Dr Virginia Hebl, MD: Greetings. I’m Dr Virginia Hebl, advanced heart failure and transplant fellow at Mayo Clinic. During today’s Mayo Clinic Talks podcast, we’ll be discussing novel therapies to prevent vasculopathy following heart transplant. I’m joined by my colleague, Dr Sudhir Kushwaha, professor of medicine and the director of the Mayo Clinic Heart Transplant Program. Welcome, Dr Kushwaha.
Dr Sudhir S Kushwaha, MD: Thank you very much, Virginia. It’s good to be here, and this is a subject that I’ve been very interested in for a long time and that I feel Mayo has contributed in significant ways to the medical literature and to the field in general.
Dr Hebl: We appreciate you being here and hearing your insights, if you don’t mind covering the basics of cardiac allograft vasculopathy following cardiac transplantation.
Dr Kushwaha: Well, heart transplantation has been around for about 48 years now. You’d think that when you put a new heart into somebody who’s got severe heart disease—severe heart failure—that that heart, if there’s adequate immunosuppression, would last for many, many years. Unfortunately, that isn’t the case. When we look at survival statistics, we can see that the survival at 10 years of patients undergoing heart transplant is about 60%. So we’re talking about a 60% 10-year survival. If we extend that to 15 years, we’re talking about a 40% survival. There are very few patients who live longer than 20 years following heart transplant.[1]
So it’s between the 10- to 20-year period of time that we start to see an increased rate of mortality. The main cause of that mortality is this disease process called cardiac allograft vasculopathy, which basically is an accelerated form of coronary disease affecting the transplanted heart.
The reasons for why vasculopathy develops are manifold but, predominantly, it’s thought to be an immune process. In very simplistic terms, although we have very good immunosuppression, that heart—when it goes in following transplant—is in a state of chronic low-grade immune assault, and that’s what promotes this accelerated coronary disease. It’s characterized by two main features: One is intimal hyperplasia, which affects the entire coronary vessel, and [another is] an element of smooth-muscle hypertrophy. Those two processes, when we look under the microscope, are what we see. As opposed to focal disease—which we could call traditional coronary disease, where you get focal lesions, lipid-rich plaque, and plaque rupture—[vasculopathy] is a diffuse disease process, and that’s why it’s so difficult to treat.
Dr Hebl: How does it end up resulting in a patient’s demise?
Dr Kushwaha: Well, what ends up happening is that we can see progressive narrowing of the coronary vessels over time, and this is one of the reasons why we do annual angiograms to follow these patients. We compare angiograms from one year to the next. In our program at Mayo, we also do an intravascular ultrasound, or IVUS for short, where we look at the vessel from the inside using ultrasound, and that gives us an idea of the degree of intimal thickening, which happens on the inside of the vessel. If we see progression, that gives us some cause for concern, and we follow that patient more carefully.
The way it affects outcome is that we can get the vessel narrowing to such a degree that it becomes occluded, and then that patient might develop worsening of cardiac function or an acute myocardial infarction and, basically, failure of the transplanted heart. [That can] ultimately result in death unless the patient can be retransplanted in time.
Dr Hebl: I see. So what are the potential approaches to prevent or slow down this process?
Dr Kushwaha: Well, as I said earlier, it’s a multifactorial process, and many of the traditional risk factors for coronary artery disease also apply. For instance, we try to treat high blood pressure, hyperlipidemia, which is also fairly common (sometimes as a result of the steroids that patients are on), and high blood sugar and diabetes. All of the traditional risk factors, we also work hard trying to control. But even controlling those factors is not enough.[2]
What we’ve done at Mayo is adopted a program where we use a drug called sirolimus. This is a mammalian target of rapamycin (mTOR) inhibitor that is a powerful antiproliferative drug and has been shown to inhibit and slow down intimal proliferation, which is one of the hallmarks of the disease process. This drug, some of you may know, is used in the sirolimus-coated stent, which is used in interventional therapy for precisely that reason. One of the major problems with stent therapy for coronary artery disease, was that we see some intimal hyperplasia and stent restenosis. Using sirolimus on the stent prevented that.
So [sirolimus is] a powerful immunosuppressive. It slows down intimal hyperplasia and so retards the process of vasculopathy development. That’s been the main approach we’ve adopted in trying to slow down this process and extend the lives of patients and extend the lifespan of the transplanted donor heart.
Dr Hebl: Are there any other benefits of sirolimus-based immunosuppression?
Dr Kushwaha: Well it’s an interesting drug because it’s in the category of what we call “cell-cycle inhibitors,” and there are really only two commercial drugs available in that category here in the United States. One is sirolimus and the other is everolimus, which is a derivative, actually, of sirolimus.[3] They’re made by two different companies. We’ve tended to stick with sirolimus here because it’s the one that was first available.
There are some other benefits of this medication. Because it’s a cell-cycle inhibitor, it inhibits cellular activity and proliferation at many different levels. As you know, one of the other problems of the posttransplant situation is an increased tendency to cancer because the immune system is suppressed. Again, the immune system’s ability to fight off or deal with aberrant cancer cells that might develop is suppressed. The most common type of cancer we see is a disease process called posttransplant lymphomatous disease, or PTLD for short. That’s basically a B-cell type of lymphoma, which can occur anywhere, and is one of the other causes of long-term mortality following transplant. All solid-organ transplants are at risk of this process. Now it seems that using sirolimus, because of its antiproliferative tendencies, the ability of PTLD-like cells to proliferate is greatly slowed down; and there’s a lot of basic science today to support that, but there’s also emerging clinical data as well.[4] When we’ve looked at rates of PTLD in our program compared with other programs, we see that the rate of PTLD is significantly less. So that’s one major benefit.
There are two other [benefits of sirolimus treatment] that I want to mention. One is the fact that renal disease is greatly attenuated as well. One of the problems following heart transplant is that the use of traditional immunosuppression or calcineurin-inhibitor drugs, such as cyclosporine or tacrolimus, over time cause significant renal damage. When we looked at this data about 10 years ago, before we started using sirolimus in a more widespread fashion, we saw that about 10% of our patient population either were on a renal-transplant waiting list, had undergone renal transplant after heart transplant, or were undergoing dialysis. Most of that renal failure is a result of the toxicity of the medications. Sirolimus doesn’t affect the kidneys in the way calcineurin inhibitors do, so we don’t see that same sort of renal side effect.[5] That’s the huge benefit of the medication because patients’ renal function just tends to stay steady if they tolerate sirolimus.
The other observation we’ve made, which I think is quite interesting, is that left ventricular hypertrophy is diminished after patients have been on sirolimus.[6] Obviously, when you take a transplanted heart, the heart is explanted from the donor; it goes in a cardioplegic solution in ice; and then it’s put into the recipient. In that process, there’s quite a lot of cellular damage that occurs [that] we call reperfusion injury. But on top of that, depending on the mode of death of the donor, there might have been some catecholamine-induced injury, particularly if there’s been traumatic brain injury. So that donor heart has some element of compromise even at the very start of the process.
How does the heart respond to this? Once we’ve gone over some of the acute injury mechanisms, we see that there’s a tendency toward left ventricular hypertrophy. Left ventricular hypertrophy, following heart transplant, results in a certain amount of diastolic dysfunction. So the heart just isn’t quite as efficient as a normal native heart, and many patients report this. We see it when we do exercise testing, that the exercise capacity of most heart-transplant recipients is diminished compared with nontransplant patients even though they may be otherwise fit.[7]
One of the other observations we’ve made over the years is that we see, when we look at left ventricular hypertrophy and left ventricular mass in the transplanted heart, those patients who are on sirolimus, their LV mass goes down after converting to sirolimus from the calcineurin inhibitors. And so we also see indirect measures of diastolic dysfunction improve. So that, I think, is another benefit in terms of long-term quality of life and survivability as well. So we see an improvement in renal function. We see an improvement in left ventricular hypertrophy and, by implication, an improvement in diastolic function parameters as well.
Dr Hebl: You give compelling reasons to get patients on sirolimus after transplant. Is it generally well-tolerated?
Dr Kushwaha: Well, I’d say that it’s tolerated reasonably well by about 70% to 80% of patients. There are some side effects. All these drugs—all these immunosuppressive drugs—have a side-effect profile that is quite impressive, as you know from working in the program. We see side effects from calcineurin inhibitors as well, but the side effects for some patients [taking sirolimus] are particularly bad, and they can’t tolerate it. So, I’d say that there is a small cohort of patients who are truly intolerant, and those side effects mostly are gastrointestinal side effects. Some patients can get mouth ulcers, which are difficult to treat, and [another] major side effect is peripheral edema. We try to work with them. We try to back off when we see these side effects and try reintroduction at a later stage and at a lower dose and see if we can get around them, but there are some patients in our program who really can’t tolerate the drug, and we have to go back to calcineurin inhibitors.
Dr Hebl: Do other solid-organ transplant programs use sirolimus?
Dr Kushwaha: Well, that’s a good question. In fact, when the drug first came out in the late 1990s, it was used for renal transplant and liver transplant. I think there were multicenter studies, but it ended up not being generally favored because the drug wasn’t properly understood. In the renal-transplant studies, which are out there, there was a high rate of breakdown of the wounds because, as I mentioned earlier, it’s an antiproliferative drug.
[Sirolimus] also impairs wound healing. When we talk about side effects, I suppose that’s something to be aware of: If a patient needs a major operation, the wounds don’t heal as well on sirolimus compared with standard immunosuppression.
I’m kind of getting off track here a bit, but if we have a patient who needs, for instance, elective surgery, we will switch that patient back for that period of time—for typically 3 to 4 weeks before the elective surgery. Then, when all the wounds have healed, we’ll convert the patient back [to sirolimus] afterward.
The other interesting aspect, and it’s worth discussing in the context of allograft vasculopathy, is that we do a number of combined organ transplants here, particularly heart and liver. What we noticed some time back is that the combined heart/liver patients don’t seem to develop much vasculopathy. Their IVUS data, when we examine them, shows very little intimal proliferation. So, it seems that the liver has a protective effective. The mechanism, probably, is that it removes circulating antibodies from the circulation. By so doing, it decreases the degree of immune assault on the transplanted heart.
When we looked at those data, comparing standard heart transplant alone with combined heart/liver transplant, we saw that there was almost complete freedom from allograft vasculopathy in the combined heart/liver program.[8] It reinforces the immune etiology of the disease and has given us more understanding that antibody-mediated processes probably affect vasculopathy as well and also, I think, has allowed us to work toward this newer approach of doing combined organ transplant for highly sensitized patients who have very high levels of circulating antibodies in whom we have done that combined operation, but putting the liver in first to try to, if you will, “mop up” the circulating antibodies.
It’s not uncommon for particularly female patients who are being evaluated for heart transplant to have fairly high levels of circulating antibodies, particularly if they’ve had children. So this is an approach where, if the patient has liver disease as well, offers an option to get that patient appropriate organs because we can use the liver as almost like a sponge to remove those circulating antibodies. I hope that was helpful.
Dr Hebl: Yes, these are fascinating insights. Thank you, Dr Kushwaha, and thanks to our listeners for tuning in to Mayo Clinic Talks at theheart.org on Medscape.
Dr Kushwaha: Thank you, Virginia.