{"doi":"10.1093/cvr/cvaa036","title":"NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis","abstract":"AIMS: NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. METHODS AND RESULTS: In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed 'transient inward current' events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. CONCLUSION: The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.","journal":"Cardiovascular Research","year":2020,"id":94093,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9627,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":469219,"name":"Joyce Bernardi","orcid":"0000-0001-9599-0948","position":1,"is_corresponding":false},{"id":469220,"name":"Manuela Mura","orcid":"0000-0001-5435-8241","position":2,"is_corresponding":false},{"id":454044,"name":"Manuela Stefanello","orcid":null,"position":3,"is_corresponding":false},{"id":469221,"name":"Beatrice Badone","orcid":"0000-0003-4128-4487","position":4,"is_corresponding":false},{"id":469222,"name":"Marcella Rocchetti","orcid":"0000-0001-9191-4550","position":5,"is_corresponding":false},{"id":344941,"name":"Lia Crotti","orcid":"0000-0001-8739-6527","position":6,"is_corresponding":false},{"id":469223,"name":"Paul A. Brink","orcid":"0000-0001-8538-5824","position":7,"is_corresponding":false},{"id":30332,"name":"Peter J. Schwartz","orcid":"0000-0003-0367-1048","position":8,"is_corresponding":false},{"id":469224,"name":"Massimiliano Gnecchi","orcid":"0000-0001-7435-4328","position":9,"is_corresponding":false},{"id":469225,"name":"Antonio Zaza","orcid":"0000-0001-9355-4958","position":10,"is_corresponding":false},{"id":469218,"name":"Carlotta Ronchi","orcid":"0000-0002-7217-1146","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T22:32:04.778261Z","pmid":"32061134","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}