I'm Michelle Kittleson here from Cedars-Sinai in Los Angeles, California. We're going to talk about heart transplantation outcomes and complications. I have no disclosures. When we look at survival after heart transplantation, this is a figure from the ISHLT registry, and I show it to you to illustrate a few points. Number one, if we look at successive survival in eras post-transplant, we see that survival has improved as the eras progress. Number two, you look at the ends here. There have been over 100,000 heart transplants performed internationally in the past two and a half decades, really cementing transplantation as an established therapy for end-stage heart failure. And number three, if we look at median survival in the current era, it's about 12 and a half years, which is certainly better than anyone can expect with end-stage heart failure. Of course, survival does vary by indication. The most important thing to know is patients with non-ischemic cardiomyopathy have the best survival, likely related to the lack of associated comorbidities, and patients undergoing re-transplantation tend to have the worst survival, likely for the same reason, increased comorbidities as they go through the process. When you're looking at your patient after transplant and trying to figure out what are their risk factors for survival, mortality, the most important things to keep in mind when we're thinking about discrete variables, transplant era matters, having a VAD or not matters, re-transplantation, as we talked about, and no surprise, being on ECMO, being unstable going into transplant, is a big deal. When we think about continuous variables, a lot of these are common sense too. The greater the age of the recipient, the donor, the BMI, the creatinine, the ischemic time, the bilirubin, and a lower predicted heart mass, those things portend worse survival. Now, it's not only enough to live longer after transplantation. Quality of life matters too, and these are some figures from the ISHLT registry about quality of life. So, Karnofsky's score defines the functional capacity of patients after transplant, and anything with a score of 70, 80, 90 is essentially independent functioning, and you can see that pretty much 90% of patients up to five years after transplant have great physical, emotional functioning, and we think about return to work, almost 40% of patients have returned to work by five years post-transplant. But to every silver lining, there is a cloud, and it's important to talk about causes of death after transplantation as well. Now, I've broken a cardinal rule of presentations by showing you this incredibly busy slide, but I show it to you for a reason. What I want to illustrate to you is the patterns this data is showing us. So, if we look at causes of death early after transplant, we see multi-organ failure, rejection, and infection. If we look at causes of death later after transplant, we see cardiac allograft vasculopathy, malignancy, renal failure. So, there's this push and pull, this tension. Early after transplant, patients are battling rejection and infection, and early after transplant, CAV, malignancy, and renal failure. Those are really two sides of the same coin of the extremes of immunosuppression. Too little immunosuppression, rejection. Too much immunosuppression, infection. And the same is true long-term. And our goal after transplant, ultimately, is to achieve a balance of immunosuppression, where we achieve a state of quiescence, and the body accepts the donor heart as its own. Early on, you can get rejection. Long-term, with too little immunosuppression, there can be allograft vasculopathy, a form of chronic rejection. And too much immunosuppression can lead patients early after transplant to infection and long-term to cancer, since our immune system is responsible not just for looking for bacteria, viruses, and parasites, but for malignant cells as well, and long-term toxicity like renal failure. So, we're going to take some of these comorbidities, causes of mortality, one by one, and cover them. So, we'll talk about cardiac allograft vasculopathy, infection, malignancy, and renal failure. So, this is a figure from the ISHLT registry, looking at the incidence of allograft vasculopathy, freedom from allograft vasculopathy at time post-transplant. And I think really what's extraordinary is that 50% of patients, by the time they're 10 years post-transplant, will have some evidence of allograft vasculopathy. And the second more sobering point is if you look at eras, there's really no improvement over time. Cardiac allograft vasculopathy is the Achilles heel of heart transplantation. And we have to remember that CAV is not the same as non-transplant CAD. In a non-transplant recipient, they'll often be symptomatic because their hearts are innervated, and they may have angina and end-stemmy-stemmy. There's mostly epicardial focal lesions, very stentable. There's slow progression. In angiogram, one year later, you're unlikely to have significant coronary artery disease. There are often eccentric lesions, which are well seen on angiography, and they're lipid-rich with atherosclerotic plaques. Contrast that to cardiac allograft vasculopathy. These patients are often asymptomatic because of denervation, which is why serial surveillance is done. They might have fatigue or a reduced EF. It's a panvascular disease, often without focal lesions for distal pruning. Rapid progression, an angiogram that's normal one year doesn't guarantee a normal one year later. There can be concentric lesions, underestimated by angiography, and these are generally lipid-poor with fibrointimal proliferation, not so much an atherosclerotic process as a form of chronic rejection. And when you look at this sample patient, year 1, 2, and 4, year 0, 2, and 4, you see rapid progression, distal pruning, and you see on this histology of a postmortem examination this exuberant fibrointimal proliferation. What are the risk factors for CAV? Increased donor age, male donor, positive donor CMV, recipient smoking, ischemic etiology for transplant, recipient hypertension, diabetes, hyperlipidemia. Why do I highlight those? Those are the only modifiable CAV risk factors. So if we think about prevention of CAV, we give our patients aspirin, we control hypertension, we give statins, control of diabetes, mycophenolate better than azathioprine, and of course the proliferation signal inhibitors are superior to both. Statins ultimately are the wonder drug, and the classic New England Journal article now from many decades ago, had a statin given 12 months post-transplant, led to less rejection with hemodynamic compromise, less CAV, better survival, which is why the ISHLT guidelines tell us that statin therapy improves long-term outcomes regardless of lipid levels. And the guidelines also note that primary prevention of CAV, control of cardiac risk factors, hypertension, diabetes, hyperlipidemia, smoking, obesity, is crucial, as well as prevention of CMV infection. What about the guidelines for surveillance for CAV? The guidelines tell us that annual or biannual coronary angiography should be considered to assess the development of CAV, and patients free of CAV at three to five years may undergo less frequent invasive evaluation. The guidelines also say that treadmill or droputamine stress echo and myocardial perfusion imaging may all be useful for the detection of CAV, and it may be treated with PCI-CABG or Reedy transplant. It's worth noting that these ISHLT guidelines are from 2010. There are new guidelines in the making that should be published soon, though I think the general themes here of CAV surveillance will remain much the same. There are standard nomenclature for CAV. Low angiographic disease, grade zero. Mild would be any vessel with a non-significant stenosis. Moderate vessels with significant stenosis. And severe, which is what you really care about, would be significant main disease, significant disease in multiple vessels. And this is the important one, I think. Any CAV with a low EF or restricted physiology. That portends worse prognosis, and CAV grade three is likely the time when you're going to be considering redo transplant evaluation in eligible and interested patients. What about IVUS? The guidelines tell us that IVUS at four to six weeks and at one year after heart transplant is an option to exclude donor coronary artery disease to detect rapidly progressive CAV and provide prognostic inflammation. As you can see here, the angiogram looks like there's not much disease, but in fact you see this semi-lunar plaque very nicely highlighted on intravascular ultrasound. The prognostic information comes from this classic study. We look at the maximal intimal thickness change of the coronary artery between six weeks and one year post-transplant. And that there was worse outcomes in those patients who had increased progression by IVUS in their maximal intimal thickness. At a consensus conference in 2010, IVUS-detected change in MIT was considered a putative surrogate marker for prognosis, though generally it is considered investigational. What about infection? I'm going to talk about the infections you need to know about as a heart transplant cardiologist. CMV is a big one. Latent CMV can turn into active CMV, either that in the recipient or that in the donor heart, and there's two different consequences. There's CMV disease with the direct effects, CMV syndrome, with fever, malaise, myalgias, myelosuppression, increased liver enzymes, as well as end-organ disease. Colitis and pneumonitis can be seen in transplant recipients, retinitis is rare. And then there's the cellular effects, the indirect effects, that having CMV then increases the risk of other opportunistic infections, e.g. the associated post-transplant lymphoproliferative disorder, rejection, and CAV. Patients are treated with IV ganciclovir or oral van ganciclovir in conjunction with recommendations from the transplant infectious disease specialist. The duration often depends on the clinical acuity, viral load, response of viral load to therapy. It's important to remember when it comes to other infections that the risk changes over time. Early after transplant, we think about resistant species like MRSA, VRE, candida, aspiration, catheter wound infection, C. diff, donor-derived, which are fortunately uncommon, and then recipient-derived colonization like aspergillus or pseudomonas. One to six months after, C. diff is still on the list, adenovirus influenza, cryptococcus, mycobacterium, and in patients who are not adequately prophylaxed, some opportunistic infections. And finally, over six months after transplant, there can be community-acquired pneumonias, urinary tract infections, aspergillus, myocardia, and late viral infections. So, of course, we try very hard to prophylax against what we can, and we have the ISHLT guidelines, class one indications for prophylaxis. So, mucocutaneous candidiasis by statin or clotrimazole. CMV. So, you give IV or, more commonly, oral vanganciclovir. Passive CMV immunoglobulin can be used at those of high risk for infection, though it's not standard. EBD cannot be treated, so routine surveillance is not established. When it comes to pneumocystis, trimethoprim, sulfamethoxazole, which is also good for toxoplasmosis. In those sulfa-allergic patients, you'll reach for a tovacron or dapsone. This dapsone increases the risk of hemolysis. You'll check for G6PD activity before starting. And the indications for infection prophylaxis. For the first year after transplant, the duration will vary by center anywhere from three to 12 months. It is very center-specific. And after augmented immunosuppression for rejection. What about vaccines? Remember that inactivated vaccines are allowed. Influenza, Shingrix, don't forget about COVID. Live vaccines are contraindicated, and that includes MMR, Varicella, and Zostavax. Let's move on now to malignancy. Let's talk about post-transplant malignancies. So if we think about post-transplant malignancies, they're quite common. 28% of patients by 10 years post-transplant will have some form of cancer. The most common being skin cancer. And lymphoma, while classic, is actually rarer. What do we do when patients get cancer? Well, you may recall from the lecture on immunosuppression management that these are patients for whom we try to get rid of the calcineurin inhibitor. While it's the cornerstone for rejection prevention, it also carries the highest risk of malignancy. And we extrapolate from this classic study from the kidney transplant literature. Kidney transplant recipients who had one squamous cell skin cancer and then were randomized to transition from a CNI to a PSI. And the two-year recurrent rate of squamous cell skin cancer was 22% if the CNI was stopped versus 39% if the CNI was continued. So a pretty powerful effect size of getting rid of the CNI in patients to prevent recurrent skin cancer in kidney transplant recipients. So the ISHLT guidelines on malignancy, Class I, recommendations regarding screening for breast, colon, and prostate cancer in the general population should also be followed in heart transplant recipients. And it's recommended that heart transplant recipients have close skin cancer surveillance, including education on preventive measures, and yearly dermatologic examinations speaking to the high incidence of skin cancer. Class IIa, chronic immunosuppression should be minimized in heart transplant recipients, particularly in patients at high risk for malignancy. And then let's conclude the malignancy section with a high-yield PTLD, one to know about. So post-transplant lymphoproliferative disorder, classic though not common, it's a B-cell lymphoma, PDD associated in about 50% of cases, occurs within the first two years or five years after transplant of bimodal distribution. More immunosuppression increases risk, especially the use of T-cell depleting agents like ATG, either for induction or treatment of rejection. Presentation, fever, malaise, pharyngitis, extranodal masses classically abdominal with perforation, CNS disease. The first line of treatment is minimization of immunosuppression, and then rituximab, which is an anti-CB20 on B-cells, plus CHOP. And oftentimes, PTLD is very successfully treated with these measures. So to conclude with our last important comorbidity and cause of mortality after heart transplantation, let's talk about renal dysfunction. Renal dysfunction, of course, classically caused by the calcineurin inhibitor. And if we look at renal dysfunction after transplantation, severe renal dysfunction increases as patients get farther out from transplant. And severe renal dysfunction has one of three categories, creatinine over 2.5, chronic dialysis, renal transplant. And you can see within 10 years of transplant, 6% of patients are in chronic dialysis, and 2% have undergone renal transplant. So if we look at the ISHLT guidelines on renal failure, it tells that an EGFR less than 30 or proteinuria is a reason to send your patient to a nephrologist for management and consideration of renal transplantation. I would argue that perhaps it should be even more permissive, an EGFR less than 40, even less than 50, to send them to the nephrologist for further optimization of comorbidities. CNI exposure should be lowered to the minimal level required for effective immunosuppression. And owing to the potential for precipitating rejection, CNI-free regimens should be used with caution in heart transplant recipients with significant renal deficiency that persists despite CNI reduction. It's all about balancing the benefit to the kidney with the risk to the heart on a case-by-case basis. So to summarize, cardiac allograft vasculopathy is distinct from non-transplant coronary artery disease and can portend a poor prognosis. When it comes to infections, think about prophylaxis and that CMV is the classic post-transplant infection. When it comes to malignancy, remember that skin cancer is the most common, PTLD the most classic. And then when you have patients with renal failure, very common if they progress post-transplant, attempt CNI minimization and select low-risk individuals for rejection, CNI-free regimens. Thanks so much for your attention. Okay, now we're here live with Dr. Kittleson after those excellent talks and your questions are coming in, but please feel free to add more or upvote the ones that are in the queue. You can upvote the ones you're particularly interested in. And we will get to questions we don't cover in the whole chair question and answer session which follows this. So Dr. Kittleson, thank you so much. Let's talk about transitioning between immunosuppression. You talked a lot about why you might choose one medicine over another. How do you do this? Do you just stop one and start the other? Do you overlap them? Do you down titrate and up titrate? Yes, great question. I think it depends what you're transitioning from to. So for example, you have a patient on standard TAC and MMF and now they have CAV and you wanna get them on a proliferation signal inhibitor, let's just say sirolimus. That's better in the sense that you're transitioning them to a regimen that's gonna have them offer increased protection against rejection, right? So in that situation, we generally just start the sirolimus, overlap four days with the MMF and then stop the MMF. But it's gonna take about four days for some of that sirolimus to work into your system to a reasonable level, check the level a week later, two weeks later. So that's a pretty reasonable, easy, straightforward transition. You can even do it over the phone with the patient. When you're switching to a CNI-free regimen, that's a much more high stakes situation, right? You're not gonna pick a person who's at high risk for rejection and if you do, because you're worried about the kidneys but you're less worried about the heart, then you're willing to do that regimen. And if you do it, we generally cut the CNI dose in half. So cut the TAC dose in half as you add the sirolimus on board and then check a level in a week or two and only stop the TAC completely when the sirolimus level is therapeutic because you really wanna make sure you've got good immunosuppression on board when you're taking away the quarterstone of the CNI and then check an echocardiogram about four weeks later just to document that their function is normal. So that's generally the protocol we follow and we don't do it over the phone generally. We really wanna make sure that the patient understands it's written down, the follow-ups are arranged because that's not the kind of regimen you wanna fall through the cracks. Great. How about using the drug interactions to administer lower doses of calciner and antagonists to patients? So historically in the olden days, things like diltiazem were given to transplant recipients early after transplant. So in order to give them less cyclosporine, it's very historic. It's back when cyclosporine was the standard CNI. That's not done anymore because it's not a cost issue. We don't pay by the milligram. And second, it's not clear that the nephrotoxicity of the calciner inhibitors is related to the milligrams you give. It's more likely related to the levels in the blood. So there's really no benefit to leveraging your drug-drug interactions to give diltiazem for hypertension to also give them less milligrams of their calciner inhibitor. And in addition, we actually try to avoid that because you don't want this unpredictable impact on your calciner inhibitor levels that they may lead to worse nephrotoxicity. The one situation where we'll often leverage the benefit of drug-drug interactions is those black American patients who are rapid metabolizers of the CNI and you just can't get those levels up. So you go to 2BID, 3BID, 5BID, nothing, 6BID, 5TID, and you're really having trouble, then add quinoconazole, 100, 200 milligrams, slip that in there, activate your, inhibit your cytochrome P450 and then bring your levels up. So that's one situation where we'll use it. Excellent. How about tolerability of everolimus versus serolimus? Yes, that is what I like to call a data-free zone. So, you know, I tend to like serolimus better because it's once a day, it's older, sometimes cheaper. Some drug prescription plans will cover serolimus better than everolimus, it'll be cheaper for the patient. That's generally the go-to. There's really no clear evidence that one is superior to the other. But if, say the patient, but 30% of people who start PSI stop them. The mouth ulcers, the edema, the stomach upset, the fatigue, the malaise, the ennui, there's all kinds of weird PSI stuff that people get. If they get something like that, some non-life-threatening but quality-of-life-impairing side effect to one PSI, absolutely try another one. But if they get pneumonitis, then all PSIs are off the table. So that's generally how I think about it. And then again, PSI side effects. If you have someone who you'd like to have on a calcineurin-free regimen and they develop proteinuria with serolimus, how do you manage that to put them back on? Yeah, I like to phone a friend, a lead nephrologist in that situation for counseling and therapy. Because I think it's a balance of what's actually worse. Is the CNI-related renal dysfunction that's dropped their EGFR less than 50, less than 40, we're really in the danger zone, we're worrying? Or is it just a touch of proteinuria when they're actually, their creatinine, their EGFR has actually gotten better? So I tend to try to balance that counseled by a nephrologist if it's a little low-level proteinuria and it's stable and their EGFR has actually improved, maybe you continue it and you simply monitor the EGFR. But if they just have rampant proteinuria, then you say no dice, they are better off on a CNI minimization regimen where instead of running their attack level standard five to 10, you might say four to eight or three to six, something like that. Great, so let's turn to the physiology now. How do you manage chronotropic incompetence after heart transplant when a patient's really bothered? When do you add a beta agonist? When do you put in a pacemaker? Yeah, so early after transplant, there are sometimes patients who have relative bradycardia, right? The perfect patient coming out of the OR is gonna have a heart rate of 110 and a right atrial pressure of two and a creatinine of 1.0 on no epinephrine, right? That's the dream patient coming out of the OR. But we never see those patients because if they were that healthy, they probably wouldn't need a transplant. So more likely, right, you'll see this relative bradycardia and there's a lot of reasons for it. It might be that awful scourge of the post, of the pre-op amiodarone that's just sitting around their liver leeching out slowly over months or it can be some primary graft dysfunction. So when does relative bradycardia become symptomatic bradycardia early post transplant? Really, if you see a heart rate in the 50s or 60s, I mean, that's just bad, right? If that persists more than a week or two after transplant, you're pretty much giving the patient a pacemaker. Well, what if the heart rate's 70s and they walk around the halls and they feel fine and their blood pressure's okay and they're not volume overloaded and their creatinine's fine, then you probably let them ride. So for me, the cutoff is one, fatigue or exertional intolerance. That may be a little hard to parse out early after transplant with everything else going on. But if they're volume overloaded, difficult to diurese, creatinine's rising, that tells you they're not happy at that heart rate and they often need a pacemaker. Interestingly enough, the renervation happens in almost everyone. By the time they're a year out or even using that pacemaker, maybe not, but you gotta get them through the hump of that early period. You have to do everything you can to preserve their volume status, especially their precious renal function early on. So you talked a lot about medications that may not behave as expected because of the denervation, but you just mentioned that almost everyone does re-enervate to some extent. So how do you judge response to medications? Do you actually truly avoid medications or do you try them? So those are three types of nerves, right? There'll be the efferents that go back to, the ones that make you give you chest pain. So the ones that give you chest pain probably grow back to some extent because there are patients with CAV who actually have classic angina. So you really only know if those nerves grow back because patients tell you they have chest pain later after transplant. Then there's the parasympathetic, the vagus nerve, which makes the heart rate relatively higher. By the time they're a year out, most patients are now running in the eighties for their heart rate. So they must have some re-enervation. And then there's the sympathetic nervous or the post-ganglionic release of the epi and the neuropine response to exercise. I mean, there's no way to know that for sure unless you do fancy studies that no one's going to do in clinical practice. So really, how does that matter when you're thinking about medications? Well, number one, if you have someone with unstable bradycardia, are you going to try atropine in them? You probably still will never do that because you'll just feel foolish that you don't understand the vagus nerve. You'll use isoproteinol. The second thing is what about the beta blockers? What about beta blockers post-transplant? We avoid them because we're going to blunt their exercise response because they already don't have the sympathetic innervation. Well, I think about it another way. When are beta blockers going to be actually useful post-transplant? We know they're very poor antihypertensives anyway. So even regardless of the innervation issue, what's my algorithm for managing hypertension in a transplant recipient? Often a calcium channel blocker first, a dihydropyridine like amlodipine or nifedipine because I know it won't hurt the kidneys early when everyone's worried about the kidney function. Though often they have the limiting lower extremity edema. Second line's going to be an ARB ACE inhibitor or thiazide diuretic. If that doesn't work because their kidneys are bad or their potassium won't tolerate it, then you're going to go more to your clonidine and guanfacine. I mean, hydrolysin doesn't work anyway, but probably slip it in there. And then only then and only then are you going to even get to the beta blocker because we know it doesn't work well anyway. So if you've gotten to your fifth line agent, then sure, you're not going to let this concern about exercise, blunting exercise tolerance bother you. You're just going to give them something to treat their blood pressure, probably levatolol, probably more bang for your buck. But you'll be very vigilant for any quality of life related side effects of fatigue and exercise intolerance, recognizing you should pull back if that's likely the culprit. Super. Okay, we have a few minutes remaining. We're going to talk about non-board questions now. None of these will be on the boards, I guarantee it. Okay, so virtual histology IVAS to manage CAV. Does this have a role? What's your approach? You know, I don't know. I'm going to be totally honest. I think this is an area in inception. It's a data-free zone. I like to call myself the Andy Rooney of cardiology. Probably most people listening aren't old enough to remember him, but he was the cranky guy at the end of 60 Minutes who hated everything and didn't believe anything. And so I don't know. I don't know where we are yet. I think IVAS in the present age, it's hard to know where it matters. But what I'm really excited about when it comes to CAV is the CAV trajectory score. So disclaimer, two of my colleagues, Dr. Patel and Kobashigawa were the co-authors in this really interesting study that came out in CERC two years ago, where they took a testing cohort and a validation cohort and used six criteria, donor and recipient characteristics, donor age, smoking, recipient LDL, donor-specific antibodies, there were six in total. And you could predict very accurately what CAV trajectory a patient would fall in. There are four trajectories, one with really no CAD up to 10 years, one with a little bit, one with a moderate amount, and then the last was accelerated vasculopathy. And by calculating which trajectory someone falls in, then you can limit the number of surveillance studies you do to assess for CAV. We know we can't rely on symptoms because the heart's denervated. We have to do something, but the question is, how often do you need to do that something? And can you risk stratify to do it in the right person? So I think the future is in the correct application of machine learning models in a clinically relevant way so we can minimize testing on our patients. Super. How about co-stimulation inhibitors like bilaticept to reduce renal toxicity? I am so excited about the concept of bilaticept. And I've seen the case reports here and there, and I'm thrilled by the case reports, but someone out there needs to put together, Dr. Switzer needs to put together a clinical trial so that we can figure out the who, what, where, when, why, because I think it would be huge. It's great for kidneys. I think it would be great for hearts. God forbid I ever need a transplant, I plan to switch myself to a CNI-free regimen as soon as possible and then get myself some bilaticept. Yes. Excellent. And then how about, where is it? Oh, DCD hearts. Do you immunosuppress them differently? I don't think we know enough to say, but I also don't, so I think when you don't know, you should always err on the side of less is more and do the standard approach. I'm delighted about DCD. I think it's an extraordinary step forward for mankind to widen our donor pool. And I suppose you could say if there may be some more inflammatory milieus somewhere in that functional ischemic time and waiting for the systolic to fall and the five minutes standoff. I don't think we know, at least in our clinical practice, we have treated them exactly the same where you give induction if there's other reasons like renal dysfunction or sensitization, but otherwise exactly the same management. Great. And a question about propranolol for tremor. Yeah. So again, the right answer is what works. And I think you have to balance with the patient. How bad is the tremor? How bad are the side effects to propranolol? How well is the propranolol actually working to control their tremor? And, you know, the CNI-related tremor, Tacrolimus tremor, that happens mostly in older people, tends to be dose-sensitive, so it's really bad for the first three months. Then as you target lower levels, it generally improves. So generally we tell people for those first few months, just hang in there. You will be able to sign your name and eat soup, just not right now. And then as time goes on, it often improves to the point they don't need it. But if they have another essential tremor, something else going on, we'll absolutely try it, but then recognizing the patient has to choose what's worse, the tremor or the side effects of the propranolol. Okay. Last couple of minutes. One final question. Talk about when you can't get a patient off their CNI, but they have significant CKD, you know, how low can you go? Do you do sort of partial sparing regimens? What's your strategy? Yeah, a hundred percent. So the people who you worry about are the people who've had prior rejection, donor-specific antibodies, don't tolerate a lot of CellCept as their buffer because they're going to be off the CNI, maybe a previously weaned off predative, no interest in going on five as a placeholder, issues of non-adherence in the past, we're just not going to come back and check their levels frequently. Those are the kinds of people that even when their kidneys start to go, you'll sacrifice their kidney for their heart. But in that scenario, if you can't go straight to CNI free, you can try a CNI minimization regimen. So in that situation, instead of running five to 10, do you run four to six, three to five, two to, yeah, how low can you go? I think the patient in a way tells you how low you can go, meaning if I have a multiparous woman who is in her 30s, I'm not going to run her as low as an 80-year-old white man, right? So there's many advantages to being an old white man and one of them is you're at less risk for rejection. And so I think it really matters in that sense. You have to take it into the context of the patient. The other time we do CNI minimization is often in patients who have cancer, who we feel very uncomfortable taking away the CNI altogether. And yeah, we run as low as two to five, but if you pick the right patient, they'll do well with that regimen. Yeah, and as you point out, younger patients, the questioner asked about a 35-year-old, it's hard to really minimize in the 35-year-old because their immune systems are robust and they will reject on you. So, you know, you go as low as you can, right? Yeah, treat the patient, exactly. Awesome, well, thank you so much, Michelle. Dr. Kittleson's talks are always, you know, you just want to listen to them over and over. We're going to go out to the main question and answer area, but you will be able to watch these videos. It takes us a day or two to upload them, but you can watch these again if you would like. And we'll see you in the question and answers. Thanks, Michelle. Thank you.

heart transplantation

survival

complications

quality of life

immunosuppression

cardiac allograft vasculopathy

malignancy