{"doi":"10.1101/2025.09.17.676863","title":"Atorvastatin suppresses cardiac fibrosis and dysfunction induced by HIV and certain antiretroviral drugs in mice by blocking platelet TGFβ1","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Cardiovascular disease (CVD) both atherosclerosis-related and heart failure with preserved ejection fraction (HFpEF) and linked to cardiac fibrosis, contributes to morbidity and mortality in people with HIV (PWH) receiving antiretroviral therapy (ART). In the REPRIEVE trial, pitavastatin reduced atherosclerotic CVD risk to a magnitude inconsistent with pitavastatin’s impact solely on LDL-cholesterol and inflammation. We hypothesized that HFpEF in PWH relates to HIV-induced fibrosis mediated by platelet TGFβ1, that it is accelerated by certain contemporary ART, and may also be inhibited by statins. ART drugs used in REPRIEVE, including a nucleoside/nucleotide, integrase inhibitor-based regimen (tenofovir (TDF), emtricitabine (FTC), and dolutegravir (DTG)), and the protease inhibitors ritonavir (RTV) and darunavir (DRV), and the impact of atorvastatin, were examined in two HIV mouse models: transgenic\n                  <jats:italic>Tg26</jats:italic>\n                  mice and HIV-PDX mice engrafted with HIV-infected T cells.\n                  <jats:italic>Tg26</jats:italic>\n                  and HIV-PDX mice had higher cardiac fibrosis than littermate controls without HIV (p&lt;0.05). Administration of TDF-FTC-DTG or RTV, but not DRV, resulted in a further ∼2-fold increase in fibrosis (p&lt;0.01). Higher cardiac fibrosis with intracardiac fat accumulation correlated with reduced diastolic function. Mice depleted of platelet TGFβ1 (\n                  <jats:italic>TGFβ1</jats:italic>\n                  <jats:sup>\n                    <jats:italic>Platelet-Δ</jats:italic>\n                  </jats:sup>\n                  <jats:italic>Tg26)</jats:italic>\n                  , or treated with atorvastatin, were partially protected from HIV- and ART-induced cardiac fibrosis, steatosis, and diastolic dysfunction. Atorvastatin effects occurred independently of changes in inflammatory cytokines and total cholesterol. They correlated with reduced platelet activation and TGFβ1 signaling in cardiac endothelial cells, fibroblasts, and macrophages undergoing mesenchymal transition. These results indicate that certain ART regimens accelerate HIV-associated CVD characterized by HFpEF via platelet TGFβ1-dependent processes and mitigated by atorvastatin. They enhance understanding of the pleiotropic effects of statins in HIV/ART CVD and suggest a mechanism that might be targeted by antiplatelet agents or inhibition of TGFβ signaling.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Key Points</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Contemporary ART regimens induce release of platelet TGFβ1 and are associated with cardiac fibrosis and diastolic dysfunction with ectopic fat deposition in HIV-infected mice.</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Depleting platelet TGFβ1 and/or treating with atorvastatin therapy suppresses HIV-ART-induced cardiac fibrosis, suggesting use of anti-platelet strategies to prevent heart failure among PWH.</jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>","journal":null,"year":null,"id":609282,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1565949,"name":"Denys Babii","orcid":null,"position":1,"is_corresponding":false},{"id":1565950,"name":"Brienne Cole","orcid":null,"position":2,"is_corresponding":false},{"id":1565951,"name":"Tayyab A. Afzal","orcid":null,"position":3,"is_corresponding":false},{"id":1565952,"name":"Thamizhiniyan Venkatesan","orcid":null,"position":4,"is_corresponding":false},{"id":1565953,"name":"Trevor Word","orcid":null,"position":5,"is_corresponding":false},{"id":1565954,"name":"Sandra Gostynska","orcid":null,"position":6,"is_corresponding":false},{"id":501238,"name":"Sixia Chen","orcid":"0000-0001-5082-281X","position":7,"is_corresponding":false},{"id":431442,"name":"Kar-Ming Fung","orcid":null,"position":8,"is_corresponding":false},{"id":369379,"name":"Ali Danesh","orcid":"0000-0002-0383-1040","position":9,"is_corresponding":false},{"id":809974,"name":"Itzayana G. Miller","orcid":"0000-0001-9199-8985","position":10,"is_corresponding":false},{"id":1565955,"name":"Paul Klotman","orcid":null,"position":11,"is_corresponding":false},{"id":1565956,"name":"Brad R. Jones","orcid":null,"position":12,"is_corresponding":false},{"id":347662,"name":"Jeffrey Laurence","orcid":"0000-0002-8274-3144","position":13,"is_corresponding":false},{"id":347661,"name":"Jasimuddin Ahamed","orcid":"0000-0001-6455-0296","position":14,"is_corresponding":false},{"id":890382,"name":"Kumar Subramani","orcid":"0000-0002-8478-3625","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Atorvastatin suppresses cardiac fibrosis and dysfunction induced by HIV and certain antiretroviral drugs in mice by blocking platelet TGFβ1","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Cardiovascular disease (CVD) both atherosclerosis-related and heart failure with preserved ejection fraction (HFpEF) and linked to cardiac fibrosis, contributes to morbidity and mortality in people with HIV (PWH) receiving antiretroviral therapy (ART). In the REPRIEVE trial, pitavastatin reduced atherosclerotic CVD risk to a magnitude inconsistent with pitavastatin’s impact solely on LDL-cholesterol and inflammation. We hypothesized that HFpEF in PWH relates to HIV-induced fibrosis mediated by platelet TGFβ1, that it is accelerated by certain contemporary ART, and may also be inhibited by statins. ART drugs used in REPRIEVE, including a nucleoside/nucleotide, integrase inhibitor-based regimen (tenofovir (TDF), emtricitabine (FTC), and dolutegravir (DTG)), and the protease inhibitors ritonavir (RTV) and darunavir (DRV), and the impact of atorvastatin, were examined in two HIV mouse models: transgenic\n                  <jats:italic>Tg26</jats:italic>\n                  mice and HIV-PDX mice engrafted with HIV-infected T cells.\n                  <jats:italic>Tg26</jats:italic>\n                  and HIV-PDX mice had higher cardiac fibrosis than littermate controls without HIV (p&lt;0.05). Administration of TDF-FTC-DTG or RTV, but not DRV, resulted in a further ∼2-fold increase in fibrosis (p&lt;0.01). Higher cardiac fibrosis with intracardiac fat accumulation correlated with reduced diastolic function. Mice depleted of platelet TGFβ1 (\n                  <jats:italic>TGFβ1</jats:italic>\n                  <jats:sup>\n                    <jats:italic>Platelet-Δ</jats:italic>\n                  </jats:sup>\n                  <jats:italic>Tg26)</jats:italic>\n                  , or treated with atorvastatin, were partially protected from HIV- and ART-induced cardiac fibrosis, steatosis, and diastolic dysfunction. Atorvastatin effects occurred independently of changes in inflammatory cytokines and total cholesterol. They correlated with reduced platelet activation and TGFβ1 signaling in cardiac endothelial cells, fibroblasts, and macrophages undergoing mesenchymal transition. These results indicate that certain ART regimens accelerate HIV-associated CVD characterized by HFpEF via platelet TGFβ1-dependent processes and mitigated by atorvastatin. They enhance understanding of the pleiotropic effects of statins in HIV/ART CVD and suggest a mechanism that might be targeted by antiplatelet agents or inhibition of TGFβ signaling.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Key Points</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Contemporary ART regimens induce release of platelet TGFβ1 and are associated with cardiac fibrosis and diastolic dysfunction with ectopic fat deposition in HIV-infected mice.</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Depleting platelet TGFβ1 and/or treating with atorvastatin therapy suppresses HIV-ART-induced cardiac fibrosis, suggesting use of anti-platelet strategies to prevent heart failure among PWH.</jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23304386","pmcid":null,"openalex_id":"https://openalex.org/W4414373433","authors":[],"funders":[{"funder_name":"","grant_id":"HL167656","title":null},{"funder_name":"","grant_id":"HL148123","title":null}],"total_grants":2,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/09/20/2025.09.17.676863.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/09/20/2025.09.17.676863.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.09.17.676863","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.09.17.676863","host_type":"repository"}],"fields_of_study":["HIV-related health complications and treatments","Lipoproteins and Cardiovascular Health","GDF15 and Related Biomarkers"],"mesh_terms":[],"keywords":["Cardiac fibrosis","Atorvastatin","Myocardial fibrosis","Darunavir","Heart failure","Fibrosis","Diastole","Cardiac function curve","Ejection fraction","Pitavastatin"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-31T05:30:52.799568Z","pmid":null,"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":[]}