{"doi":"10.1101/2023.01.29.526082","title":"Cardiac sympathetic denervation prevents sudden cardiac arrest and improves cardiac function by enhancing mitochondrial-antioxidant capacity","abstract":"ABSTRACT RATIONALE Sudden cardiac arrest ( SCA ) and heart failure ( HF ) are leading causes of death. The underlying mechanisms are incompletely understood, limiting the design of new therapies. Whereas most autonomic modulation therapies have not shown clear benefit in HF patients, growing evidence indicates cardiac sympathetic denervation ( CSD ) exerts cardioprotective effects. The underlying molecular and cellular mechanisms remain unexplored. OBJECTIVE Based on the hypothesis that mitochondrial reactive oxygen species ( mROS ) drive the pathogenesis of HF and SCA, we investigated whether CSD prevents SCA and HF by improving mitochondrial antioxidant capacity and redox balance, to correct impaired Ca 2+ handling and repolarization reserve. METHODS AND RESULTS We interrogated CSD-specific responses in pressure-overload HF models with spontaneous SCA using in vivo echocardiographic and electrocardiographic studies and in vitro biochemical and functional studies including ratiometric measures of mROS, Ca 2+ and sarcomere dynamics in left ventricular myocytes. Pressure-overloaded HF reduced mitochondrial antioxidant capacity and increased mROS, which impaired β-adrenergic signaling and caused SR Ca 2+ leak, reducing SR Ca 2+ and increasing diastolic Ca 2+ , impaired myofilament contraction and further increased the sympathetic stress response. CSD improved contractile function and mitigated mROS-mediated diastolic Ca 2+ overload, dispersion of repolarization, triggered activity and SCA by upregulating mitochondrial antioxidant and NADPH-producing enzymes. CONCLUSIONS Our findings support a fundamental role of sympathetic stress-induced downregulation of mROS scavenging enzymes and RyR-leak mediated diastolic Ca 2+ overload in HF and SCA pathogenesis that are mitigated by CSD. This first report on the molecular and cellular mechanisms of CSD supports its evaluation in additional high-risk patient groups. BRIEF SUMMARY Cardiac sympathetic denervation ( CSD ) confers cardioprotective effects via unclear mechanisms. In a guinea pig model that uniquely mimics human pressure-overload heart failure ( HF ) with spontaneous sudden cardiac arrest ( SCA ), we interrogated CSD-specific responses using echocardiographic, electrocardiographic and biochemical measures, and ratiometric measures of mitochondrial reactive oxygen species ( mROS ), Ca 2+ and sarcomere dynamics. Consistent with our hypothesis, CSD rescued cardioprotection by upregulating mitochondrial antioxidant and NADPH-producing enzymes, which mitigate mROS-mediated Ca 2+ derangements, repolarization lability, triggered activity, HF and SCA. Our findings provide the first molecular and cellular mechanistic basis for evaluating CSD therapy in a broader group of high-risk patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398333,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":850411,"name":"Pooja Joshi","orcid":null,"position":1,"is_corresponding":false},{"id":270498,"name":"Brian O’Rourke","orcid":"0000-0002-5548-4853","position":2,"is_corresponding":false},{"id":1093756,"name":"Shanea Estes","orcid":null,"position":3,"is_corresponding":false},{"id":709504,"name":"Deeptankar DeMazumder","orcid":null,"position":4,"is_corresponding":false},{"id":1093320,"name":"Swati Dey","orcid":"0000-0003-4692-6848","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:47.744358Z","pmid":"36778270","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":[]}