Publications

Selected

The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction

David Y. Chiang, Arie O. Verkerk, Rachelle Victorio, Boris I. Shneyer, Babet van der Vaart, …, Tuomas Kiviniemi, Paul W. Burridge, Connie R. Bezzina, Anna Akhmanova, Calum A. MacRae

Circulation Research  ·  05 Jan 2024  ·  doi:10.1161/CIRCRESAHA.123.323231

Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram

Svetlana Maurya, Robert W. Mills, Konstantin Kahnert, David Y. Chiang, Giorgia Bertoli, …, Eli Rothenberg, Alfred L. George, Calum A. MacRae, Mario Delmar, Alicia Lundby

Nature Cardiovascular Research  ·  13 Jul 2023  ·  doi:10.1038/s44161-023-00294-y

Atrial Standstill in the Pediatric Population

Taylor S. Howard, David Y. Chiang, Scott R. Ceresnak, Virginie Beausejour Ladouceur, Robert D. Whitehill, …, Doug Y. Mah, Jeffrey J. Kim, Santiago O. Valdes, Dianna M. Milewicz, Christina Y. Miyake

JACC: Clinical Electrophysiology  ·  01 Jan 2023  ·  doi:10.1016/j.jacep.2022.08.022

Targeting the Microtubule EB1-CLASP2 Complex Modulates Na _V 1.5 at Intercalated Discs

Gerard A. Marchal, Mariam Jouni, David Y. Chiang, Marta Pérez-Hernández, Svitlana Podliesna, …, Paul W. Burridge, Mario Delmar, Niels Galjart, Vincent Portero, Carol Ann Remme

Circulation Research  ·  23 Jul 2021  ·  doi:10.1161/CIRCRESAHA.120.318643

Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

David Y. Chiang, Jeffrey J. Kim, Santiago O. Valdes, Caridad de la Uz, Yuxin Fan, Jeffrey Orcutt, Melissa Domino, Melissa Smith, Xander H.T. Wehrens, Christina Y. Miyake

Circulation: Arrhythmia and Electrophysiology  ·  01 Oct 2015  ·  doi:10.1161/CIRCEP.115.003098

3. Inherited cardiac arrhythmias

During my clinical training, I took on two clinical projects under the mentorship of Christina Miyake, MD, a pediatric electrophysiologist at Texas Children’s Hospital and BCM. The first study sought to determine whether there are genetic reasons for poor pacemaker lead capture, which may complicate cardiac device implantation. Using genetic data, retrospective chart review, and bioinformatic analyses, I found a novel association between loss-of-function SCN5A variants and poor pacemaker capture, the recognition of which is critical for planning device implantation strategies and patient follow-up.¹ In the other study, I systematically described all documented arrhythmias in the largest cohort of patients with Duchenne and Becker muscular dystrophies, and found that arrhythmias increased with decreasing ejection fraction regardless of age, but that age was also a significant predictor of arrhythmia development.² These results have important implications for prognostication and clinical management of these unfortunate patients with inherited arrhythmias. More recently, during my post-doctoral training, I again worked with Dr. Miyake and described the association between loss-of-function SCN5A variants and atrial standstill, with implications for their management.³ On a personal level, working on these projects was what inspired me to pursue basic and translational research on inherited cardiac arrhythmias in order to come up with novel treatment strategies.

4. Zebrafish models of cardiac arrhythmias

One of the greatest challenges faced by our field has been the inability to translate promising findings in mice to patients, which may be partly due to the dissimilarities between mouse and human cardiac EP. With this in mind, I pivoted to zebrafish, whose cardiac EP is more similar to human. Combined with its fecundity, ease of genetic manipulation, and scalability for drug screening, this makes zebrafish an excellent model organism for studying the genetic basis of cardiac arrhythmias and testing novel therapeutics at scale. During my time in the MacRae lab, I have learned and optimized a range of EP techniques including voltage and calcium mapping of isolated hearts, patch clamping of isolated cardiomyocytes, and ECG measurements on adult zebrafish. I also created more than 20 different mutant lines relevant to clinical arrhythmias. In collaboration, I have applied some of these approaches to studying different aspects of cardiac EP, including the regulation of the cardiac NaV by LITAF¹, as well as novel gene candidates for early-onset cardiac conduction diseases² and physical interactors of key cardiac ion channels.³ Recently, I generated a cardiac sodium channel knockout model which phenocopies BrS and cardiac conduction disease. Using this model, I designed and executed two phenotypic screens using two libraries totaling 5,462 compounds and identified several promising lead compounds. Based on this Dr. MacRae and I submitted a patent application (No. PCT/US2025/029882 filed on May 16, 2025). I also presented this work as winner of the Eli S. Gang Most Innovative Abstract award at the 2025 Heart Rhythm Society annual meeting.⁴

5. Role of microtubule plus end-binding proteins (EBs) in cardiac arrhythmias.

Through participating in the Leducq network, “The sodium channel as a therapeutic target for prevention of lethal cardiac arrhythmias,” I became interested in understanding the genetic and molecular bases of BrS, which is characterized by genetic heterogeneity with no disease-modifying therapeutics. Led by members of the network, a large genome-wide association study was completed in BrS patients, identifying a number of novel candidate genes. Based on bioinformatic analyses, I acutely knocked out mapre2 (which encodes microtubule end-binding protein 2, EB2) in zebrafish embryos and observed a cardiac EP phenotype reflective of a decrease in NaV function, a hallmark of BrS.¹ In a follow-up study, I generated germline mapre2 knockout zebrafish mutants and confirmed the role of EB2 in maintaining normal ventricular conduction.² In another collaborative study, I showed that acute knockout of mapre1b (which encodes EB1) also shows a similar phenotype in zebrafish embryos, suggesting that EBs share a general function in the regulation of NaV function.³ Since EBs are known to regulate microtubule dynamics and stability, I am now interested in understanding how the microtubule network affects ion channel localization and function and how its dysregulation leads to cardiac arrhythmias. This represents a paradigm shift in our understanding of cardiac arrhythmias and could have profound implications for both currently approved drugs that affect the microtubules and novel therapeutics.