ORLANDO — Physicians on the lookout for badly needed new treatments for heart failure continue to have high hopes for immunoregulatory therapies, even after anti-tumor necrosis factor biologics were ineffective in large randomized trials.
Researchers now think they understand why anti-TNF therapy failed, and are now focusing on developing more nonspecific, broad-spectrum anti-inflammatory/immunologic strategies. Among the approaches showing early clinical promise are plasmapheresis, intravenous immunoglobulin infusions, nonpharmacologic immune modulation therapy aimed at harnessing cell apoptosis to decrease chronic inflammation, extracorporeal immunoabsorption of cardiac autoantibodies, and statin therapy.
“We're perhaps on to something here with immune modulation and heart failure. We have to define the patient population for whom this will be most beneficial, but we seem to be inching ever so slowly toward that conclusion,” Kenneth L. Baughman, M.D., said at a symposium on novel therapies for heart failure held during the annual meeting of the American College of Cardiology. But immunologic therapies aren't the only favorable prospect on the horizon for heart failure.
Speakers also described a novel drug class—the vasopressin antagonists—that shows considerable promise, as does erythropoietin for correction of the anemia that frequently accompanies heart failure.
Many observers were surprised when etanercept (Enbrel) failed to improve symptoms or survival in major clinical trials totaling roughly 1,500 heart failure patients. In hindsight, the drawback of anti-TNF therapy for heart failure may have been its very specificity. Solid evidence indicates that all elements of the inflammatory cascade are involved in the progression of heart failure, including not only proinflammatory cytokines such as TNF, but also activated B and T cells, antimyocardial antibodies, peripheral monocytes, and the complement system.
“Elimination of the biologic activity of one proinflammatory cytokine alone may not be enough,” observed Guillermo Torre-Amione, M.D., Ph.D., medical director of the cardiac transplant service at the Methodist DeBakey Heart Center, Houston.
Dr. Baughman said broadly immunosuppressive agents such as prednisone and azathioprine have demonstrated good efficacy in several recent placebo-controlled trials in patients with cardiomyopathy of at least 6 months' duration. Responders had no viral presence on pretreatment myocardial biopsies but did have antibodies directed against the heart.
“This indicates viral persistence is a bad thing and having antibodies or being in a state of immune activation is a good thing if you're treating with immunosuppressives,” said Dr. Baughman, professor of medicine at Harvard Medical School and director of the advanced heart disease section at Brigham and Women's Hospital, Boston.
Dr. Torre-Amione noted that although nonspecific immunoregulatory therapies such as plasmapheresis and immunoabsorption are unfamiliar to cardiologists, these therapies are scoring successes in other fields, particularly for autoimmune and neuroinflammatory diseases. He and Dr. Baughman provided an update on the current status of these novel therapies in heart failure.
Plasmapheresis
This involves removal of the patient's plasma from withdrawn blood, followed by retransfusion of the formed elements. The regimen typically involves five to seven cycles of plasmapheresis, with or without intravenous immunoglobulin (IVIG) infusions to enhance the anti-inflammatory effect. The mechanism of action remains unclear.
“No one really knows how plasmapheresis works. The more I look, the less I understand,” Dr. Torre-Amione said. “But clearly there are benefits of this technology in a variety of noncardiac conditions.”
“When there's unexplained left ventricular dysfunction in the absence of cellular rejection or coronary artery disease, we and others have used nonspecific forms of enhancing immunosuppression—among them, plasma exchange—that have led to remarkable results, including sustained and remarkable improvement in ejection fraction. There is significant experience in that setting. It follows logically that this ought to be tested in heart failure, especially if you have the bias that inflammation contributes to the progression of heart failure,” Dr. Torre-Amione said.
Building on a favorable experience in two patients, Dr. Torre-Amione is in the midst of a formal prospective study of plasmapheresis followed by IVIG in 20 patients with dilated cardiomyopathy and sustained left ventricular dysfunction of more than 6 months' duration. The primary end point will be change in left ventricular ejection fraction at 6 months.
In one European study involving patients with chronic ischemic or nonischemic cardiomyopathy, IVIG infusions resulted in an increase in ejection fraction from 26% to 31%.
The rationale for its use in dilated cardiomyopathy is that IVIG may neutralize harmful circulating antigens and antibodies, block complement, and down-regulate proinflammatory cytokines. It also binds to the Fc receptor on IgI, according to Dr. Baughman.
Extracorporeal Immunoabsorption of Cardiac Autoantibodies
The German investigators who pioneered this therapy have presented several studies showing improvement or stabilization of heart function in treated patients with nonischemic dilated cardiomyopathy. For example, in one trial that targeted beta-1 antimyocardial antibodies, 5 days of immunoabsorption resulted in a marked improvement in ejection fraction that was sustained at 12 months.