Cardiologists at the Cedars-Sinai Heart Institute in Los Angeles, CA report that they have developed a minimally invasive gene transplant procedure that changes unspecialized heart cells into “biological pacemaker” cells that keep the hearts of persons with heart rhythm disorders beating steadily, and potentially eliminate the need for electronic pacemakers in the future.

Results of the Cedars Sinai large animal laboratory study published online and in the latest print edition of the peer-reviewed journal Science Translational Medicine represent the culmination of a dozen years of research with the objective of developing biological treatments for patients with heart rhythm disorders who currently are treated with surgically implanted pacemakers. An estimated 300,000 patients in the United States receive pacemakers every year.

The study, entitled “Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block,” (Sci Transl Med 16 July 2014: Vol. 6, Issue 245, p. 245ra94 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3008681)  is coauthored by Yu-Feng Hu, James Frederick Dawkins, Hee Cheol Cho, Eduardo Marbán, and Eugenio Cingolani, of Cedars-Sinai Heart Institute, Los Angeles, CA. Yu-Feng Hu is also affiliated with the Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital and National Yang-Ming University in Taipei, Taiwan.

“We have been able, for the first time, to create a biological pacemaker using minimally invasive methods and to show that the biological pacemaker supports the demands of daily life,” says Eduardo Marbán, MD, PhD, research team leader and director of the the Cedars-Sinai Heart Institute, in a release. “We also are the first to reprogram a heart cell in a living animal in order to effectively cure a disease.”

The study co-authors note that somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. They tested the hypothesis that this function could be utilized as a viable therapeutic avenue for pacemaker-dependent patients who have device-related complications. In aid of investigating that objective, the researchers say they tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model (specifically, pigs) of complete heart block.

The researchers report that biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2, and the effect persisted for the 14-day duration of the study with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, the TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. They note that induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. It was also encouraging that no local or systemic safety concerns were observed.

In summary, the article’s coauthors conclude that although this was a short-duration study, their determination that minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block constitutes evidence for therapeutic somatic reprogramming in a clinically relevant disease model. They say their laboratory findings could lead to clinical trials for humans who have heart rhythm disorders but who suffer side effects, such as infection of the leads that connect the device to the heart, from implanted mechanical pacemakers.

Eugenio Cingolani, MD, the director of the Heart Institute’s Cardiogenetics-Familial Arrhythmia Clinic who worked with Marbán on biological pacemaker research team, says that in the future, pacemaker cells could also help infants born with congenital heart block.

“Babies still in the womb cannot have a pacemaker, but we hope to work with fetal medicine specialists to create a life-saving catheter-based treatment for infants diagnosed with congenital heart block,” says Dr. Cingolani. “It is possible that one day, we might be able to save lives by replacing hardware with an injection of genes.”

In a companion Science Translational Medicine Perspective article entitled “Improving cardiac rhythm with a biological pacemaker” (Science 18 July 2014 345:268-269) Dr. Nikhil V. Munshi of UT Southwestern Medical Center’s Department of Internal Medicine, Division of Cardiology, and McDermott Center for Human Growth and Development; and Dr. Eric N. Olson of UT Southwestern’s Department of Molecular Biology and Center for Regenerative Science and Medicine, both located in Dallas, note that electronic device therapies, including implantable pacemakers and defibrillators, have revolutionized the management of cardiovascular disease. For example, they observe that patients with certain slow cardiac rhythms (bradycardia) can experience exercise intolerance, easy fatigability, or circulatory collapse.

And given that currently available drugs are unable to safely and sustainably elevate heart rate, the only proven treatment for symptomatic bradycardia is permanent pacemaker implantation, a technology that continues to evolve and improve. For example, the authors point to extended battery life with the latest electronic pacemakers, which contain leads that minimize inflammation and scarring, as well as featuring advanced variable algorithms to accommodate and contend with heart rate elevations during exercise.

Drs. Munshi and Olson observe that these cutting-edge feature sets help today’s electronic pacemakers to improve longevity and quality of life in patients who require them, but that these devices simply can’t recapitulate all aspects of the endogenous sinoatrial node, the dominant pacemaker in the uninjured heart.

In this regard, they point to the biological pacemaker/pigs study by Hu et al. that demonstrates the feasibility of a somatic cell reprogramming strategy for creating a biological pacemaker in a large animal preclinical model, raising prospects for clinical translation.

“This work by Dr. Marbán and his team heralds a new era of gene therapy, in which genes are used not only to correct a deficiency disorder, but to actually turn one kind of cell into another type,” comments Shlomo Melmed, dean of the Cedars-Sinai faculty and the Helene A. and Philip E. Hixson Distinguished Chair in Investigative Medicine.

In the study, laboratory pigs with complete heart block were injected with the TBX18 gene during a minimally invasive catheter procedure. On the second day after the gene was delivered to the animals’ hearts, pigs who received the gene had significantly faster heartbeats than pigs who did not receive the gene. The stronger heartbeat persisted for the duration of the 14-day study.

“Originally, we thought that biological pacemaker cells could be a temporary bridge therapy for patients who had an infection in the implanted pacemaker area,” says Dr. Marbán. “These results show us that with more research, we might be able to develop a long-lasting biological treatment for patients.”

Dr. Marbán projects that if future research is successful, the procedure could be ready for human clinical studies in about three years.

Eduardo Marbán, MD, PhD, a native of Cuba who came to the United States with his parents at the age of six as a political refugee, is now an international leader in cardiology and a pioneering heart researcher. Dr. Marbán’s 25-plus years of experience in patient care and research into heart disease have led to key discoveries in gene and stem cell therapies and new drug treatments for heart attacks, heart failure and strokes.

Dr. Marbán became founding director of the Cedars-Sinai Heart Institute in 2007. This multidisciplinary facility brings together adult and paediatric cardiologists, cardiac surgeons, imaging specialists and researchers to foster discovery and enhance patient care. The institute is built on Cedars-Sinai’s a long tradition of excellence and innovation, including invention of the Swan-Ganz catheter and development of a laser system to vaporize blockages in blood vessels affected by coronary artery disease. The Cedars-Sinai Heart Institute is ranked as the #1 cardiology and heart surgery program west of the Mississippi, and among the nation’s top ten, by US News & World Report. Dr. Marbán also directs Cedars-Sinai’s Board of Governors Heart Stem Cell Center, which is focused on cardiac regeneration.

Dr. Eugenio Cingolani, MD, is Director of the Cardiogenetics-Familial Arrhythmia Clinic at Clinical Cardiac Electrophysiology Section of the Cedars-Sinai Heart Institute. HIs lab’s’s research and clinical practice focus on heart rhythm disorders and electrophysiology. Dr. Cingolani’s clinical interests are focused on familial arrhythmia syndromes (such as Brugada syndrome, Long QT syndrome, ARVD, idiopathic ventricular fibrillation), pacemaker and ICD implantation and catheter ablation for cardiac arrhythmias. He has been involved in multiple research projects, investigating basic mechanism of arrhythmias and developing novel therapies for heart rhythm disorders.

Sources:
Cedars-Sinai Heart Institute
UT Southwestern Medical Center
Science Translational Medicine

Image Credits:
Cedars-Sinai Heart Institute
UT Southwestern Medical Center