Dr Nero: [00:00:00] So welcome Nehal. I've really been looking forward to our conversation today. Clearly, , inflammation and cardiovascular disease is a very, very, , I hate to use this pun, but a very hot topic. So, um, I am really looking forward , to walking through this all of you today.
Dr Mehta: Thanks.
Dr Nero: So You describe yourself as a cardiorheumatologist.
Uh, I think that really, cardio immunologist may be a better term. , you've done , so many different research studies on not just, , cardiovascular disease, and vascular disease in general, inflammation, rheumatologic diseases, , diseases involving, , different types of cholesterol, HDL, LDL. How did this all start for you?
Dr Mehta: You know, Tom, thanks for having me and I do think that it's so important that we get a good understanding that. Inflammation is at the cornerstone of most diseases of chronic aging , I'll tell you the root of it all was seeing that, , back in 2006 in Philadelphia, [00:01:00] there was a paucity of cardiovascular risk factors, but a ton of heart attack.
in patients with obesity coming through my clinic. So I started getting interested in what was it about the obesity and the obesity epidemic, and I started biopsying adipose tissue, and we found early on adipose inflammation. And so I got into this just by way of understanding that inflammation, , sort of what I call immunohyperreactivity, really are at the cornerstone of.
Driving obesity, insulin resistance. That was the first axis. And then we realized that we really could not recapitulate the model very well, unless we had a chronic human inflammatory disease to study. And then I, uh, Very luckily, a PENN bumped into somebody who was studying psoriasis as a risk factor for heart disease, and then that really set the stage of skin inflammation, driving adipose inflammation, driving blood inflammation.
Um, so the root of the story came down to why were obese [00:02:00] people having heart attacks when they had a paucity of cardiovascular risk factors. Yeah.
Dr Nero: a lot of your focus, at least as a model for research, since It's only been, I would say, in the last five or ten years that people have really been talking about rheumatologic diseases as being a risk factor for cardiovascular disease, and clearly it is.
, , and as you said, we don't really have good models for it, not just in humans, but we don't really have good models for it in animals as well. Uh, you know, when we stimulate vascular disease in, in the animal models, it's really a, a fake model. It's not really the same thing as what we experience as, as people.
Dr Mehta: Yeah, and it's interesting you bring that up, because how we probed the initial adipose inflammation story just a step before that, was I was involved with Garrett Fitzgerald, Dan Rader, and Murdoch Riley, giving a series of LPS, lipopolysaccharide injections, To healthy humans to [00:03:00] elicit an inflammatory response.
So that's how we turn to psoriasis. We said it's not a physiologic model to inflame. Similarly, in animal models, they're not great models to recapitulate the human diseases. So we're really left with using epidemiological observations to then back up into translational and preclinical understanding.
Dr Nero: So before we get into some of the more, uh, nuanced issues with the different rheumatologic diseases and how you're looking at them, because each of them are going to be slightly different. Um, do you want to just walk us through for a second what you see as the, um, sort of the basics for the model for atherosclerotic disease, as well as other chronic inflammatory disorders that involve the heart?
It's
Dr Mehta: so I think the biggest appretiation that I had was as a cardiology fellow early understanding that you could not have, uh, athero without two things, injury. and lipids. And so the cholesterol hypothesis was borne out pretty true with all the statin [00:04:00] trials, but the inflammation that really started this process was endothelial damage.
So the basics for atherosclerotic cardiovascular disease are lipids in excess, will then deposit into tissues, elicit an inflammatory reaction for macrophages, foam cells. And what we appreciated was the critical role of the bone marrow myeloid cells in this process, namely the neutrophils. And that to me, when Peter Libby and others had started bringing up the critical role of neutrophils and Paul's CRP axis, that's when I started realizing that the basics for atherosclerotic cardiovascular disease.
overlap directly with what I was studying in rheum and immunology. , and in fact, the initiators of a, for example, psoriatic plaque actually had a lot to do with the initiators of atherosclerosis. So that therein lied, you know, sort of the first question, [00:05:00] which was. Is this just a manifestation of one disease just in various tissue beds?
And so that's what the next 10 years of work, ensued to understand the different rheumatologic diseases that all drive various manifestations of cardiovascular diseases.
Dr Nero: And so do you think, that the immune response actually may precede even the development of the, of the plaque and that it is part and parcel with the development of the plaque. I was talking to another researcher earlier this week about that there's some beds that just don't develop atherosclerotic disease and a lot of it we were thinking, well, maybe this is a hemodynamic factor or flow issue, but there has to be something that allows the, those neutrophils to interact with the cell walls and that it is actually a primary part of the Inflammation beginning the process and then having the secondary issues and then the heightened inflammatory response giving us a vicious cycle.
Dr Mehta: Yeah, and the tissue based inflammation is what I think I [00:06:00] learned over time, um, after having left Penn and then going over to the NHLBI Intramural Program at the NIH and learning that really the tissue based inflammation is the key. It's the fact that you may have blood borne inflammation, which is the immune cells that have made their way into the blood.
But yes, the reason why certain beds are, protected from athero or may not get it. There is a need for initiation to happen with injury and then subsequent damage. And I think that the tissue based idea that we need to get to the tissue in order to get to the disease is what we are now understanding with the systemic inflammation piece.
The blood is only representing one component of the inflamed, system. Could be the skin, could be the gut, could be the gums, whatever it happens to be, that primary source of inflammation needs to be curbed. If not, this will, as you said, be a vicious cycle.[00:07:00]
Dr Nero: And , one of the problems that we tend to do in medicine is we tend to reduce everything and try to make it all one answer. And it seems like it is a very complex system here. Uh, when we're looking at the inflammatory response that you've been studying, Uh, you know, there's the you The inflammasome, there's IL 6, there's IL 1 beta, there's IL 18, there's, there's, there's a ton of different cytokines.
, how do you like to look at this as a systems based process? And , what have you studied as far as trying to evaluate the process? And what do you think is going to be the, the way that we're going to be focusing in on this over the next few years?
Dr Mehta: You know, it's interesting that you bring up the systems based approach, Tom, because I think the biggest factor in tying all of this together was the fact that high amounts of comorbid disease predilection in psoriasis started, uh, becoming, you know, pretty, it became pretty evident over the first three years of the large [00:08:00] cohort study that liver disease was upregulated, uh, uh, anxiety, depression were upregulated.
Arthritis was upregulated, and this is all in a skin disease called psoriasis. So clearly, the idea of looking at this as one system, what we started doing was saying, well, let's understand first the plaque. Where's the source of inflammation? We characterized blood and tissue, uh, lipidomics and metabolomics of those plaques.
Then we followed those into the blood and then we did whole tissue phenotyping of the blood, which included flow cytometry as well as other means of, of access. And then we finally ended with a round of vascular phenotyping, which was aortic. Femoral coronary and carotid and what was very evident was when the system was inflamed when the whole system whether it be because the neutrophil lymphocyte ratio was up the CRP was up the glycate was up, or they had a psoriatic flare their whole plaque [00:09:00] just around all their bodies were red and beefy.
The whole system demonstrated slowing of sugar handling so they became insulin resistant. The system became constipated of lipids so you became. , , a walking body of, of ready to go cholesterol, everywhere. And then the biggest one we were surprised that there was a definite defined immune reaction that would accompany.
Um, this with different cytokines. So let me go through that. If you think about the cytokines as being innate immune activation, so your body sees something like a bacteria, something with a cell wall, TLR4, TLR1 get activated and that goes and stimulates the innate immune system. Those cytokines tend to be those related to TNF alpha IL 6 and what we would call classically the IL 6 CRP pathway.
What we appreciated was that there was a unique signature that we thought was driven by IL 1223, [00:10:00] which later became IL 1323. More specifically, IL 23, and another signature driven by IL 17, A and F. Those three fami those two families, if you will, the 23s and the 17s, and those species of cytokines, drive most of the skin disease.
So, if you look at what it is that the cytokines do, each one brings a certain cell type to become more active. When you looked at, and then we got involved with folks at the NIH, um, who involved themselves in lupus, involve themselves in rheumatoid arthritis, HIV disease, and we have a few other inflammatory diseases.
And when we looked at that, their cytokines were different. There's an interferon signature, uh, in lupus that is absent in psoriasis. There's a B cell signature that is present in rheumatoid arthritis absent in psoriasis. And so what this starts to really make you think about is, This could be an overactive immune [00:11:00] system because of the cytokines.
Now, why are the cytokines overactive? That's I think in the in the genetics. So people will manifest their hyper inflammatory syndromes Maybe as a vasculopath have serial M. I. S. Sometimes they define themselves by inflammatory bowel disease have relapsing bowel problems. Some people have psoriasis along with psoriatic arthritis.
So the genes that are telling the cells by protein stimulation of cytokines, each of these inflammatory syndromes has a signature. We're nowhere near understanding that, Tom. We're just scratching the surface. Different types of inflammation. I mean, we're still at the textbook definitions of is it acute versus chronic, but we are well beyond that now.
Dr Nero: , when you're looking at other forms of disease that you can then, uh, create, um, so to speak. So poor diet, . , how is that then stimulating this immune response? And, specifically how does the visceral fat [00:12:00] affect the immune response and the, the adipose tissue being the, uh, crucible for creation of these inflammatory mediators.
Dr Mehta: You know, before we, you know, move to the fat, I think that's a great question, Tom, because that is probably where the action all epicenters and kind of forms. It's a massive, uh, deleterious effects on cardiometabolic disease. But I would say that the smoking and the tobacco and the poor diet, let's just say that all of the Lifestyle things you have poor sugar control because you're diabetic all of those things do stimulate an immune reaction very Specifically and
Dr Nero: Bye
Dr Mehta: like psoriasis What ends up happening is you have exaggerated responses to those?
So smoking for example may trigger an immune response in the lungs that is exaggerated in those with psoriasis But the bigger one of diet, if you just take that for a moment, we learned over a [00:13:00] very early period of our research program that if you feed a patient with psoriasis an egg, they will hold on to 10 to 15 milligrams of that cholesterol compared to an age and gender match control.
They don't dispose and handle cholesterol the same. So the immune response then also stimulated Then reduces that even more. So you have a maladaptive response of hanging onto more fat, more sugar, more carbohydrate. There is an epidemic of obesity in our country, which is even more of an epidemic in psoriasis.
65 percent of patients with psoriasis are obese. The immune response collects adipose tissue macrophages. You asked about the crucible, right? Why is this the epicenter? If you will, the adipose tissue macrophages are primed And ready to go so that when anything gets into the fat, the fat is not just a storage organ.
The fat is very metabolically [00:14:00] active. And so in particular, the visceral fat, what we learned was psoriatic flares increase the space of it or increase the volume of visceral fat. There's more adipose tissue macrophages, we've biopsied and proven that, and those adipose tissue macrophages, when pulled out, have a more aggressive phenotype for more atherosclerosis foam cell formation, as well as more insulin resistance.
So it sounds like these patients with psoriasis should therefore then be predisposed to stroke, heart attack, diabetes, and they are. And so this is where the critical role of then understanding how BMI or waist to hip ratio fits into all patients with chronic inflammatory diseases. If you're not looking at that, you're probably missing a risk factor.
But again, going back just a few minutes to our conversation about different types of inflammation. Patients with rheumatoid arthritis and lupus tend not to be obese, so clearly their cytokine profile [00:15:00] is not one that's driving adipose tissue macrophages and visceral adiposity expansion.
Dr Nero: , on a side note of this issue of inflammation and, and diabetes and coronary heart disease, the patients who have elevated levels of inflammation for whatever reason have, I believe that from various trials, they set up 40 percent increased risk of developing diabetes over the course of the next five years, right?
So , what is driving that? Is it the initial inflammation part that's driving it? Or is it the fact that you're then. Holding on to those carbohydrates differently, creating different, uh, different types of fat.
And then that's driving the cycle.
Dr Mehta: And it's interesting, the initial, , inflammation that people are unaware of, actually goes pretty well in checking. for a long period of time in most people. The people who have the issue are those who have added inflammatory insults, whether it's sedentary lifestyle, poor life choices, not looking [00:16:00] at AHA simple sevens, and then compounded by that.
They ignore their primary inflammatory, , disease. So, this is not just about psoriasis and psoriatic arthritis, but a whole host of diseases that we have to treat as physicians because it's unethical not to. So, we have to treat rheumatoid arthritis. It destroys the joints. We have to treat inflammatory bowel disease.
But psoriasis leaves a very open of discussion with the patient on what they want to treat, how they want to treat it, and whether or not they want to treat it. We in fact had 30 or 40 percent of our severe population take at least a year before they started therapy. It's not unheard of in other inflammatory diseases.
And so that allows us this. initial inflammatory assessment of the drive of what's going to happen. And then look, if it's genetically driven, it is something that can't be ignored. You know, and you really do have to do something about that amount of inflammation that you're seeing. Okay.
Dr Nero: So , let's talk a [00:17:00] little bit more about what's happening now on the level of the coronary arteries,
Dr Mehta: so I think the biggest. question that we need to first talk about is when people bring up cardiovascular disease and MACE and MACE plus that we're all on the same page. So , when we're going to talk about cardiac disease, vascular disease, and then cardiovascular disease, Tom, you bring up three big, maybe four big topics that I think are very important to keep in mind for not only healthcare providers, but also patients.
You brought up the coronary arteries, which is kind of like the plumbing, Um, the walls, which would be the, uh, you know, myocardium are also at risk in this, in this disease state. Uh, the electricity is also at risk. There's more AFib and there's more electrical abnormalities in these patients. They have a lot of PACs.
Um, and then finally you brought up the pericardium, , that can be, um, highly inflamed in these patients. . And what's going [00:18:00] on in each of these beds of tissue in the heart or the vascular system is that the chronic inflammation is denuding in some cases for the coronaries and the vasculature, or in heart failure, we really don't quite understand what it is about chronic inflammation.
We've shown time and time again, diastolic dysfunction in those with active psoriasis. We've shown hypertensive disease in those with psoriasis. So could this all just be blood pressure, right? Number three when you look at the risk factors for vascular disease Those themselves are upregulated in psoriasis.
So there's more diabetes. There's more tobacco use. There's more family history There's more hyperlipidemia So you're ready in a population that's going to get disease in the vascular system. In terms of , what's going on in the coronary arteries, we have dissected that over a 10 year cohort study and we have a pretty good idea.
The coronary inflammation that's [00:19:00] detected by pFAI or the vascular inflammation that's in the coronaries, that is not luminal disease, right? That is actually in the wall, there's a change in the edema in the wall, right? So we've shown that even anybody walking in with severe psoriasis in their 40s has elevated coronary inflammation, which responds to biologic therapy. If you track a person, we said we had about 30 percent who did not start for a year any biologic therapy. So if you track them for a year, about half of the people who have elevated coronary PFI, will then develop a coronary plaque and it usually starts as a small shaggy non calcified plaque lipid, um, maybe a little bit of high risk features to it.
And then we had a group of people who still didn't take any treatment from years one to four and by four years All of those who had elevated pFAI and a plaque progressed, all of them, um, and all of them progressed into a lipid rich necrotic core containing [00:20:00] high risk plaque coronary artery. And one person actually had a myocardial infarction.
So if you look at that, that is without fail telling you that the coronary develops over time. Coronary inflammation, non calcified plaque, and notice I have yet to even bring up dense calcified plaque or CAC. CAC in this population is going to underestimate and miss disease. They tend not to calcify their disease because they're so young.
, and so I think the coronaries are easy to follow. The myocardium, I think if you look at the amount of patients, about 55 percent of all my patients walking into a clinical trial, one in two, Tom, will not know that they have high blood pressure. So could that be the diastolic dysfunction you're seeing that's leading to , heart failure and myocardial disease, possibly.
And then finally, in terms of what we do about these things is education awareness and screen for risk factors, right? So if you actually treat their disease, screen for risk factors, I think that the patients can actually live normal and long, healthy lives. [00:21:00] It's just a matter of actually making the diagnosis and how to do that is not
Thomas SN: So getting to the diagnosis, I think is going to be part of the problem. One of the things that we just saw in, the Select trial where they were looking at changes in ventricular function and that they saw improvement in diastolic dysfunction, which they think was an inflammatory response.
In coronary disease, it's quite different what we're looking at, and I think that when you, you had talked about CAC scoring and I, and I think the CAC scoring is super helpful for large populations, but on the individual level, on the more granular level, I do think that we're missing things and we're definitely missing things in earlier patients.
Um, when they looked at the orphan trial, there was about 45 percent of them that had low risk sorry, low risk findings on their plaque analysis, but who had elevated inflammation and they still had increased cardiovascular risk. So we're clearly missing things if we wait until they develop [00:22:00] enough plaque and that they have enough response that they develop a calcification.
, so a big question for us about how to identify those patients earlier. Should we be doing more carotid IMTs? Or should we just be looking at coronary inflammation , , using CTAs and potentially doing some type of, , PVAT analysis?
Dr Mehta: So, Tom, the first thing is I'd like the healthcare providers and people who do treat these patients to remember that the guidelines don't do a great job here, but you should still use the guidelines. So, looking for risk factors and then treating age appropriately, that's said and done. Beyond that, identification of patients earlier, , this is a time when I use markers in the blood in conjunction with some imaging based markers to make the case for the patient for early statin initiation.
Remember, our guidelines actually have our backs [00:23:00] here. , 2018, very proud moment for my lab, , we were able to get the ACC AHA guidelines saying if you have psoriasis, it warrants early statin initiation discussions. Great. The discussion itself though is only a discussion, Tom. You need to show them the value and the worth of the other things.
And so the two things I use, I'm not somebody who's selling images, so I'm not telling people to go and image away, but if you have the ability and access to get an IMT, that's great. Great. Because an elevated IMT would also tell the patient they have early features of vascular disease. I didn't say no to getting a CAC.
I would just avoid doing it, a coronary calcium score, coronary artery calcium score, but I would avoid getting it as the only way of making the assessment. Because if it's zero and you withhold a statin, I believe you've actually done this patient a disservice. So I use the CAC as a different tool and I can talk to you about that later.
If everybody in the country could get a single lumenography [00:24:00] CTA that then gets assessed for pFAI or coronary inflammation, I think, of course, we know that that works very well in the research world, but it may not very well be practical. So what do I recommend is usually for the diagnostics, three B's. Blood pressure, body mass index and get blood, the blood for lipids and glucose and the body mass index should be less than obese and the blood pressure should be normal.
Those three, coupled with a consultation with a physician or a health care provider, looking at those labs. keeping one's psoriasis under control. There's really not much else we can do except then start looking at blood biomarkers. So there are a few markers that we have used over a 10 year period that showed when elevated at baseline and unaddressed, coronary disease ensues.
When, when elevated at baseline and unaddressed, you may have more worsening response to biologics and psoriasis. And then a third one, which is an inflammatory marker, which when elevated [00:25:00] suggests persistent elevation suggests that you have vascular disease. So we could use blood biomarkers or blood markers to make some of these assessments as well.
But my, my sense of what I tell patients is we're just chasing things. I don't recommend getting tests in the blood just to look for things. If they're asymptomatic and you're looking for screening, the guidelines will say in order to prevent the disease, look for risk factors, keep their disease under control.
And if they have the ability to get an image of something that shows they have vascular disease to keep them compelled on staying on lipid lowering therapy, you should. But most of my derms and most of my rheums are now feeling comfortable even recommending starting statins, 10 20 milligrams, right?
So there is something to be said about do you need the imaging? Um, if you can get it, it may help the patient stay on the drug.
Thomas SN: , one of the, general issues that we see in clinical cardiology is people coming in [00:26:00] looking for the risk assessment, but mainly because, for example, they have a family history. And so in a little bit, you're, you're shooting in the dark here trying to figure out, well, what was their family history?
You have a younger person who has a coronary calcium score of zero because their doctor , got one for them before they got to the office. And they said, well, does this make me at low risk? And clearly, as you're indicating. it doesn't necessarily indicate low risk. It really, in those situations, it really is only going to help you if they're high risk.
, but , when you're looking at inflammatory markers, are there other ones that you are looking at other than HSCRP? And one of the reasons why I ask that is that we know that HSCRP and the coronary inflammation, although they're related, , as far as PFI is concerned, they're not one to one.
We have a number of patients who have low HSCRPs and high coronary inflammation, and then we have a number of patients, who have the opposite. So the question is the sensitivity and the specificity of the, , inflammatory markers and how this [00:27:00] is going to help you a little bit in talking to your patients.
And part of this is for now, and part of it is where do you think this is going to go as far as markers are concerned over the next five or 10 years?
Dr Mehta: There's very little reason, in my opinion, to look for an inflammatory marker in a patient that you know has chronic inflammatory disease. So the HSCRP If it's low, you're not going to believe it because they have an inflammatory disease. If it's high, you're going to believe it and think it's from the inflammatory disease.
But nowhere in there do I use it for cardiovascular risk stratification. And the reason is, is that in states of chronic inflammation, it's hard to track a CRP. Um, with disease activity and, and, and sort of separate them. But in terms of other markers, so I brought up three earlier ones that I kind of alluded to, and I'll give them the names now.
But the first marker that I really do think is clinically actionable is the neutrophil lymphocyte ratio. So you have an [00:28:00] NLR, and it basically shows you have a tremendous amount of myeloid inflammation in the blood. We've shown NLR with Paul Ritker's group to be Associated with, MI, second MI, post MACE MI, post, uh, stent MI.
You could just keep going down the line. It was six contemporary cardiovascular trials. And then a second study we did, um, we looked at NLR with non calcified coronary burden, and we found a very tight relationship that the higher the NLR over a cut point, the gave you that sense. And then third, um, we've also shown that the NLR responds to biologic therapy and parallels the skin.
So we do believe it's a good marker for tracking, uh, systemic inflammation following biologic therapy. Um, after NLR, I also very much, and that's clinically available on a CBC with DIF. Neutrophil lymphocyte to make a ratio. The second one is only available through LabCorp or it's a test called [00:29:00] Liposcience's NMR spectroscopy.
And I do track GlycA over time. So GlycA is a glycan marker of acute phase reactants that's measured by NMR spec. You can get an LDL particle size and number in that, you know, sort of exact test. But why I like GlycA for markers of inflammation beyond CRP is we've done the test in psoriasis. GlycA predicts disease outcome for CVD, psoriasis, NCB, lipid rich necrotic core better than CRP.
We don't like to pit things against each other. CRP still provided incremental value beyond risk factors, but our glycA marker was a bit stronger. Finally, , I don't measure insulin in the clinic, but I do try to calculate how insulin resistance someone may be. So I use their body mass index, insulin resistance, maybe a waist to hip ratio to look at overall cardiometabolic disease activity.
And that [00:30:00] helps me with inflammatory markers. So we used to actually, when we'd get the glycA, there's also an LPIR score, and it would tell you how insulin resistant someone is based on their triglyceride to glucose ratio. We had done one last paper where we did a triglyceride, um, index. It was called the TGI, triglyceride glucose index.
That's yet another way of finding insulin resistance. So, if you have clinical markers in the blood measured, you can do those three or at least two of them pretty simply. Because most people have a triglyceride and a glucose. The NMR spec, I don't recommend getting checked unless you have a concern of your cardiovascular history or you happen to be getting blood drawn and , the test can be sent out, but it goes under the LDL particle number.
Dr Nero: So onto, , therapies. We have a recent paper that was published, I guess it was at TCT with a on Colchicine. . Clear Oasis 6. Showed that Colchicine didn't work after Ladoco, [00:31:00] Ladoco 2, Colcat all showed some improvement with Colchicine.
Um, I guess the next question is, Why do you think it didn't work, and what do you think is involved here in trying to find a therapy that does work for treating inflammation in cardiovascular disease?
Dr Mehta: You know, the why it didn't work, Tom, is very hard to answer after we saw Colcott and Ladoco, um, in the patient populations, which were similar, I'd have to dig deeper in and understand whether there was some difference in the patient population tested in some way that may have, you know, precluded a positive trial.
Regardless, I do believe that the Ladoco and Colcott trials taught me that treating in the right patient population, maybe it's the frequent flyer to the cath lab, the veteran who's had 17 stents. Maybe it's the person who needs the fire put out. I think that the therapies Colchicine offers a very Uh, you know, effective way of [00:32:00] testing that hypothesis.
I don't think that this trial is going to change any of the practicing behaviors of Colchicine, which were nil anyway, in this country. I don't know how many, you know, you know, partners of mine. That
Dr Nero: a fairly big user. I don't think I wouldn't say it was above 5%, but I was certainly used it in patients
Dr Mehta: is really great of you.
Thomas SN: I was noticing , had chronic inflammation. Um, now I'm uncertain. I did look at some of the early results from, uh, from clear and also from the other ones.
I was surprised that in Colcott. Um, the ones who seem to get the greatest benefit were the ones who were early, uh, and who started early. And all of the patients in CLEAR were started early. And so I had originally thought that CLEAR wasn't positive because they were going to not be treating the patients who had chronic inflammatory issues, and that they were just treating, they were treating all comers.
Um, but that's what Colt got sort of treated. And so You know, it [00:33:00] really does bring up a lot of questions. It did seem, though, that the patients who had the greatest CRP drops seem to get the greatest benefit. And we've seen that in a number of different trials. , and we saw that, for example, in your, , oxidized LDL, study .
Uh, and we'll get to that in a second. So, I'm wondering whether , part of the question on how we're treating this is that we just can't treat all the patients the same and that what we were talking about by systems, diseases and that we have to really look at the processes that are causing them.
Part of part of that issue.
Dr Mehta: Really brings up the idea of personalized medicine, Tom, in the sense that, you know, we, towards the end of my cohort, 10 year cohort, we asked the question, well, let's label people, whether they're high IL 17s or high IL 6s or high IL 18s, right? And what we found was it was very hard because there's so much colinearity of these with other things.
So what you're actually saying was, The high 17s were the [00:34:00] ones with uncontrolled psoriasis and high PASI scores, right? So i'm not sure the the next route, but I do know that personalized medicine could be as specific as what we just discussed which is You tailor the therapy based on what you see in the blood rather than just by guidelines in cookbook medicine You look for evoked or response testing if they respond to something You know that that's going to be something along the pathway you could use but I think you're right a little bit more data is going to be necessary in terms of understanding Are there the right folks for colchicine, right?
Thomas SN: So we'll, we, um, we've also looked at different, , other immunologic agents, um, methotrexate was studied. , I think that there's a lot of question about the trial, how it was done because it was low dose methotrexate. It did not decrease CRPs, um, in the trial. So maybe we were missing an opportunity there.
Uh, Canakinumab. Did demonstrate benefit, but with a significant, um, uh, off target [00:35:00] effect of increasing sepsis, although an interesting also off target effect that it decreased, uh, for different forms of cancer. So now being studied as a chemotherapy agent. Um, we have two studies that are ongoing, or I'm sorry, three studies that are ongoing right now for, um, Ziltivekimab, uh, with, , Paul Rickers Group.
, we were involved with Hermes, um, their Zeus and, um, I think it was Artemis. It's the third one. So I think all those three are going to really move the needle forward on how we understand, uh, use of anti inflammatory agents. Although each of these is very different, right? The action of Colchicine is extremely different than the action of methotrexate, which is extremely different from these specific I L 6 blockers.
Dr Mehta: Right. Absolutely. It's a great point, Tom.
Dr Nero: , are there any, other kinds of therapies that you've been looking into? You had a very, very nice, uh, paper that I think you put out in 2022 on CETP inhibitors, , uh, Otacetramab. [00:36:00] I'm getting that wrong, I'm sure, um, is being studied in a trial , the sixth CETP inhibitor.
Um, and, but your discussion on the CETP inhibitors was , very interesting on the, um, inflammatory response. That it, um, helps to block and the potentials of decreasing a number of different disease states outside of cardiovascular disease, but specifically with diabetes and maybe neurologic diseases.
Uh, do you want to go over that just a little bit
Dr Mehta: yeah, I mean, for other kinds of therapies, it's interesting you bring this up. I think that you nailed it, anti IL 6s, anti IL 1 betas, and the CERT study with methotrexate gave us an idea that there are, you know, three tenable options that we can test, and each one of them is going to be very informative in its own ways.
In terms of the CTP inhibitors, it's interesting you bring up Obacetrafib in the sense that they're using it very creatively. The CTPs really failed in what they were hopeful for, which was cardiovascular outcome trials related to [00:37:00] HDL raising. And what we learned from those trials was that they had a steep reduction in LDL for those patients who Um, we're on the drug long enough.
And so I think that for an inflammatory population, hard to see what's going to happen with the CTP inhibitors in terms of whether they're going to find any mainstay or whether they're going to have any great benefit in those. I can see them being off target beneficial and inflammatory disease states in terms of what they're going to do to HDL function.
Um, I do think that there is. Um, this idea that there are new anti inflammatories down the pike, and I think what I'm most excited about, Tom, is actually the oral IL 23 inhibitors, the fact that there are oral medicines that can be made in a way that allows us to not have monthly or weekly , injectable dosing.
So, for me, I think the future of this is going to be continuing to curb oral IL 23. 70 or 80 percent of [00:38:00] the model's risk for having another event. And that last 20 to 25 percent that we're treating with inflammation, or treating inflammation for, I should say, I think is going to actually take on a few different strategies.
There'll be an anti inflammatory, but then there's also going to be an appreciation for optimizing the person's weight. Um, I do think that we have ignored the fact that we're in the ozempic revolution and nobody's really thinking about what that's going to do in terms of weight loss in inflammatory diseases.
And then 3rd, I think the last kind of therapy that I'm most excited by is. progressively better biologics in psoriasis. Like, I mean, think about that. We're at PASI 100s within three weeks of starting an IL 23 inhibitor like bimekizumab. So I think that's what I'm most excited about is seeing those drugs move their way into cardiology.
Dr Nero: Um, The, um, my, my take on all of this is that we have to be very careful on how we're going to be looking at these drugs and making sure that [00:39:00] we're really focusing on the right patients for therapy. Um, I've been a, um, uh, strong advocate for utilizing some other forms of indication of who are going to be involving in these trials that we get, uh, patients who are at risk.
A, who are at very high risk, so that we can see events, and B, so that we're getting patients who, um, we can follow something to see whether or not we have early response. Uh, that's one of the reasons why I like, um, I like Matt Budoff's work that he was doing in Reprieve, for example. Uh, they published that result showing that in the short term on Reprieve, they had plaque stabilization that they could already identify.
Um, I know that that group is going to be looking at, uh, perivascular, uh, adipose tissue imaging. Um, I'm not sure that they're using the exact right, um, marker for doing that, but I think that they were going to get some good information on early decrease in inflammatory response for that. But, but also they've indicated in both of [00:40:00] those is that they had an increased inflammatory response at the beginning.
So, , before we give these patients, these drugs, uh, For the entire cohort, we really have to start looking at, Okay, are these patients going to be the ones who are likely to respond? And then, then we can then see the response, , that dovetails nicely into your, , antioxidant LDL trial that you did, uh, that you, uh, released at the ACC this past year.
Um, why don't you walk us through that? Because I thought it was extremely interesting, both on a diagnostic , follow up side, and also on the therapeutic piece. Okay. Okay. Okay.
Dr Mehta: moiety and it targets it directly. So targets in the tissue. Um, the hypothesis was use of the drug over a 4 month window and their co primary exploratory endpoints would improve PFI.
As well as improve, uh, [00:41:00] psoriatic features and, , 30 percent decrease in psoriasis at the peak, which is, you know, not bad for an adjunct or a topical, um, you know, sort of medicine, not a primary biologic. But what we found was. Very interesting. , so first of all, very large cardiometabolically challenged population, 75 people, their average body mass index was in the 35 to 38 range.
Um, a lot of latent coronary disease that we didn't know about, all asymptomatic about 25 percent plaque prevalence. And then we found that those who had high PFI at baseline responded beautifully to the drug. Um, in a statistically significant manner and reducing PFI in all three vessels. However, when you look at the entire group, if you did not have an elevated PFI, you actually didn't have anything to move in the coronary.
So we didn't see anything there. It was safe. It was tolerated. And I think the most important lesson of the of the trial was using tissue based or tissue specific [00:42:00] measures such as pFAI on a tissue based antibody like Abcentra's Orticumab, I do think that you could get a really nice future now CVOT trial or some sort of a trial where this is what the next step is in this drug development pathway
Dr Nero: Yeah, the enrichment in that in that way, I think, is going to be helpful and ultimately I think that it's going to be helpful in the way that we're going to be focusing on our other therapies for patients just in general.
Dr Mehta: Yeah, totally. Right.
Dr Nero: that we look at and my patients always ask me, so how am I doing?
And the answer is, well, when you turn 90, I'll let you know, um, if you don't turn 90, then we go and we failed. And if you do make it to 90, then we've been successful. And I don't think that that's really something that we can stomach very easily and just saying, yeah, we got your LDL down and we'll see you next year.
Um, so being able to follow something up more closely, I think is going to be very helpful. Um, and that's why I'm, I'm. Excited about the results from [00:43:00] your trial because that did show that pFAI was something that was modifiable. It was a good question on whether or not it was sort of tattooed into the adipocyte that those changes were made and then you wouldn't see the, the differentiation over time.
But now, but we can, um, I think that the reprieve trial, if that comes back demonstrating that, , their version of FAI. that it decreases, with the treatment with, , pitivostatin, then that will let us know whether or not we've been successful with statin therapy, for
Dr Mehta: That's exactly right.
Dr Nero: And maybe we don't have to go beyond statin therapy.
We're, we've been very involved in the lipoprotein A trials and, um, I'm very proud of our team right now. We're the national lead, , for, , recruitment for ACCLAIM , and so we're extremely excited about this, but You know, you, you sort of wonder whether, A, if you get their LDLs down to extremely, extremely low levels, does that then decrease the amount of inflammation that they're going to be having in their vasculature, which [00:44:00] will then decrease the prevalence of events and such that you don't need to treat their LPA.
Um, which would be great, you know, not having to spend $10, 000 a year on a drug when statins and ezetimibe can do. Or do you have to treat all of them, which would be fine too if we, you know, once you know the answer, then we can tailor our, , drugs to that answer. And maybe it's just that when patients have coronary disease and a stable, but they don't need a lot of these things.
, it's a very interesting question of which you've really been on the forefront of trying to figure out how to make those diagnoses and then how to deliver those drugs. So I, I did want to get while we have an opportunity to talk a little bit about, you had mentioned some more of your recent research that you're doing with retinal arteries, , which I love as a model because that's one of the few arteries that we can actually see, , and evaluate.
And looking at, , the cholesterol, , deposition and fat deposition there and potentially how that is, uh, going to [00:45:00] be a model for how we might be able to evaluate other, vascular disease states and potentially, uh, deliver drug.
Dr Mehta: So, it's great that, , we have the opportunity to think about that you, you brought up early on that this, this idea of. the system, right? This idea of accessing the systems based process. What we appreciated over time by the 14th, you know, sort of observation year of the cohort was that lipid accumulation over time in the vasculature led to non calcified burden and the carotids led to stroke, both of which were upregulated.
In the skin, more psoriasis flares, which we saw, We appreciated fat in the bone marrow and it was inflaming the bone marrow, probably why we're seeing more cancers in these patients and other, you know, sort of bone marrow failures. But along the way I started thinking about where else would you see this metastatic lipid deposition or accumulation when it's everywhere and one of the areas that I got very interested in was.
, [00:46:00] neurons, and the optic nerve. And it's actually part of the retina brain barrier, and I learned that the retina actually, uh, does collect cholesterol and lipid over time, and it does oxidize, and there's a lot of stuff that happens that's very similar to coronary disease.
So I've taken it upon myself to figure out what that lipid accumulation does. Um, and there's a good amount of literature on that. It causes vision loss, causes holes in the eye in the form of geographic atrophy. But I've also taken time now to figure out how we can remove that lipid. And there is a way you can actually go in there and figure out what the pathogenic lipid is.
And I think what I'm most excited about over the next 10 years is The continued appreciation across multiple disciplines that lipid accumulation drives several processes that are associated with diseases of aging. So now we have blindness, atherosclerosis or myocardial [00:47:00] infarction , and then you think about the other ones that people are most after.
Um, they have without fail shown a role of cholesterol handling or mishandling in their inception. In fact, some of the chronic diseases of the CNS are now start to thought to be due to lipid accumulation. And so I think we're in a very exciting time to make therapies to actually address those. Okay.
Dr Nero: ability to actually change lipids within the CNS. , most of our drugs do not cross the blood-brain barrier. , so our ability to sort of address that systemically is somewhat limited. Um. Um, I've always been, careful to talk about my patient to my patients about, when they say that it causes them to have fogginess or decreased mental status and the trials did not seem to support that.
But on the flip side I, I do [00:48:00] agree with you that there's something else happening here with cholesterol management with lipid management in the CNS, that is part of that process and maybe it is, you know, that's a chicken egg question with inflammation itself. Um, What are your thoughts on how that is being driven , since it is a different blood pool of cholesterol?
Dr Mehta: You know it's, that's a hard one. That's going to take some time to reconcile and understand because the cholesterol in the eye actually does not move from the body to the eye and back. Actually it is. cells that are turning over at the most rapid rate in the body. And that cholesterol that's coming from those cells is actually what's being accumulated.
When you have cardiovascular risk factors, you have a weakened vascular system, choroid, you know, all of those things that ends up driving the process. There's some genetic mutations and they happen to be in the pathways of Funny enough, CETP and HDL metabolism that suggests that people who have constipated metabolism of cholesterol, [00:49:00] it's happening everywhere.
And so I guess my, my, my
Dr Nero: Um, but
Dr Mehta: sense is that we're going to do well if we can find a drug that does cross the blood brain barrier and can address this directly. Until then, I would remind patients that even having less bioavailable cholesterol in the blood pool will help this because if it's lower than what's in the choroid, it'll passively transport in there, right?
So I do try to tell my patients that yes, you have dry AMD, it's lipid driven, and it will help that you treat your cardiovascular risk factors and also see your eye doctor.
Dr Nero: Of course, you know, it does really all come back to if we can start treating the risk factors that we already know will be a lot, a lot further ahead of the game than if we just wait until we're trying to treat the disease.
You know, every, every conversation starts with, we need to improve your diet. We need to improve your exercise. Can you please do those things? Because we know those help regardless. [00:50:00] And it helps people with CNS disease as much as it helps people with coronary artery disease. And I'm sure, and I have a feeling that it probably helps in, in rheumatologic diseases as well.
Dr Mehta: Yeah, for sure. Absolutely.
, I would just like to close by saying thanks for shedding light on this. I've been doing 20 something years of work in both preventive and general cardiology. And it makes me very happy that these discussions are now becoming dinner table discussions and now scientific discussions that really do mean that we can tackle this epidemic of inflammation and heart disease, but we need systematic ways to do it.
I think the advent of what we started as Cardio Rheumatology Clinics is one way to do it. Another way to do it is to just get it out there to the patients and do more of these types of communications. So I really appreciate you spotlighting the
Dr Nero: again. Um, I am very excited again to be working with you on other, uh, issues with inflammation. One of these days I may have you come back [00:51:00] on and we'll talk more about HDL cholesterol because I think that's going to be another, you know, really ripe area of research and understanding. Uh, and, um, we will be speaking again soon.
Thanks again. All right,
Dr Mehta: Thanks.
Dr Nero: So You describe yourself as a cardiorheumatologist.
Uh, I think that really, cardio immunologist may be a better term. , you've done , so many different research studies on not just, , cardiovascular disease, and vascular disease in general, inflammation, rheumatologic diseases, , diseases involving, , different types of cholesterol, HDL, LDL. How did this all start for you?
Dr Mehta: You know, Tom, thanks for having me and I do think that it's so important that we get a good understanding that. Inflammation is at the cornerstone of most diseases of chronic aging , I'll tell you the root of it all was seeing that, , back in 2006 in Philadelphia, [00:01:00] there was a paucity of cardiovascular risk factors, but a ton of heart attack.
in patients with obesity coming through my clinic. So I started getting interested in what was it about the obesity and the obesity epidemic, and I started biopsying adipose tissue, and we found early on adipose inflammation. And so I got into this just by way of understanding that inflammation, , sort of what I call immunohyperreactivity, really are at the cornerstone of.
Driving obesity, insulin resistance. That was the first axis. And then we realized that we really could not recapitulate the model very well, unless we had a chronic human inflammatory disease to study. And then I, uh, Very luckily, a PENN bumped into somebody who was studying psoriasis as a risk factor for heart disease, and then that really set the stage of skin inflammation, driving adipose inflammation, driving blood inflammation.
Um, so the root of the story came down to why were obese [00:02:00] people having heart attacks when they had a paucity of cardiovascular risk factors. Yeah.
Dr Nero: a lot of your focus, at least as a model for research, since It's only been, I would say, in the last five or ten years that people have really been talking about rheumatologic diseases as being a risk factor for cardiovascular disease, and clearly it is.
, , and as you said, we don't really have good models for it, not just in humans, but we don't really have good models for it in animals as well. Uh, you know, when we stimulate vascular disease in, in the animal models, it's really a, a fake model. It's not really the same thing as what we experience as, as people.
Dr Mehta: Yeah, and it's interesting you bring that up, because how we probed the initial adipose inflammation story just a step before that, was I was involved with Garrett Fitzgerald, Dan Rader, and Murdoch Riley, giving a series of LPS, lipopolysaccharide injections, To healthy humans to [00:03:00] elicit an inflammatory response.
So that's how we turn to psoriasis. We said it's not a physiologic model to inflame. Similarly, in animal models, they're not great models to recapitulate the human diseases. So we're really left with using epidemiological observations to then back up into translational and preclinical understanding.
Dr Nero: So before we get into some of the more, uh, nuanced issues with the different rheumatologic diseases and how you're looking at them, because each of them are going to be slightly different. Um, do you want to just walk us through for a second what you see as the, um, sort of the basics for the model for atherosclerotic disease, as well as other chronic inflammatory disorders that involve the heart?
It's
Dr Mehta: so I think the biggest appretiation that I had was as a cardiology fellow early understanding that you could not have, uh, athero without two things, injury. and lipids. And so the cholesterol hypothesis was borne out pretty true with all the statin [00:04:00] trials, but the inflammation that really started this process was endothelial damage.
So the basics for atherosclerotic cardiovascular disease are lipids in excess, will then deposit into tissues, elicit an inflammatory reaction for macrophages, foam cells. And what we appreciated was the critical role of the bone marrow myeloid cells in this process, namely the neutrophils. And that to me, when Peter Libby and others had started bringing up the critical role of neutrophils and Paul's CRP axis, that's when I started realizing that the basics for atherosclerotic cardiovascular disease.
overlap directly with what I was studying in rheum and immunology. , and in fact, the initiators of a, for example, psoriatic plaque actually had a lot to do with the initiators of atherosclerosis. So that therein lied, you know, sort of the first question, [00:05:00] which was. Is this just a manifestation of one disease just in various tissue beds?
And so that's what the next 10 years of work, ensued to understand the different rheumatologic diseases that all drive various manifestations of cardiovascular diseases.
Dr Nero: And so do you think, that the immune response actually may precede even the development of the, of the plaque and that it is part and parcel with the development of the plaque. I was talking to another researcher earlier this week about that there's some beds that just don't develop atherosclerotic disease and a lot of it we were thinking, well, maybe this is a hemodynamic factor or flow issue, but there has to be something that allows the, those neutrophils to interact with the cell walls and that it is actually a primary part of the Inflammation beginning the process and then having the secondary issues and then the heightened inflammatory response giving us a vicious cycle.
Dr Mehta: Yeah, and the tissue based inflammation is what I think I [00:06:00] learned over time, um, after having left Penn and then going over to the NHLBI Intramural Program at the NIH and learning that really the tissue based inflammation is the key. It's the fact that you may have blood borne inflammation, which is the immune cells that have made their way into the blood.
But yes, the reason why certain beds are, protected from athero or may not get it. There is a need for initiation to happen with injury and then subsequent damage. And I think that the tissue based idea that we need to get to the tissue in order to get to the disease is what we are now understanding with the systemic inflammation piece.
The blood is only representing one component of the inflamed, system. Could be the skin, could be the gut, could be the gums, whatever it happens to be, that primary source of inflammation needs to be curbed. If not, this will, as you said, be a vicious cycle.[00:07:00]
Dr Nero: And , one of the problems that we tend to do in medicine is we tend to reduce everything and try to make it all one answer. And it seems like it is a very complex system here. Uh, when we're looking at the inflammatory response that you've been studying, Uh, you know, there's the you The inflammasome, there's IL 6, there's IL 1 beta, there's IL 18, there's, there's, there's a ton of different cytokines.
, how do you like to look at this as a systems based process? And , what have you studied as far as trying to evaluate the process? And what do you think is going to be the, the way that we're going to be focusing in on this over the next few years?
Dr Mehta: You know, it's interesting that you bring up the systems based approach, Tom, because I think the biggest factor in tying all of this together was the fact that high amounts of comorbid disease predilection in psoriasis started, uh, becoming, you know, pretty, it became pretty evident over the first three years of the large [00:08:00] cohort study that liver disease was upregulated, uh, uh, anxiety, depression were upregulated.
Arthritis was upregulated, and this is all in a skin disease called psoriasis. So clearly, the idea of looking at this as one system, what we started doing was saying, well, let's understand first the plaque. Where's the source of inflammation? We characterized blood and tissue, uh, lipidomics and metabolomics of those plaques.
Then we followed those into the blood and then we did whole tissue phenotyping of the blood, which included flow cytometry as well as other means of, of access. And then we finally ended with a round of vascular phenotyping, which was aortic. Femoral coronary and carotid and what was very evident was when the system was inflamed when the whole system whether it be because the neutrophil lymphocyte ratio was up the CRP was up the glycate was up, or they had a psoriatic flare their whole plaque [00:09:00] just around all their bodies were red and beefy.
The whole system demonstrated slowing of sugar handling so they became insulin resistant. The system became constipated of lipids so you became. , , a walking body of, of ready to go cholesterol, everywhere. And then the biggest one we were surprised that there was a definite defined immune reaction that would accompany.
Um, this with different cytokines. So let me go through that. If you think about the cytokines as being innate immune activation, so your body sees something like a bacteria, something with a cell wall, TLR4, TLR1 get activated and that goes and stimulates the innate immune system. Those cytokines tend to be those related to TNF alpha IL 6 and what we would call classically the IL 6 CRP pathway.
What we appreciated was that there was a unique signature that we thought was driven by IL 1223, [00:10:00] which later became IL 1323. More specifically, IL 23, and another signature driven by IL 17, A and F. Those three fami those two families, if you will, the 23s and the 17s, and those species of cytokines, drive most of the skin disease.
So, if you look at what it is that the cytokines do, each one brings a certain cell type to become more active. When you looked at, and then we got involved with folks at the NIH, um, who involved themselves in lupus, involve themselves in rheumatoid arthritis, HIV disease, and we have a few other inflammatory diseases.
And when we looked at that, their cytokines were different. There's an interferon signature, uh, in lupus that is absent in psoriasis. There's a B cell signature that is present in rheumatoid arthritis absent in psoriasis. And so what this starts to really make you think about is, This could be an overactive immune [00:11:00] system because of the cytokines.
Now, why are the cytokines overactive? That's I think in the in the genetics. So people will manifest their hyper inflammatory syndromes Maybe as a vasculopath have serial M. I. S. Sometimes they define themselves by inflammatory bowel disease have relapsing bowel problems. Some people have psoriasis along with psoriatic arthritis.
So the genes that are telling the cells by protein stimulation of cytokines, each of these inflammatory syndromes has a signature. We're nowhere near understanding that, Tom. We're just scratching the surface. Different types of inflammation. I mean, we're still at the textbook definitions of is it acute versus chronic, but we are well beyond that now.
Dr Nero: , when you're looking at other forms of disease that you can then, uh, create, um, so to speak. So poor diet, . , how is that then stimulating this immune response? And, specifically how does the visceral fat [00:12:00] affect the immune response and the, the adipose tissue being the, uh, crucible for creation of these inflammatory mediators.
Dr Mehta: You know, before we, you know, move to the fat, I think that's a great question, Tom, because that is probably where the action all epicenters and kind of forms. It's a massive, uh, deleterious effects on cardiometabolic disease. But I would say that the smoking and the tobacco and the poor diet, let's just say that all of the Lifestyle things you have poor sugar control because you're diabetic all of those things do stimulate an immune reaction very Specifically and
Dr Nero: Bye
Dr Mehta: like psoriasis What ends up happening is you have exaggerated responses to those?
So smoking for example may trigger an immune response in the lungs that is exaggerated in those with psoriasis But the bigger one of diet, if you just take that for a moment, we learned over a [00:13:00] very early period of our research program that if you feed a patient with psoriasis an egg, they will hold on to 10 to 15 milligrams of that cholesterol compared to an age and gender match control.
They don't dispose and handle cholesterol the same. So the immune response then also stimulated Then reduces that even more. So you have a maladaptive response of hanging onto more fat, more sugar, more carbohydrate. There is an epidemic of obesity in our country, which is even more of an epidemic in psoriasis.
65 percent of patients with psoriasis are obese. The immune response collects adipose tissue macrophages. You asked about the crucible, right? Why is this the epicenter? If you will, the adipose tissue macrophages are primed And ready to go so that when anything gets into the fat, the fat is not just a storage organ.
The fat is very metabolically [00:14:00] active. And so in particular, the visceral fat, what we learned was psoriatic flares increase the space of it or increase the volume of visceral fat. There's more adipose tissue macrophages, we've biopsied and proven that, and those adipose tissue macrophages, when pulled out, have a more aggressive phenotype for more atherosclerosis foam cell formation, as well as more insulin resistance.
So it sounds like these patients with psoriasis should therefore then be predisposed to stroke, heart attack, diabetes, and they are. And so this is where the critical role of then understanding how BMI or waist to hip ratio fits into all patients with chronic inflammatory diseases. If you're not looking at that, you're probably missing a risk factor.
But again, going back just a few minutes to our conversation about different types of inflammation. Patients with rheumatoid arthritis and lupus tend not to be obese, so clearly their cytokine profile [00:15:00] is not one that's driving adipose tissue macrophages and visceral adiposity expansion.
Dr Nero: , on a side note of this issue of inflammation and, and diabetes and coronary heart disease, the patients who have elevated levels of inflammation for whatever reason have, I believe that from various trials, they set up 40 percent increased risk of developing diabetes over the course of the next five years, right?
So , what is driving that? Is it the initial inflammation part that's driving it? Or is it the fact that you're then. Holding on to those carbohydrates differently, creating different, uh, different types of fat.
And then that's driving the cycle.
Dr Mehta: And it's interesting, the initial, , inflammation that people are unaware of, actually goes pretty well in checking. for a long period of time in most people. The people who have the issue are those who have added inflammatory insults, whether it's sedentary lifestyle, poor life choices, not looking [00:16:00] at AHA simple sevens, and then compounded by that.
They ignore their primary inflammatory, , disease. So, this is not just about psoriasis and psoriatic arthritis, but a whole host of diseases that we have to treat as physicians because it's unethical not to. So, we have to treat rheumatoid arthritis. It destroys the joints. We have to treat inflammatory bowel disease.
But psoriasis leaves a very open of discussion with the patient on what they want to treat, how they want to treat it, and whether or not they want to treat it. We in fact had 30 or 40 percent of our severe population take at least a year before they started therapy. It's not unheard of in other inflammatory diseases.
And so that allows us this. initial inflammatory assessment of the drive of what's going to happen. And then look, if it's genetically driven, it is something that can't be ignored. You know, and you really do have to do something about that amount of inflammation that you're seeing. Okay.
Dr Nero: So , let's talk a [00:17:00] little bit more about what's happening now on the level of the coronary arteries,
Dr Mehta: so I think the biggest. question that we need to first talk about is when people bring up cardiovascular disease and MACE and MACE plus that we're all on the same page. So , when we're going to talk about cardiac disease, vascular disease, and then cardiovascular disease, Tom, you bring up three big, maybe four big topics that I think are very important to keep in mind for not only healthcare providers, but also patients.
You brought up the coronary arteries, which is kind of like the plumbing, Um, the walls, which would be the, uh, you know, myocardium are also at risk in this, in this disease state. Uh, the electricity is also at risk. There's more AFib and there's more electrical abnormalities in these patients. They have a lot of PACs.
Um, and then finally you brought up the pericardium, , that can be, um, highly inflamed in these patients. . And what's going [00:18:00] on in each of these beds of tissue in the heart or the vascular system is that the chronic inflammation is denuding in some cases for the coronaries and the vasculature, or in heart failure, we really don't quite understand what it is about chronic inflammation.
We've shown time and time again, diastolic dysfunction in those with active psoriasis. We've shown hypertensive disease in those with psoriasis. So could this all just be blood pressure, right? Number three when you look at the risk factors for vascular disease Those themselves are upregulated in psoriasis.
So there's more diabetes. There's more tobacco use. There's more family history There's more hyperlipidemia So you're ready in a population that's going to get disease in the vascular system. In terms of , what's going on in the coronary arteries, we have dissected that over a 10 year cohort study and we have a pretty good idea.
The coronary inflammation that's [00:19:00] detected by pFAI or the vascular inflammation that's in the coronaries, that is not luminal disease, right? That is actually in the wall, there's a change in the edema in the wall, right? So we've shown that even anybody walking in with severe psoriasis in their 40s has elevated coronary inflammation, which responds to biologic therapy. If you track a person, we said we had about 30 percent who did not start for a year any biologic therapy. So if you track them for a year, about half of the people who have elevated coronary PFI, will then develop a coronary plaque and it usually starts as a small shaggy non calcified plaque lipid, um, maybe a little bit of high risk features to it.
And then we had a group of people who still didn't take any treatment from years one to four and by four years All of those who had elevated pFAI and a plaque progressed, all of them, um, and all of them progressed into a lipid rich necrotic core containing [00:20:00] high risk plaque coronary artery. And one person actually had a myocardial infarction.
So if you look at that, that is without fail telling you that the coronary develops over time. Coronary inflammation, non calcified plaque, and notice I have yet to even bring up dense calcified plaque or CAC. CAC in this population is going to underestimate and miss disease. They tend not to calcify their disease because they're so young.
, and so I think the coronaries are easy to follow. The myocardium, I think if you look at the amount of patients, about 55 percent of all my patients walking into a clinical trial, one in two, Tom, will not know that they have high blood pressure. So could that be the diastolic dysfunction you're seeing that's leading to , heart failure and myocardial disease, possibly.
And then finally, in terms of what we do about these things is education awareness and screen for risk factors, right? So if you actually treat their disease, screen for risk factors, I think that the patients can actually live normal and long, healthy lives. [00:21:00] It's just a matter of actually making the diagnosis and how to do that is not
Thomas SN: So getting to the diagnosis, I think is going to be part of the problem. One of the things that we just saw in, the Select trial where they were looking at changes in ventricular function and that they saw improvement in diastolic dysfunction, which they think was an inflammatory response.
In coronary disease, it's quite different what we're looking at, and I think that when you, you had talked about CAC scoring and I, and I think the CAC scoring is super helpful for large populations, but on the individual level, on the more granular level, I do think that we're missing things and we're definitely missing things in earlier patients.
Um, when they looked at the orphan trial, there was about 45 percent of them that had low risk sorry, low risk findings on their plaque analysis, but who had elevated inflammation and they still had increased cardiovascular risk. So we're clearly missing things if we wait until they develop [00:22:00] enough plaque and that they have enough response that they develop a calcification.
, so a big question for us about how to identify those patients earlier. Should we be doing more carotid IMTs? Or should we just be looking at coronary inflammation , , using CTAs and potentially doing some type of, , PVAT analysis?
Dr Mehta: So, Tom, the first thing is I'd like the healthcare providers and people who do treat these patients to remember that the guidelines don't do a great job here, but you should still use the guidelines. So, looking for risk factors and then treating age appropriately, that's said and done. Beyond that, identification of patients earlier, , this is a time when I use markers in the blood in conjunction with some imaging based markers to make the case for the patient for early statin initiation.
Remember, our guidelines actually have our backs [00:23:00] here. , 2018, very proud moment for my lab, , we were able to get the ACC AHA guidelines saying if you have psoriasis, it warrants early statin initiation discussions. Great. The discussion itself though is only a discussion, Tom. You need to show them the value and the worth of the other things.
And so the two things I use, I'm not somebody who's selling images, so I'm not telling people to go and image away, but if you have the ability and access to get an IMT, that's great. Great. Because an elevated IMT would also tell the patient they have early features of vascular disease. I didn't say no to getting a CAC.
I would just avoid doing it, a coronary calcium score, coronary artery calcium score, but I would avoid getting it as the only way of making the assessment. Because if it's zero and you withhold a statin, I believe you've actually done this patient a disservice. So I use the CAC as a different tool and I can talk to you about that later.
If everybody in the country could get a single lumenography [00:24:00] CTA that then gets assessed for pFAI or coronary inflammation, I think, of course, we know that that works very well in the research world, but it may not very well be practical. So what do I recommend is usually for the diagnostics, three B's. Blood pressure, body mass index and get blood, the blood for lipids and glucose and the body mass index should be less than obese and the blood pressure should be normal.
Those three, coupled with a consultation with a physician or a health care provider, looking at those labs. keeping one's psoriasis under control. There's really not much else we can do except then start looking at blood biomarkers. So there are a few markers that we have used over a 10 year period that showed when elevated at baseline and unaddressed, coronary disease ensues.
When, when elevated at baseline and unaddressed, you may have more worsening response to biologics and psoriasis. And then a third one, which is an inflammatory marker, which when elevated [00:25:00] suggests persistent elevation suggests that you have vascular disease. So we could use blood biomarkers or blood markers to make some of these assessments as well.
But my, my sense of what I tell patients is we're just chasing things. I don't recommend getting tests in the blood just to look for things. If they're asymptomatic and you're looking for screening, the guidelines will say in order to prevent the disease, look for risk factors, keep their disease under control.
And if they have the ability to get an image of something that shows they have vascular disease to keep them compelled on staying on lipid lowering therapy, you should. But most of my derms and most of my rheums are now feeling comfortable even recommending starting statins, 10 20 milligrams, right?
So there is something to be said about do you need the imaging? Um, if you can get it, it may help the patient stay on the drug.
Thomas SN: , one of the, general issues that we see in clinical cardiology is people coming in [00:26:00] looking for the risk assessment, but mainly because, for example, they have a family history. And so in a little bit, you're, you're shooting in the dark here trying to figure out, well, what was their family history?
You have a younger person who has a coronary calcium score of zero because their doctor , got one for them before they got to the office. And they said, well, does this make me at low risk? And clearly, as you're indicating. it doesn't necessarily indicate low risk. It really, in those situations, it really is only going to help you if they're high risk.
, but , when you're looking at inflammatory markers, are there other ones that you are looking at other than HSCRP? And one of the reasons why I ask that is that we know that HSCRP and the coronary inflammation, although they're related, , as far as PFI is concerned, they're not one to one.
We have a number of patients who have low HSCRPs and high coronary inflammation, and then we have a number of patients, who have the opposite. So the question is the sensitivity and the specificity of the, , inflammatory markers and how this [00:27:00] is going to help you a little bit in talking to your patients.
And part of this is for now, and part of it is where do you think this is going to go as far as markers are concerned over the next five or 10 years?
Dr Mehta: There's very little reason, in my opinion, to look for an inflammatory marker in a patient that you know has chronic inflammatory disease. So the HSCRP If it's low, you're not going to believe it because they have an inflammatory disease. If it's high, you're going to believe it and think it's from the inflammatory disease.
But nowhere in there do I use it for cardiovascular risk stratification. And the reason is, is that in states of chronic inflammation, it's hard to track a CRP. Um, with disease activity and, and, and sort of separate them. But in terms of other markers, so I brought up three earlier ones that I kind of alluded to, and I'll give them the names now.
But the first marker that I really do think is clinically actionable is the neutrophil lymphocyte ratio. So you have an [00:28:00] NLR, and it basically shows you have a tremendous amount of myeloid inflammation in the blood. We've shown NLR with Paul Ritker's group to be Associated with, MI, second MI, post MACE MI, post, uh, stent MI.
You could just keep going down the line. It was six contemporary cardiovascular trials. And then a second study we did, um, we looked at NLR with non calcified coronary burden, and we found a very tight relationship that the higher the NLR over a cut point, the gave you that sense. And then third, um, we've also shown that the NLR responds to biologic therapy and parallels the skin.
So we do believe it's a good marker for tracking, uh, systemic inflammation following biologic therapy. Um, after NLR, I also very much, and that's clinically available on a CBC with DIF. Neutrophil lymphocyte to make a ratio. The second one is only available through LabCorp or it's a test called [00:29:00] Liposcience's NMR spectroscopy.
And I do track GlycA over time. So GlycA is a glycan marker of acute phase reactants that's measured by NMR spec. You can get an LDL particle size and number in that, you know, sort of exact test. But why I like GlycA for markers of inflammation beyond CRP is we've done the test in psoriasis. GlycA predicts disease outcome for CVD, psoriasis, NCB, lipid rich necrotic core better than CRP.
We don't like to pit things against each other. CRP still provided incremental value beyond risk factors, but our glycA marker was a bit stronger. Finally, , I don't measure insulin in the clinic, but I do try to calculate how insulin resistance someone may be. So I use their body mass index, insulin resistance, maybe a waist to hip ratio to look at overall cardiometabolic disease activity.
And that [00:30:00] helps me with inflammatory markers. So we used to actually, when we'd get the glycA, there's also an LPIR score, and it would tell you how insulin resistant someone is based on their triglyceride to glucose ratio. We had done one last paper where we did a triglyceride, um, index. It was called the TGI, triglyceride glucose index.
That's yet another way of finding insulin resistance. So, if you have clinical markers in the blood measured, you can do those three or at least two of them pretty simply. Because most people have a triglyceride and a glucose. The NMR spec, I don't recommend getting checked unless you have a concern of your cardiovascular history or you happen to be getting blood drawn and , the test can be sent out, but it goes under the LDL particle number.
Dr Nero: So onto, , therapies. We have a recent paper that was published, I guess it was at TCT with a on Colchicine. . Clear Oasis 6. Showed that Colchicine didn't work after Ladoco, [00:31:00] Ladoco 2, Colcat all showed some improvement with Colchicine.
Um, I guess the next question is, Why do you think it didn't work, and what do you think is involved here in trying to find a therapy that does work for treating inflammation in cardiovascular disease?
Dr Mehta: You know, the why it didn't work, Tom, is very hard to answer after we saw Colcott and Ladoco, um, in the patient populations, which were similar, I'd have to dig deeper in and understand whether there was some difference in the patient population tested in some way that may have, you know, precluded a positive trial.
Regardless, I do believe that the Ladoco and Colcott trials taught me that treating in the right patient population, maybe it's the frequent flyer to the cath lab, the veteran who's had 17 stents. Maybe it's the person who needs the fire put out. I think that the therapies Colchicine offers a very Uh, you know, effective way of [00:32:00] testing that hypothesis.
I don't think that this trial is going to change any of the practicing behaviors of Colchicine, which were nil anyway, in this country. I don't know how many, you know, you know, partners of mine. That
Dr Nero: a fairly big user. I don't think I wouldn't say it was above 5%, but I was certainly used it in patients
Dr Mehta: is really great of you.
Thomas SN: I was noticing , had chronic inflammation. Um, now I'm uncertain. I did look at some of the early results from, uh, from clear and also from the other ones.
I was surprised that in Colcott. Um, the ones who seem to get the greatest benefit were the ones who were early, uh, and who started early. And all of the patients in CLEAR were started early. And so I had originally thought that CLEAR wasn't positive because they were going to not be treating the patients who had chronic inflammatory issues, and that they were just treating, they were treating all comers.
Um, but that's what Colt got sort of treated. And so You know, it [00:33:00] really does bring up a lot of questions. It did seem, though, that the patients who had the greatest CRP drops seem to get the greatest benefit. And we've seen that in a number of different trials. , and we saw that, for example, in your, , oxidized LDL, study .
Uh, and we'll get to that in a second. So, I'm wondering whether , part of the question on how we're treating this is that we just can't treat all the patients the same and that what we were talking about by systems, diseases and that we have to really look at the processes that are causing them.
Part of part of that issue.
Dr Mehta: Really brings up the idea of personalized medicine, Tom, in the sense that, you know, we, towards the end of my cohort, 10 year cohort, we asked the question, well, let's label people, whether they're high IL 17s or high IL 6s or high IL 18s, right? And what we found was it was very hard because there's so much colinearity of these with other things.
So what you're actually saying was, The high 17s were the [00:34:00] ones with uncontrolled psoriasis and high PASI scores, right? So i'm not sure the the next route, but I do know that personalized medicine could be as specific as what we just discussed which is You tailor the therapy based on what you see in the blood rather than just by guidelines in cookbook medicine You look for evoked or response testing if they respond to something You know that that's going to be something along the pathway you could use but I think you're right a little bit more data is going to be necessary in terms of understanding Are there the right folks for colchicine, right?
Thomas SN: So we'll, we, um, we've also looked at different, , other immunologic agents, um, methotrexate was studied. , I think that there's a lot of question about the trial, how it was done because it was low dose methotrexate. It did not decrease CRPs, um, in the trial. So maybe we were missing an opportunity there.
Uh, Canakinumab. Did demonstrate benefit, but with a significant, um, uh, off target [00:35:00] effect of increasing sepsis, although an interesting also off target effect that it decreased, uh, for different forms of cancer. So now being studied as a chemotherapy agent. Um, we have two studies that are ongoing, or I'm sorry, three studies that are ongoing right now for, um, Ziltivekimab, uh, with, , Paul Rickers Group.
, we were involved with Hermes, um, their Zeus and, um, I think it was Artemis. It's the third one. So I think all those three are going to really move the needle forward on how we understand, uh, use of anti inflammatory agents. Although each of these is very different, right? The action of Colchicine is extremely different than the action of methotrexate, which is extremely different from these specific I L 6 blockers.
Dr Mehta: Right. Absolutely. It's a great point, Tom.
Dr Nero: , are there any, other kinds of therapies that you've been looking into? You had a very, very nice, uh, paper that I think you put out in 2022 on CETP inhibitors, , uh, Otacetramab. [00:36:00] I'm getting that wrong, I'm sure, um, is being studied in a trial , the sixth CETP inhibitor.
Um, and, but your discussion on the CETP inhibitors was , very interesting on the, um, inflammatory response. That it, um, helps to block and the potentials of decreasing a number of different disease states outside of cardiovascular disease, but specifically with diabetes and maybe neurologic diseases.
Uh, do you want to go over that just a little bit
Dr Mehta: yeah, I mean, for other kinds of therapies, it's interesting you bring this up. I think that you nailed it, anti IL 6s, anti IL 1 betas, and the CERT study with methotrexate gave us an idea that there are, you know, three tenable options that we can test, and each one of them is going to be very informative in its own ways.
In terms of the CTP inhibitors, it's interesting you bring up Obacetrafib in the sense that they're using it very creatively. The CTPs really failed in what they were hopeful for, which was cardiovascular outcome trials related to [00:37:00] HDL raising. And what we learned from those trials was that they had a steep reduction in LDL for those patients who Um, we're on the drug long enough.
And so I think that for an inflammatory population, hard to see what's going to happen with the CTP inhibitors in terms of whether they're going to find any mainstay or whether they're going to have any great benefit in those. I can see them being off target beneficial and inflammatory disease states in terms of what they're going to do to HDL function.
Um, I do think that there is. Um, this idea that there are new anti inflammatories down the pike, and I think what I'm most excited about, Tom, is actually the oral IL 23 inhibitors, the fact that there are oral medicines that can be made in a way that allows us to not have monthly or weekly , injectable dosing.
So, for me, I think the future of this is going to be continuing to curb oral IL 23. 70 or 80 percent of [00:38:00] the model's risk for having another event. And that last 20 to 25 percent that we're treating with inflammation, or treating inflammation for, I should say, I think is going to actually take on a few different strategies.
There'll be an anti inflammatory, but then there's also going to be an appreciation for optimizing the person's weight. Um, I do think that we have ignored the fact that we're in the ozempic revolution and nobody's really thinking about what that's going to do in terms of weight loss in inflammatory diseases.
And then 3rd, I think the last kind of therapy that I'm most excited by is. progressively better biologics in psoriasis. Like, I mean, think about that. We're at PASI 100s within three weeks of starting an IL 23 inhibitor like bimekizumab. So I think that's what I'm most excited about is seeing those drugs move their way into cardiology.
Dr Nero: Um, The, um, my, my take on all of this is that we have to be very careful on how we're going to be looking at these drugs and making sure that [00:39:00] we're really focusing on the right patients for therapy. Um, I've been a, um, uh, strong advocate for utilizing some other forms of indication of who are going to be involving in these trials that we get, uh, patients who are at risk.
A, who are at very high risk, so that we can see events, and B, so that we're getting patients who, um, we can follow something to see whether or not we have early response. Uh, that's one of the reasons why I like, um, I like Matt Budoff's work that he was doing in Reprieve, for example. Uh, they published that result showing that in the short term on Reprieve, they had plaque stabilization that they could already identify.
Um, I know that that group is going to be looking at, uh, perivascular, uh, adipose tissue imaging. Um, I'm not sure that they're using the exact right, um, marker for doing that, but I think that they were going to get some good information on early decrease in inflammatory response for that. But, but also they've indicated in both of [00:40:00] those is that they had an increased inflammatory response at the beginning.
So, , before we give these patients, these drugs, uh, For the entire cohort, we really have to start looking at, Okay, are these patients going to be the ones who are likely to respond? And then, then we can then see the response, , that dovetails nicely into your, , antioxidant LDL trial that you did, uh, that you, uh, released at the ACC this past year.
Um, why don't you walk us through that? Because I thought it was extremely interesting, both on a diagnostic , follow up side, and also on the therapeutic piece. Okay. Okay. Okay.
Dr Mehta: moiety and it targets it directly. So targets in the tissue. Um, the hypothesis was use of the drug over a 4 month window and their co primary exploratory endpoints would improve PFI.
As well as improve, uh, [00:41:00] psoriatic features and, , 30 percent decrease in psoriasis at the peak, which is, you know, not bad for an adjunct or a topical, um, you know, sort of medicine, not a primary biologic. But what we found was. Very interesting. , so first of all, very large cardiometabolically challenged population, 75 people, their average body mass index was in the 35 to 38 range.
Um, a lot of latent coronary disease that we didn't know about, all asymptomatic about 25 percent plaque prevalence. And then we found that those who had high PFI at baseline responded beautifully to the drug. Um, in a statistically significant manner and reducing PFI in all three vessels. However, when you look at the entire group, if you did not have an elevated PFI, you actually didn't have anything to move in the coronary.
So we didn't see anything there. It was safe. It was tolerated. And I think the most important lesson of the of the trial was using tissue based or tissue specific [00:42:00] measures such as pFAI on a tissue based antibody like Abcentra's Orticumab, I do think that you could get a really nice future now CVOT trial or some sort of a trial where this is what the next step is in this drug development pathway
Dr Nero: Yeah, the enrichment in that in that way, I think, is going to be helpful and ultimately I think that it's going to be helpful in the way that we're going to be focusing on our other therapies for patients just in general.
Dr Mehta: Yeah, totally. Right.
Dr Nero: that we look at and my patients always ask me, so how am I doing?
And the answer is, well, when you turn 90, I'll let you know, um, if you don't turn 90, then we go and we failed. And if you do make it to 90, then we've been successful. And I don't think that that's really something that we can stomach very easily and just saying, yeah, we got your LDL down and we'll see you next year.
Um, so being able to follow something up more closely, I think is going to be very helpful. Um, and that's why I'm, I'm. Excited about the results from [00:43:00] your trial because that did show that pFAI was something that was modifiable. It was a good question on whether or not it was sort of tattooed into the adipocyte that those changes were made and then you wouldn't see the, the differentiation over time.
But now, but we can, um, I think that the reprieve trial, if that comes back demonstrating that, , their version of FAI. that it decreases, with the treatment with, , pitivostatin, then that will let us know whether or not we've been successful with statin therapy, for
Dr Mehta: That's exactly right.
Dr Nero: And maybe we don't have to go beyond statin therapy.
We're, we've been very involved in the lipoprotein A trials and, um, I'm very proud of our team right now. We're the national lead, , for, , recruitment for ACCLAIM , and so we're extremely excited about this, but You know, you, you sort of wonder whether, A, if you get their LDLs down to extremely, extremely low levels, does that then decrease the amount of inflammation that they're going to be having in their vasculature, which [00:44:00] will then decrease the prevalence of events and such that you don't need to treat their LPA.
Um, which would be great, you know, not having to spend $10, 000 a year on a drug when statins and ezetimibe can do. Or do you have to treat all of them, which would be fine too if we, you know, once you know the answer, then we can tailor our, , drugs to that answer. And maybe it's just that when patients have coronary disease and a stable, but they don't need a lot of these things.
, it's a very interesting question of which you've really been on the forefront of trying to figure out how to make those diagnoses and then how to deliver those drugs. So I, I did want to get while we have an opportunity to talk a little bit about, you had mentioned some more of your recent research that you're doing with retinal arteries, , which I love as a model because that's one of the few arteries that we can actually see, , and evaluate.
And looking at, , the cholesterol, , deposition and fat deposition there and potentially how that is, uh, going to [00:45:00] be a model for how we might be able to evaluate other, vascular disease states and potentially, uh, deliver drug.
Dr Mehta: So, it's great that, , we have the opportunity to think about that you, you brought up early on that this, this idea of. the system, right? This idea of accessing the systems based process. What we appreciated over time by the 14th, you know, sort of observation year of the cohort was that lipid accumulation over time in the vasculature led to non calcified burden and the carotids led to stroke, both of which were upregulated.
In the skin, more psoriasis flares, which we saw, We appreciated fat in the bone marrow and it was inflaming the bone marrow, probably why we're seeing more cancers in these patients and other, you know, sort of bone marrow failures. But along the way I started thinking about where else would you see this metastatic lipid deposition or accumulation when it's everywhere and one of the areas that I got very interested in was.
, [00:46:00] neurons, and the optic nerve. And it's actually part of the retina brain barrier, and I learned that the retina actually, uh, does collect cholesterol and lipid over time, and it does oxidize, and there's a lot of stuff that happens that's very similar to coronary disease.
So I've taken it upon myself to figure out what that lipid accumulation does. Um, and there's a good amount of literature on that. It causes vision loss, causes holes in the eye in the form of geographic atrophy. But I've also taken time now to figure out how we can remove that lipid. And there is a way you can actually go in there and figure out what the pathogenic lipid is.
And I think what I'm most excited about over the next 10 years is The continued appreciation across multiple disciplines that lipid accumulation drives several processes that are associated with diseases of aging. So now we have blindness, atherosclerosis or myocardial [00:47:00] infarction , and then you think about the other ones that people are most after.
Um, they have without fail shown a role of cholesterol handling or mishandling in their inception. In fact, some of the chronic diseases of the CNS are now start to thought to be due to lipid accumulation. And so I think we're in a very exciting time to make therapies to actually address those. Okay.
Dr Nero: ability to actually change lipids within the CNS. , most of our drugs do not cross the blood-brain barrier. , so our ability to sort of address that systemically is somewhat limited. Um. Um, I've always been, careful to talk about my patient to my patients about, when they say that it causes them to have fogginess or decreased mental status and the trials did not seem to support that.
But on the flip side I, I do [00:48:00] agree with you that there's something else happening here with cholesterol management with lipid management in the CNS, that is part of that process and maybe it is, you know, that's a chicken egg question with inflammation itself. Um, What are your thoughts on how that is being driven , since it is a different blood pool of cholesterol?
Dr Mehta: You know it's, that's a hard one. That's going to take some time to reconcile and understand because the cholesterol in the eye actually does not move from the body to the eye and back. Actually it is. cells that are turning over at the most rapid rate in the body. And that cholesterol that's coming from those cells is actually what's being accumulated.
When you have cardiovascular risk factors, you have a weakened vascular system, choroid, you know, all of those things that ends up driving the process. There's some genetic mutations and they happen to be in the pathways of Funny enough, CETP and HDL metabolism that suggests that people who have constipated metabolism of cholesterol, [00:49:00] it's happening everywhere.
And so I guess my, my, my
Dr Nero: Um, but
Dr Mehta: sense is that we're going to do well if we can find a drug that does cross the blood brain barrier and can address this directly. Until then, I would remind patients that even having less bioavailable cholesterol in the blood pool will help this because if it's lower than what's in the choroid, it'll passively transport in there, right?
So I do try to tell my patients that yes, you have dry AMD, it's lipid driven, and it will help that you treat your cardiovascular risk factors and also see your eye doctor.
Dr Nero: Of course, you know, it does really all come back to if we can start treating the risk factors that we already know will be a lot, a lot further ahead of the game than if we just wait until we're trying to treat the disease.
You know, every, every conversation starts with, we need to improve your diet. We need to improve your exercise. Can you please do those things? Because we know those help regardless. [00:50:00] And it helps people with CNS disease as much as it helps people with coronary artery disease. And I'm sure, and I have a feeling that it probably helps in, in rheumatologic diseases as well.
Dr Mehta: Yeah, for sure. Absolutely.
, I would just like to close by saying thanks for shedding light on this. I've been doing 20 something years of work in both preventive and general cardiology. And it makes me very happy that these discussions are now becoming dinner table discussions and now scientific discussions that really do mean that we can tackle this epidemic of inflammation and heart disease, but we need systematic ways to do it.
I think the advent of what we started as Cardio Rheumatology Clinics is one way to do it. Another way to do it is to just get it out there to the patients and do more of these types of communications. So I really appreciate you spotlighting the
Dr Nero: again. Um, I am very excited again to be working with you on other, uh, issues with inflammation. One of these days I may have you come back [00:51:00] on and we'll talk more about HDL cholesterol because I think that's going to be another, you know, really ripe area of research and understanding. Uh, and, um, we will be speaking again soon.
Thanks again. All right,
