{"doi":"10.1098/rsif.2020.0066","title":"Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson–Gilford progeria syndrome","abstract":"Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS ( Lmna G609G/G609G ) using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.","journal":"Journal of The Royal Society Interface","year":2020,"id":97806,"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":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9403,"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":77673,"name":"Yuki I. Kawamura","orcid":"0000-0003-2137-6464","position":1,"is_corresponding":false},{"id":248223,"name":"Alexander W. Caulk","orcid":null,"position":2,"is_corresponding":false},{"id":483252,"name":"H. Ahmadzadeh","orcid":"0000-0002-2424-1867","position":3,"is_corresponding":false},{"id":484026,"name":"Nicole Mikush","orcid":null,"position":4,"is_corresponding":false},{"id":484027,"name":"K. Zimmerman","orcid":null,"position":5,"is_corresponding":false},{"id":394153,"name":"Dillon Kavanagh","orcid":null,"position":6,"is_corresponding":false},{"id":356043,"name":"Dar Weiss","orcid":"0000-0001-6097-6038","position":7,"is_corresponding":false},{"id":338675,"name":"Marcos Latorre","orcid":"0000-0003-4142-0207","position":8,"is_corresponding":false},{"id":245125,"name":"Zhen W. Zhuang","orcid":"0000-0002-1515-8543","position":9,"is_corresponding":false},{"id":483253,"name":"Gerald S. Shadel","orcid":"0000-0003-2899-8717","position":10,"is_corresponding":false},{"id":361096,"name":"Demetrios T. Braddock","orcid":"0000-0002-0541-4689","position":11,"is_corresponding":false},{"id":245130,"name":"Jay D. Humphrey","orcid":"0000-0003-1011-2025","position":12,"is_corresponding":false},{"id":245123,"name":"Sae‐Il Murtada","orcid":"0000-0002-6578-4585","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T22:36:02.818637Z","pmid":"32453981","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":[]}