Autoantibodies Point to Precision Approach in Systolic Heart Failure

For many years, autoantibodies have been implicated in idiopathic dilated cardiomyopathy (DCM). Although autoantibodies that act against the adrenaline system (especially against the beta-1-adrenergic receptor, or β1Ar-AAbs) have been most often studied, the mechanisms behind their role in DCM continue to be poorly understood. Now, recent research led by Cleveland Clinic heart failure and cardiac transplantation cardiologist W.H. Wilson Tang, MD, has identified in about one-fifth of DCM patients a subtype of these β1Ar-AAbs that appears to be linked to a positive response to beta-blocker therapy.

The finding could lead to more-tailored treatments and might even allow for prophylaxis to prevent heart failure in at-risk individuals. “More than half of all heart failure is idiopathic, an enigma,” says Dr. Tang, a clinician-scientist who also heads the Center for Clinical Genomics that spearheads precision medicine initiatives at Cleveland Clinic. “When the heart fails, we give everyone the same six or seven types of medicine, but some people may not respond. It’s not one-size-fits-all.”

Insights from IMAC-2

The new data come from analysis of samples collected from a prospective multicenter study known as Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC-2).The trial is an investigation of myocardial recovery in 353 patients with recent-onset nonischemic DCM who were receiving contemporary therapies, including beta-blockers in 82 percent of patients. Cleveland Clinic is a major contributor to this study, which is led by Randall Starling, MD, MPH, who is also co-author of the current analysis, published in the Journal of American College of Cardiology earlier this year.

For the current analysis, Dr. Tang and colleagues tested the patients’ blood samples specifically for immunoglobulin G subclass 3 (IgG3) β1Ar-AAbs, since prior research had found that elimination of IgG3 autoantibodies by immunoadsorption appeared to be associated with better recovery in DCM.

The 353 patients broke down as follows:

• 18 percent were positive for IgG3-β1Ar-AAbs (IgG3 group)
• 16 percent were positive for β1Ar-AAbs but not IgG3 (non-IgG3 group)
• 66 percent were negative for β1Ar-AAbs

Between patients positive versus negative for β1Ar-AAbs, there were no significant differences at baseline in heart rate, systolic blood pressure or left ventricular ejection fraction (LVEF), and likewise no difference in LVEF change at six months. However, baseline LV end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other two groups (P ≤ .03).

At six months, however, the IgG3 group had significantly higher LVEF than did the other two groups (P = .007), and the presence of IgG3-β1Ar-AAbs independently predicted LVEF (P = .01).

Moreover, among patients with New York Heart Association class III or IV disease, the IgG3 group had a lower incidence of the composite end point of all-cause death, cardiac transplantation or hospitalization due to heart failure, while the non-IgG3 group had the highest incidence of the combined end point (P = .03).

Implications and next steps

The findings imply that β1Ar-AAb IgG subclasses may play differential roles in the pathophysiology of cardiomyopathies, the researchers concluded. While the presence of IgG3 subclass antibodies appears to be associated with greater myocardial injury and remodeling at baseline, they noted, beta-blockers may be particularly effective in countering those antibodies’ pathogenic effects, since more than 8 in 10 patients were taking beta-blockers and since the IgG3 group had superior clinical outcomes among patients with severe heart failure.

“We think there’s an interaction between the autoantibody and the drug response, but we don’t actually know what it is,” says Dr. Tang. To that end, he is now collaborating with his colleague in Cleveland Clinic’s Lerner Research Institute, Sathyamangla Prasad, PhD, to elucidate potential mechanisms.

“If we figure out the mechanism, we can try to develop beta-blockers to utilize this mechanism for stronger responses to generate recovery of myocardial function,” Dr. Tang explains.

The promise of precision medicine

He also speculates that in the future certain patients could be identified — such as those with a family history of DCM or known autoimmune disease — to be screened for biomarkers like IgG3-β1Ar-AAbs that can identify a precise mechanism of injury or disease process. For example, if patients test positive, they might be offered beta-blockers prophylactically to prevent DCM.

Dr. Tang cautions that this is still a hypothesis that needs to be rigorously tested. “Still, the ability to identify the right patient at the right time with the right drug is the promise of precision medicine,” he remarks. “Our goal is to get more people with heart failure to respond to drugs that can improve their health and well-being.”

An additional perspective

In an editorial accompanying Dr. Tang’s study in the Journal of the American College of Cardiology, Cedars-Sinai Heart Institute cardiologist Jignesh Patel, MD, PhD, underscored the significance of this research — and the questions still ahead.

“The presence of autoantibodies to the β1AR in DCM lends credence to the potential role of the immune system and failure of self-tolerance in the development of the disease,” wrote Dr. Patel. He then added that it’s nevertheless “noteworthy that only a minority of patients in this study demonstrated β1AR antibodies,” pointing out that this has been a consistent finding in the literature.

He concluded: “The authors are nonetheless to be commended for their continuing efforts to dive deeper into the dark and mysterious waters of the immune system to elucidate its role in the development of DCM.”

The work reported here is supported in part by grant funding from the Myocarditis Foundation, the National Institutes of Health and the Cleveland Clinic Research Programs Committee.