The third speaker is Dr. Menhao Itzi, assistant professor at Vanderbilt University. Title is cirrhotic cardiomyopathy. Good morning everyone. I would like to take this opportunity to thank the organizers for inviting me today to talk about cirrhotic cardiomyopathy. My only disclosure is that I'm not a cardiologist. I'm a transplant hepatologist. By the end of this talk, we should be able to understand the concept, pathophysiology, and diagnostic criteria of cirrhotic cardiomyopathy. And we should be able to recognize the clinical implications of this entity pre- and post-transplant. Cirrhotic cardiomyopathy is defined as cardiac muscle dysfunction in patients with cirrhosis in the absence of known cardiac disease. While this entity could be subclinical or clinical, it's in fact mostly subclinical. So how does it happen? The pathophysiology of cirrhotic cardiomyopathy is multifactorial, and it happens in the setting of hyperdynamic circulation, which we see often in our patient population. And in that setting, three main cardiac pathologies are happening, which are myocardial fibrosis, myocardial hypertrophy, and subendocardial edema, leading to cirrhotic cardiomyopathy. The easiest to conceptualize among these three is subendocardial edema, because these patients have volume overload. Now, how can we explain myocardial hypertrophy? So there's actually an entity that's called sodium-induced cardiac hypertrophy, and it was first proven in the RAT model in studies in the 90s and early 2000. And it showed that high sodium intake to the RAT will increase the myocardial muscle thickness, regardless of the development of hypertension. And another study showed actually the trigger for this myocardial hypertrophy is increased cardiac aldosterone synthesis. And as you know, in our patient population, sodium retention is very prevalent. With regard to myocardial fibrosis, this study from last year assessed the myocardial fibrosis through cardiac MRI. So what they measured is actually the extracellular volume in the myocardium. And they realized that healthy controls have the lowest extracellular volume, followed by patients with cirrhosis, but low child pew, compared to patients with cirrhosis and high child pew, which have the highest extracellular volume, which means the highest magnitude of myocardial fibrosis. So this speaks to the evolution of cirrhotic cardiomyopathy between patients with low child pew compared to high child pew. When they further analyzed these patients, they realized that 14 out of the 52 cirrhotic patients died or underwent liver transplant. And in those 14, the myocardial extracellular volume was higher. In other words, the myocardial fibrosis was more pronounced. But somebody would ask, how can a cirrhotic patient develop myocardial fibrosis? What's the connection? We really didn't have an idea until very recently when this study came out in hepatology and showed in a mouse model where the bile duct was ligated to induce secondary biliary cirrhosis. And then the heart and the liver were examined 14 days later. And they realized that in the liver, there's massive hepatic inflammation and fibrosis. And in the heart, there is very prominent myocardial inflammation and myocardial oxidative stress. And when they assessed the heart function, they realized that there is systolic and diastolic dysfunction. The experiment time was 14 days, so they did not have time to appreciate fibrosis. But later today, there will be a presentation by our colleagues from Baylor who will show that in an autopsy-based study of 22 pediatric patients with liver disease who died before or within one year after transplant, 50% of the cirrhotic group had myocardial fibrosis as opposed to none in the non-cirrhotic group. I would encourage you to attend that presentation later today so our colleagues can elaborate on further details. So to put things together, it's likely that cirrhosis leads to myocardial inflammation and oxidative stress, which eventually leads to myocardial fibrosis, which eventually leads to remodeling and cardiac dysfunction. Now with regard to remodeling, the American Heart Association in 2013, in their guidelines, described four stages for development of heart failure, which are stage A, at which there are only risk factors for heart failure. For example, metabolic syndrome, but there are no structural changes and no clinical symptoms. Stage B, there are structural changes, but there are absolutely no clinical symptoms or signs for heart failure. Stage C is the development of symptoms and signs, and stage D is the refractory nature of that clinical presentation. What we're talking about here is mainly stage B, the cirrhotic cardiomyopathy patients where there are structural changes, but they have not manifested yet. But how can we diagnose this remodeling? So the first attempt to diagnose this was in 2005 during the World Congress of Gastroenterology in Montreal, and hence the name Montreal Criteria, in which cirrhotic cardiomyopathy was described, or the systolic component of cirrhotic cardiomyopathy was described as blunted response to stress or ejection fraction less than 55%. But there are barriers or challenges when we try to apply these criteria. So with blunted response to stress, when we try to apply it, the first barrier is beta blockers, which a lot of our patients are on for variceal bleeding prophylaxis. And even if we hold the beta blockers for one to three days, depending on the agent that we're using and its half-life, the other barrier is the lack of universal definition of blunted response to stress. So there's actually not a validated definition or criteria for blunted response to stress. With regard to ejection fraction, our patient population, as you all know, they have systemic vasodilation. So their afterload is decreased, and therefore their ejection fraction is usually normal or increased. So the bottom line here is that ejection fraction may overestimate the contractile function or the systolic function in this patient population. So we tend to use 50% as the cutoff, or in the cirrhotic cardiomyopathy criteria from 2005, 55% was used as the cutoff. But we don't really know what's the cutoff in our patient population. So data started to emerge in this study that was published very recently in Hepatology from South Korea. It evaluated almost 2,800 liver transplant patients, of whom 460 had ejection fraction less than 60%, and these patients were followed for over five years. During the follow-up period, 12% died, of whom one-third died in the first 90 days. They analyzed the outcomes based on an ejection fraction cutoff of 60%, not 50. They used 60 to see if this would correlate with the outcome. So here they categorized patients to melt of more than 20 with the ejection fraction less than 60, melt more than 20 with ejection fraction more than 60. And you see that the 90-day mortality is significantly higher with patients with melt of more than 20 and ejection fraction less than 60, and hazard ratio approaching two. And this effect of low ejection fraction was even more pronounced in the group where melt was more than 35, again within 90 days. When they analyzed the long-term outcomes based on a median of 5.4 years follow-up time, they saw the same concept but more pronounced. So melt of more than 20 with ejection fraction less than 60 had 26.7% mortality, which is almost double of that of melt of more than 20 and ejection fraction more than 60%. And here again, at 5.4 years, this effect was more pronounced in the melt more than 35 group. So this calls for reconsideration of what the cutoff for ejection fraction in our patient population should be. Earlier this week, Dr. Kwon, the first author of the article that we just mentioned, graciously sent me these two graphs that show that likely heart failure. And according to the European guidelines of heart failure, a BNP of more than 400 is considered likely heart failure. So they analyzed the BNP of these patients post-transplant. As you can see, within 30 days, patients with ejection fraction less than 60 were more likely to have likely heart failure or BNP more than 400 than patients with ejection fraction more than 60. And the same for seven-day pulmonary edema based on X-ray analysis. Over the past several years, a new surrogate has emerged for evaluation of the contractile function, which is global longitudinal myocardial strain, which is defined as the percentage of myocardial longitudinal shortening, basically the change in fiber length from diastole, which is a relaxed state, to systole, which is a contraction state. So if you think about it, it's a subtraction of a large number, which is length at relaxation, or myocardial fiber length at relaxation, from a small number, which is myocardial length at systole, which is contraction. So because of this subtraction, strain is usually a negative number, and the range of it is minus 18 to minus 22%. However, the American Society of Echocardiography figured that most physicians are not great with math, so they said when you consider talking about strain or strain changes, just think of the absolute value. And they mentioned that in their guidelines and said to minimize confusion, which is true. So here, hopefully this will work. So on each side, you see yellow dots. The difference between each two yellow dots is representative of the myocardial fiber length. So during systole, these yellow dots are getting closer, and diastole are getting farther. And the software in the Echo device will provide you with the picture on the right, which will divide the heart into segments and will provide you the strain for each segment. Now, which one would perform better, ejection fraction or strain? There are multiple studies addressing that, but I found this study very relevant to what we are doing. So they evaluated 464 patients who were undergoing either CABG or left-sided valvular heart surgery. And the patients here are the ones with ejection fraction more than 50%, in another word, the ones that we would clear for transplant or for TIPS. But they checked their strain, and those with decreased strain and normal ejection fraction had a higher 30-day mortality post-operatively. It actually more than doubled the mortality. And they had higher need for use of endotropic agents during surgery. The data about strain are limited. There are four studies addressing this. Two of them showing that patients with cirrhosis have normal ejection fraction and normal strain. And two, which are the more recent ones, showed in their cohorts that these patients have normal ejection fraction, but the strain was abnormal. Now we get to the diagnostic dysfunction component of cirrhotic cardiomyopathy. This is the most measurable component of diastolic dysfunction. And the reason we can measure it, because there are multiple variables to measure it. Well, in case of strain, it's not widely applicable in our echo labs. And for ejection fraction, as we said, it could overestimate the contractile function. So if we were to diagnose cirrhotic cardiomyopathy, more than likely it would be through the diastolic dysfunction component. So the Montreal criteria characterize diastolic dysfunction as EA ratio of less than 1, deceleration time of more than 200 milliseconds, or isovalimetric relaxation time of more than 80. These criteria come with challenges. So EA ratio is preload dependent. In fact, there are studies showing if you check EA before paracentesis versus after paracentesis, it would be different. It also could be different due to other factors, such as aging. And if you look at this graph, you see here in a normal patient, EA looks like this. And it looks exactly the same in a patient with grade 2 diastolic dysfunction. So it exhibits what we call a U-shaped phenomenon. So it's not really reliable if we use it alone. Isovalimetric relaxation time is another surrogate that's not specific. It could be prolonged early in the disease, and it shortens later in the course of diastolic dysfunction. And I would like to take this opportunity to remind everybody that prolonged QTC is not a criterion for cirrhotic cardiomyopathy, despite all the literature that was done to evaluate that possibility. So the bottom line is that the criteria that we had from 2005, from Montreal meeting, as the time evolved, we realized they're not very reliable. So we formed a multidisciplinary international consortium consisting of hepatologists, anesthesiologists, cardiologists, and critical care physicians to address this need. And based on the remarkable developments in the sphere of echocardiography, we suggested or proposed new criteria, which were recently published in Hepatology. And if you compare the two criteria or the two sets of criteria, which are 14 years apart, you see that the only common factor is ejection fraction. And we used 50, not 55, to be in line with the American Heart Association recommendations. And I understand that we talked earlier about the cutoff of 60%, but that's one study that just came out now, and we're hopeful that the future will bring more studies like that to consider modifying these criteria. Now, with regard to diastolic dysfunction, it's more tricky. You need three of these four criteria to determine that the patient has this dysfunction, which is average E over E prime more than 14, tricuspid regurgitory velocity of more than 2.8 meter per second, septal E prime less than 7 centimeter per second, or left atrial volume index more than 34. So if we look at the diastolic dysfunction, it says you need three. So what about patients who have two? These patients will need further evaluation by checking other surrogates of diastolic dysfunction, such as EA or IVRT or strain. IVRT is isovolumetric relaxation time that we just mentioned. Now, if we take these criteria and we apply it to our patients or the new criteria and apply it to our patients, what will we see? So we applied these criteria to 141 patients who underwent liver transplant at my prior institution, Mayo Clinic, and we realized that 18% of these patients had definite diastolic dysfunction. In other words, they had three of the four criteria that we mentioned. And 14% had indeterminate diastolic dysfunction, which means they had only two of the four criteria. So they have diastolic dysfunction, but we can't really determine the stage of it. And there was no difference between patients of different liver disease etiologies in terms of the prevalence of diastolic dysfunction. Now, for the same cohort, we applied the old criteria, and the cirrhotic cardiomyopathy prevalence was 68%. When we applied the new criteria, the prevalence was 18%. So cirrhotic cardiomyopathy might not be as common as it was thought. More importantly, with regards to outcomes, over a follow-up of 4.6 years post-transplant, patients with indeterminate or definite diastolic dysfunction had higher risk of major adverse cardiovascular events. It actually doubled the risk, the presence of diastolic dysfunction. And some of the surrogates of diastolic dysfunction were associated with higher risk of heart failure and dysrhythmia, and those surrogates were E prime and EE prime. This is in line with prior literature suggesting that pre-transplant diastolic dysfunction increased the risk for post-transplant heart failure and it impairs the post-transplant survival, although these studies used some of the criteria that we mentioned, they did not use all of them because, as I said, these criteria just came out. And we have to remind ourselves that heart failure is in the setting, in our patient population, is actually on the rise. So if you look at this study that evaluated 4,763 patients from the nationwide inpatient sample, 20% of the hospitalizations were due to cardiovascular disease, and if you look at the trend between 2002 and 2011, heart failure has been uptrending. On the other hand, ischemic heart disease has been downtrending, and probably because we're getting better at prevention strategies, but with heart failure, we haven't done that yet. Now back to the pre-transplant life, or to the cirrhosis life, so the MRI-based study that we just talked about, it also showed that increased myocardial extracellular volume is associated with weightless mortality, and these patients were observed for two years. Another study used one of the surrogates of diastolic dysfunction, which is EE prime, and they used a cutoff of more than 10, and those patients who were decompensated cirrhotic patients, they had higher mortality. Earlier this year, this fascinating study was published in Hepatology Communications, and they evaluated, retrospectively, 114 patients who underwent TIPS. All of these patients had normal ejection fraction, but they analyzed the strain of these patients, and they used 16.6 as a cutoff, and they demonstrated that patients with impaired strain had impaired survival at three months, six months, and 24 months after TIPS. And because of these implications, our consortium recommended that transthoracic echocardiography should be done in patients with cirrhotic cardiomyopathy every six months until two years after transplant to monitor for interval changes in cardiac function. And someone might wonder, how would this change the management? Well, the patient is listed for transplant, and you're monitoring the ejection fraction and the diastolic dysfunction surrogates every six months, and there is change in diastolic dysfunction to grade three, which is severe, or there's downtrend in ejection fraction that can impact transplant eligibility. On the other hand, in the post-transplant setting, if you see a downtrend in ejection fraction over the surveillance period, if you start ACE or ARB at that time, which is an anti-remodeling agent, could significantly impact the survival and the heart failure possibility in that patient. In fact, there is a current discussion in some of the transplant societies about even extending these two years to a longer observation period or longer surveillance period. So in conclusion, sorority cardiomyopathy reflects the liver-heart pathogenic axis. The new criteria should be incorporated in the epipardiographic assessment in patients with cirrhosis. We need further studies to validate and modify these criteria, and sorority cardiomyopathy is not harmless. I would like to mention this study that was published recently in a cardiology journal, and it showed that dog ownership is associated with improved outcomes, improved cardiovascular outcomes. So it may be the case that the best thing that a sorority cardiomyopathy patient can do is to have a dog. Thank you very much for your attention, and I would like to acknowledge. I would like to acknowledge the support of my colleagues and collaborators at the Sorority Cardiomyopathy Consortium, Mario Alteri, Jim Finley, Sam Lee, Grace Lynn, J.O., Lisa Van Wagner, and my very supportive mentor, Dr. Kimberly Watt. Thank you. Thank you so much, Dr. Itzi. We have a 10-minute panel discussion. If I can invite the speakers back up to the stage to take questions from the audience. Up to the microphone. I'm just gonna tell it. Okay. Go ahead, please. Yeah, Mike Dunn from Pittsburgh. Dr. Tannen talked in her presentation about the importance of myostatin as a mediator of skeletal muscle injury. It's driven by ammonia excess. There's a fair amount of literature on heart failure where myostatin is considered to be beneficial and to limit pathologic remodeling. What I'd like to ask Dr. Itzi is, what is known about myostatin in cirrhotic cardiomyopathy, and would you be willing to speculate on where we're going with that particular critical mediator? Thank you. So because of the redefinition and the new criteria for cirrhotic cardiomyopathy, which provides a more accurate estimate of the prevalence and more accurate characterization of the entity, at this point, we don't have data about how myostatin would impact this entity and its new definition, but that's a very good point, and that's something definitely we should consider for the future. Thanks. Again, so I was wondering if your new definition of cirrhotic cardiomyopathy is just updating the diagnostic criteria for the diastolic dysfunction. Basically, we still consider cirrhotic cardiomyopathy as some systolic dysfunction plus some with some diastolic dysfunction, but in reality, how we can make the diagnosis, how we can make sure that cirrhotic cardiomyopathy is not just something else, okay? Thank you, very good question. So at this point, in reality, the best way to assess it would be, in addition to ejection fraction, is the new diastolic dysfunction surrogates, and right now, most of the ECHO labs in the country are using these new surrogates, not because we suggested them, but two years before us, the American Society, or actually three years before us, the American Society of ECHO suggested them, and we see them now more and more implemented in the care. So as long as the ECHO lab is utilizing these criteria, the possibility of making accurate diagnosis of cirrhotic cardiomyopathy would be more and more going forward. Strain will take time to be applied. To my knowledge, only two centers probably in the whole country is doing it on a routine basis for cirrhotic or transplant patients, but hopefully within the next few years, the implementation of strain in our care would be more and more. Thank you for the wonderful talk. I also have a question regarding cirrhotic cardiomyopathy. You talked about prolonged QT interval as not being a predictor. Multiple studies have suggested that before. What was the rationale behind, you know, what is the correlation of QT with cirrhotic cardiomyopathy, and why do you not think that it is a true predictor now? And then my second question would be, did you notice any difference between patients who had NAFLD versus alcohol-induced cirrhosis? You know, any difference in cirrhotic cardiomyopathy in both these different groups of patients? Two great questions. So for prolonged QTc, it's very nonspecific, so it could be affected by thyroid disorder, female gender, BMI, medications, especially, you know, in post-transplant setting. Everybody's on Tacro, and everybody on antibiotics, you know, every now and then they're on antibiotics that can impair QTc. So that's one thing, which is the multifactorial nature of its etiology. The other thing, we can think about it as simple as this. This is a cardiomyopathic phenomenon, so the best way to assess it is imaging the heart rather than assessing allicatrical characteristics of the heart. So, you know, and which is the case with almost every cardiomyopathic phenomenon. With regard to the different etiologies of liver disease, in our small study, because we only had 141 patients, there was no difference between patients who had NASH versus alcohol-related disease versus others. So we clustered all others in one category and compared them to NASH and alcohol-related liver disease. Steve Zucker from Boston. I'm gonna switch to nutrition. So my question is, very nice talk. You didn't comment on fat. And when we prescribe protein to patients, does the quality of the fat matter? Should we be avoiding saturated fats, or how does that work? Yeah, I mean, so fat is also clearly important. And saturated fat, we should all be reducing that to less than 10% of the fat, right? So, yeah, so I think that would follow the standard dietary recommendations with regards to fat, but definitely still important to take good quality fat. Thanks for the great talk, Sluti Kramer-Wiener. I wanted to address the question whether spironolactone is also able to reverse fibrosis in the myocardium, because we use spironol a lot in our patients, but did you have any evidence that strain improves? So I'm not aware of evidence that it would help that. I'm aware of evidence that in a down-trending injection fraction, it would be helpful in that context, which could be applicable to worsening cirrhotic cardiomyopathy, thank you. Thank you. Thanks a lot, this is for Dr. Izzi again. I'm Dr. Izzi from Texas Children's Hospital. I'm trying to make everybody aware that cirrhotic cardiomyopathy is not just an adult condition, but a pediatric condition, too. And I'm struggling right now to let the cardiologist know that this is a problem. Have you, do you have any guideline for when you would catch somebody? I'm not talking of left side, I'm talking of right side. Or do you do it routinely, or is it certain echo findings then suggest that you go for a cat? So if the findings are suggestive of right heart strain, then that could, at that point, right side cat could be considered. But if we don't have evidence for that, I wouldn't do it as routine. This is a hep C question from your neighbor, Charlottesville. How often have you found SVR not sustained, you know, past 12 weeks? And do you determine then, is it reinfection or the treatment didn't work? So I'm, of the thousands and thousands of patients that we've treated, I can recall one individual who states he had no additional risks, who developed recurrence of his hepatitis C beyond the SVR 24 visit, one. Now, he was a co-infected patient, and we went back to try to figure out, was this a new virus, or was it his same virus, and could we do, you know, testing on him? I was able, I think to get some, sent it off to somebody, and they said it looked like it might be the same virus. But it is rare. So you've had one? I don't know, has anyone had a, in a, and again, you have to decide, do they have ongoing risks? Now, he was, again, he was a co-infected patient, and we just kept asking him, you know, this has gotta be a new infection. But he swore up and down that he didn't have any other risks. So, I mean. I think, yes, I think I did try to retreat him, and I think the second time, also after a prolonged period of being negative, his virus came back. So I treated him, I think, with a prolonged course of Vosevi. So, fortunately, during all this, his, at least his non-invasive testing, he's had a biopsy a long time ago, but his non-invasive testing looks a lot better, and I think he's resolved to the fact that I have nothing else to offer him. I think I've given him Vosevi and ribavirin, you know, what I call the kitchen sink. So I think, but that's a one. So we all may have one. I think interesting, it might be to collectively collect and to figure out what's going on with them, but it's such a rare event. Andy Skango, Vanderbilt. This is for Dr. Tandon, though. What do you do for all those patients that you tell, you tell them everything they need to do to try to increase their protein intake, but they just can't tolerate the supplement shakes, very poor intake still. I mean, they're definitely resistant to doing tube feeds. Is there anything that you have up your sleeve that you've done to try to get them to take in their protein supplements and all that? What have you? Yeah, I think I've given you everything I have up my sleeve, and the main thing I have up my sleeve is the dietician, really, and I think intensive, sort of more intensive follow-up with that person has really helped to try and give any tips and strategies and address any barriers, but there's no magic. Yeah. That's the hard part. Yeah. Yeah, I have a question. Yeah, sorry. In regard to that, in terms of access to dieticians, sometimes we struggle to get our patients there unless they have coverage. Coverage, you know, underlying diabetes or things. Any suggestions there? Which is why I think we all need to upregulate our skills. Yeah, and we need to add this to our clinic visits. So my follow-up question for that was how often and when do you start this nutritional intervention? Because if you wait until they're obviously sarcopenic, then you're really pushing rope uphill. All of our patients get that nutrition guide that we've developed, compensated, decompensated, everybody, and I try and address it with everybody. Yeah. Question? Yeah, take a mic. Regarding that point, is there any personal or any data regarding is it may case in those people who have decompensated cirrhosis as a- Appetite stimulant? Yeah, I don't think there's any strong data to support it. If it perhaps increases fat, if what I remember in other patients, but again, there's lots of opportunity to look at these interventions, I think, in the future. Any additional questions? We have one. I have a question for Dr. Sterling. I think a pretty common scenario of HCV eradication in somebody who had SVR anywhere from months to often years ago, and you have no signs, or they had a prior diagnosis of cirrhosis, but you really have no signs of it at this point, including like a fiber scan with minimal fibrosis. Besides, as you mentioned, the sort of pre-post-Fib4 testing, is there anything else that we could use to say, hey, you don't need to have ongoing HCC surveillance? Yeah. Unfortunately, no. I mean, I think that the guidelines for the continuing monitoring for the cirrhotic patient are clear. I really had struggled for a long time with the stage three fibrosis patients who may have had a stiffness in the sort of nine to 11 and a half range at the time, and are they really still at risk? So it was nice to see, when George and I did that paper, can we use a Fib4 to help identify the subgroup that might not? So the non-invasive guidelines committee is looking at that, and hopefully this time next year, we'll have those data, but looking at so far what evidence is available, there's not a lot of great testing out there to help identify fibrosis regression in a non-invasive way. There's some data that shows that if you don't treat the patients and their scores go higher, then they're getting sicker. There's some evidence in NAFLD that non-invasive tests are associated with improved histology, but unfortunately, there are very few follow-up liver biopsies being done, and so I'm not really sure we're ever gonna have that data. So only longer-term follow-up to look at outcomes. We'll know whether or not those tests are helpful. So unfortunately, we're stuck with what we've got right now. That'll conclude our session today. I wanna say thank you very much to the speakers for such an excellent job. If you have any additional questions, they can take them. Thank you.

cirrhotic cardiomyopathy

Dr. Menhao Itzi

Vanderbilt University

cardiac muscle dysfunction

myocardial fibrosis

ejection fraction

diastolic dysfunction