New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development

Abstract

Irreversible degeneration of the cardiac conduction system is a common disease that can cause activity intolerance, fainting, and death. While electronic pacemakers provide effective treatment, alternative approaches are needed when long-term indwelling hardware is undesirable. Biological pacemakers are composed of electrically active cells that functionally integrate with the heart. Recent findings on cardiac pacemaker cells (PCs) within the sinoatrial node (SAN), along with developments in stem cell technology, have opened a new era in biological pacing. Recent experiments that have derived PC-like cells from non-PCs have brought the field closer than ever before to biological pacemakers that can faithfully recapitulate SAN activity. This review discusses these approaches in the context of SAN biology and addresses the potential for clinical translation.

Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells

“…We provide an efficient approach to differentiate stem cell-derived pacemaker-type cells that develop in clusters and possess the characteristic properties of nodal-type cardiomyocytes. Different from most previous strategies [ 55 ], our approach is based on human cells and does not require genetic manipulation to achieve pacemaker cell differentiation. Phenotypic features include not only electrical oscillation but also electrophysiological, cellular, and morphological properties of endogenous pacemaker cells.…”

Atrial Fibrillation Associated Genetic Variants and Left Atrial Histology: Evaluation for Molecular Sub‐Phenotypes

“…The rs7164883 SNP is intronic within the HCN4 gene, which encodes the hyperpolarization activated cyclic nucleotide gated potassium channel 4. Within cardiac tissue, HCN4 localizes primarily to the sinoatrial node and is responsible for generating the funny current, I f , critical for pacemaker activity . In addition to the association of this common genetic variant with AF, multiple rare loss‐of‐function mutations in HCN4 have also been identified in patients with AF .…”

Shox2: The Role in Differentiation and Development of Cardiac Conduction System

“…Recent studies on biological pacemakers will probably provide a complete solution to this series of issues in the near future (Kapoor et al 2013;Vatta and Zipes 2013;Hu et al 2014;Saito et al 2015;Protze et al 2017). The biological pacemaker is formed by electroactive cells, not only with the corresponding morphological and electrophysiological characteristics, but also with the dynamic gene expression program of autonomic response and pacemaker cell specificity (Ma et al 2011;Vedantham 2015). Recently, with the maturation of experimental techniques for various pluripotent stem cells (Braam et al 2009;Bernstein and Srivastava 2012;Burridge et al 2012;Priori et al 2013;Karakikes et al 2015;Broughton and Sussman 2016;Atmanli and Domian 2017;Ratajczak et al 2017), the research on induction of stem cells to directionally differentiate into pacemaker cells to form biological pacemakers has shown a breakthrough and thus should promote the CCS regeneration and in vivo transplantation therapies (Davis et al 2011;Bernstein and Srivastava 2012;Xin et al 2013;Broughton and Sussman 2016;Kishore and Khan 2016).…”

“…Many factors can disrupt cardiac rhythms, including myocardial ischemia, prescription drugs, electrolyte disorders, smoking, alcohol, coffee, physical exercise, mental stimulation, ion channel abnormalities, or genetic defects (Kathiresan and Srivastava 2012;Peyronnet et al 2016;Weisbrod et al 2016;Chrysant 2017;Du et al 2017;Goyal et al 2017). Undoubtedly, defects of cardiac pacemaker cells and the corresponding tissues also disrupt cardiac rhythms (Yazawa et al 2011;Vedantham 2015). As for the CCS, many unsolved mysteries regarding the differentiation and development of SAN tissue specifically need to be studied and resolved urgently.…”