Implementing Biological Pacemakers: Design Criteria for Successful Transition from Concept to Clinic

• Type of Material: Article
• Authors: Elizabeth R. Komosa, University of Minnesota Twin Cities; David W. Wolfson, Georgia Institute of Technology; Michael Bressan, University of North Carolina; Hee Cho, Emory University; Brenda M. Ogle, University of Minnesota Twin Cities
• Language: English
• Date: 2021-10-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCEP.121.009957
• Title of Journal or Parent Work: CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY
• Volume: 14
• Issue: 10
• Start Page: e009957
• End Page: e009957
• Grant/Funding Information: This work was supported by the NIH T32GM008347 (E.R.K), R01HL137204 (E.R.K. and B.M.O.), F31HL149272-01A1 (D.W.W.), R01HL143065 (H.C.C.), R01HL111646 (H.C.C.), R01HL146626 (M.B.), R01HL157363 (H.C.C.), and the American Heart Association CDA34760248 (M.B.) and 20TPA35260085 (H.C.C.).
• Keywords: CONDUCTION SYSTEM; RYANODINE RECEPTOR; ACTION-POTENTIALS; Life Sciences & Biomedicine; heart rate; cell differentiation; sinoatrial node; Cardiovascular System & Cardiology; 2ND HEART; pacemaker; SICK-SINUS SYNDROME; CARDIAC TISSUE; IMPULSE PROPAGATION; SINOATRIAL NODE CELLS; GENE-TRANSFER; cellular reprogramming; stem cell niche; Cardiac & Cardiovascular Systems; PLURIPOTENT STEM-CELLS; artificial; Science & Technology

Abstract

Each heartbeat that pumps blood throughout the body is initiated by an electrical impulse generated in the sinoatrial node (SAN). However, a number of disease conditions can hamper the ability of the SAN's pacemaker cells to generate consistent action potentials and maintain an orderly conduction path, leading to arrhythmias. For symptomatic patients, current treatments rely on implantation of an electronic pacing device. However, complications inherent to the indwelling hardware give pause to categorical use of device therapy for a subset of populations, including pediatric patients or those with temporary pacing needs. Cellular-based biological pacemakers, derived in vitro or in situ, could function as a therapeutic alternative to current electronic pacemakers. Understanding how biological pacemakers measure up to the SAN would facilitate defining and demonstrating its advantages over current treatments. In this review, we discuss recent approaches to creating biological pacemakers and delineate design criteria to guide future progress based on insights from basic biology of the SAN. We emphasize the need for long-term efficacy in vivo via maintenance of relevant proteins, source-sink balance, a niche reflective of the native SAN microenvironment, and chronotropic competence. With a focus on such criteria, combined with delivery methods tailored for disease indications, clinical implementation will be attainable.