DANIEL S. YIP: So I'm just going to talk a little bit about contraindications and indications to transplant. It really it's more of what kind of goes through our minds when we assess somebody determining whether or not they're a suitable candidate for transplant. And really that the evaluation, whether it's official or not official, begins when we first meet them. There's a number of different factors that we kind of look at. And it's all data driven. There's a reason why we look at what we do in sort of from a outcome standpoint. So we'll kind of go through that, and please stop me any time if you have any questions.

So, you know, when would be a good time to think about someone maybe needing advanced heart failure treatment or transplant evaluation? And what we say is, well, if you've had a multidisciplinary heart failure care-- so it's not just medical therapy, but sort of making sure that they're doing the best they can from a lifestyle standpoint, and exercise, and sort of pharmacologic as well not pharmacologic strategies to treat heart failure-- let's say they've done the best you can. They're sort of optimized, and maybe they're limited for whatever reason to optimal dosing.

But they're really limited and they've had recurrent hospitalizations and they have a decreased exercise capacity. And I think very importantly, that they find that their lifestyle is unacceptable. There are going to be individuals who maybe have recurrent heart failure, but they're OK with that. They don't feel that it's worthwhile doing the necessary steps and the hoops to jump through to undergo evaluation for transplant or ventricular device implantation.

But for those people, they probably wouldn't think about that. But for others, whatever their lifestyle, whatever their norm is, it's just unacceptable. Those are the times that we kind of think about transplant or at least advanced heart failure operation. So let's start with the case.

We've got a 50-year-old gentleman referred with two years onset of heart failure from non-ischemic cardiomyopathy. Currently New York Heart Association III to IV, symptoms-- he's been hospitalized three times in the past six months. His left ventricle ejection fraction has decreased at 15%, his left ventricular end diastolic diameter is increased at 70 millimeters-- 7 centimeters, 70 millimeters.

He's got at least moderate mitral regurgitation. He's got renal sufficiency with the cranial 1.8. Sodium is a little low at 135. We did a treadmill test, they couldn't get out of stage one of the Bruce protocol. On exam he's pretty comfortable. His blood pressures 100 over 75. His CVP is certainly elevated. He's got an S3. His livers a little bit enlarged. The extremities have got some mild edema, but they're somewhat cool. He's taken for a guideline directed medical therapy including an ACE inhibitor, beta blocker, aldosterone blocker, a diurectic, Warfarin, for whatever reason, as well as digoxin.

So looking at that, what would be the reason why you would think about transplant? Because ejection fraction, which was up to 15%, the serum sodium is 135, the LV sounds a little bit big-- the LV end diastolic diameter is 7 centimeter. Is it because their creatine is 1.8 or is it because of their functional capacity? So what would be the main indication for transplant? Why would you think about transplanting this person?

So we'll get to that a little bit later. Let's go to get some sort of background to help try and understand the question. So when someone is referred for advanced heart failure care, first thing we do is we look to see have they been optimized medically. Surgically have they been optimized? Do they have the optimal devices in place? How about the non-pharmacological non-medical treatment, such as lifestyle changes, fluid limitations, sodium limitation, exercise? Has that been optimized, and we've done the best we can with them?

And then certain people or certain patients are going to be inotrope dependent. They come to us on inotropes, can't get them off, it's a legitimate dependency on inotropes. And if that's the case, then we really will think about should they be considered for transplants, should they be considered for mechanical assist device, or investigational drug, or perhaps it's just an end of life discussion. That's just an important part of heart failure care.

But if they're not inotrope dependent, we're going to figure out what their prognosis is. So cardiopulmonary stress test, New York Heart Association heart failure scores-- they are all tools to help us assess prognosis on patients with heart failure. It turns out the ejection fraction is not a great prognosis, a great predictor of advanced heart failure prognosis. It's an easy thing to look at. It's an easy thing to measure.

You can measure by left ventricular graph. You can measure it by a MUGA scan. You can measure it with an echo. It's a number you can hang your hat on. Patients are many times for good or bad, right or wrong, are fixated on their ejection fraction. They have access to their portal, so let's say their ejection fraction is 25%, and now they had an echo repeat and now it's 30%. So they'll say, hey, I must be doing much better, right? I went from 25% to 30%.

Then you have to sit down and have a discussion with them and say, you know what, the ejection fraction calculation vary in what methodology you use. It's not an exact science. It's really not an exact science. It's really an eyeball thing. We all know you move the cursor around and the EF goes from 25 to 40 just by moving things around a little bit.

And it turns out that there is a lot of people with an ejection fraction between 20% and 35%. There are people who never need a transplant. They are class I. They're playing basketball. They're so active that you never figure out they have heart disease. And there's other people with ejection fractions more than 35%, 40%. And they're very symptomatic [INAUDIBLE].

So it turns out that ejection fraction by itself is not a very good predictor of advanced heart and prognosis in people with advanced heart failure. So what is? Well, actually it turns out New York Heart Association classification is. And how much walking you can do in six minutes is a great predictor too. And so you can see the worst your New York Heart Association class is, the worst your prognosis is going to be in one year.

The class IV patients usually have a 50% to 60% one year mortality. Those are the people that we're most concerned about. But hopefully, you're getting to them in class II, class III. Because many of these people, if you intervene on them early on, they will never get to class IV.

Six minute walk is a very powerful tool. If you can do 450 meters in six minutes, your prognosis is good. You're more likely not to need-- you're probably going to do better without a transplant. You'll probably going to be better with just medical therapy than undergoing either a transplant or [INAUDIBLE]. So 450 meters in six minutes, that's sort of the mark that would make you feel pretty confident that the prognosis is going to be pretty good.

And it's just not a one time thing. You want to tread that over time. And so doing that periodically every year, for sure if they're stable, is a valuable tool. What we do, and most heart failure programs will do, is do a cardiopulmonary stress test or oxygen consumption study.

So basically what you're doing is just a treadmill test, routine treadmill test, monitoring blood pressure, EKG, heart rate, but also measures oxygen consumption. And it turns out that if your peak VO2 is more than 14 milliliters per kilogram per minute, your three year survival is probably about the 95% range-- compared to if it's less than 14, or between 10 and 14, your three your survival is going to be less than 30%-- really, it's at the one year-- less than-- it's going to be 80% survival in three years.

And really it's the first year that this makes a difference. And it's important to note that the one year survival after transplant is going to be 85% to 90% in sort of national program. So if your VO2 max is less than, in this case, 14 millimeters per kilogram per minute, their prognosis is going to be better than transplant. So regardless of what your ejection fraction is, that's what we're really going to look at.

But equally important is percent predicted. So if you can imagine someone who's 20 years old. They're expected exercise capacity on a treadmill is going to be much different than someone who's let's say 60, 70 years. And so that's where the predicted becomes very powerful. And so that if you're more than 50% predicted, your survival is still in that high 90% range at three years.

If you combine the two-- so if your VO2 max is greater than 14, but your VO2 max is less than 14, but it's more than 50% of predicted, your prognosis is about the same as those whose VO2 max is greater than 14. So let me just say that again. So these are usually people who are sort of 60 years old and maybe about, somewhere in there. If their VO2 max is less than 14, but their percent predicted is greater than 50%, their prognosis is just as good as other people whose VO2 max is greater than 14, which is the old traditional sort of number that transplant centers will look at to see should they be evaluated for transplant or not.

So this is a key thing, and we'll review that in a second. Also what's important, what's the peak blood pressure that was achieved during the stress test? If their peak blood pressure is greater than 120 at peak exercising and their VO2 is less than 14, their prognosis is better than if your VO2 max is less than 14 and you were not able to get your systolic blood pressure greater than 120.

So these are the folks who are at the highest risk. People who have had a [AUDIO OUT]

And so there are other parameters that have been showing up-- the VE VCO2 slopes of the oxygen consumption-- sorry, total consumption-- versus divided by the CO2 expired. If their slope is greater than 34, then that is also a poor prognostic sign. So the limitations of the cardiopulmonary stress test is many times people with advanced heart failure, particularly if they've not been exercising, cannot really reach a true VO2 plateau, because their efficiency of exercise is actually quite poor, and they're deconditioned.

And so it's very difficult sometimes to get a true reading on a VO2 stress test. And so what we do is optimize medical therapy. In the meantime, we get them to exercise either in a formal cardiac rehab program or at least do that at home and then not doing the cardiopulmonary stress test until they've had some time to get in better condition and optimized medically. So that is actually the optimal time to do a cardiopulmonary stress test.

And again, just reiterating that the things that we look for are peak VO2 of 14 or VO2 max of greater than 50%-- greater than 50% for a good prognosis-- but they're VO2 max is less than 14 or less than 50% of predicted or their VE VCO2 is greater than 34, 35, that's a poor prognostic sign. And that's when we would think about transplant or advanced heart failure care.

Now the VO2 max 14 milliliters per kilogram per minute was done at a time where people have not been really using beta blockers very much. And as you know, when people are on beta blocker, their heart rate response to exercise is going to be a little bit decreased. And as a result, their oxygen consumption may be a little bit less. And so there are some guidelines that which suggest if you are a beta blocker, the poor prognosis really may not start until you're VO2 max is less than 14. So if you're on a beta blocker, the number may be a little bit different in some studies.

So going back to the question, what's the primary indication for transplant in this man. Would it be EF, serum sodium, LV size, renal function, or functional capacity? Turns out its functional capacity. Remember, this person could not get on stage I of Bruce protocol, so his exercise capacity is quite limited. Now what you don't know is this a maximal study or a submaximal study. But presumably, those are the things that make us most concerned.

I will say in the story other things that make me really concerned is the fact that he was hospitalized three times in six months. That's a big concern. It's someone who gets rehospitalized. Someone who we have who is perhaps not tolerant of guideline directed therapies, you've had to decrease their beta blocker and decrease their ACE, RE, or ARB because of blood pressure, those are people at high risk-- those whose functional capacity decreased, those who had recurrent hospitalizations-- those are the people that we're most concerned about and we'd want to see those folks sooner rather than later.

Questions so far? So these are the conditions. There's a whole slew of conditions that affect morbidity and mortality after transplant. And they goes through our minds-- like irreversible renal dysfunction, irreversible hepatic disease, severe obesity, diabetes with end organ damage. All of these sort of play in our minds when we are thinking about [AUDIO CUT] that would decrease survival.

Generally when you're getting beyond more than 10 years, it's not their heart or the graph that limits survival. It's usually something else. So even up to 15 years-- so the sweet spot really is the 50 to 60, but we're doing better with folks in their 60s. So back to the patient.

So he gets by heart catheterization and blood pressure's 175 with a mean at 85, the RA is 10, the PA is 65 over 24 with a mean of 35. The wedge pressure is not too bad, it's 15. The cardiac output is 3.6. And the pulmonary vascular resistance is 440. If you do it in Wood units, it's about 5 1/2 Wood units. So he's got pretty high pulmonary pressure, that's for sure. SVR is up as well too.

So looking at the questions, which one of the following is true. The pulmonary vascular resistance is not reversible because the transpulmonary gradient is too high-- we'll go through those definitions in a second-- intravenous furosemide will lower PVR, blood pressure is too low to assess the PVR with nitroprusside-- blood pressure is only 100 systolic-- milrinone is going to decrease the pulmonary vascular resistance primarily by increasing cardiac output.

So in order to answer these questions, we have to go through some definitions. Because yes, irreversible pulmonary hypertension is one of the significant risk factors that affects morbidity and mortality after the transplant. So it turns out that if during the pre-transplant phase, if your pulmonary artery systolic pressure is less than 50, your prognosis is a little better after transplant than if it's greater than 50. And so let's talk about the different calculations.

So transpulmonary gradient, our TPG, is simply the mean pulmonary pressure minus the wedge pressure. So that's really looking at what's the pressure gradient across the pulmonary vasculature, right. The mean pulmonary artery pressure is on the preload side of the lungs, so to speak. The wedge pressure is, so to speak, the output load of the pulmonary vascular [INAUDIBLE].

So what's the difference in pressure there? Pulmonary vascular resistance is simply the same thing-- the mean pulmonary pressure minus the wedge pressure divided by cardiac output-- or transpulmonary gradient divide by the cardiac output. Just if you understand what these are, you can pretty much answer the questions that were posed earlier.

So remember I told you earlier if your systolic pulmonary pressure is greater than 50 your prognosis is slightly better than if it's less than 50, but if you look at the transpulmonary gradient-- so that mean PA pressure minus the wedge pressure-- the bigger the difference, the worse the prognosis. So if you mean PA minus the wedge pressure is, in this case, less than 12-- in this study less than 12, 13-- your prognosis is pretty good post transplant as opposed to if you have a large pulmonary gradient or there's a big difference between the mean pulmonary artery pressure and the wedge pressure.

Some people would use the difference between the diastolic pulmonary pressure minus the wedge pressure. It's analogous. You can do it that way too. So does it make a difference? Yeah, it makes a difference. And you can see, this is a 10 year mortality. So even going at 10 years, there is significance in what the transpulmonary gradient is pre-transplant-- that's 10 year mortality beyond. And so really again, probably after 13, 14, 15 millimeters of mercury transpulmonary gradient difference, that's when you start seeing the excess mortality.

So let's go to our patient. So baseline-- we've told you the RA is 10, the wedge is 15, the PA pressure is 60 over 24 with a mean at 35. So that means 35 minus 15 gives you a transpulmonary gradient at 20. So your cardiac output was 3.6, so pulmonary vascular resistance is simply 20 divided by 3.6. It's 5.6, that's pretty high. SVR is 1600 or almost 1700.

So let's use nitroprusside. So with nitroprusside, you're right atrial pressure drops. You're pulmonary wedge pressure actually went up-- we'll talk a little bit about that, maybe why that's the case. The PA pressure went down. So the PA systolic went to 40. The diastolic is about the same, about 24. The pulmonary artery pressure mean dropped to 32. Transpulmonary gradient, now it's 10-- so 30 minus 20 is 10.

Cardiac output is 4.5. Pulmonary vascular resistance is now 2.2. So it's a better pulmonary vascular resistance and your cardiac output went up. So all you've done is unloaded the patient, right. You've improved their afterload. So you have presumably better flow. You're unloading the right ventricle. So you have better right ventricular contractility. You probably have better filling in the left ventricle, and that's why you're wedge pressure went up-- you're actually now able to fill the left ventricle a little bit better.

So you have better flow across the pulmonary vasculature, that has resulted in a lower right atrial pressure, better transpulmonary gradient, and better pulmonary vascular system. So how about if you use now milrinone? So if you use milrinone, your RA pressure didn't really change that much. Pulmonary pressures really didn't change that much. It's a little bit lower. Transpulmonary gradient is a little bit lower-- from 20 to 17. But your cardiac output is much better. It went from 3.6 to 5.3. And as a result, your pulmonary vascular resistance went from 5.6 to 3.2 .

So in milrinone the example is you haven't really done that much to the pulmonary pressures. You really haven't. But all you've really done is increase cardiac output. And because pulmonary vascular resistance is really just a math calculation, you've improved your pulmonary vascular resistance because you've improved the cardiac output. Remember, the pulmonary vascular resistance is simply the transpulmonary gradient divided by the cardiac output. So it's a math problem, right. So you can improve the pulmonary vascular resistance simply by increasing cardiac output.

And so if you continue on-- so we'll get back to that point in a second. So is that a big deal? Is doing this a big deal? Is going to nitroprusside, dropping the transpulmonary gradient, dropping the pulmonary vascular resistance, is that a big deal or not? It turns out that it is. And so again, this is old data, but we still use it.

And so basically what happened was they took everybody who was being evaluated for transplant. You figure out what their pulmonary vascular resistance was. And so if they're in group A is your-- group A were people who had high pulmonary vascular resistance. And even with nitroprusside you cannot reduce their pulmonary vascular resistance to less than 2.5. It just stayed high regardless of what you did-- regardless of the dose of nitroprusside.

The second group is you are able to reduce the pulmonary vascular resistance to less than 2.5, but you did it at expense of hypertension. You dropped their systolic blood pressure less than 80. That was the only way you can get your pulmonary vascular resistance less than 2.5.

Third group is they were reduced-- the pulmonary vascular resistance was high at baseline. You were able to give them nitroprusside to reduce the pulmonary vascular resistance to less than 2.5. But you were able to keep their systolic blood pressure greater than 80. And then the last group were a group with normal pulmonary pressures at baseline.

So if you look at the data, people with normal pulmonary vascular resistance at baseline-- so their PVR is less than 2.5-- or people who had an elevated pulmonary vascular resistance, but you were able to get their pulmonary vascular resistance less than 2.5 without developing hypotension, their prognosis after transplant was quite good. People who you were not able to reduce their pulmonary vascular resistance to less than 2.5 or you were able to reduce it to less than 2.5, but an expense of their blood pressure, those people had quite high three month mortality.

So during the evaluation phase when we're looking at patients, these two groups of people-- people with high pulmonary pressures that we cannot quote unquote "fix" pulmonary hypertension, we could not drop their pulmonary artery pressure or drop their pulmonary vascular resistance, or we were only able to do that at the expense of their systolic blood pressure-- those are the people that we're looking at. If they're a transplant candidate, we need to ensure that we can treat their pulmonary hypertension adequately.

Those are people that we would put on a durable LVAD, a ventricular assist device, to fully unload their left ventricle. Or maybe use a balloon pump or Impella or something like that to see if we can drop their pulmonary vascular resistance, drop their transpulmonary gradient at least acutely.

These are people who if they do have pretty severe hypertension, these are the folks that we tell them we're going to try to see what we can do to reduce your pulmonary pressures, but if we're not successful, you're not going to be able to transplant. So a lot of discussion there. But basically the data bears out that if you're able to, at the time of transplant, if your pulmonary vascular resistance is less than 3, your survival post-transplant is significantly better than if you're greater than 3.

And most of that mortality is early on because of acute right heart failure. People that we transplant with very high pulmonary pressures, they're right ventrical will fail, and their three and six month mortality is quite high. So most of the mortality is very early post transplant. if you're transplant is somebody with severe pulmonary hypertension, the new right ventricle just fails.

So how much pulmonary hypertension is too much? That's a moving target. We're really concerned with the pulmonary vascular resistance is no more than 4 to 6 Wood units, transpulmonary gradient is greater than 15, systolic pulmonary pressure is consistently in the 60s. And regardless of unloading with medical management, with sodium nitroprusside or even long term milrinone, they really can't get the pulmonary pressures lower. Those are the people that were really most concerned about.

So when do we do right heart catheterizations? We pretty much do right heart catheterization on everybody during their transplant evaluation phase. If you had demonstrated elevated pulmonary pressures and you're listed for transplant, we're usually going to repeat the right heart cath every three to six months-- or if there's a change of symptomatology.

Anyone with a pulmonary artery systolic pressure greater than 50 at baseline or transpulmonary gradient of greater than 15 or PVR greater than 3, we're going to give them vasodilators to try to see-- sodium nitroprusside in particular-- to see if there is opportunity to vasodilate them to normalize, or at least get the pulmonary pressures towards normal. And if not, then we need to think about the ventricular assist device plantation or something else to see if they can be fully unloaded what happens to the pulmonary pressures.

So going back to the question, so pulmonary vascular resistance is not reversible because the transpulmonary gradient is too high, and hopefully I've demonstrated that there is no transpulmonary gradient that's too high that you can't really try to see if you can drop the pulmonary vascular resistance. Intravenous furosemide will lower the pulmonary vascular resistance. Remember pulmonary vascular resistance is the transpulmonary gradient, which is the mean PA minus the wedge, divided by cardiac output.

Intravenous furosemide usually won't decrease the pulmonary vascular resistance. It will decrease preload. But it really doesn't affect pulmonary vascular resistance very much. So it will drop your right atrial pressure but maybe not necessarily the rest of the vasculature. Blood pressure's too low to assess the pulmonary vascular resistance. Again, I take the example of blood pressure is 105. Again, if your blood pressure, I would say, is above 90 systolic and especially if you do the calculation the baseline systemic vascular resistance is quite high, then there is an opportunity to use nitroprusside to see if you can lower the pulmonary pressure.

And then this is the math question. Milrinone will lower the pulmonary vascular resistance by increasing cardiac output. That's true remember because, going back to the formula, pulmonary vascular resistance-- mean PA minus the wedge divided by cardiac output. So if your cardiac output goes up, because of math your pulmonary vascular resistance will go down.

So the answer is milrinone lowers the pulmonary vascular resistance by decreasing cardiac output. So what are the indications? So we kind of talked about people with refractory symptoms despite optimal medical therapy. That includes not only heart failure symptoms but people with intractable angina, intractable ventricle arrhythmias that are not amenable to revascularization or ablation if you talk about ventricular arrhythmias. If you're VO2 max is less than 14 milliliters per kilogram per minute or less than 50% predicted, that's an indication.

Just because your ejection fraction is low, just because your New York Heart Association class is III or IV, doesn't always mean that you need them. You really need to do a functional study to determine whether or not they would benefit from a survival standpoint from a transplant.

There are some sort of contraindications-- certainly people with malignancy, people with a systemic illness with a life expectancy less than two years or so. People with irreversible renal or a hepatic disease would be a contraindication to heart alone, although consideration can be made for a combination of heart and kidney transplant or heart and liver transplants. Those are going to be people who are more physically fit, because it's a bigger surgery.

People with severe COPD-- it's sort of a relative contraindication. Really from a pulmonary standpoint are they going to be a pulmonary cripple after you do a heart transplant. They remain on the bed because they have bad lung disease. So those are sort of things to keep in mind. And really other sort of systemic diseases that would decrease survival and worsening outcomes, I think those are sort of relative contraindications.

Active smoking, active substance abuse-- those are contraindications. Also somebody who does not have an adequate caregiver plan, who has limited psychosocial means, they're certainly not a good candidate for transplant. And so it's more than just the medical things. It's also how much support do they have. Are they able to manage their complex medical regimen? Those are all contraindications or things that we'd sort of look at to determine whether or not someone could sort of handle a managed transplant.

As far as age goes, we sort of talked about-- I would say anyone under the age of 70 should be considered. If they're about 70 it could be individualized. We've had really great success in transplanting some selective patients above the age of 70. More and more programs are using age 70 as a cutoff to using the ventrical assist device implantation for destination therapy. So many, many programs will use age as a reason to put destination LVAD in somebody rather than transplanting them.

Optimal body mass index is less than 35-- less than 30-- although a BMI greater than 35 carries excess mortality. And so in the heart transplant world, a BMI less than 35 is considered sort of acceptable, but optimal certainly is BMI less than 30.

So during our evaluation it's pretty much a history and physical looking to see if there are any contraindications that would influence the survival or outcomes after transplant. We looked at immuno compatibility, your ABOs, if they've developed tissue antibodies in the past. Really look to see if there's any other signs of end organ injury-- kidney, liver, vasculature, carotid artery, any signs of malignancy, malignancy screening, psychosocial evaluation-- all those things go into part of the evaluation process.

And so in simple terms, when I talk to patients for the first time-- they come to us to determine do we need a transplant, yes or no. I tell them it two simple but very involved questions. The first question is, do you really need a transplant, yes or no. And so part of that is have they been optimized medically. Are there any surgical alternatives? Are they a candidate for mitral valve repair if that's what's necessary? Do they need high risk [INAUDIBLE]? Do they need, perhaps, better controls arrhythmias?

Have they been optimized from a lifestyle standpoint? Are they limiting their fluid intake? Are they exercising? Things like that-- have you done everything you can to put yourself in the best situation to succeed. And then when you do that, do you still need a transplant, yes or no based on what we've talked about-- VO2 max, exercise capacity, recurrent hospitalizations, things like that. So that first simple but very involved question, do you really need a transplant, yes or no-- or LVAD or other advanced heart [INAUDIBLE].

And then the second question is also simple but very involved, is are there any things that will interfere with your ability to be successful after a transplant? Is there anything that would interfere with your ability to successful? So for example, it's as simple as you don't have a caregiver plan, you cannot manage a complex medical regimen, or do you have a malignancy or do you have any other condition that would limit your survival, or is your BMI 40, and we know that BMI 40 carries excess mortality post transplant. So those things-- so those are things that we look at from the very initial evaluation.

Very first time we see them is, do you really need a transplant? Can we optimize your medical therapy? And then why we're doing that, is there anything that I see during the initial screening that would make me concerned? Are you actively smoking? Are you morbidly obese? Do you have a malignancy? These are things that from the first time that we see them, we're sort of going through our minds to say is there something that we need to do to get those things in order. Because some of these things take time-- like smoking cessation may take some time, weight loss may take some time.

So what you don't want to do is you optimize them medically, do their VO2 max, and say, oh, we should evaluate for transplant. Oh, you know what? We should have told you a month or two ago that you need to start losing weight. We should have told you a month or two ago you need to stop smoking. So those are things that are all happening simultaneously. And we try to do that in a multidisciplinary fashion.