A therapy currently under development for spinal cord injuries stimulates nerve regeneration in the heart and provides resistance to arrhythmias following a heart attack, according to a new study published today in the journal Nature Communications by researchers at Oregon Health & Science University (OHSU), Case Western Reserve University and UC Davis.
Millions of people have heart attacks each year, and those who survive have increased risks of arrhythmias — or abnormal heart rhythms — and sudden cardiac death. Recent clinical trials showed that the severity of nerve degeneration in the heart caused by heart attack predicts increased arrhythmia susceptibility. Surgical implantation of a cardioverter defibrillator (ICD), a device that tracks and restores heart rate, is one of the only effective therapies for treating arrhythmias following a heart attack.
“Our study initially sought a therapy that would stimulate nerve regeneration after a heart attack. It was a surprising and thrilling discovery that not only could this regeneration be achieved through both genetic and pharmaceutical approaches, but that it also decreases the heart’s susceptibility to arrhythmias,” said Beth Habecker, senior author and professor of physiology and pharmacology in the OHSU School of Medicine. “We are excited to use these findings to pursue the development of therapeutics for post-heart attack care.”
Habecker led a team of researchers in determining why nerves were excluded from cardiac scars after a heart attack. OHSU graduate student Ryan Gardner found that factors preventing nerve regrowth after a spinal cord injury were also present in the heart and that by blocking their actions in mice, via genetic knockout or pharmaceutical therapy, nerve regeneration occurred and arrhythmia susceptibility decreased. The therapy that proved successful was a chemical compound known as intracellular sigma peptide, which was developed for traumatic spinal cord injury by Jerry Silver and colleagues at Case Western Reserve University.
Crystal Ripplinger and Lianguo Wang of UC Davis used high-speed optical imaging of whole mouse hearts in action to assess the effects of nerve regeneration on electrical activity, calcium handling and arrhythmia susceptibility. This technique, available at just a handful of labs in the U.S., allowed the investigators to precisely visualize the cellular events that triggered lethal rhythms and was key to understanding why nerve regeneration prevented arrhythmia.
"Arrhythmia is one of the most unpredictable and life-threatening outcomes of a heart attack," said Ripplinger, assistant professor of pharmacology at the UC Davis School of Medicine. "Until now, we had always assumed that arrhythmias were mainly due to damage and death of heart cells. Our study is the first to suggest that treatments targeting nerve regeneration can normalize electrical activity and prevent arrhythmias in heart attack survivors. This finding opens the door to an entirely new avenue of anti-arrhythmic therapy."
Habecker and Ripplinger hope their research will be applied to future studies in humans and may one day lead to an alternative treatment to ICD therapy.
Additional authors of the study, titled "Targeting Protein Tyrosine Phosphatase After Myocardial Infarction Restores Cardiac Sympathetic Innervation and Prevents Arrhythmias,” were Jared Cregg and Bradley Lang of Case Western Reserve University, and Cassandra Dunbar and Bill Woodward of OHSU.
This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers HL093056, HL068231 and HL111600; the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number NS25713; the American Heart Association under award number 12SDG9010015; and an Oregon Brain Institute Neurobiology of Disease Fellowship.
More information about OHSU is at http://www.ohsu.edu.
More information about Case Western Reserve University is at http://www.case.edu.
More information about the UC Davis School of Medicine is at http://medschool.ucdavis.edu.