with just spottex of blood pressure to have a true continuous uh ambulatory BP monitor I mean that that would really be a game changer in medicine again when you think about the heart when you think about the brain when you think about the kidneys it's such an important thing I agree with you I think that said the intervention that was used in Sprint still showed a remarkable benefit and so we can't exist with the tools we have yeah and while they're not optimal they're uh they're probably adequate and they're definitely better you know if you go back and look and this is part of this lecture I used to give if you look at sort of the percentage of people that have um either diagnosed blood pressure right so uh how many people are are known to have hypertension um who actually do have it how many people are treated at all right even have on any medicine and how many people are controlled if you look back in in time when this was first done in the first Indian sermon in the whatever 1975 76 whatever that was only 50 of people who had hypertension were even aware of it only 30 percent were actually ever treated and only 10 were controlled and I don't know what the most current numbers are but the awareness has gone up but it must be north of 80 now treatment is probably 75 or 80 and control is probably somewhere around 50 percent so we're still missing 50 the opportunity to treat 50 of people with this disease so let's go back to Sprint this was that this trial was drug agnostic right is this the one that basically said you know start with a thiazide move to a calcium channel blocker and then an ace or vice versa no that uh actually I don't remember the algorithm for Sprint but I think it was relatively agnostic so all hat was the first NIH sponsored blood pressure trial that was in early 2000s like 2002 2003 and that tested five different classes of medications okay two of which were discontinued so I believe it was calcium channel blockers uh ACE inhibitors and the calcium channel blocker at the time was amlodipine ACE inhibitors diuretics thiazide diuretics or chlorthalidone um beta blockers and uh I don't remember this oh it was Alpha uh it was it was uh Alpha Agonist um so because at the time they were being used for blood pressure and both the alphas and the betas were stopped early because they were harmful and so what the result of that trial was that using any of the other three classes was first line and primary hypertension treatment of primary hypertension so and that was lysinopril amlodipine and a thiazide correct yes and I believe the thighs that they used was chlorthalidone and we can talk a little bit about the difference between quartality and Hydrochlorothiazide but um in general chlorthalidone is more potent and that's the one that was I think used in the all had trial but I didn't have to double check and and if I recall the amlodipine lysinopril and the thiazide all ended up having similar outcomes better yeah yeah and I think there were maybe some stroke if I it's been like so long since I've reviewed it but I think there might have been like a minor difference in stroke risk and they amlodipine but the take home of that and what became contemporary practice was use any of these three agents first line in primary hand retention and and if you need more you add another and the target was 120 over 80. well that was yeah I mean it was the target uh it certainly wasn't a the emphasis was not the definitions definitely changed right because there was this sort of category in I don't remember which jnc so you know I think it was jnc6 or something there was there was a category for a normal Ah that's right so it was normal was actually 120 to 130 over 80 to 85. borderline was 130 to 140 over 85 to 90. and it was only then hypertension if you were greater than 140 over 90. and then they called it stage one two and three so then they redid it jnc7 it was normal was less than 120 over 80. pre-hypertension was then at 120 to 140 and hypertension was then above 140 over 90. that was the that was the difference in between jnc 7 and GNC six um jnc eight I believe uh gosh I can't remember what happened there was some controversy and they stopped after that there was like basically they had and nhlbi said we can't do this anymore because there was too much controversy over these so what was the impetus for Sprint the impetus was to test the new hypothesis that was should we be more aggressive in the management of hypertension so the impetus was that there were epidemiological observational studies and I can send you one or two that showed that it appeared that the risk of of bad outcomes mostly coronary cardiovascular disease was lower step function lower in patient had optimal blood pressure this is you know according to the old classification people whose blood pressure was 120 over 80 or less optimal and then a small step increase in people who had what was then classified normal and then a large step increase in people who were considered high normal or even early stage hypertension and so but this was all observational it wasn't you know there was it was it was on a prospective study so the NIH designed a study to prospectively evaluate whether treating people to these two different goals and these were aspirational goals foreign a change in outcomes and so they randomized these people again the doctors were given leeway as to which agents to use and you can look through the supplemental tables and see which ones were used but there was really nothing at least to my recollection there was nothing about the different agents that was that meaningful uh clearly people got to the two goals that they were assigned to randomly it was obviously not blinded because you couldn't be blind to your blood pressure but they got to the two goals so the people assigned to the more aggressive 120 over 80 got to like 123 or whatever it was 82 and the people into that 140 over 90 were more like 137 you can look at the the Curves in the New England Journal paper and they separated yeah it was 121 versus 136. it was something like that but it was a significant difference and obviously the amount of medication usage was much higher in the people who were assigned to that more aggressive arm and there are some questions there was well was it a benefit of the medicines or was it a benefit of the blood pressure look I mean we can ask all these questions forever and ever but the reality is this was a really striking difference such that the NIH stopped the trial early because of benefit in that lower group and I think it was one of the most important and practice changing trials that we've had I don't think that it came without some cost risk right I mean it would be silly to just completely dismiss this there were real issues right there was a greater increase in the risk of Falls and syncope and I think even in the risk of significant kidney dysfunction that was all reversible but it was all there and so what we took away or what I took away from that trial was it looks like you get a mortality benefit for getting closer to 120 over 80. so let's get there if we can without creating one of these problems so obviously if you're falling all over the place because you're dizzy or if your kidney function deteriorates because your kidneys aren't getting enough blood flow or whatever something else bad happens then we're not going to do that but we're going to get you as low as we can as close to that Target as we can without making a mess yeah and I think that's that's sort of why my doc has been relatively unexcited about doing anything in me is he he still remembers a year and a half ago or less than that just over a year ago when under my normal set of relatively low blood pressure I stood up in the morning too quickly fell face planted split my head on the table and That Was An Occurrence like once maybe twice a week I'd get up and need to sit back down again in the mornings um and so understandably his appetite for trying to correct an average blood pressure of 120 over 78 is pretty low um and and I'm not I'm not keen to take any medication either clearly well and there is no doubt in blood pressure unlike and in cholesterol if we want to go back there is a U-shaped correct but too low is definitely bad and uh I think your body was telling you that your blood pressure is probably right about where it ought to be and maybe even a tattoo maybe you're just like a little dehydrated in the morning or have some orthostasis but it sounds like your doctor made the right decision I don't think there's any evidence that I'm aware of that treating you to below 120 over 80 is advantageous no it was more just my question was should we treat such that I never have a reading above 120 over 80. you know yeah and again I think that's probably too aggressive based on these based on these side effects well I don't think it's even feasible um I mean the way you exercise I would be a shop there's just no way I would imagine if you were a 24-hour ambulatory blood pressure when you're exercising especially doing you know isometric you know resistant chain your blood pressure is going to go way up yeah yeah no actually I think that's a great idea I I I've I've wasted a little bit of time in the last uh two years looking for new technology to measure blood pressure in a continuous ambulatory way and every device I've tried has failed so I think I just need to bite the bullet and do the old school uh low-tech way if some smart engineer out there wants to figure out a great important thing to work on this is definitely at or near the top of my list I I would agree so I would so I would go for it it would be great right as you're as you say that there isn't really anything now other than the old school old-fashioned single manometer just attached to your arm yeah so so what about the step trial last year did that did that sharpen our thinking at all I think it just assuaged any fears that people had that there was something unusual that Sprint and of course there was this concern over the trial being stopped early which you know does risk you know does risk uh what is it a type you know this stuff better than I do but it does risk the possibility that the result was spurious yeah so I think step does sort of is a nice confirmation that because because I think that uh I think Sprint was stopped at like three and a quarter or something three and a half yeah something like that it was definitely stopped early and again that was because it was pre-specified and there was a dsmb in the whole deal and again it was an industry that stopped it it was it was the government that stopped it and um because of overwhelming benefit and you know you could have made the argument to keep going a lot of people did um they felt like this was an important you could calculate the number of people who were under treated and that they could calculate the impact on mortality even here within the United States for every day that you didn't get this result out there and so they made the decision to go ahead and stop the trial and Report the results and like I said there were a lot of reasons people didn't like the trial lots and that's fine uh there are lots of reasons that we can all find fault with a lot of different things we do anyone who's done a scientific experiment knows that there's plenty of people out there to find fault with all of the things that you did or didn't do correctly so I think that what I took away from the step was that it was a nice confirmation that that Sprint was probably not spurious that the result of this print was real and robust and repeatable I think the other thing step had going for it over Sprint is it included patients with type 2 diabetes which I believe were excluded so you you had a longer trial you had a more representative population um and yeah I again so I'll tell you and we can leave this after we're done with this because I want to make sure you have some time to talk about the metabolic stuff but do you have any thoughts on the specifics of various agents so you have these two really good trials that were largely drug agnostic yeah and and yet I still when I'm hanging out at the bars at night talking to no I'm kidding this is not barred I was gonna say that um you hear this little bit of you know ARB versus Ace versus calcium channel blocker and and basically the question is independent of the effect on blood pressure so if you have two agents an Ace inhibitor or an Angiotensin receptor blocker for example or throw in a calcium channel blocker that can equally lower blood pressure so they you know they can all they can get everybody down to 120 over 80 and they can the symptoms and side effects become non-issue and each of those will have a slightly different set of symptoms we know do we have one reason to pres to to to to prefer one over the other for example when it comes to renal protection uh okay so my first answer is because of the conversation we had earlier about the sort of lack of awareness and lack of treatment and lack of control of blood pressure my first advice to people is get the blood pressure control and that's what I tell patients right that let's just get the blood pressure control then if we want to try to optimize and find out what the right you know combination of things is for you given your other circumstances uh the NIH used to use this term extenuating or special circumstances you know for example if somebody had an angina even the beta blockers were no longer first line for True primary hypertension if you had angina you'd have you'd included the use of a beta blocker and that hypertensive regimen it was really an anti-angional but you know it will always blood pressure so I think the first step is just get to goal uh I do tend to to do things differently in some context so age to me has a big deal um in both directions right young people don't like taking diuretics and in old people diuretics can be a little bit more challenging right so there are more electrolyte abnormalities I see a much greater incidence of sort of hyponatremia and other electrolyte problems and of course the kidney issue right is is there too um so while I think if I had to pick my favorite agent who I that I think probably among the three classes is the best at managing sort of all comers of of high blood pressure it would be chlorthalene or thiazide diuretic I don't use it as much just because it's harder to use I think amlodipine is a great drug because it's the easiest to use it doesn't require any monitoring right you don't have to monitor electrolytes you don't have to monitor kidney function it's a benign drug super easy very few side effects other than a not super infrequent amount of of what's considered to be swelling in the ankles it's not really edema but it's the sort of non-edema ankle swine that people just don't like especially women don't like having so aside from that it's a very easy drug um for ACE inhibitors or arbs and I mostly don't make the distinction between the two I probably should but I don't there are data there are data I think that do suggest that those drugs may be more indicated in certain subpopulations so for example there was the hope trial right which was um I think you know mid-2000s yeah and so it suggests that there may be a benefit in people that have atherosclerotic coronary disease to have to have an Ace inhibitor on board so maybe in people with with uh you know with ascbd or scbd risk I'll use that one over the others as a first line it's also you know there's the whole ARB and and aortic diameter thing right so people who may have a little um you know increase whether you want to call it an uh an aneurysm but just an increase in aortic size that there may be a benefit to arbs um you can start begin to weave together all these little things I like ACE inhibitors and arbs probably the best they do require monitoring right so they do require but you get you know electrolytes because there can be in some patients there can be issues especially with with potassium and they can impact kidney function so it's this weird thing where uh the benefit to people with kidney disease is high but then kidney doctors are also very nervous about the potential toxicity kidney toxicity of ACE inhibitors and arbs so it's this weird thing to answer your question I think in people with existing kidney disease that that's probably the drug the other place that I use ACE inhibitors ARB first line is in patients with diabetes because that's been shown to they've been shown to reduce the progression of the diabetic nephropathy again and again so I think so somewhat renal protective again renal protective yeah so I think they are probably the most renal protective Beyond just getting the blood pressure lower that which is not is still to me primary yeah so really what you're saying is look the the first second third order term is take that 50 up to a hundred percent in terms of effectively lowering blood pressure and when everybody's at 120 over 80 we can and we're doing it without causing ancillary side effects so that's the third fourth fifth order term the tail end of this polynomial is the Nuance around actual class of drug inside that yeah I think that makes a lot of sense and tolerability uh because I do think you know we probably don't pay enough attention to that it's probably the biggest reason for non-compliance today yeah I kind of include that in the second bucket right is anything whether it be ankle swelling or a dry cough that obviously tends to occur in some people with ACE inhibitors those older people who tend to get more orthostatic right I'd stay away from that again staying away from directors because Falls and older people I mean you're not old and you're obviously not at risk for having a significant injury from falling but it's a huge Source did you see my face after I fell well you had a good sleep because you had a great story about the bar you were in the night before yeah yeah no it's um look I think falling is a is an enormous risk uh for for an elderly population and it's I mean between the head bleed and the femur fracture I mean these are devastating consequences for someone in their eighth decade and Beyond I mean absolutely life-changing and sadly often life-ending yeah they are yep yeah and I say that with a 81 almost 82 year old father who has unfortunately fallen down several times and uh it's a bad it's a bad thing so let's spend a minute Ethan talking about one other thing kind of bringing it all the way back full circle in the atherosclerosis World um I generally tell my patients that there are four big pillars of risk in ascvd uh smoking hypertension APO B and metabolic health and that last one is kind of squirrely because you know I can't point to one number that tells me like I can point to your APO B I can point to your blood pressure you're either smoking or you're not smoking um but here I talk about the sources of fat that exist outside of your subcutaneous uh you know Depots of fat and I typically talk about five of them but I know you tend to focus on a couple so I want to double click on those but just for folks listening right I think the generally accepted principle of this is we as a species one of our remarkable advantages in evolution was our ability to store energy uh you know without this capacity we wouldn't exist and so we have this vast network of subcutaneous adipose tissue white adipose tissue that is incredibly Adept at storing triacylglycerides and I think what appears very clear is that different people have a different genetic capacity for how much they can store so I kind of liken this to a bathtub everybody has a different size bathtub um and you the water coming in the bathtub is how much you're eating in the water leaving through the drain is how much energy you're expending and if you're accumulating fat you are you know obviously consuming more than you're expending but at some point you could fill that bathtub up and water can escape the bathtub and that's when really bad stuff happens right that's when it gets into you know the floorboards the electrical stuff and that's a disaster and you don't need to get a lot of water out of the tub for really bad things to happen right ask anybody who's gone through a leaking a leak in their house so you can you might have a hundred gallons in the bathtub if two gallons Escape in the wrong place it can be a disaster so talk about the places where it escapes so around the viscera within the muscle itself in the pancreas specifically which we can talk about maybe why that's so problematic pericardial fat tell us a little bit about why this is so problematic well first of all I'm so incredibly impressed at how you tell that story because it's exactly how we tell the story and we learned it from Steve O'Reilly who I think is the sort of Godfather of this concept uh I think we've all appreciated for some time that there's a relationship in terms of risk and weight that that's imperfect and BMI right that they're BMI is not a great measure of risk it is in epidemiology it is in large population right we also know that how much fat you carry so overall adiposity is important but what we've learned really in the past 20 years is that to as you've said that it's not so much even how much fat you have it's where you carry it and that that we are evolutionarily programmed to store energy in these places around our hips and our butt and our legs and not as much up here in our bellies and definitely not in our organs right that that's a bad thing uh and that has been shown to be a very potent predictor of risk and that there are a number of genetic alleles that predispose to both these differences in body composition but also to differences in risk of developing diseases like Cornish season and diabetes so super fascinating area that I'm going to devote the rest of my life to understanding and trying to to fix the [Music] question you ask which is why is it that if you overwhelm the bathtub and leaks out gets into the floorboards why is that why is that rot why is that so bad the answer is not what I can give you but I we started our sort of process and thinking about this problem and thinking about extreme the extremes of biology in particular these rare genetic diseases that are called lipodystrophies where people are born with the inability to store fat at all in generalized lipidystrophy or with just an isolated inability to store fat in the gluteofemoral and subcutaneous regions in the legs so they they have a selective loss of adipose tissue in their and their butt in their legs and therefore a huge overabundance of fat in the abdomen and the viscera in the liver and the pancreas and the heart as we talked about and those people have tremendous metabolic disease and extraordinary levels of risk right I mean there's small numbers of people there rare diseases and all of these studies are observational but there's uh there's a you know beautiful paper from from Canada from 20 years ago showing that people born with these sort of congenital forms of severe insulin resistance be it either lipodystrophy or type A insulin resistance have astronomical coronary disease risk they're women who are having bypass operations in their 30s and 40s which is basically unheard of and uh you know in women so I think the question of why that is remains unanswered I think there are lots of different potential hypotheses um you know I think the role of insulin and you know its impact on different organs and tissues and cells is is interesting we don't have an answer yet uh what we do know is that there's this very strong now association between these different shapes body shapes right the apple pear thing and risk of developing these diseases and so I think if you look at the epidemiology curves of say coronary disease over the past 30 years we've done an amazing job of reducing the risk of coronary artery disease events using all the tools we have at our disposal whether that's you know blood pressure smoking cessation lipid management etc etc yet as you mentioned at the very beginning it's still the number one cause of death in the world and even in the covet era and so it's still a huge problem so the question then to all of us is what is what is what what is that is that just that we're not adequately using the tools we already have or is it that we're missing something else or is it a combination and I guess I would sort of probably bet that it's some combination of sort of we're just not doing a good enough job with what we have and there's probably something else there and so that's the focus of sort of what I want to spend like I said the rest of my life thinking about yeah I would agree with you I think it's really a combination I think we start too late and don't go low enough on lipids we fail to recognize and don't get enough traction on blood pressure I mean I still think nearly 20 percent of people still smoke so it's not like we've taken that one out of the gate and then I do think that this pillar of poor metabolic Health uh is is is so improperly understood um and I don't think we're identifying people at risk because I mean you think about how little I know about my own State here I mean I you know have a pretty good sense from any blood test you can do I can do a dexa scan it tells me how much vat I have my you know my transaminases are adequate so I kind of assume and based on last test no liver fat but I don't other than that it's a real blind spot right I mean I don't have the clarity that that I would have about my APO B for example or my blood pressure and that and that's I think because we're sort of increasing our very poor resolution of this problem starting with like the most blunt tool of all which is BMI and then moving to other things yeah and even what you just said I think it still represents probably a very low resolution image into this right just focusing on that we know that's bad but so here's a question right that's just a thought experiment is what is is the problem with that is that a defect and the ability to store fat where it should be stored including ephemeral Depot and is that just a manifestation of that or is there something different about that is there truly a benefit to having more fat in the gluteal fineral so in other words to your bathroom analogy if you could make a bigger bathtub would you be more metabolically healthy well certainly there's one experiment that Gerald Shulman did that you know obviously it's a contrived experiment but it it would certainly suggest in the model so he looked at a mouse model where the mice had profound insulin resistance and he would just put more and more subcutaneous fat into those mice and they got fatter and they got less insulin resistance they actually got paradoxically fatter and healthier so in at least that intervention allowing them to get fatter making them have a bigger bathtub improved them but it's not clear that that's the that that's the same thing right in other words that doesn't answer the question is that bad simply because it's not in the subcutaneous space or is it doing something fundamentally different and yeah and I think that's where we want to sort of eventually understand right is are there cytokines that are coming out of those cells that are different from the cytokines coming out of the other cells there are all kinds of things that we're learning about the difference in life basal lipolytic rate between the two Depots and again we're just describing these Depots based on what we can see and how we can describe them based on a dexa scanner and MRI I think uh right it's just so low resolution it's very low resolution at this time I think what we can say is that in a patient with lipedestria is an extreme who has normal lipids right not normal triglycerides so it may be a modest elevation in April B but APO B triglyceride that those people have extreme increases in Risk independent of their traditional risk factors we think that there's a group of people and I've now as I've been thinking about this begun to see these people all over and once you see them you can't not see them but we think there are good people here who represent probably some polygenic version of this where there's a relative decrease and fat in the legs like I can think of patients now who come to my practice who may have a tiny little pot belly but you know they're lipids were sort of not that bad and their legs are super skinny and they had a bypass of 38 or 40 or 41. and the number of people I can think of like that keeps getting bigger and bigger and I think what we're going to learn is that sort of that gluteal gluteofemoral storage capacity is going to be an important driver of risk in this in this context and finding ways to change that if it's possible would be of great benefit I think it remains to be seen if it can be changed there is some you know very poor evidence right if you talk to the plastic surgeons they've begun to understand that there are metabolic consequences to taking fat out of places like the legs and the hips that are very different from taking fat out of the belly and so I think you know again we're just getting it sort of something it's like Jerry's you know experiment of putting in more subcutaneous fat it's just helping to guide us towards this idea that there's something there's something there and especially where it's oh go ahead no no it's fine no I was just gonna say where I think it's really going to be interesting Ethan is when you start to look at this in the much larger and less extreme population of those without lipodystrophy so so the cases you're describing are profound and but but but the question is this is probably also playing a very big role in people who aren't the ones showing up for bypass at 38 years old who don't have the complete lipodystrophy where they have no ability to store uh fat on their on their legs and hips um and so the question is are there targeted and directed therapies that that can be aimed at the metabolic tip of that spear well uh that's what we're doing so my answer to you is we think so we need to do the experiment to demonstrate that but there if using human genetics as a guide there are a number large number of alleles that seem to confer this concordance of changes that in both directions so for example people who are born with have alleles that confirm more gluteal ephemeral so really what's important is not so much the amount of visceral fat you have in an absolute sensory amount of gluteal ephemeral fat it's really the ratio it's called index of terms and it may be on your Dex reports called fat Mass ratio so and they're different levels that are normal or abnormal for women and men but having a high fat menstruation meaning having more fat up here and less fat down here is bad and there are alleles that confer that and that they do also confer a bunch of changes into other things that we know are bad including you know lipid-based biomarkers and then diseases like coronary disease and how can according to these alleles so if you do you have enough data to look at identical twins and say that the genes are completely uh concordant between them and the phenotype uh I don't know of any twin data but I do know that there are it's a that there are certain of these that are common enough that you can find heterozygous and homozygons and it looks like there's a dose response and and again it's not just one right it's not like there's just one of these things so I do think there will be targeted therapies and we'll test one sooner than later um we'll probably Begin by testing it in patients with lipodystrophy but the hope and expectation is that we'll move beyond that and and to eventually try and Target other metabolic Associated diseases and ultimately that most metabolic Associated disease which is you know coronary diseases what what percentage of the patients with a a phenotypically appreciated lipodystrophy have an identify identified set of genes or Gene that is the result that results in that oh it's probably uh it's probably on the order of 50 it's a great question because we don't really look uh the recognition and diagnosis of lipodystrophy is a abysmal and Steve O'Reilly at some point if you ever convince him to come on he's one of the most entertaining human beings I've ever been around and I love every moment I spend with them um but and Reed is Banting metal lecture from 2019 which was just astonishingly brilliant um he gave it at the Ada which was here in San Francisco that year but Steve um Steve will will say that the problem is that we don't take our patients clothes off and and then if you don't take if you don't undress your patient you'll never see it and actually we have some patients with lipid history who are big in the advocacy groups and they've been incredibly helpful to us and they often tell the story that their own diet personal diagnosis of Life of History happened by accident because it happened to be a warm summer month and they were wearing a skirt and a doctor was able to see that their legs were super skinny and muscular so I can't answer your question because we just don't know what the denominator is uh there is this force of partial labor history is characterized or classified and you know how it's been defined historically and there's called familial partial life industry one two three four and Beyond fpld1 doesn't have a monogenic cause it's by far in a way going to be the most common but there's not an agreed upon way to make that diagnosis today which I think is a major problem and it's going to need to be addressed because a doctor if you talk to an average doctor will never have heard of lipodustry which clearly never even be thinking about it and I'm saying this having had the experience myself where I probably just never thought about it were conditioned to think that leanness is good leanness and muscularity are good and if you see leanness and muscularity if you happen to even see it it's a good thing you never would think well this is a problem yeah I mean look to me this is interesting in that it becomes the index upon which you can build a far greater set of insights because again while I think this population experiences such an extreme consequence of this um I think I share your your belief that this even absent to lipodystrophy this is still a problem you know yeah well and again they just you know the lipid history patient has a broken bathtub of course it's not like a normally shaped bathtub it's a jagged bathtub that is more quick to overflow because it's simply smaller um and therefore they show up much sooner with this problem and and to your point if the clinician would simply walk in the bathroom and go how come that's not an oval oh right I need to be looking harder and and I think that's the expectation is that they represent a very rare uh version of what happens when the whole thing goes awry but that they're going to be more common versions of this that exist and it's very similar I think to the distinction between familial hypercholesterolemia and hypercholesterolemia and we learn a lot from rare diseases I think uh this is the case where we're learning in in this case we already have uh abundance of human genetic data that suggests this sort of polygenic version of this thing and there will be some papers coming out soon with collaborators of ours that will show that the fmr itself conveys more risk even than smoking status and and that's a pretty amazing finding right that if you have a high fmr I mean you have a lot of fat up here and not very much fat down here that your risk of significant bad things in the form of coronary disease defense is higher than it would be even if you smoke cigarettes which is not astonishing and I think none of us would have believed that yeah and I do like the analogy of of FH because FH is also you know a very very heterogeneous wastebasket of genetic things more than 3 000 different genotypes that produce this phenotype but interestingly at least one of them has now become I think the most powerful drug we have on the market right which is the pcsk9 mutation so it'll be interesting to know if how much the genetic insights will also form therapeutic options for the people that don't have lipodystrophy yeah I think for in this case at least what I can say with some confidence is that the rare genetics are probably not going to be in as informative certainly not as informative as p6k9 which is I think you know stands alone in terms of the quality of it it it's informativeness both as a rare disease mutation but also as a common disease variant but the genes that underlie the common variation in these phenotypes are I think going to be very interesting and so I think that's where we're focused because the rare disease the the single gene mutations you know one of the most common the underlying the disease underlying fpld2 is a mutation in laminae I mean we know that this leads to Progeria it leads to cardiomyopathy it leads to you know muscular dystrophy at least you know it's a whole it's a complicated mess of it Protein that's expressed in the nuclear lamina it's a it's hard to kind of Imagine a common variation in that Gene is going to lead to to yeah problems it might but it's not it's not obvious well Ethan this has been this has been really interesting um we've covered a lot of ground some of it we repeated from before but I think it was necessary both because I just don't think everybody has the capacity to go back and listen but I also think we have a couple more years of insight um so so thanks again for making time and and for me and for me personally this this whole getting deeper down the rabbit hole and blood pressure thing I'm hoping that enough other people are equally becoming interested in this because I I just worry that there are too many people walking around out there who have no idea what their blood pressure is and even if they're just 10 millimeters of mercury above normal as you pointed out you know the consequences are significant uh and and again it's just such an imminently treatable thing it's a it's a tragedy yeah it's uh and it's been that way this is not a new problem and I'm glad that you're latched on because it is one of these you know in terms of things that probably our lowest bang for the buck and public health these days maybe short of vaccines this is at the top of the list if we could just raise awareness and treat this because I think we've done a really good job on the lip but excuse me the lipids the lipids you know what's left over now is probably it's not awareness but blood pressure is one of these funny things uh for whatever reason it's just not sexy and it's very hard to convince somebody to do something that doesn't make them feel better and in some cases may make them feel worse and we've known that for a long time and this is one of these things where you're trying to get somebody to understand that it's not going to have any impact on positive impact on them for years decades yeah foreign thanks very much and good luck thank you Peter I look forward to seeing you yeah I look forward to seeing you in person someday hopefully I'll we'll uh hook up sounds good man thank you all right yeah thank you [Music]

Channel: Peter Attia MD

Views: 102,044

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Id: vxA2jKZylnE

Length: 144min 55sec (8695 seconds)

Published: Mon Mar 20 2023