BACKGROUND Congenital long QT syndrome (LQTS) is an inherited arrhythmia linked to a high risk of sudden cardiac death. LQTS type 2 is mainly caused by KCNH2 mutations. Even among carriers of the same pathogenic KCNH2 variant, clinical manifestations and disease severity vary, with the underlying mechanisms remaining unclear. AIM To investigate mechanisms underlying variable clinical severity among carriers of the same KCNH2 mutation using patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs).<\/p>\n
METHODS iPSCs were generated from the peripheral blood mononuclear cells of a family trio: A symptomatic proband, an asymptomatic carrier mother, and a mutation-negative father. Using nonintegrating Sendai virus, these iPSCs were then differentiated into cardiomyocytes using a monolayer-based protocol. The functional properties of the iPSC-CMs were assessed using patch-clamp recordings, calcium imaging, and multi-electrode array recordings.<\/p>\n
RESULTS The proband iPSC-CMs exhibited a significant prolongation of action potential duration compared with the mother and father iPSC-CMs. Both the proband and mother iPSC-CMs, carrying the heterozygous KCNH2 p.Y427H variant, demonstrated a significant reduction in the rapid delayed rectifier potassium current, consistent with a loss-of-function mutation. Notably, the proband iPSC-CMs showed an enhanced L-type calcium current and exaggerated calcium transients. These abnormalities were accompanied by increased arrhythmogenicity, manifesting as early afterdepolarizations and triggered arrhythmias. Treatment with nifedipine partially restored repolarization and effectively suppressed all these arrhythmic events.<\/p>\n
CONCLUSION Calcium dysregulation is a critical modifier of phenotypic severity. Patient-specific iPSC-CMs provide a powerful platform for modeling intra-familial phenotypic variability in LQTS type 2, highlighting their potential for individualized risk assessment and therapeutic evaluation.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[34],"resource_type":[75],"application_areas":[53,77],"therapeutic_areas":[143],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-19596","resource_library","type-resource_library","status-publish","hentry","products_tags-cardioexcyte-96","resource_type-publication","application_areas-assay-development-and-validation","application_areas-cell-ipscs-profiling","therapeutic_areas-assay-development-and-validation"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/19596","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=19596"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=19596"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=19596"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=19596"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=19596"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=19596"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=19596"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=19596"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=19596"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}