So, we're gonna talk about assessing cardiopulmonary reserve and renal function in the NASH candidate in particular, and these are my disclosures. So first off, cardiovascular complications, as you heard previously, is the leading cause of morbidity and mortality following liver transplant for all candidates, but in particular for NASH. In addition, renal function, of course, is a major driver of cardiovascular risk, both after liver transplant and in the NASH candidate. But unfortunately, current guidelines for preoperative cardiac pulmonary vascular and renal function evaluation and management in patients who are undergoing non-cardiac surgeries really lack specific guidance for the liver transplant population. And so, there's significant management variations between our centers in terms of how we evaluate for risk and how we then make management decisions once we identify pathology. And so, to address this major practice gap, within the past two years, the American Society of Transplantation, Liver and Intestine Community of Practice, and the Thoracic and Critical Care Communities of Practice have convened and done a systematic review and written and published some consensus guidance on many of these topics, and I've listed these references for you here. And most of what I'm gonna talk about today is drawn from these documents. So our objectives are gonna be to describe the typical NASH transplant candidate in 2019, specifically in terms of the cardiopulmonary and renal risk, we'll then summarize the impact of NASH itself on cardiac and renal complications, and then we'll end with demonstrating an evidence-based approach for assessing cardiopulmonary and renal reserve in the NASH candidate. So our NASH candidate in 2019, as you saw previously, is older, they have a high prevalence of diabetes, they're obese, they have high prevalence of CKD, and they have higher frailty when you compare them to other indications for transplant, and most commonly compared to patients with alcohol liver disease. In addition to traditional cardiac risk factors present in NASH, there are, of course, several explanations as to why NASH itself might be involved in the development of cardiovascular disease. And really first is that NASH, of course, is frequently accompanied by the inability of the heart to respond appropriately to stress in an entity known as cirrhotic cardiomyopathy. In addition, you have an increasing number of individual vascular risk factors, including increased liver-derived circulating IGF-1 and GGT, ongoing inflammation, microvascular endothelial dysfunction, all of these in concert can contribute to progression of cardiovascular and renal disease. And then finally, you have the presence of NASH, independent of comorbidities, which has been shown to increase thrombosis risk, increase myocardial remodeling and dysfunction, cardiovascular dysfunction, and increased prevalence of coronary artery calcification. So it's the cumulative ongoing effect of these things over time that's thought to result in clinical microvascular and macrovascular disease. Now, of course, you add the hemodynamic stress of a liver transplant, the ongoing metabolic effects of long-term immunosuppression, and it's really not surprising that the leading ongoing complications that we see in this population are cardiovascular and renal related. So as we heard earlier, NASH, of course, is linked to increased perioperative poor outcomes in this population. This is the older paper that we published in 2012 in Hepatology that compared cardiac events compared to NASH versus those with alcohol-induced liver disease shown in the light purple. But you can see that long-term cardiovascular mortality versus other indications for NASH is actually similar. And that's because the major driver of cardiovascular disease risk is actually renal dysfunction. So this was a paper that we published in Liver International a couple of years ago that actually looked at underlying EGFR categories in NASH candidates, and you can see that as EGFR category decreases that you have a nice layering of increase in cardiovascular-specific mortality. So assessment of renal function is really an important key factor in understanding the cardiovascular risk profile in the NASH candidate. So let's move and talk about assessment and preservation of renal function in NASH. So when we think about preservation of renal function in general in patients with end-stage liver disease, it's really accomplished through a couple of different things. And one of the best practices is accurate estimation of renal function. In order for us to understand the exposure of renal function on outcomes, we need to accurately assess. And so first off, it's well established that we know that blood-based equations may both over- or underestimate measured GFR. And this is particularly poignant in the NASH candidate, in which we tend to see an increased prevalence in women, who we know have under-representation with the MELD score, and often can have false estimations of renal dysfunction due to EGFR. In a meta-analysis of solid organ transplant recipients, the CKD-EPI equations and the MDR-D4 equations have been shown to be the most accurate compared to measured GFR. And so those are, in the current guideline recommendations, what we should be using when estimating EGFR. Of course, there have been some newer models that have been proposed in liver transplant candidates. Both of these were published this year in Hepatology, the GRAIL model and the reverse model. They have not specifically been looked at in NASH, but I think that I look forward to more data that comes out in the NASH population to see whether these might help us reclassify risk better in this population. But regardless of what model you're going to use to estimate GFR, the most important thing that's been shown over and over, it's not a single time point estimate in GFR that predicts risk. It's really important to look at change over time in GFR, and that's the most important marker of what's going to help us understand the risk profile. So of course, the second tenet in terms of best practices for assessment of renal function is going to be accurate diagnosis of both AKI and CKD. And I've listed the accepted definitions for you here, again, as part of these consensus documents that have been published. And then finally, the last two tenets are going to be prevention of acute kidney injury and then control of the comorbidities and ongoing risk factors that we know contribute to CKD. So for the hepatologists in the room, of course, that means ongoing SBP prophylaxis, using IV albumin, antibiotics in the setting of GI bleeding, avoiding nephrotoxic medications and minimizing radiocontrast dye exposure. And then again, from a medical standpoint, making sure we're aggressively controlling risk factors like glucose and blood pressure. So in the second half of the talk, we'll talk about specifically cardiovascular disease risk in the NASH candidate. And for those who attended the transplant course earlier yesterday, one of the ways that we think about approaching cardiovascular risk, no matter we're talking about a NASH candidate or any liver transplant candidate, is the first step is to assess global risk. What's the global risk of this patient having any sort of cardiac complication after transplant? And I showed many of you this data yesterday. This is one tool that is available that we developed at Northwestern that looked at over 300 different perioperative and postoperative variables, over 1,000 patients over our 10-year center experience at Northwestern. And these were the variables that came out in the final multivariable model that were most predictive of outcomes. The score is known as the CARL-T score. You can go to this website, you can calculate the score, and it gives you a one-year absolute predicted risk of having a composite one-year cardiovascular hospitalization or death, with a risk ranging from less than 5% all the way to greater than 45%. But we're in a NASH talk today, and what you notice in these variables is that NASH is not one of the variables that's in the CARL-T score. And that's not to say that NASH is not an important predicting risk factor for cardiovascular disease outcome, but that the data over and over show that when you take into account some of the other comorbidities that are competing risks for early mortality, that NASH in and of itself doesn't actually seem to be predictive of at least that early short-term risk independent of other comorbidities. That doesn't mean it doesn't impact long-term. So then in terms of candidacy, the next thing, of course, we want to do is we want to assess for prevalent cardiovascular disease. And given our time limitations today, I'm going to focus predominantly on coronary artery disease in the NASH candidate, and then cardiomyopathy and heart failure. So the strongest principles, of course, that determine whether or not somebody's going to have underlying obstructive coronary disease is going to be whether or not they have diabetes or greater than or equal to two traditional cardiac risk factors, which the majority of our NASH patients are going to have. However, as I've shown you previously, NASH in and of itself does impact on at least early cardiac morbidity, even though it may not impact on long-to-early cardiac mortality, and the presence of renal dysfunction is really going to increase that risk. So it's really the combination of these factors that are going to increase the chance of bad outcomes. However, the severity or extent of CAD does not impact post-transplant survival if the patient can be appropriately revascularized. So again, for those who attended the transplant course yesterday, who also may have gone to the very lively liver debates last night, we had a nice discussion and debate about the role of stress imaging in non-invasive versus invasive testing. And I think it's been well-established now in multiple series over and over again that non-invasive stress testing for detection of coronary artery disease does not have good positive or negative predictive value. And so it's pretty much a useless test in a population in which you have a high pretest probability, like a NASH candidate, that they're going to have underlying disease. And so our consensus recommendations were that coronary angiography, either invasive or non-invasive, is the gold standard for detection of coronary artery disease in NASH. And so what tools do we have in our toolkit in order to evaluate non-invasively for coronary artery disease? You can use CT angiography, or you might be able to use the additive effect of knowing somebody's CAC score to help reclassify risk. Now I've shown you what the positive and negative predictive values are for CT angiography in the general population compared to cardiac catheterization. This has not been specifically looked at compared to CAC in a liver transplant population, but it has been looked at in terms of prediction of risk in long-term outcomes, and it predicts very similarly to invasive CAC. A CAC score greater than 400 is the threshold that we would use to help us predict CAD requiring revascularization and one-month post-transplant complications. So really the recommendation is to consider CTCA in patients who have a body habitus who can tolerate it, whose renal function can tolerate it, and who can lie still on a table and are in a non-tachycardic rhythm. However, that's a smaller majority of our patient population with NASH, and so for a lot of people, they're going to require invasive angiography. And the key principle here is that, again, the newer data suggests that invasive angiography is very safe in patients with end-stage liver disease despite coagulopathy and renal dysfunction. Best practices include using a transradial approach, which is really standard of care now in this patient population. Bare metal stents are preferred over the early-generation drug-eluting stents, but now in 2019, we have new-generation drug-eluting stents, and actually those are probably superior to bare metal and the early generation, and really probably we need to be moving forward with using these types of stents in our patients, but we need a little bit more data in liver transplant. And then finally, of course, in patients who have established CKD, consultation with nephrology for prevention of contrast-induced nephropathy is recommended. So in the last couple minutes, I want to briefly talk about cardiomyopathy and heart failure risk assessment in NASH, since this really comprises the bulk of the early events that we're seeing in this population. And so we're going to do a tiny bit of a primer, we're going to talk about another organ in the body, it's above the diaphragm, it's called the heart. If we remember back to biology, the heart has three different fiber orientations, it's longitudinal, radial, and circumferential. And there's several different parameters in which that we can use to measure what's known as myocardial deformation imaging. We can look at how far the fibers actually move between diastole and systole and look at displacement of tissues. So this is, TAPC is a measure you get on an echocardiogram that's a marker of RB function. You can look at how fast the fibers actually move over time, that velocity is known as E-primed velocity. And then finally, you can look at the change in length, and that's known as strain measurement. So you measure strain on an echocardiogram by performing something known as speckle or tissue tracking. And basically, what speckle tracking is, is that it generates natural acoustic reflections that are referred to as speckles or markers, that then can be tracked consecutively, frame by frame on the echocardiogram, and then they're basically graphed over time. And so each color in this image here represents a different segmental strain, and the strain is averaged to basically show you a global strain measurement based on the tissue fiber orientation. It's really the peak or the valley of this tissue deformation that then is shown to be a marker of prediction of heart failure events. So as you can see here, all three of these patients have the exact same ejection fraction on a 2D echocardiogram, but the speckle tracking analysis is very different. So a normal result on speckle tracking is somewhere between a negative 18 to negative 22%. You can see that as the ventricle gets stiffer, so a patient with hypertension has impaired global longitudinal strain with a negative 15%, and then you can see that you have a very stiff ventricle that doesn't distend well in somebody who has cardiac amyloid. So speckle tracking gives us a lot more information about underlying function than ejection fraction. And this has been looked at in patients with cirrhosis. This was a very nice study that came out of China looking at cirrhosis patients versus age, sex, and BMI match controls, and you can see across all the different fiber orientations that patients who have cirrhosis had impairment in absolute global longitudinal strain. Well what about myocardial deformation imaging in NASH? Well NAFLD has been shown to have lower LV strain and progression of worsening strain over a five year time period in population studies, as well as studies have shown that histologic NASH is associated with other markers that can be picked up in deformation imaging, including left ventricular concentric remodeling and impaired subclinical diastolic dysfunction. So thus in the evaluation of heart failure risk and reserve in the NASH candidate, it's really important to think about cirrhotic cardiomyopathy. And so recently we've proposed new criteria for cirrhotic cardiomyopathy that now encompasses not just the assessment of ejection fraction, but actually using strain measurements and strain parameters in all patients. And this is something we really need to be testing in all of our patients pre-transplant and following long term so we can better understand the natural history of this condition, particularly in NASH. So finally I just want to make one comment on the fact that cardiomyopathy risk is something that actually can be better assessed as well through additional functional testing. Although dobutamine stress echocardiography does not play a role in the detection of CAD, it perhaps might have a role in underlying assessment of underlying subclinical dysfunction. So we don't have enough data to recommend it universally, but there are reasons why some of us are still performing this. But I think more importantly, I think there's stronger data to support potentially the use of cardiopulmonary exercise testing and six-minute walk tests, especially in our ambulatory patients, to really help us identify those patients who might benefit from prehabilitation measures to improve not just measures of frailty, but cardiopulmonary function and reserve. So finally, after you've done this risk evaluation, you've assessed global risk, you've evaluated for prevalent cardiovascular disease, of course we have to consider the implications of our screening protocols in the setting of a liver transplantation, and that's going to absolutely require a multidisciplinary discussion in terms of what our thresholds will be for transplant. So in summary, cardiovascular disease is the leading cause of mortality in the early and late post-transplant course, particularly in patients with NASH. And NASH and renal dysfunction are really the primary drivers behind what the increase in cardiovascular risk that we've seen over the past decade. Change in GFR provides the most prognostic value in terms of renal outcomes in this population, and assessing cardiopulmonary reserve really starts with a global assessment of risk, and one tool for that is the CARL-T score. Non-invasive or invasive angiography should be performed in all NASH candidates in order to assess underlying risk of CAD. And subclinical cardiomyopathy, which can be unmasked with liver transplant, is highly prevalent in NASH, and there is a role for speckle tracking, echocardiography, and functional testing in that regard. Thank you.

cardiopulmonary reserve

renal function

NASH candidates

liver transplantation

cardiovascular risk assessment