{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:25:27Z","timestamp":1790735127355,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"NIH NHLBI","doi-asserted-by":"publisher","award":["K08HL141995"],"award-info":[{"award-number":["K08HL141995"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH NHLBI","doi-asserted-by":"publisher","award":["R01HL161038"],"award-info":[{"award-number":["R01HL161038"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Arrhythmias in the setting of right-ventricular (RV) remodeling contribute to majority of deaths in patients with pulmonary hypertension. However, the underlying mechanism of electrical remodeling remains elusive, especially ventricular arrhythmias. Here, we analyzed the RV transcriptome of pulmonary arterial hypertension (PAH) patients with compensated RV or decompensated RV and identified 8 and 45 differentially expressed genes known to be involved in regulating the electrophysiological properties of excitation and contraction of cardiac myocytes, respectively. Transcripts encoding voltage-gated Ca2+ and Na+ channels were notably decreased in PAH patients with decompensated RV, along with significant dysregulation of KV and Kir channels. We further showed similarity of the RV channelome signature with two well-known animal models of PAH, monocrotaline (MCT)- and Sugen-hypoxia (SuHx)-treated rats. We identified 15 common transcripts among MCT, SuHx, and PAH patients with decompensated RV failure. In addition, data-driven drug repurposing using the channelome signature of PAH patients with decompensated RV failure predicted drug candidates that may reverse the altered gene expression. Comparative analysis provided further insight into clinical relevance and potential preclinical therapeutic studies targeting mechanisms involved in arrhythmogenesis.<\/jats:p>","DOI":"10.3390\/ijms24054633","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T03:00:38Z","timestamp":1677553238000},"page":"4633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Electrical Remodeling in Right Ventricular Failure Due to Pulmonary Hypertension: Unraveling Novel Therapeutic Targets"],"prefix":"10.3390","volume":"24","author":[{"given":"John F.","family":"Park","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soban","family":"Umar","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2045894019845611","article-title":"Right Heart in Pulmonary Hypertension: From Adaptation to Failure","volume":"9","author":"Ren","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1161\/CIRCRESAHA.118.313650","article-title":"Medical Therapy for Heart Failure Associated With Pulmonary Hypertension","volume":"124","author":"Zelt","year":"2019","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.pcad.2012.06.002","article-title":"Arrhythmias in Pulmonary Arterial Hypertension","volume":"55","author":"Rajdev","year":"2012","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fmed.2019.00169","article-title":"Arrhythmic Burden and Outcomes in Pulmonary Arterial Hypertension","volume":"6","author":"Middleton","year":"2019","journal-title":"Front. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40949-017-0004-8","article-title":"Arrhythmias in Pulmonary Arterial Hypertension","volume":"1","author":"Temple","year":"2017","journal-title":"J. Congenit. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCEP.111.967265","article-title":"Spontaneous Ventricular Fibrillation in Right Ventricular Failure Secondary to Chronic Pulmonary Hypertension","volume":"5","author":"Umar","year":"2012","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"H2230","DOI":"10.1152\/ajpheart.01226.2010","article-title":"Arrhythmogenic Substrate in Hearts of Rats with Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy","volume":"300","author":"Benoist","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.21037\/cdt-20-400","article-title":"Animal Models of Right Heart Failure","volume":"10","author":"Andersen","year":"2020","journal-title":"Cardiovasc. Diagn."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e007058","DOI":"10.1161\/CIRCHEARTFAILURE.120.007058","article-title":"Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of EMT in Human Right Ventricular Failure","volume":"14","author":"Park","year":"2021","journal-title":"Circ. Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/s44161-022-00113-w","article-title":"Identification of LTBP-2 as a Plasma Biomarker for Right Ventricular Dysfunction in Human Pulmonary Arterial Hypertension","volume":"1","author":"Boucherat","year":"2022","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"H1725","DOI":"10.1152\/ajpheart.1999.277.5.H1725","article-title":"Downregulation of Voltage-Gated K+ Channels in Rat Heart with Right Ventricular Hypertrophy","volume":"277","author":"Lee","year":"1999","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.acvd.2019.10.009","article-title":"Excitation-Contraction Coupling and Relaxation Alteration in Right Ventricular Remodelling Caused by Pulmonary Arterial Hypertension","volume":"113","author":"Antigny","year":"2020","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3345\/kjp.2018.06457","article-title":"Change of Voltage-Gated Potassium Channel 1.7 Expressions in Monocrotaline-Induced Pulmonary Arterial Hypertension Rat Model","volume":"61","author":"Lee","year":"2018","journal-title":"Korean J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/j.hrthm.2021.04.008","article-title":"Cardiac Potassium Inward Rectifier Kir2: Review of Structure, Regulation, Pharmacology, and Arrhythmogenesis","volume":"18","author":"Reilly","year":"2021","journal-title":"Heart Rhythm"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Shah, K., Seeley, S., Schulz, C., Fisher, J., and Gururaja Rao, S. (2022). Calcium Channels in the Heart: Disease States and Drugs. Cells, 11.","DOI":"10.3390\/cells11060943"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00424-009-0753-0","article-title":"CaV1.2 Channelopathies: From Arrhythmias to Autism, Bipolar Disorder, and Immunodeficiency","volume":"460","author":"Liao","year":"2010","journal-title":"Pflug. Arch."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1161\/CIRCEP.113.000407","article-title":"T-Type Calcium Current Contributes to Escape Automaticity and Governs the Occurrence of Lethal Arrhythmias After Atrioventricular Block in Mice","volume":"6","author":"Benito","year":"2013","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Daimi, H., Lozano-Velasco, E., Aranega, A., and Franco, D. (2022). Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031381"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.3389\/fphys.2018.01372","article-title":"SCN5A Variants: Association With Cardiac Disorders","volume":"9","author":"Li","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e003703","DOI":"10.1161\/CIRCHEARTFAILURE.116.003703","article-title":"Use of \u03b2-Blockers in Pulmonary Hypertension","volume":"10","author":"Perros","year":"2017","journal-title":"Circ. Heart Fail."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1183\/09031936.00215514","article-title":"Outcomes of \u03b2-Blocker Use in Pulmonary Arterial Hypertension: A Propensity-Matched Analysis","volume":"46","author":"Bandyopadhyay","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1093\/eurheartj\/ehac237","article-title":"2022 ESC\/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: Developed by the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG)","volume":"43","author":"Humbert","year":"2022","journal-title":"Eur. Heart J. Oxf. Acad."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11912-021-01102-1","article-title":"Bruton\u2019s Tyrosine Kinase Inhibitors and Cardiotoxicity: More Than Just Atrial Fibrillation","volume":"23","author":"Sestier","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Giudice, V., Vecchione, C., and Selleri, C. (2020). Cardiotoxicity of Novel Targeted Hematological Therapies. Life, 10.","DOI":"10.3390\/life10120344"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1080\/19336950.2019.1697127","article-title":"PI3K\u03b1 in Cardioprotection: Cytoskeleton, Late Na+ Current, and Mechanism of Arrhythmias","volume":"13","author":"Zhabyeyev","year":"2019","journal-title":"Channels"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e136939","DOI":"10.1172\/JCI136939","article-title":"Disrupted PI3K Subunit P110\u03b1 Signaling Protects against Pulmonary Hypertension and Reverses Established Disease in Rodents","volume":"131","author":"Berghausen","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/s41569-018-0145-2","article-title":"Transient Receptor Potential Channels in Cardiac Health and Disease","volume":"16","author":"Hof","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H157","DOI":"10.1152\/ajpheart.00457.2014","article-title":"Role of TRP Channels in the Cardiovascular System","volume":"308","author":"Yue","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.ekir.2019.12.007","article-title":"Polycystins, ADPKD, and Cardiovascular Disease","volume":"5","author":"Kuo","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1161\/CIRCULATIONAHA.118.034731","article-title":"Polycystin-1 Assembles With Kv Channels to Govern Cardiomyocyte Repolarization and Contractility","volume":"140","author":"Altamirano","year":"2019","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.hrthm.2007.10.014","article-title":"Antiarrhythmic Effects of Beta3-Adrenergic Receptor Stimulation in a Canine Model of Ventricular Tachycardia","volume":"5","author":"Zhou","year":"2008","journal-title":"Heart Rhythm"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Michel, L.Y.M., Farah, C., and Balligand, J.-L. (2020). The Beta3 Adrenergic Receptor in Healthy and Pathological Cardiovascular Tissues. Cells, 9.","DOI":"10.3390\/cells9122584"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1161\/CIRCULATIONAHA.118.035326","article-title":"Right Ventricular Fibrosis","volume":"139","author":"Andersen","year":"2019","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez, J., Trenor, B., Saiz, J., D\u00f6ssel, O., and Loewe, A. (2021). Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology. Cells, 10.","DOI":"10.3390\/cells10112852"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e002628","DOI":"10.1161\/CIRCIMAGING.114.002628","article-title":"Systemic Right Ventricular Fibrosis Detected by Cardiovascular Magnetic Resonance Is Associated with Clinical Outcome, Mainly New-Onset Atrial Arrhythmia, in Patients after Atrial Redirection Surgery for Transposition of the Great Arteries","volume":"8","author":"Rydman","year":"2015","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4633\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:44:12Z","timestamp":1760121852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4633"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,27]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054633"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054633","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,27]]}}}