Hello and thank you for taking time out of your busy schedule to join us today. My name is Dr. David Blyweiss, Chief Medical Officer for Cell Science Systems. The purpose of this webinar series is to broaden your understanding of the immunological differences between innate and specific immunity, and how those differences manifest in disorders ranging from gluten and other food sensitivities, to more severe manifestations such as celiac disease.
In this next lecture titled “Gluten in the Heart: The Rest of the Story,” board-certified cardiologist, Dr. Joel Kahn, discusses the research surrounding the effects of gluten on the cardiovascular system. Be sure to stick around at the end of the lecture as I’ll be giving you information on some of Cell Science Systems’ innovative laboratory testing.
Thank you. And after one of the most mind-bending lunches I’ve ever had when I met David, I felt a little like a de-mentee because he changed everything I thought I knew about medicine in about 60 minutes, quite an amazing force. I actually tried to put together something like Dr. Perlmutter, a little, quick photo bio of David Blyweiss as a young child. But turns out the family was so poor in northern Philadelphia, it was either spaghetti and meatballs or Sears’ pictures, and there was none left for Sears’ pictures, so I’ve nothing that interesting to share with you.
But I do want to say before I jump into the material, that I think you’ll find, I hope, interesting, probably more questions at the end than answers, a lot of preliminary data that’s out there that I pieced together is that there was a phone call about six months ago from Dr. Blyweiss, “Would you be interested in coming out to L.A. and doing a conference?”
It never was very clear what the conference was. It was never very clear what the topic was. It was just, “Do whatever you want,” and after I committed and said, “Yes,” which, of course, I’m very glad I did, did I find out that it was Dr. Fasano, Dr. Davis, Dr. Perlmutter, Dr. Brady, some of the most accomplished and amazing speakers in the world.
So I feel a little bit like a fish out of water partly because this is the vegan in the lion’s den here. If I hear one more time about how good animal fat is for your brain, for every joint in your body, and for longevity, I’m going to have difficulty with this coming from…I actually started an organization in Detroit called “Jews for Juicing.” That’s how far out there I am into the holistic world.
I used to do cast, now I do colonics, but I’ve made some changes. I say about that, I am an integrative cardiologist now, but I still do, I guess, the other part is segregated cardiology. What do you call it when you still give the statin? I do a little of both.
But for you paleos, what your friends think you eat because it sounds so healthy, your family thinks you’re doing perfect, what society thinks you’re the hunter gatherer, the media, of course how I think I eat, and my dearest paleo friend who’s at CrossFit twice a day, every day in Detroit always wears a shirt that says “I Love Bacon.” So he has my card, he has my cellphone. I’m waiting for that day. It’s going to happen, the black will rupture.
And I did want to thank him especially because for a little while, I thought maybe David was the devil inviting me to such an amazing format. But again, I’ll jump in. Hope you enjoy. And maybe show you there may be some devil in the heart out of wheat and such that is some really fascinating data.
So it’s probably not appropriate to give a big discourse about celiac disease after Dr. Fasano has lectured for four hours, but at least in terms of general practice and for my colleagues in cardiac practice, I think we don’t appreciate how frequent and potentially serious a disease it is.
This is from the Grain Society website, of course consistent with the U.S.D.A. food plate, that whole grains, including wheat, are a source of many health benefits, and here we are hearing the other side of the story, and I’m going to share a little bit of the cardiovascular aspects of it that may make you wonder where these data came from. I’ll go by that.
So, the question I’m going to ask is what’s been called the iceberg of celiac disease, where there’s a lot of latent disease, with a genetic predisposition positive serology, but not yet villous atrophy to the more full-blown disease of inflammation, to those that actually have clinical symptoms. Does the heart fit in this iceberg somewhere, and should we start to consider evaluation of celiac disease and wheat sensitivity in some of our cardiac patients?
I ate lunch next to a gentleman who was in the room who was describing to me his atrial fibrillation, and another man just walked up to me, a physician with atrial fibrillation, we’ll see a little data on the topic, but until now, I’m sure none of you ever thought there might possibly be a connection between your dinner roll and your level of cardiac regularity or not, but it is the case. So I just do want to point out my two other raw, vegan style kind of drinkers brought me some kale celery juice just to sustain myself through this. I do want to thank them for that.
So, we’re going to go a little bit through the general topic briefly about cardiomyopathy and the immune aspects of cardiomyopathy, and then get into celiac disease and various possible cardiovascular implications. And it’s still a very nascent field. There’s a lot of work to do, and a lot of conflicting data, as sometimes happens. But this is up there more for me to remind me of just how inflammatory and hyperproliferative a patient with celiac disease is in terms of the amount of damage to the small intestine.
But let me go to the heart for a while where I feel more comfortable so I can just relax and settle in here a little bit. So, we’re going to talk a little bit about cardiomyopathy, but I’m going to bring it back to gluten and diet in a little bit, so just let me run for a little while.
And this is a pathologic sample of a normal heart. We heard about fat on the heart, maybe I’ll just talk about that for a second, and this is a pathologic example of an actual cardiomyopathic heart. And normal heart, for most people, weighs 350 grams or less, about three quarters of a pound. And some of these cardiomyopathic hearts weigh 1,000 grams, 1,100 grams, another two, three, or four times bigger than normal, and it’s a very serious disorder as autopsy specimens would suggest.
Dr. Davis who spoke about it, this has nothing to do with my talk, but I will go off on little rabbit trails now and then, coming from probably the number one hunting state in America, that fat on the heart is just an absolutely fascinating topic right now. Epicardial adipose tissue, EAT, is a new term. And as your weight goes up and as your visceral adiposity goes up, we’re finding that the measurements on CT particularly, and probably by MRI, you could actually measure and come up with the mass of fat around the heart. It does go up, literally, with overall body fat and visceral fat.
But just like visceral fat, we’re finding that cardiac fat is metabolically active, makes hormones, makes many pro-inflammatory mediators, and it’s just an awesome and probably a horrifying idea that as America gets obese and his body weight goes up, the heart is making inflammatory mediators that go right back into the coronary arteries, and impair, potentially, endothelial function in the very organ on which they sit. So that’s a whole new syndrome. That’s not the point of what I’m talking about.
I got a relatively normal slice of a left ventricle, a right ventricle, and some of the fat on top of the heart, and the pathologic cardiomyopathic heart, it’s very dilated, both the left ventricle, just huge, and the right ventricle over here in this example.
So, as cardiologists for the last 30 to 40 years have struggled with, since we had basically echocardiography, which made the diagnosis of the dilated heart, that was about 1965, so almost 50 years, made the diagnosis of a dilated heart very simple by echocardiography.
Many studies have been done and there is still a giant subset, the ideopathic dilated cardiomyopathy. These are just people that are waiting for functional medicine to define what nutritional deficiency, or heavy metal access, or other environmental toxin has weakened their heart, but that’s the largest group. We don’t know, sort of like essential hypertension until you start taking a functional medicine approach.
But an active inflammatory destruction of the heart, myocarditis, exists. Coronary artery disease, of course, can cause a dilated heart. Infiltrative diseases like glycogen storage disease is peripartum cardiomyopathy, which probably is a type of myocarditis, severe hypertensive heart disease, HIV, connective tissue diseases like lupus, and certainly cocaine can cause a cardiomyopathy.
We will get to a loaf of bread. I was actually thinking, I don’t know if this has been said before, but is a gluten-free diet the best thing since sliced bread? Sorry. Bill, you can use that from now on if you haven’t used it already. That came to me in the lunch. I think that’s when I came in, too much sun.
So, as we saw, the chambers of the heart get dilated. There’s often hypertrophy, there may be fibrosis, there may be inflammatory infiltrates, but then it would probably be called myocarditis, not ideopathic. The valves get stretched apart, and the arteries are not the cause if it’s an ideopathic dilated cardiomyopathy.
We don’t generally, as cardiologists, draw any specific genetic tests for this syndrome. There aren’t any that are enough predictive or clinically available. We’ve looked over the years, I’ll show you in a minute, for actual evidence of viral infection in the blood or in biopsy of the heart.
We can check immunologic measurements. None of these are routine. And ultimately the heart fails because of various disorders in ATP generation, and the mitochondria and the whole field of metabolic cardiology. And Steve Sinatra, Mark Houston, Jim Roberts and such goes into nutritional and nutraceutical support of mytochondrial function and mytochondrial biogenesis.
But in terms of just a little more data, this is hardcore cardiology right after lunch, it’s a bad deal. But this is an interesting study – 183 people with a dilated cardiomyopathy, their family members were dragged in, and these were family members that were not known to have a cardiovascular disorder, and surprisingly, about 5% of them were found to have a ventricle that was dilated, a little under 5% had a ventricle that wasn’t contracting well, specifically the left ventricle itself was enlarged in some, and there were some, because of these echo findings, that underwent biopsy and found a variety of inflammatory markers.
I don’t know how much you’ve considered coronary artery disease. Of course, it’s very avant-garde to speak about it being an inflammatory disorder. We measure our CRPs and our myeloperoxidases and our galactans and such, but congestive heart failure is very much in the vogue as also a disorder of inflammatory activation.
This is a technique that’s been around for about 40 years. It’s through a vein in the neck or a vein in the leg, a little bioptome goes into the right ventricle, and closes, and then right there would be the little absinth muscle, usually a fairly benign procedure, not without risk, now done predominately. And I’ll tell you why it’s the case in post-transplant survivors in terms of their surveillance for myocarditis and rejection.
But many studies were done on dilated cardiomyopathy to define the ideology of a patient with an enlarged heart, and patholgoic findings, this looks only slightly like the villous atrophy of celiac disease because there’s a lot of infiltrates of white blood cells, monocytes, macrophages, neutrophils, depends on what stage. And ultimately there will be tissue destruction and replacement with a fibrous material.
So, over a whole large period of experience, and I trained in cardiology mainly in the ’80s, this was a very active field when I was a fellow and a student. About 10% of patients presenting just with run-of-the-mill congestive heart failure due to a dilated ventricle, not due to a heart attack, about 10%, if biopsied, showed evidence of active inflammatory infiltrates.
But very provocatively, although a very small study out of Mass General, very small numbers, but if you were to identify a person that had just presented with their congestive heart failure in the last four weeks, the incidence of finding inflammatory disease on their biopsy was very high, and fell down to 26 weeks. And if you go much out further than that, it gets to be very low. It also may be that this was the referral center for the country at this time, so they may have higher numbers because they were getting people that were either more acutely sick or coming over for research protocols.
You can also, and actually we still do this clinically, you can order an MRI of the heart. There’s specific appearances of the myocardium where the myocardium will look adenitis from an active inflammatory infiltrate in the muscle itself, and is fairly diagnostic for myocarditis inflammation as opposed to ideopathic, unknown, alcoholic, toxic, and such. And it is pretty useful, although the treatment differences are unclear.
There are some genetic defects. None of these tests are standardly available. You don’t have to write any of them down or worry that you’re not ordering them. This is more still in the research realm. There is no panel of snips and such that is a routinely done in congestive heart failure patients to look at a disorder of ATP generation or mytochondrial function or any such thing.
One of the reasons that biopsies have become uncommon in modern cardiology of the last 10 to 15 years is it didn’t seem to make a difference if you were diagnosed with an ideopathic or an inflammatory type of cardiomyopathy, that when followed over time, this is from Mayo, there wasn’t much difference. And there was one very famous trial using high-dose prednisone steroids and azathioprine done by Jay…hold on, I’m blanking. Jay Mason was his name.
This study, long ago, took forever to complete, way under-powered in terms of what they hope. And although this is not that trial, the curve looked the same. It was kind of therapeutic nihilism that biopsies, immunosupressives, these were people that were biopsy-positive for inflammatory heart disease, showed no clear benefit for the whole trouble they went through. And pretty much after that came out 20, 25 years ago, the number of biopsies done for new onset heart failure and the treatment options just became standard congestive heart failure treatment options.
It still remains, although the data’s a little old, it’s not too much different, a serious disorder. Forty-nine people that were followed with ideopathic new onset heart failure compared to people that had chronic dilated cardiomyopathy, and looking for if they improve their ejection fraction with time, and if they didn’t improve their ejection fraction, you can see out of 49, within the first 12 months, either 12 died or 10 were transplanted, but a little under half of them had very serious outcomes, of course, and about a third of them had improved.
And If you go out a little longer and follow up, a few more will cross over and improve. But it’s always been pretty much, if you present with new onset heart failure, dilated cardiomyopathy, the chances are about a third will die, a third will stay in a chronic congestive state if they survive, and a third may see rather dramatic improvement.
And I point this out partly for general education, but partly when some of the case studies I’m going to show you are reported about the relationship between gluten and cardiac function, and a case report indicates that a patient improved and their ejection fraction went up, it’s very hard to interpret a single or a small series of cases because we’ve seen many cases.
And now with the use of drugs like carvedilol and metaprolol, which have been shown to improve outcome in congestive heart failure. And if you’re a believer, as I am completely a believer, that the Steve Sinatra metabolic cardiology awesome foursome, or I use fivesome, I add touring to the program, improves cardiac function. It’s very hard to interpret these single case studies.
So there have been a number of cases of spontaneous improvement. The shorter you catch somebody, the quicker in, the better. Their sodium, which is a common renal aldosterone system, they’ll lower their filling pressures, the better are the odds that they’re going to recover.
So if the new onset cardiomyopathy, and you can observe over the first six months, if their ejection fraction’s improving, the odds are they’re going to do pretty well long-term. And if they presenting with new onset heart failure and there is no improvement in ejection fraction over the first six months, they got a rather wicked course, and should be referred to transplant centers and such. I’ll go past that.
Stan and I we’re just about done with this section, but standard treatment still remains, ACE inhibitors. Other than the Sinatra metabolic approach, this is still very much the segregated approach to cardiology, not the integrated approach. It’s a lot of drugs for these patients – ACE inhibitors, if they have a problem with that, angiotensin receptor blockers, maybe like Benicar, we’ll talk about Benicar more in a minute, the study that was done in African Americans, that hydralazine and nitrates are an advantage in African Americans with this syndrome, diuretics, electrolyte replacement, particularly carvedilol and maybe nebivolol, Bystolic and other agents, without question.
So just to close the chapter on the life of the immune system in congestive heart failure, this remains actually a very active area of clinical research, although this particular paper’s a decade old. This is a small study looking at Enbrel etanercept in advanced heart failure, an agent that lowers TNF levels. This is a double blind randomized study in 47 patients with rather bad heart failure, treated with twice a week injections of Enbrel or placebo, followed up for three months.
They were well-tolerated, treatment with Enbrel led to a significant and dose-dependent improvement in ejection fraction and remodeling, and there was a trend towards improvement in the way people actually felt. Now, I couldn’t really talk about long-term survivals, a relatively short study, but the idea that a stoked up immune system is present in congestive heart failure, and that methods of modifying the overall activity of the immune system may be beneficial in congestive heart failure remain active.
There’s a very large trial that’s about to be embarked by the National Institutes of Health using this same drug in people with unstable angina and coronary artery disease due to the last decade of so much data that atherosclerosis is an active and inflammatory vascular phenomenon, and a lot of people say, “Why not just study turmeric? Why are you using a drug that is significantly more expensive and toxic?” Everybody knows about patents, so that’s why Enbrel’s being studied. Well, it’s true.
This is actually interesting also, and I just put it out there for those of you that are seeing patients with heart failure and sometimes struggling, what to do next, as I often do, but it has been observed that uniformly tumor necrosis factor, TNF alpha, is elevated in heart failure patients as a sign of activated immune function and immune mediators that are harmful to vasculature.
Endothelial dysfunction is widespread in congestive heart failure. So pentoxifylline, which you might remember as a drug called Trental, only approved for intermittent claudication, and largely abandoned now in its generic form as there’s better drugs for claudication like diet, exercise, and cardio and others. But at any rate, pentoxifylline has been suggested as a TNF alpha inhibitor that may have some role in congestive heart failure, and this has been discussed in the literature.
There’s the idea that TNF alpha is secreted by activated mononucleal sites and such. It may cause apoptosis, TNF alpha may directly damage myocardial sites, damage endothelium, and may lead to release of a variety of cytokines that are harmful to the heart, so lowering TNF alpha and lowering inflammation in a heart failure may be important. And pentoxifylline only has a bunch of proposed mechanisms by which it inhibits many of the steps where TNF alpha activates IL-8, metallo-proteinases, and such.
So it’s very interesting. It’s not FDA-approved. You would be a little cautious in using pentoxifylline in your heart failure patients. It’s inexpensive. People do respond. I’ve used it on a couple occasions, in refractory cases, and maybe James Roberts in Toledo, if you’ve seen him lecture or know any of his writing and books, has had probably the largest experience and is rather excited about it. It definitely lowers cytokine levels that are activated in heart failure.
So that was a little background, hopefully not too painful. But maybe a basis to understand a little better some of this interesting and preliminary data about the question, is there a connection beyond gaining weight, beyond metabolic syndrome, beyond particle size, and number, and triglyceride level that Dr. Davis has characterized so well for us in his book and his lectures.
So, in terms of the overall question, and a lot of these are one-study answers to questions, is there any known connection between celiac disease and an overall risk of increased vascular disease? If we looked at rheumatoid arthritis, lupus, psoriasis, there’s quite a bit of data that those inflammatory disorders are related to a generalized vasculopathy. It’s been suggested that celiac disease might do it.
So this is a large study with 4,000 people diagnosed with celiac disease, 17,000 people that were age-matched controls in a database. Interesting data – adults with celiac disease were less likely to have a diagnosis of hypertension. It may be that they’re not healthy and they’re thinner, and they therefore at least have that component of hypertension better controlled, and they also had a lower risk of hyperlipidemia, hypercholesterolemia, maybe for the same reason. This is just an observational study.
But here’s the first time this will show up. More likely, celiac disease, to have atrial fibrillation, the numbers aren’t overwhelming, the odds ratio’s not overwhelming, but it is potentially a connection between celiac disease and cardiac disorders. The hazard risk for myocardial infarction was lower than the control group, the stroke risk was a little higher.
The overall finding was that there wasn’t any dramatic and mind-blowing connection in a large database between the presence of celiac disease and the presence of some of the most dangerous and frequent maimers and killers in at least this European population in the United States.
But lo and behold, about eight years ago, a series of reports started showing up, and I believe this is the first one, suggesting a connection between celiac disease and cardiac performance, and specifically cardiomyopathy. Single study out of Mayo – a patient with celiac disease was cardiac in function, which was abnormal, improved substantially with a gluten-free diet. Cardiomyopathy associated with celiac disease is serious and potentially lethal with early diagnosis and treatment.
Again, study of one, people do improve on their own spontaneously with standard treatment, but it was, time-wise, correlated with the removal of wheat and other gluten-containing food items from the diet, but it’s a single study.
I’m just going to show you a few case reports to start with. Eighteen-year-old male, one month history of progressive heart failure. Biopsy showed a series of inflammatory abnormalities, might be called myocarditis, small bowel biopsy diagnosed celiac disease the first time. And they reported in the Polish literature that the patient improved and the patient seemed improved most when the diet was adjusted to be free of gluten.
This is a hodge-podge – two cases of ideopathic dilated cardiomyopathy, also presenting with heart block, found to have celiac disease at the time of presentation. Cardiac function improved in one of the two. So we said maybe a third of people improved generally, so this was 50%, but not quite yet time to get too excited.
Dilated cardiomyopathy diagnosed 12 years before in a patient presenting with diarrhea. Markers of celiac, zero positivity were present, and then diagnosis confirmed by a small biopsy. And at least suggested in this paper that cardiomyopathy was a consequence of years and years of inflammation and such.
A 24-year-old woman, severe heart failure, chronic diarrhea at the time. Had for the first time a diagnosis by serology and biopsy celiac disease went on to have a heart transplant. Inflammatory cells throughout the heart. Simply again, another case report raising the question, is there potentially a pathophysiology or is this just random of two diseases that aren’t so completely rare?
Here’s a child, 27-years-old, a month of diarrhea, confirmed to have celiac disease, found to have a cardiomyopathy. Got worse, wasn’t complying well with diet. And another young child in there with a heart failure found to have serology that suggested some sensitivity to celiac proteins, and found to have actual celiac disease in autopsy of their death. More questions, single cases.
And just two more case reports. We’ll go back to that issue about atrial fibrillation and maybe other conduction diseases. They’re so small it’s hard to come to giant conclusions. AV block in the French bread, too. Cases of celiac disease presented as ideopathic dilated cardiomyopathy with heart block in one. No symptoms of GI disorder. The diagnosis of celiac disease was confirmed by serologies and also biopsy.
Gluten-free diet improved cardiac function in one patient, but it didn’t do anything about their heart block. The other patient didn’t get better. So they went out and said it highlights the possibility of a connection between the inflammation in the gut to gluten antibodies and its consequences in cardio-esque performance.
So, just questions to ask. Is the heart part of this overall body-wide syndrome that Dr. Fasano told us is present only in humans and not in other mammals of a variety of autoimmune – I think he said 60 – autoimmune diseases, and is myocardial inflammation affecting the conduction system of inflammation leading to arrhythmia and heart block, part of that overall syndrome? Interesting questions, and nobody could conclude. From what I presented, that there’s really much there.
So, I’m going off now for the second time, and I’m going to come back, about the general topic before I come back to celiac disease, about at least a glimpse in the literature. Because although you have two interventional cardiologists in the room right now that have talked more about the gut than we have about stents and bypass, it’s still quite rare both in practice and quite rare in the literature to really have a firm foundation that focusing on gut health is a path to better cardiac health, although I’m sure most people in the room would say that certainty is the case, even if the studies and the practice pattern are relatively infrequent.
So, some of the most provocative data in this connection between the gut and the heart deals with endotoxemia. This is a study of patients with chronic congestive heart failure, looking at function of the barrier, the GI barrier, the mucosal barrier, to transport various mediators that need to be transported. Heart failure patients had half of the ability to actively transport nutrients and other factors across the lining of the gut.
It was strongest, as you might imagine, as we were all taught in medical school or other places, if they were in an edematous state, the reduction in active transport of important nutrients across the gut was severely reduced because of the edema and further distortion of cellular function. And there’s passive nutrients and passive agents that cross the GI barrier. They were also reduced strongest in edematous patients, above active and passive.
And they showed that as they converted from an edematous to a more human anatomically favorable situation, as their heart failure got better from a variety of treatments, there was return of these active and passive mediated functions across the intestinal barrier. And in 42 of these patients that were decompensated, they had high lipopolysaccharide and high endotoxin levels determined in the blood.
And they also, as a marker of barrier, gut barrier, leaky gut problems during acute decompensation of heart failure. And as their heart failure improved, endotoxemia improved. Edematous patients had the highest levels of endotoxemia and other inflammatory markers and they improved as they got better.
So very provocative data that, I don’t know if you’ve heard Jim LaValle talk about some of this, but he does speak, Dr. LaValle, about endotoxemia and congestive heart failure. As I’ll show you, it has not gotten to the point of any clinical evaluation to see if there’s a role of addressing the gut barrier in patients with chronic or acute congestive heart failure, but it’s very ripe and open for that.
The theory that endotoxemia may have a role in congestive heart failure is that by activation of toll-like receptor 4, there’s a variety of inflammatory mediators in the cytoplasm, and NF- kappa B gets transported into the nucleus where a variety of inflammatory mediators will be released into the blood stream and cause widespread systemic inflammation. So nothing good about endotoxemia, whether you get it from a Big Mac in the morning or whether you get it from being an acute congestive heart failure with an edematous bowel. Very, very interesting.
This is just a paper they put out in a review form, the concept that bacterial endotoxemia and leaky gut may have an important role. This wasn’t a new scientific study, I just put it up. There literally are three or four pieces of literature out there that talk about it, but we’re not yet ready. I’ll show you just one more piece of data in a minute on the topic.
The other aspect between gut function and cardiovascular function is that these edematous and impaired bowel walls may be very poor at transporting micronutrients into the body and there are frequent, frequent micronutrient deficiencies in heart failure. I have become quite a fan of drawing micronutrient testing profiles in congestive heart failure patients, and find a variety of depleted markers of antioxidant and immune function. So copper and zinc are required for superoxide dismutase, selenium for glutathione peroxidase.
In a very small study in heart failure patients, there was almost uniform reduction in selenium concentrations in the serum and in red cells, and a very high frequency of zinc deficiency in the serum. There is a specific cardiomyopathy from selenium deficiency that’s seen in China because without glutathione, you’re obviously not going to be controlling oxidative stress through the body, and in the heart specifically.
A relatively new area is hypovitamin D in congestive heart failure, and at least very small studies suggesting that in addition to all the other reasons, people are low in vitamin D on average, and edematous bowel wall, and chronic or acute congestive heart failure is very bad at transporting vitamin D, even if you’re giving patients a good amount orally. And this overall topic is one that’s growing, but still relatively nascent.
So this is what I wanted to show you. If you go to Pub Med and try and match probiotic therapy and congestive heart failure, there’s nothing. It is pretty amazing despite many good theoretical reasons to have it out there. And whether you practice that or not as a general principle, it’s just begging for some kind of study to be done, whether just by measuring the effects on serum endotoxin levels, or maybe more importantly, how people do short-term and long-term, but that word “patent” is going to keep that from being done.
And I’ve had some chance to talk to Dr. Fasano, I don’t think he’s in the room right now, which means I can talk about him, because I would be certainly stepping past my scientific border if I go too far into this. But he told me that they’ve had very little experience in measuring zonulin in congestive heart failure.
He did mention one patient they’ve had where it was suspected they had a gluten-related cardiomyopathy patient, and the zonulin level was the highest, I think he said, he’s ever seen in any situation at any time. And since he’s not here to defend that statement, we’ll all write that down and accept that and brag about it.
But there’s absolutely no data yet accumulated in a small or large series on the possibility that, like type 1 diabetes and like celiac disease, that the acute phase of inflammation of myocarditis and cardiomyopathy might be related to, or at least associated with, elevated zonulin level. So it’s totally a theory that needs to be looked at.
So I wanted to take a break for a minute as I go into some of the larger series on this topic. I am not Italian, but I wish most days I would, like the lead character of “Breaking Away” if any of you are old enough to remember that. So I learned Italy because it has the best grapes in the world, in my opinion.
That’s where Dr. Fasano’s from, Salerno, which is a beautiful town. Many of you have probably seen it on your way to Capri, and full of lemon trees and make delicious limoncello, which my five-year-old daughter, at our first visit in Italy, had for breakfast, lunch, and dinner. And now that she’s in college it’s pretty hard to keep her away from the limoncello in Boston. But she’s doing pretty good, she’s a good kid.
What else could I tell you? Of course, the Vatican. I don’t know, how many of you here are Italian wine fans? It’s the best way to learn Italy, because…I’ll show you another slide or two further on, but here we go with Piedmont, which is where Barolo and Barbaresco, and Dolcetto owns some of the great, great classic wines, and then Florence and the whole Tuscany, and San Marino are such fun.
But if you’re into longevity, since this is the anti-aging society, as you may know, Sardinia is one of the five or six blue zones worldwide. You’re probably familiar with Dan Buettner’s work with the National Geographics and now his two books on blue zones.
And at least part of the theory why inhabitants of this little island just west of Italy and part of Italy, is the wine. There’s a specific grape that grows only in Sardinia called Cannonau, and it has extremely high resveratrol and other polyphenyl content. It’s one of my favorites, I’ll show you that in a moment. But if you’ve never tried Sardinian wine, you can spend $10, you can spend $300, you pick your range, but it’s very helpful wine if it has Cannonau in it. Very, very tasty stuff.
So these are a few larger studies. This in fact, is the largest one, though it’s just an association population study. This looked at arrhythmia, and this looked at atrial fibrillation. We’ve seen a couple little snippets that suggest that there may be association with celiac disease.
This was 28,000 patients with diagnosed celiac disease in Sweden, and they were compared to 141,000 patients in a registry that did not have celiac disease. They were age and sex-matched. They also had data on who had atrial fibrillation and who did not. So pretty amazing data for such an obscure topic, really, just two case reports.
But for this report, 941 individuals in the celiac disease cohort developed atrial fibrillation, 3,000 in the non-celiac disease and the corresponding adjusted ratio, risk ratio for atrial fibrillation was one point three. Confidence intervals didn’t cross one. It was statistically significant. The absolute risk of developing atrial fibrillation was 321 in 100,000 years, 81 extra people, and 100,000 person years would get atrial fibrillation, predicted by them having celiac disease.
Atrial fibrillation is more common, both before and after diagnosis of celiac disease, although the risk is small, the excess risk. Potential explanations are chronic inflammation, maybe shared risk factors, although as far as I know, atrial ADQ has no known connection to atrial fibrillation, and I don’t know another shared risk factor between people with celiac disease.
And we usually think hypertension, which already is seen as lower in celiac disease, alcoholism. Maybe thyroid disease could be a connection. Autoimmune thyroid disease and autoimmune celiac disease could potentially intersect in the development of atrial fibrillation.
I showed the map of Italy in part because almost every study that’s a little larger than a case report on the topic of gluten, and the heart comes from Italy. If Dr. Fasano was here, I would imagine, know most of these people who study out of Rome, Dr. Curione, 52 patients with ideopathic dilated cardiomyopathy, three of them had celiac disease, suggesting the increased prevalence.
Of course, if you believe it’s about a percent, it should have been half of the patient, and it was six times higher. So it may not be time to run out and announce to the world there’s a connection, but at least someone suggested. This is a referral center for celiac disease in Italy, and again, there may be some bias for that reason.
Another study, this is a very prestigious cardiology journal, you’ve gotta have pretty good science to get through this peer review. A study out of Rome, patients with myocarditis – bless you in the back – 187 were screened with serology for antibody reaction to gliadin, 13, or 4%, had positive antibodies. For reasons I’m not sure, they only selected the anti-endomysial antibody patients for biopsy, and they were positive for celiac disease, small bowel villous atrophy.
Five of them had active myocarditis and got gluten-free diets and immunosuppression. This was at a time frame that azathiaprine and prednisone and such were being used a little bit more frequently, but they improved. Patients with biopsy-proven myocarditis, especially in the presence of clinical finds of malabsorption, should be screened for celiac disease.
Sort of a new syndrome that isn’t really in the cardiologist radar screen, may or may not be on your radar screen, but some suggestive data, of course that ought to be in 187 patients, maybe one and a half, not 4%, if you just want to go with what the literature suggests.
A little larger series, this one’s out of Pavia, Italy, 238 consecutive patients with cardiomyopathy, they also screened relatives and just some healthy volunteers who were donating blood, screened for antibodies that suggest the immunologic reaction to gliadin. Tissue transglutaminase was positive in 26, 16 of the controls, that’s out of 2,000, 0.8, 5 of the dilated cardiomyopathy out of the 238 or 2%; actually 7% of the relatives had had abnormal echoes, because they did follow up with an echo, 1% of the relatives that had normal echoes. But 2% versus, again, the expected maybe 1%, slight increase.
Higher prevalence of celiac disease in patients with cardiomyopathy suggests that immune-mediated mechanisms are active in their develop of a cardiomyopathy. All kind of little pieces of a puzzle that are not dramatically overwhelming, but they are interesting and somewhat consistent.
So, we are back. We are off the peninsula of Italy to somewhere else in the world. Seventy-four patients awaiting a heart transplant, they drew blood looking for, again, antibodies, evidence of a gliadin reaction. Two of the 74 were positive for anti-endomysial antibody, 5 for tissue transglutaminase or 7 overall, biopsy positive in 3%. None of the control patients, age and sex-matched, had these antibodies.
Again, recommend screening. We should start screening our patients with cardiomyopathy for celiac disease as potentially a treatable form of inflammation that’s at the root cause of their cardiovascular inflammation. Provocative. Other than case reports, nobody yet has tried any kind of randomized and prospective evaluation of small or large numbers in this manner.
We’re back to northern Italy now. Sliced thin cured beef famous in this town. I would probably have the olives and the wine, but that’s what they do. Three hundred and fifty consecutive patients with a dilated cardiomyopathy, mix of ideopathic, mix of coronary artery disease, screened for anti-tissue transglutaminase.
If it was positive, they went on to a biopsy. They found small numbers of a biopsy positive and antibody positive. They had some suggestive symptoms that went along with they actually had celiac disease, and they didn’t even improve. So, again, maybe, I know, and nobody has any idea why this particular series was a little bit less positive and encouraging that there’s some shared communication.
So this was a review that took place out of Rome, but it was a review of the data of a number of other series that came up with more than 1,000 cases of cardiomyopathy and 16,000 control patients. They came overall on the literature, the prevalence. There was 3.4% of the cardiomyopathy patients had celiac disease, versus a pretty typical number, about 0.4% of celiac disease in the controls.
Two to three times higher than expected. Low ejection fraction. Gluten-free diet in this review, this combination study of multiple other studies, gluten-free diet overall tended to improve cardiac performance in patients with cardiomyopathy, and appropriate screening for celiac disease should be performed. Probably the strongest data, the largest numbers, by just lumping together a number of other small studies.
This was an attempt at a cardiology clinic to use a point of care, finger blood stick that gave you an antibody result right away in terms of whether you had an antibody tissue transglutaminase or anti-endomysial antibody. It was more an evaluation of this new technique than it was of the topic, but it provided some data.
They tried it on patients with dilated cardiomyopathy, some of their relatives, some disease controls, heart failure of a different cause, and some healthy controls. The antibody’s single, quick, blood drop test was positive in 3% of cardiomyopathy patients, 2% of relatives, 1% of controls. Those were positive, frequently anemic, and they probably did have some intestinal villous atrophy and deficiencies in nutrition. Two of the patients had a rise in ejection fraction with a gluten-free diet. The third didn’t respond quick enough and went on to transplant.
So you get the same theme in other Italian study, and the point of this was, should the cardiologist be taught and thinking about early testing in people with new onset dilated cardiomyopathy. So pass this on to your peers, in your communities and tell them that you’ve learned something new about celiac disease. And when they see their next new onset heart failure patient, maybe particularly there’s anemia, particularly there’s any diarrhea or wasting, they should think about undiagnosed tip-of-the-iceberg celiac disease.
This is from that same giant Swedish database. a different twist. That other data was on atrial fibrillation itself. This is overall the link to cardiomyopathy and celiac disease. There were 29,000 celiac, 144,000 controls, 17 patients with celiac disease and 52 control subjects that did not have cardiomyopathy at the onset of this annual database developed a cardiomyopathy, it’s one point seven. So almost a doubling of risk in this giant study, a modestly increased risk of cardiomyopathy in people with biopsy-proven celiac disease. So very consistent with what we had.
Some of you may be seeing more children than I see, but this a study specifically in children and adolescents, same topic, just a different patient group. Fifty six patients with a cardiomyopathy or myocarditis tested just randomly for antibodies that would identify gliadin immune response. Two percent, which is just one of the children, had a positive tissue transglutaminase antibody level, but a negative endomysial antibody. There was a biopsy positive. They went ahead and did this. GI symptoms were frequent.
So there were a lot of symptoms in these kids with cardiomyopathy, but very low frequency of actually finding celiac disease to account for their GI symptoms. But they still went on to suggest that in cardiomyopathy patients with GI symptoms, consider celiac disease, if not previously diagnosed, as a possible underlying condition, and maybe some link to pathophysiology.
I wanted to take a moment to get back to fun, and maybe teach you something, or maybe just repeat what you know. You may or may not know something called the Killer Bees, and it’s nothing to do with thiamine or pyridoxal phosphate. But in Italy, these are the three – you could always argue what three – but these are the three most famous wine classes: Brunello di Montalcino, which is from Tuscany. Montalcino means “the mount of oaks,” and wine that’s been made for about 150 years and has to sit in a cask for a very long time and becomes a real treasure.
You don’t want to mess around with the Italians, this is just a little side story, but there’s been a real rift amongst makers of this particular wine in the town. You can only make this in Montalcino. You make it five miles away, it can’t be called Brunello di Montalcino. You have to be in Montalcino. It’s very specific.
And there was a feud between two of the families, the Biondi Santi family and I cannot remember…Soldera, Soldera, Gianfranco Soldera. And there was such a feud that about three months ago, somebody broke into Soldera’s wine cellar where he had his entire stock, took an ice pick and put a hole in every single cask, which is probably about 15 years of wine sitting there. But I understand that Soldera was an insurance agent and had so much insurance on his wine, that I’m not sure if he was dancing or crying when he walked in.
And Barolo and Barbaresco, as you may or may not know…somebody was just saying, “In Italy, every glass of wine tastes so good that even if grandma made it,” that’s the table wine all the way up to the most prestigious and regulated wines. And this is, if you ever have a chance, is wine from Sardinia made from the grape Cannonau. It’s a rather high-end, expensive choice, but we have a local restaurant in Detroit that has a really good collection and when the market’s up, I’ll go in and share one with my wife.
All right, so we’re going to change the approach to the idea that there may be something for you to think about in the future between cardiomyopathy…David is giving me a score. I got 45 out of 100 so far. So I either got to pick up the excitement, show more wine data, or take my bags to LAX. Thank you. But there is some provocative data using simple technology like echocardiography. Do patients with celiac disease have impairments of cardiac function that may not be so obvious and may cause some concern?
So this was a group of children with celiac disease, 60 of them, 45 healthy children, all studied with echocardiography. Very interesting data. And mild cardiac involvement was found in 13 of the 60 children, 22%. Whereas there was only 1 of the 45 healthy child that had even the most minor echocardiographic abnormality. Rather dramatic differences there. There was reduced ejection fraction, and there was regurgitation of valves as some of the findings.
Overall contractility, when you just looked at mean levels of ejection fraction, mean levels of cardiac chamber volume, there was lower ejection fraction, higher chamber volume in the celiac patients, and kids that really adhered to their gluten-free diet, on follow-up echocardiography did actually demonstrate some improvement in these silent, sub-clinical abnormalities in cardiac function.
So no biopsy. We don’t know if there was inflammatory disorders within the myocardium of these children. But if you’re looking for another reason to give your patients some motivation to adhere to their restricted diet, there’s one that perhaps might help you point out to them that they’re actually doing it. If they don’t want to do it for their gut, they can do it for their heart.
Small case studies of adults with celiac disease, this is really underwhelming data, but there’s not a lot. Three people with celiac disease that had ejection fractions that were quite low, prescribed a gluten-free diet. The first patient was followed for a little over two years. His LV size decreased, which is a good thing, from dilated back to normal, and the ejection fraction rose a bit. He described feeling much better on a gluten-free diet in terms of cardiovascular symptoms.
Second patient was followed for two and a half years. The ejection fraction rose a bit. Of course, there is some subjectivity to measuring ejection fraction. He also reported, or she, on a gluten-free diet, that quality of life in terms of cardiac disability was better.
The third patient was the one that didn’t care at all, and the ejection fraction dropped further. The LV size dropped further. Quality of life dropped more. So this is the bad patient. Preliminary data that a gluten-free diet in patients with celiac disease and cardiomyopathy may improve both symptoms as well as cardiac parameters.
This is back to children, using echocardiography, 75 compared to 30 age-matched controls. The diastolic dimensions were larger in the children with celiac disease, which none of these are in a pathologic range, but you don’t want a dilated heart. Rather small differences as the group means, but they were highly statistically significant.
And the thickness of the septum was actually a little bit thicker, which can be a response to wall stress and abnormal performance of the heart in children with celiac disease. The actual ejection fraction wasn’t different. And again, that an echo in a patient with celiac disease may be a reasonable consideration to look for sub-clinical signs of cardiac involvement.
All right. That’s all we got for cardiac function, and whether you choose to do an echo and whether the insurance company’s going to pay for it, I can’t predict for you, but we definitely need more academic studies on the topic.
Autonomic nervous system is a source of a couple literature citations in terms of celiac disease and cardiovascular function. I won’t review with you all the various sympathetic and parasympathetic functions that are throughout the body, but we know how important it is in the GI tract in terms of motility and such.
So, in untreated adult celiac disease, a study was performed on upper gut motor activity and the role that the autonomic nervous system had in gut motility. Thirty untreated celiac disease patients, 50% demonstrated delayed gastric emptying with autonomic testing being positive in the high percentage of this group. Autonomic scores correlated with the abnormal gut motility activity. This study confirms upper gut motor abnormalities are frequently present. Autonomic neuropathy may play a role, although other pathophysiologic mechanisms are likely to occur.
So of course there were no biopsies of the autonomic nervous system. This is the breathing deep, and heart rate variability, and standing up, and response to the blood pressure to standing in terms of orthostasis, which is the standard way, R-to-R variability during breathing. Standard, simple tests of autonomic function, but provocative, although there’d be no theory why autonomic function might be altered in celiac disease. As far as I know, autonomic nervous system function isn’t typically an immune-mediated abnormality.
And then there was a second study done, I believe this is the only other one. Altered gut motility seen in celiac disease could be due to autonomic nervous system dysfunction. Eight patients were assessed – Valsalva, deep breathing, hand grip, and 13 controls, one patient had orthostatic hypotension. Otherwise, they could not identify any differences. The study failed to confirm. So one report suggestive, 50%. One report saying not really possible to identify.
Oh, one more. This is an autonomic function laboratory, I think, at a hospital in Toronto. 164 patients during one calendar year were evaluated. Four of them happened to have celiac disease, referred for a variety of reasons that might suggest autonomic nervous system abnormalities. They all demonstrated abnormalities, these four celiac disease patients, poorly adhering to their diet.
Speculation that nutritional factors, things that we talked about, micronutrient deficiencies, or antibody damage to neurons particularly. But could suggest a screening for celiac disease in patients with ideopathic autonomic neuropathy, it might be something to consider. Maybe Dr. Perlmutter will lead the charge on that and get back to us in a year with what he found. So, I don’t think I’d sell the farm yet and say you’ve discovered the new clinic, which is the celiac autonomic clinic, the CAC, but still interesting data.
Endothelial function, we all now that the endothelium is rather sensitive to a variety of inflammatory mediators and inflammatory insults from the diet, from the environment and such. And as we now have both the older brachial occlusion technique and newer techniques like the EndoPAT and others, we can fairly easily measure endothelial function. And this has been done in patients with celiac disease. Of course, if there’s sustained endothelial function, we may see coronary artery disease to follow clinically.
Celiac disease is a reversible malabsorption syndrome associated with vitamin deficiencies. Single case report of a woman that had untreated celiac disease and hypertension – she had a slightly elevated homocysteine level. By the lab, we probably all say that’s elevated for sure.
Started on her gluten-free diet and homocysteine support. Homocysteine came down and she had, at baseline, abnormal endothelial function that, with her gluten-free diet and perhaps because of normalization of her homocysteine, her endothelial function improved. And as we know, there are reversible cases of hypertension with functional approaches, and she was one example of that. Replete her nutrition and she got better.
Little bigger study, 36 patients with celiac disease compared to 35 controls, tested for endothelial dysfunction by brachial artery occlusion. After hyperemia, the celiac disease patients rose. This is actually the diameter of their brachial artery to 30 millimeters less than in the control patients that were age and sex match. Flow mediated dilatation, the main marker of endothelial dysfunction, was lower in celiac disease than controls. As a result of the study, we believe there’s endothelial dysfunction at the macrovascular level in celiac patients. Now whether this wasn’t a dietary study and whether dietary control and remelioration of symptoms and pathology reverses this, is still very provocative.
Young adults with celiac disease may be at increased risk of early atherosclerosis. That would be very concerning and very provocative. Accelerated progression of atherosclerosis and increased cardiovascular risk has been described in other immune disorders.
Patients with celiac disease were tested for vascular function. Homocysteine levels were elevated. C-reactive protein was decreased on a gluten-free diet, where as homocysteine levels in this study didn’t follow a diet. Intimal medial thickness in the carotid was increased in celiac patients – .08 versus .05 – while endothelial dependent dilatation was decreased in patients with celiac disease.
Both parameters improved after gluten abstinence. This is a study just out for about four or five weeks, so some of the most latest and probably the most provocative data that, as we identify and treat and motivate and follow people with celiac disease, we may possibly be doing some very good things for arteries. Whether we are going to regress, carotid intimal medial thickness abnormalities wasn’t studied in this provocative paper, but give you good heart that as you move through the celiac patients, you have your…combining that heart-gut connection potentially.
It’s just an oddball study that I don’t think will change your life, but there’s, as we know, an association between type 1 diabetes and celiac disease, and that question came up, “Are there abnormalities in coagulation factors?” It might affect vascular function, cardiovascular abnormalities, so they took 94 type 1 diabetics, screened them for celiac disease, and 14% had anti-endomysial antibodies, quite a high level.
Those that were felt to have celiac disease had lower cholesterol, lower hemoglobin A1c. Some of that may be nutritional and weight and such, lower triglycerides, but they also had lower pro-coagulation factors. Celiac disease may have a protective role against the pro-thrombotic state of type 1 diabetes. I don’t understand the path of physiology of why that’s the case, but it doesn’t seem like, at least overall, the data suggests we’re about to see a major increase in coronary disease and coronary events in celiac disease patients, with the exception of that one recent study that I mentioned.
Here’s another oddball case report I just want to put in only because it’s hypothesis generating and all, but it’s a very young woman with intermittent claudication, evidence in her serologies of celiac disease. Work up for why she might have proof of vascular disease was unclear, but she was diagnosed with celiac disease. I mean, they did the obvious, the homocysteines, the lipids, diabetic work up, smoking and such. She was confirmed to have premature vascular disease and she was placed on a gluten-free diet, but she was also stented.
She’s doing fine now. A little hard to confirm if her diet, her stents, or both are the reason she’s clinically improved, but the authors thought that there is at least the possibility that inflammation from undiagnosed celiac disease can affect arteries to the point that there is a fibromuscular dysplasia type reaction. And since we don’t know why fibromuscular dysplasia occurs, it could be there’s another area to track down.
So I was just looking through the literature for any possible connection between cardiovascular-related phenomenon and diet. This is a syndrome that, I don’t know if anybody in the room is well aware of – I certainly wasn’t – but that patients that exercise and develop anaphylaxis, which is a reasonably well described clinical syndrome that can be very difficult, whether it’s just hives, whether it’s wheezing, whether it’s actually, full out dropping blood pressure and even collapse.
And whether the allergic reaction is triggered due to wheat is a hypothesis that is in the literature, and that it may be exacerbated by wheat plus alcohol or non-steroidals should be included in the differential diagnosis of idiopathic anaphylaxis and the recommendation was, don’t eat wheat before you exercise. Maybe, don’t eat wheat ever, but don’t eat wheat before you exercise. So it was somebody’s, basically, hypothesis in clinical practice without much detailed scientific analysis.
All right, so in terms of some of the pathophysiology, one that is in the literature a few times in this connection that may exist between cardiomyopathy development and celiac disease is micronutrient abnormalities and specifically L-carnitine abnormalities. Ten patients with cardiomyopathy, three with a combination of cardiomyopathy and celiac disease, and 10 healthy controls, mean serum carnitine level in controls, 38; the isolated cardiomyopathy, 27. But that combination of celiac disease and cardiomyopathy had the lowest serum levels of carnitine.
Celiac disease patients with cardiomyopathy, which there were three patients, they were treated with a gluten-free diet. Their mean carnitine level went from 17 up to 27. Supplementation with carnitine could be even more useful in patients with isolated idiopathic dilated cardiomyopathy, and certainly if they have celiac disease.
And with the current TMO rage that came out four or five months ago, maybe they ought to get their gut good and healthy so they don’t produce too much TMO. Again, carnitine will bring long chain fatty acids across the outer membrane to purchase the beta oxidation, and when carnitine is deficient, myocardial function may suffer, and obviously easy to supplement.
The whole metholation cycle has been looked at to some degree. And since we know that’s important in cardiovascular health as well as many other systems, I just wanted to include the limited data that’s out there. Celiac disease patients attending a clinic for either initial or follow up biopsy were categorized into newly diagnosed celiac patients, 35; persistent abnormalities, maybe not very compliant with diet, 24; and those that had recovered and no longer had villous atrophy in 41.
Homocysteine concentrations were higher and red cell and folate levels were lower in untreated, newly diagnosed patients, and had reached normal in those that had completely recovered. So when their gut had returned to good health, when the mucosal barrier was in tact and functioning normally to transport, they no longer showed abnormalities in homocysteine and folate transport and levels.
The ones that had persistent villous atrophy had lower vitamin levels all across the board, although in general there’s not a known big problem with B6 and riboflavin status in celiac disease. Gluten exclusion in celiac disease improves folate status, normalizes homocysteine concentrations, reduces the risk of homocysteine-related diseases, which may be why in that endothelial function study a gluten-free diet resulted in improvements in endothelial function in patients that were compliant to their diet.
So, I think the last little pearl I have for you is a syndrome that, again, if you know of this, I give you good credit, but it’s very new and has recently popped up in both the lay press as well as the medical press, and that is a new syndrome related to Benicar that’s been described in literature.
Olmesartan, one of the angiotensin receptor blockers, and for many people’s practice, one of their favorite, if not the favorite, angiotensin receptor blocker that they use in their patients. Used for hypertension and it can be used as a substitute for an ACE inhibitor after myocardial infarction and such, many, many millions of prescriptions that have been written, and a couple million patients in the United States taking Benicar.
So in the Mayo Clinic in August there was a study that reported 22 patients at the Mayo Clinic seen in the last 3 years for unexplained diarrhea, for evidence of an enteropathy, but had no serology and did not have the typical biopsy of celiac disease. These patients 70 years old taking 40 milligrams a day, which is the high end of Benicar. On average, chronic diarrhea, chronic weight loss, hospitalizations, biopsy showed atrophy and variable degree of inflammation with a lot of collagen deposition, but TTG was not found. Gluten-free diets didn’t help.
They, of course, ultimately stopped Benicar in these patients. They gained weight, they documented histologic recovery in patients that underwent repeat biopsies. So a syndrome that, for a drug that’s been out I imagine a decade now, until about nine months ago was unknown, undiagnosed, and undescribed, but was felt to be a very tight path of physiology between administration and development of a sprue-like disease.
The Mayo group described fairly typical symptoms of any enteropathy – chronic diarrhea, weight loss – although in this case, the serologies for celiac were not present. The pathology we talked about, no response to gluten. Other enteropathies were excluded, and the confirmation that things healed up when stopping Olmesartan, and as you can see, this is an example of one of these patients. This isn’t celiac disease, but might look quite a bit like that in terms of villous destruction and white cell infiltration, and somebody who had been off of Benicar for six months was re-biopsied, and showed return of anatomy and return of function in a patient that had been on Olmesartan.
This was a single case report, because other than the Mayo study, this is, again, just a few months old. There have been very other literature: 64 year old male with hypertension, 25 pound weight loss and diarrhea, colonoscopy unremarkable.
Wasn’t getting any better just watching him. Had been taking Olmesartan, 40 milligrams. It was stopped. Couldn’t find any other cause in his work up. Small bowel biopsy showed the villous atrophy. No evidence for celiac disease. No clinical response of gluten-free diet. Everything got better by stopping Benicar, so now there’s 23 patients, and that’s the biopsy that showed all kinds of infiltration, and villous blunting that was in this patient from a different center.
So, all that led to a warning that now exists – very interesting – just two reports, but in July the FDA put a black box warning on Benicar and all the other drugs that have Benicar in combination with other antihypertensives, that there is the potential for a sprue-like enteropathy, describes the symptoms and the fact that they will get better.
So you don’t see what you don’t know. We all now know that Benicar seems to have a potential to cause this. Nobody has a clue why it develops. Nobody’s measured Zinulin or any such finding. It would be very interesting actually to do that, but something we should be well aware of.
So, in conclusion, I’ve taken you through a path that, again, raises questions. Do we order echo in celiac patients? Do we order celiac tests on – I’m going to be down in just a minute, Dave, okay have a good break – cardiomyopathy patients? Do we treat congestive heart failure patients with probiotics? Do we use Benicar at all anymore? And I’m sure many other questions you can generate, but I think you’ll find that the next ten years, there is so much interest in the gut. We’re going to find more information.
I think that we can say for sure though that there does indeed seem to be an overlap between the autoimmune features that are found in congestive heart failure and particularly new onset cardiomyopathy and celiac disease particularly. And the exact mechanism of the connection isn’t clear, but it’s something that we’ll look forward to learning more of over the years. So I’m going to stop and hope you enjoyed.
I have 30 minutes? Okay. I am going to perform several of the songs from Soul Doctor on Broadway, and if you could bring the band in now, if you would just open the doors. The actors are very kind and flew from New York for you. No, it’s a little bit short and David asked me to try and end a little bit early so I took him literally, or perhaps too literally, but thank you very much and I look forward to your feedback. Thank you.
You just listened to Dr. Joel Kahn and his lecture on the research reflecting the association between cardiovascular and celiac disease, from endothelial dysfunction and atrial fibrillation up to cardiomyopathy and congestive heart failure.
Cell Science Systems has several assays relevant to this lecture series, the first being markers which determine genetic predisposition for celiac disease. This includes the HLA-DQ2 and DQ8 genes. Also available are various antibody markers such as tissue transglutaminase, TTG, and the deaminated gliadin peptide, DGP. As well, ASCA, anti-saccharomyces cerevisiae antibody, found primarily in inflammatory bowel disease patients with Crohn’s disease.
Additionally, cellular analysis for gluten and other food sensitivities using the Alcat methodology is available. These assays are available to providers in various single and multiple assay configurations. To inquire for additional literature or research, you can contact the lab at firstname.lastname@example.org.