Nora Eccles Harrison Cardiovascular Research & Training Institute

Channel Biology and Electrophysiology

Publications

Auxiliary Trafficking Subunit GJA1-20k Protects Connexin43 from Degradation and Limits Ventricular Arrhythmias.

                    This study introduces how a protein formed by internal translation of Connexin43 mRNA is essential for the gap junction based electrical communication of each                      heartbeat. Without it, arrhythmias and sudden death occur. The study introduces how cardiac ion channels can generate their own trafficking subunits.                     https://www.jci.org/articles/view/134682

                       Xiao S, Shimura D, Baum R, Hernandez DM, Agvanian S, Nagaoka Y, Katsumata M, Lampe PD, Kleber AG, Hong T, Shaw RM. Auxiliary Trafficking Subunit GJA1-20k Protects                       Connexin43 from Degradation and Limits Ventricular Arrhythmias. JCI, 2020; 130(9):4858-4870.

Cardiac BIN1 Folds T-tubule Membrane, Controlling Ion Flux and Limiting Arrhythmia. 

                    This study introduces a new concept how heart muscle is organized and identifies a new cardiac protein (cardiac BIN1 or cBIN1) which is responsible for the                     microarchitecture of heart muscle cells allowing channels such as the L-type calcium channel to localize to its correct subdomain.                     https://www.nature.com/articles/nm.3543

                      Hong T, Yang H, Zhang S, Cho HC, Kalashnikova M, Sun B, Zhang H, Bhargava A, Grabe M, Olgin J, Gorelik J, Marbán E, Jan LY, Shaw RM. Cardiac BIN1 folds T-tubule membrane,                       controlling ion flux and limiting arrhythmia. Nature Medicine, 2014; 20:624-32.

Direct Comparison of a Novel Antitachycardia Pacing Algorithm Against Present Methods Using Virtual Patient Modeling. 

                    Anti-tachycardia pacing is routinely used to terminate ventricular arrhythmias but its success can be limited. In this joint project with Medtronic and the Scientific                     Computing Institute at University of Utah, the team tested a new adaptive algorithm for ATP in computational models based on patient specific scar and arrhythmia                     data showing a higher success rate.https://www.heartrhythmjournal.com/article/S1547-5271(20)30430-6/fulltext 

                      Swenson DJ, Taepke RT, Blauer JJE, Kwan E, Ghafoori E, Plank G, Vigmond E, MacLeod RS, DeGroot P, Ranjan R. Direct comparison of a novel antitachycardia pacing                       algorithm against present methods using virtual patient modeling. Heart Rhythm, 2020; 17(9):1602-1608. 

Electrophysiological Modeling of Fibroblasts and Their Interaction with Myocytes. 

                    In this study, we developed a mathematical model of fibroblast electrophysiology based on data from whole-cell patch clamp and polymerase chain reaction                     studies. We studied electrical bridging between ventricular myocytes via fibroblast insets for various coupling resistors. The simulations support the hypothesis that                     coupling of fibroblasts to myocytes modulates electrophysiology of cardiac cells and tissues.https://link.springer.com/article/10.1007%2Fs10439-007-9405-8

                    Sachse FB, Moreno AP, Abildskov JA. Electrophysiological modeling of fibroblasts and their interaction with myocytes. Ann Biomed Eng, 2008; 36(1):41-56.  

Endocardial Activation Drives Activation Patterns During Long-Duration Ventricular Fibrillation and Defibrillation. 

                    In this study, transmural and endocardial cardiac mapping techniques were used to demonstrate that the endocardium and Purkinje fiber system plays a                     critical role in driving the rapid activation rate during ventricular fibrillation. https://www.ahajournals.org/doi/full/10.1161/CIRCEP.117.005562

                      Panitchob N, Li L, Huang J, Ranjan R, Ideker RE, Dosdall DJ. Endocardial Activation Drives Activation Patterns During Long-Duration Ventricular Fibrillation and                       Defibrillation. Circ Arrhythm Electrophysiol, 2017; 10(12). 

GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs. 

                    This study introduces how the actin cytoskeleton works with subunits of an ion channel (Connexin43) to arrange trafficking pathways for delivery of the full                     length channel. This pathway is disrupted in cardiac disease such as cardiac ischemia. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.311955

                      Basheer WA, Xiao S, Epifantseva I, Fu Y, Kleber AG, Hong TT, Shaw RM. GJA1-20k arranges actin to guide Cx43 delivery to cardiac intercalated discs. Circ Res, 2017;                       121:1069-1080. 

His Bundle Pacing Shows Similar Ventricular Electrical Activation as Sinus; Selective and Non-Selective His Pacing Indistinguishable. 

                    Traditional pacing locations with a single lead in the right ventricle may lead to ventricular dyssynchrony and the development of heart failure. In this                     study, 256 epicardial and endocardial electrodes were used to compare the activation sequence of pacing in the right ventricle, biventricular pacing, and                     selective and non-selective His bundle pacing. The activation sequence of both selective and non-selective His bundle pacing was indistinguishable from                     normal sinus rhythm, while biventricular and RV pacing had slower and more dyssynchronous ventricular activation sequences. Mechanical dysfunction is                     less likely to develop from His bundle pacing as compared to other clinically relevant pacing                     locations. https://journals.physiology.org/doi/abs/10.1152/ajpheart.00292.2020?af=R&

                      Hirahara AM, Lange M, Shah A, Khan MS, Ranjan R, Stoddard G, Dosdall DJ.His Bundle Pacing Shows Similar Ventricular Electrical Activation as Sinus; Selective and Non-Selective                       His Pacing Indistinguishable. Am J Physiol Heart Circ Physiol, 2020; doi:10.1152/ajpheart.00292.2020. 

In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling Machinery and Cardiac Function. 

                    This study introduces the role of cBIN1-microdomains in organizing intracellular distribution of SERCA2a for efficient diastolic calcium removal. Thus,                     through regulating systolic calcium release at dyads and diastolic calcium removal via SERCA2a, cBIN1-microdomains are critical in cardiac inotropy and                     lusitropy.https://www.sciencedirect.com/science/article/pii/S2452302X20301212?via%3Dihub

                      Liu Y, Zhou K, Li J, Agvanian S, Caldaruse AM, Shaw S, Hitzeman TC, Shaw RM, Hong T. In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling                       Machinery and Cardiac Function. JACC Basic Transl Sci, 2020; 5(6), 561-578.

Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. 

                    This study introduces the mechanisms of dynamic regulation of dyad microdomains during an acute stress response. Cardiomyocyte cBIN1                     microdomains are found to be responsive to acute beta-adrenergic activation for subsequent organization between L-type calcium channels and                     ryanodine receptors for efficient excitation-contraction coupling. https://www.ahajournals.org/doi/epub/10.1161/CIRCULATIONAHA.115.018535 

                      Fu Y, Shaw SA, Naami R, Vuong CL, Basheer WA, Guo X, Hong T. Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized                       Dyads. Circulation, 2016; 133(4), 388-97.

Location and Function of Transient Receptor Potential Canonical Channel 1 in Ventricular Myocytes. 

                    This study provides evidence for a role of transient receptor canonical channels 1 (TRPC1) as a contributor to sarcoplasmic calcium leak in                     cardiomyocytes, which was previously explained by ryanodine receptors only. We propose that the findings will guide us to an understanding of TRPC1                     channels as modulators of cytosolic and contractility in cardiomyocytes. https://www.jmmc-online.com/article/S0022-2828(20)30020-1/fulltext 

                      Hu Q, Ahmad AA, Seidel T, Hunter C, Streiff M, Nikolova L, Spitzer KW, Sachse FB. Location and function of transient receptor potential canonical channel 1 in ventricular                       myocytes. J Mol Cell Cardiol, 2020; 139:113-123. 

Real-Time Magnetic Resonance Imaging-Guided Cryoablation of the Pulmonary Veins with Acute Freeze-Zone and Chronic Lesion Assessment. 

                    Current ablation techniques are not geared towards seeing real time changes to tissue as it is ablated. Real time MRI can provide that capability. In this                     study, the team looked at changes to tissue and the catheter using real time MRI when doing cryo ablation. It shows the growth of the freeze zone in real                     time but changes to tissue as well while using the cryo balloon.  https://academic.oup.com/europace/article/21/1/154/5033540 

                      Lichter J, Kholmovski EG, Coulombe N, Ghafoori E, Kamali R, MacLeod R, Ranjan R. Real-time magnetic resonance imaging-guided cryoablation of the pulmonary veins                       with acute freeze-zone and chronic lesion assessment. Europace. 2019; 21(1):154-162. 

Reproducibility of Clinical Late Gadolinium Enhancement Magnetic Resonance Imaging in Detecting Left Atrial Scar After Atrial Fibrillation Ablation. 

                    MRI has been used to see atrial scar but with limited data on reliability and reproducibility. In this study, the Ranjan laboratory systematically evaluated                     post ablation atrial scar reproducibility in clinical atrial MRI scans and showed that ablation related high intensity areas are very reproducible in clinical                     scans. https://onlinelibrary.wiley.com/doi/abs/10.1111/jce.14743

                      Kamali R, Schroeder J, DiBella E, Steinberg B, Han F, Dosdall DJ, Macleod RS, Ranjan R. Reproducibility of clinical late gadolinium enhancement magnetic resonance                       imaging in detecting left atrial scar after atrial fibrillation ablation. J Cardiovasc Electrophysiol, 2020; doi: 10.1111/jce.14743.

Restitution Characteristics of His Bundle and Working Myocardium in Isolated Rabbit Hearts. 

                    In this study, we used microelectrode impalements of the His bundle and the working myocardium to investigate the restitution characteristics of the His                     bundle at different activation rates. We demonstrated that the His bundle action potential duration was shorter than that of the working myocardium at                     both slow and rapid activation rates. This may permit the His bundle to be an active part of reentrant activity in fast arrhythmias such as ventricular                     tachycardia and fibrillation. https://dx.plos.org/10.1371/journal.pone.0186880 

                      Huang S, Wu L, Huang J, Panitchob N, Hu N, Ranjan R, Dosdall DJ. Restitution characteristics of His bundle and working myocardium in isolated rabbit hearts. PLoS One,                       2017; 12(10):e0186880. 

Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional recovery by Mechanical Unloading. 

                    This study showed a new type of sheet-like t-system remodeling of human failing cardiomyocytes characterized by large distances between                     sacrolemmal L-type calcium channels and clusters of junctional ryanodine receptors in the sarcoplasmic reticulum. This resulted in asynchronous calcium                     release and ineffective excitation-contraction coupling which precluded functional myocardial recovery of failing                     hearts.https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.116.024470

                      Seidel T, Navankasattusas S, Ahmad A, Diakos NA, Xu WD, Tristani-Firouzi M, Bonios MJ, Taleb I, Li DY, Selzman CH, Drakos SG*, Sachse FB*. Sheet-like remodeling of the                       transverse tubular system in human heart failure impairs excitation-contraction coupling and functional recovery by mechanical unloading. Circulation, 2017;  25;135(17):1632 45.

Structural basis of Action for a Human Ether-a-go-go-Related Gene 1 Potassium Channel Activator. 

                    Activation of human ether-a-go-go-related gene 1 (hERG1) potassium channels mediates cardiac action potential repolarization. These findings define a                     putative binding site for the activator RPR and confirm the importance of an interaction between the S4–S5 linker and the S6 domain in electromechanical                     coupling of voltage-gated potassium channels.https://www.pnas.org/content/104/34/13827.short  

                      Perry M, Sachse FB, Sanguinetti, MC. Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator. Proceedings of the National                       Academy of Sciences, 2007; 104(34), 13827-13832.

Research Labs

Dosdall Laboratory

The Dosdall Laboratory, headed by Derek Dosdall, PhD, focuses on using whole heart mapping and microelectrode techniques to investigate the role of the ventricular conduction system on arrhythmia onset and maintenance. Link to lab summary page on CVRTI 

Drakos Laboratory

The Drakos Laboratory, headed by Stavros Drakos, MD, PhD, through an ongoing collaboration with the Sachse Laboratory, studies how cardiac ion channels are distributed and how channels clustered to specific subdomains of cardiac cell membrane affect excitation-contraction coupling in healthy, failing, and recovering heart muscle. Link to lab summary page on CVRTI 

Hong Laboratory

The Hong Laboratory, headed by TingTing Hong, MD, PhD, studies the regulation and remodeling of membrane microdomains of cardiomyocytes during heart failure progression. They study how cardiomyocyte surface microdomains are organized to concentrate ion channels and signaling proteins for proper function and regulation in normal and failing hearts. The research includes the mechanisms of scaffolding protein and cytoskeleton-based maintenance of membrane structures and subdomains important in calcium signaling, turnover mechanisms of microdomains, and the mechanisms of heart failure progression. The Hong lab’s goal is to identify, at the bench, new molecular and cellular targets that can be translated to develop new therapeutic tools for clinical management of heart failure.Link to lab summary page on CVRTI 

Ranjan Laboratory 

The Ranjan Laboratory, headed by Ravi Ranjan, MD, PhD, focuses on developing a better understanding of arrhythmia mechanisms and optimizing the ablation procedure. The lab is using a combination of high density electrical mapping and imaging in an animal model combined with computational modeling to develop a better understanding of arrhythmia mechanisms. To optimize the ablation procedure, the team uses MRI to quantify tissue changes including reversible edema over time for different energy sources and ablation parameters to develop the optimal ablation technique. Link to lab summary page on CVRTI 

Sachse Laboratory 

The Sachse Laboratory, headed by Frank Sachse, PhD, sheds light on the localization and function of ion channels in cardiac muscle cells. They also investigate how ion channels affect cell electrophysiology and calcium signaling. Link to lab summary page on CVRTI 

Shaw Laboratory

of the Shaw Laboratory, headed by Robin Shaw, MD, PhD, study how cardiac ion channels are formed and how channels are targeted to specific subdomains of cardiac cell membrane in both healthy and failing heart muscle. Link to lab summary page on CVRTI