Pioneering developments in cardiac transplant and LVAD therapy continue at Mayo Clinic

Mayo Clinic in Rochester, Minn., has an extremely active cardiac transplant and left ventricular assist device (LVAD) program, managing a wide variety of end-stage heart disease conditions. The heart transplant team has pioneered many innovative approaches to this complex group of patients. Since the program's inception, more than 500 patients have undergone cardiac transplantation at Mayo Clinic in Minnesota.

New approaches to immunosuppression

Traditional immunosuppressive therapy typically consists of a calcineurin inhibitor (CNI), azathioprine or mycophenolate, and steroids. Although this is an excellent combination for preventing rejection, it does not prevent the long-term complications that occur following heart transplantation, notably the development of cardiac allograft vasculopathy (CAV) and renal dysfunction, which often results in renal failure many years after transplant. The renal dysfunction is a known complication of CNIs and results in a progressive decline over the course of a few years. In some patients, the decline can be very dramatic and can even occur in the first year after transplant.

CAV is a progressive coronary disease that affects all the coronary vessels of the transplanted heart and remains the major cause of long-term mortality following transplant. The disease is a proliferative process characterized by smooth muscle hypertrophy and intimal proliferation. By 10 to 15 years after transplant, the majority of patients have CAV, for which there is no highly effective treatment. Although percutaneous coronary intervention (PCI) is sometimes performed, it has limited long-term benefit because the disease is generalized.

"Several years ago, our program pioneered the use of sirolimus-based immunosuppression in our heart transplant population," says Sudhir S. Kushwaha, M.D., a transplant cardiologist at Mayo Clinic in Minnesota. In place of a CNI (cyclosporine or tacrolimus), physicians treated transplant patients with sirolimus. This drug is a powerful immunosuppressive, but it also has the additional quality of being an anti-proliferative agent, thereby mitigating some of the adverse effects seen and improving survival. With sirolimus treatment, renal function improved significantly in all patients. Similarly, the progression of CAV in this patient population has declined and, in a few dramatic cases, has reversed.

Transplantation for amyloid cardiomyopathy

Amyloidosis is an infiltrative disease that can affect the heart and eventually lead to a restrictive cardiomyopathy.

AL (amyloid light chain) amyloidosis is a plasma cell disorder, and severe cardiac involvement carries a poor prognosis, despite advances in chemotherapy. To treat the restrictive cardiomyopathy, cardiac transplantation is performed; this procedure must be followed by bone marrow transplantation to treat the plasma cell abnormality causing the generation of the amyloid protein. Patients receive standard chemotherapy treatment while awaiting transplant.

TTR (transthyretin or familial) amyloidosis is caused by generation of amyloid protein from the liver; patients who go on to transplant require liver as well as heart transplantation to stop the production of amyloid protein.

Because of the very large amyloidosis practice at Mayo Clinic in Minnesota, many patients with advanced heart failure due to restrictive cardiomyopathy caused by both types of amyloidosis are seen. During the last 20 years, Mayo Clinic in Minnesota has the largest experience in the United States in combined transplantation for treatment of amyloidosis, both with heart transplant followed by bone marrow transplant for AL amyloidosis and combined heart and liver transplant for TTR amyloidosis.

Nevertheless, treatment of patients with AL amyloidosis is challenging, as they have limited long-term survival compared with nonamyloidosis patients who undergo cardiac transplantation. Thus, this procedure may be helpful in improving short-term survival, and in selected patients it may be a life-prolonging therapy.

Combined organ transplantation

The program at Mayo Clinic in Minnesota also performs combined organ transplants for indications other than amyloidosis. Patients with coexisting renal failure may be listed for combined heart and kidney transplants. Combined heart-lung transplants are performed in patients with pulmonary hypertension and severe right heart failure, and in those with complex congenital heart disease in whom pulmonary hypertension has developed.

The problem of preformed antibodies: Thinking outside the box

Many patients awaiting organ transplants may have preformed antibodies to specific antigens, and this may greatly narrow the donor pool for those patients. If a donor becomes available but expresses certain antigens to which the potential recipient has high levels of antibodies, proceeding with the transplant will result in antibody-mediated, or humoral, rejection.

This can sometimes result in a situation in which certain patients with very high levels of antibodies can become practically untransplantable because of the number of antibodies with high titers. The waiting period for these patients can become even longer than usual because finding an appropriate donor can be very difficult.

Various strategies have been tried to reduce levels of antibodies in these patients, but such desensitization protocols have been met with very limited success and do not appear to be a durable long-term solution.

First-ever liver-heart transplant

A 51-year-old woman came to the Mayo Clinic transplant program with a complex medical history of isolated right heart failure with secondary hepatic cirrhosis. She needed both heart and liver transplantation. A right ventricular assist device (RVAD) was placed as a temporizing measure but was not successful. She had multiple preformed antibodies, making it unlikely that an acceptable donor would be identified in a timely fashion.

Based on the observation that significant cardiac rejection has not occurred in any patient who has undergone a combined heart-liver transplant, she received a liver transplant first, followed by the heart transplant. It was hypothesized that the reversed transplant sequence would allow removal of preformed antibodies from the circulation. Presently, she is doing very well without a single episode of rejection more than two years after transplant.

"Interestingly, combined heart and liver transplantation appears to have a much better survival rate compared to heart transplant alone," according to Richard C. Daly, M.D., a cardiac transplant surgeon at Mayo Clinic in Minnesota. There are several potential reasons for this observation, including the fact that use of both organs from the same donor appears to provide some immunological protection for the transplanted heart.

LVAD program

Currently, LVADs are used in two situations: as a bridge to transplant or as destination therapy. The LVAD is used to keep the bridge-to-transplant patient alive until transplantation can occur; these patients are usually younger and must be transplant candidates. LVAD therapy allows many patients to resume an almost-normal lifestyle until the time of transplant. Presently, about half the patients waiting for transplant at Mayo Clinic in Rochester are supported by an LVAD.

Destination therapy patients tend to be older and are not transplant candidates. Therapy is used to treat the heart failure, with no plans for transplantation in the future. Usually, because of age and comorbidities, these patients may be frailer and severely weakened by their heart failure before LVAD implant and thus may have a longer hospital stay, with a more prolonged period of rehabilitation before they are discharged from the hospital. After rehabilitation, many of these patients are restored to an excellent quality of life with improved mortality.

LVAD therapy for restrictive cardiomyopathy

In restrictive cardiomyopathy, the heart is small, with thick walls and a small ventricular cavity. "LVAD therapy generally has not been used in these patients because the size of the ventricular cavity is not large enough to accommodate the inflow cannula of the LVAD," according to Soon J. Park, M.D., a cardiac transplant surgeon at Mayo Clinic in Minnesota. "While generally true, a small number of patients at Mayo Clinic in Minnesota have received LVADs as destination therapy and had reasonable success in situations where few other options were available."

Bridge to transplant

A 55-year-old man initially presented with severe heart failure due to restrictive cardiomyopathy secondary to senile TTR amyloidosis, and he was listed for cardiac transplant. Over the next two years, he had worsening of his cardiac and renal function, and he eventually underwent LVAD implantation. Nevertheless, his renal function continued to deteriorate, and he was listed for renal transplant in addition to cardiac transplant. After three years of bridge-to-transplant LVAD therapy, organs became available, and he underwent a combined heart and kidney transplant. He is now doing well and enjoying life to the fullest.

Summary

The cardiac transplant and cardiac assist device program at Mayo Clinic has been at the forefront in the treatment of end-stage cardiac disease. The program has distinguished itself by its ability to take on challenging cases that would not be considered elsewhere.

The transplant program has pioneered the use of innovative immunosuppressive strategies, which have improved patient survival and comorbidities, and become a world leader in the use of combined organ transplant for difficult conditions such as cardiac amyloidosis.

The LVAD program has challenged the accepted paradigms of use of this therapy for dilated cardiomyopathy, and demonstrated the feasibility of and good outcomes for the use of LVADs in restrictive heart disease.