{"doi":"10.3389/fphys.2021.656516","title":"Role of Reduced Sarco-Endoplasmic Reticulum Ca2+-ATPase Function on Sarcoplasmic Reticulum Ca2+ Alternans in the Intact Rabbit Heart","abstract":"Sarcoplasmic reticulum (SR) Ca 2+ cycling is tightly regulated by ryanodine receptor (RyR) Ca 2+ release and sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) Ca 2+ uptake during each excitation–contraction coupling cycle. We previously showed that RyR refractoriness plays a key role in the onset of SR Ca 2+ alternans in the intact rabbit heart, which contributes to arrhythmogenic action potential duration (APD) alternans. Recent studies have also implicated impaired SERCA function, a key feature of heart failure, in cardiac alternans and arrhythmias. However, the relationship between reduced SERCA function and SR Ca 2+ alternans is not well understood. Simultaneous optical mapping of transmembrane potential (V m ) and SR Ca 2+ was performed in isolated rabbit hearts ( n = 10) using the voltage-sensitive dye RH237 and the low-affinity Ca 2+ indicator Fluo-5N-AM. Alternans was induced by rapid ventricular pacing. SERCA was inhibited with cyclopiazonic acid (CPA; 1–10 μM). SERCA inhibition (1, 5, and 10 μM of CPA) resulted in dose-dependent slowing of SR Ca 2+ reuptake, with the time constant ( tau ) increasing from 70.8 ± 3.5 ms at baseline to 85.5 ± 6.6, 129.9 ± 20.7, and 271.3 ± 37.6 ms, respectively ( p < 0.05 vs. baseline for all doses). At fast pacing frequencies, CPA significantly increased the magnitude of SR Ca 2+ and APD alternans, most strongly at 10 μM (pacing cycle length = 220 ms: SR Ca 2+ alternans magnitude: 57.1 ± 4.7 vs. 13.4 ± 8.9 AU; APD alternans magnitude 3.8 ± 1.9 vs. 0.2 ± 0.19 AU; p < 0.05 10 μM of CPA vs. baseline for both). SERCA inhibition also promoted the emergence of spatially discordant alternans. Notably, at all CPA doses, alternation of SR Ca 2+ release occurred prior to alternation of diastolic SR Ca 2+ load as pacing frequency increased. Simultaneous optical mapping of SR Ca 2+ and V m in the intact rabbit heart revealed that SERCA inhibition exacerbates pacing-induced SR Ca 2+ and APD alternans magnitude, particularly at fast pacing frequencies. Importantly, SR Ca 2+ release alternans always occurred before the onset of SR Ca 2+ load alternans. These findings suggest that even in settings of diminished SERCA function, relative refractoriness of RyR Ca 2+ release governs the onset of intracellular Ca 2+ alternans.","journal":"Frontiers in Physiology","year":2021,"id":168587,"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":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1946,"name":"Rachel C. Myles","orcid":"0000-0003-4670-361X","position":1,"is_corresponding":false},{"id":698043,"name":"I‐Ju Lee","orcid":"0000-0003-3205-7741","position":2,"is_corresponding":false},{"id":229037,"name":"Donald M. Bers","orcid":"0000-0002-2237-9483","position":3,"is_corresponding":false},{"id":338682,"name":"Crystal M. Ripplinger","orcid":"0000-0002-9908-4106","position":4,"is_corresponding":false},{"id":338677,"name":"Lianguo Wang","orcid":"0000-0002-4747-0419","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:46:06.853307Z","pmid":"34045974","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":[]}