Rapamycin Slows Heart Transplant Vasculopathy
Treatment with the immune suppressant drug rapamycin appears to slow heart transplant vasculopathy, said researchers from the Columbia University College of Physicians and Surgeons, New York, NY, in a report in this week’s issue of the journal Circulation (Circulation. 2003;108:48–53).
The researchers, led by Donna M. Mancini, MD, noted that cardiac transplant vasculopathy is the most common cause of death in patients who have had a heart transplantation and survived possible complications in the immediate posttransplantation period. Because the vasculopathy is considered a proliferative disease, the scientists wanted to determine if the antiproliferative and antimigratory effects of rapamycin would prevent or delay the progression of the disease.
During their annual cardiac catheterizations, 46 patients were randomized to receive treatment with rapamycin (22 patients) versus continued immunosuppression (24 patients). Patients on rapamycin were monitored for an average of 689 days and control patients for 630. Three patients in the rapamycin group reached a final end point. That means that they died, needed a vascularization procedure such as angioplasty or coronary artery bypass grafting, suffered a heart attack, or had a greater than 25% worsening of catheterization score. By contrast, 14 patients in the usual immunosuppression group reached an end point. These results convinced the researchers that rapamycin did indeed slow the progression to proliferative disease in the coronary arteries of this special class of patients.
In an accompanying editorial (Circulation. 2003;108:6–8), Elazer R. Edelman, MD, PhD, of the Harvard-MIT Division of Health Sciences and Technology at the Massachusetts Institute of Technology, and Haim D. Danenberg, MD, of the Cardiovascular Division of The Brigham and Women’s Hospital and Harvard Medical School, noted: “What is unique about the Mancini et al report is that the effect of rapamycin was seemingly independent of its immunosuppression. . . . To the best of our knowledge, this is the first human study to demonstrate efficacy of pharmacological regulation in patients with existing advanced cardiac transplant vasculopathy.”
COMET Proves Value of Carvedilol
Carvedilol won in the first head-to-head comparison of the effects of carvedilol with those of metoprolol on patients with heart failure. The Carvedilol or Metoprolol European Trial (COMET) results were reported at the European Society of Cardiology’s 2003 Heart Failure Meeting in Strasbourg, France, June 21 through 24, 2003, and demonstrated that subjects receiving carvedilol had a significantly better survival rate than those receiving metoprolol.
COMET was a double-blind, randomized parallel study group that enrolled 3029 patients with grades of heart failure varying from mild to severe. Patients were monitored on average for more than 45 months.
In a released statement, Dr John Cleland, who is from the University of Hull in the United Kingdom and a member of the COMET Steering Committee, said, “This is a major European trial which will help doctors deliver improved care for their patients. It is the first time two agents for heart failure have been compared, head to head, in a large outcome study. And the results show a substantial difference between the two. For less than one euro per day, carvedilol increased life expectancy by almost 1.5 years—an effect greater than that of coronary artery bypass surgery for three-vessel coronary disease.”
Speaking for the European Society of Cardiology, Dr Helmut Drexler of the Medizinische Hochschule, Hannover, Germany, said, “Whilst the COMET results are clearly of major importance, there is expert opinion that the dosing of the two β-blockers may not have been completely equal. Matched dosing is crucial for appropriate interpretation of the results. It is probably fair to say that carvedilol is superior to metoprolol, but the mortality difference demonstrated by COMET does appear a little too great (17% lower in carvedilol) to be certain of confidence in these results.”
Molecular Mutation May Cause Exercise-Induced Heart Disease
A microscopic leaky channel within the cell could be at fault in young and healthy individuals whose hearts begin to beat out of sync and then suddenly stop, said researchers from Columbia University College of Physicians Surgeons, New York, NY, in a report in the June 27, 2003, issue of the journal Cell (Cell. 2003;113:829–840).
Fatal arrhythmias can occur in normal hearts in which cells become overexcited and accumulate too much calcium inside them. A protein called ryanodine receptor (RyR2) acts as a channel to release calcium inside of heart muscle cells. Another protein called FKB12.6 binds to RyR2, said Andrew R. Marks, MD, who was one of the scientists who found that protein. When FKB12.6 binds to RyR2, it prevents the release of too much calcium into the cell. When FKBP12.6 is knocked out in mice, they die suddenly after exercise because of lethal arrhythmia. Some humans who suffer from exercise-induced arrhythmias also have a mutation in FKBP12.6.
“Although our study examined channel mutations from patients with a rare form of inherited exercise-induced sudden cardiac death, the defect we found in the calcium channel, the ‘leak,’ is the same defect that occurs in patients with heart failure,” Dr Marks said in a released study. “This discovery is very exciting because it opens up the possibility of an entirely new form of therapy for cardiac arrhythmias, namely fixing the leak in the calcium channel.”