{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:47:08Z","timestamp":1785923228268,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Adv. Respir. Med.","ARM"],"abstract":"<jats:p>Cardiovascular comorbidities complicate interstitial lung disease (ILD) and represent potential therapeutic targets, yet the prevalence and clinical impact of left ventricular diastolic dysfunction (LVDD) remain poorly characterized. We aimed to evaluate LVDD as a potential treatable trait within a prospective cohort. Using data from an ILD registry (January 2021\u2013October 2024), we defined clinically relevant LVDD as echocardiographic grade 2 or 3 diastolic dysfunction. Out of 276 patients (median age 69, 44% female), 14% had LVDD, which was almost entirely in patients with fibrosis (97%, p = 0.045) and associated with lower diffusing capacity for carbon monoxide. Survival and clinical analyses restricted to the fibrotic ILD subgroup (n = 241) showed that LVDD was independently associated with a higher hazard for a combined adverse outcome of acute exacerbation, lung transplantation, or death (adjusted HR 1.82, 95% CI 1.03\u20133.38, p = 0.043), which persisted after 1:2 propensity score matching (HR 2.04). LVDD also independently predicted increased all-cause mortality (adjusted HR 2.10) and reduced 6-min walk distance (median 413 vs. 465 m, \u03b2 = \u22120.14, p = 0.036). In conclusion, LVDD is prevalent in fibrotic ILD and carries significant prognostic implications. Given its objective measurability and actionable treatment pathways, LVDD represents a potentially important treatable trait requiring multi-disciplinary care.<\/jats:p>","DOI":"10.3390\/arm94040057","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:08:09Z","timestamp":1785856089000},"page":"57","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Left Ventricular Diastolic Dysfunction in Patients with Interstitial Lung Disease\u2014A Potential Treatable Trait"],"prefix":"10.3390","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-5284","authenticated-orcid":false,"given":"Ophir","family":"Freund","sequence":"first","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Center of Excellence for Interstitial Lung Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uriel","family":"Katsoff","sequence":"additional","affiliation":[{"name":"Center of Excellence for Interstitial Lung Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0468-5162","authenticated-orcid":false,"given":"Tzlil","family":"Hershko","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Center of Excellence for Interstitial Lung Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayala","family":"Ron","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Center of Excellence for Interstitial Lung Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8882-9109","authenticated-orcid":false,"given":"Shir","family":"Frydman","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"},{"name":"Cardiology Department, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doron","family":"Cohn-Schwartz","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Center of Excellence for Interstitial Lung Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviv","family":"Kupershmidt","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neta","family":"Mano","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Melloul","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9720-9246","authenticated-orcid":false,"given":"Eyal","family":"Kleinhendler","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Bar-Shai","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0965-3326","authenticated-orcid":false,"given":"Avraham","family":"Unterman","sequence":"additional","affiliation":[{"name":"Institute of Pulmonary Medicine, Sourasky Medical Center, Tel Aviv 6423906, Israel"},{"name":"Center of Excellence for Interstitial Lung Diseases, Tel Aviv Medical Center, Tel Aviv 6423906, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"240261","DOI":"10.1183\/20734735.0261-2024","article-title":"Insights into interstitial lung disease pathogenesis","volume":"21","author":"Vasarmidi","year":"2025","journal-title":"Breathe"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"240259","DOI":"10.1183\/20734735.0259-2024","article-title":"A new era in the treatment of progressive fibrosing interstitial lung diseases","volume":"21","author":"Denis","year":"2025","journal-title":"Breathe"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17534666221117002","DOI":"10.1177\/17534666221117002","article-title":"Immunomodulatory treatment of interstitial lung disease","volume":"16","author":"Luppi","year":"2022","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1056\/NEJMoa2414108","article-title":"Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis","volume":"392","author":"Richeldi","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1056\/NEJMoa1908681","article-title":"Nintedanib in Progressive Fibrosing Interstitial Lung Diseases","volume":"381","author":"Flaherty","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1183\/13993003.01359-2015","article-title":"Treatable traits: Toward precision medicine of chronic airway diseases","volume":"47","author":"Agusti","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2300404","DOI":"10.1183\/13993003.00404-2023","article-title":"Treatable traits: A comprehensive precision medicine approach in interstitial lung disease","volume":"62","author":"Khor","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1186\/s12931-023-02554-8","article-title":"Walking the path of treatable traits in interstitial lung diseases","volume":"24","author":"Amati","year":"2023","journal-title":"Respir. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"160027","DOI":"10.1183\/16000617.0027-2016","article-title":"Comorbidities in interstitial lung diseases","volume":"26","author":"Margaritopoulos","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41572-024-00540-y","article-title":"Heart failure with preserved ejection fraction","volume":"10","author":"Hamo","year":"2024","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e010454","DOI":"10.1161\/JAHA.118.010454","article-title":"Metabolic Risk Factors and Left Ventricular Diastolic Function in Middle-Aged Chinese Living in the Tibetan Plateau","volume":"8","author":"Zheng","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.rmed.2014.01.008","article-title":"How does comorbidity influence survival in idiopathic pulmonary fibrosis?","volume":"108","author":"Hyldgaard","year":"2014","journal-title":"Respir. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103614","DOI":"10.1016\/j.autrev.2024.103614","article-title":"Cardiovascular disease in connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis of observational studies","volume":"23","author":"Hu","year":"2024","journal-title":"Autoimmun. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Koteci, A., Morgan, A.D., Portas, L., Whittaker, H.R., Kallis, C., George, P.M., and Quint, J.K. (2022). Left-sided heart failure burden and mortality in idiopathic pulmonary fibrosis: A population-based study. BMC Pulm. Med., 22.","DOI":"10.1186\/s12890-022-01973-5"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1080\/03009742.2016.1206963","article-title":"Prevalence and risk factors for left ventricular diastolic dysfunction in a scleroderma cohort","volume":"46","author":"Vemulapalli","year":"2017","journal-title":"Scand. J. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yamazaki, R., Nishiyama, O., Yoshikawa, K., Saeki, S., Sano, H., Iwanaga, T., and Tohda, Y. (2021). HFpEF without elevated right ventricular systolic pressure is a favorable prognostic indicator in patients with IPF requiring hospitalization for heart failure. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0245778"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1183\/09031936.00102107","article-title":"Left ventricular diastolic dysfunction in idiopathic pulmonary fibrosis: A tissue Doppler echocardiographic study","volume":"31","author":"Papadopoulos","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hershko, T., Freund, O., Schneer, S., Segel, M.J., Wand, O., Bar-Shai, A., Shitrit, D., Levy, L., Adir, Y., and Unterman, A. (2025). Interstitial Lung Diseases in Israel: Large Variability in Close Geographic Proximity. Diagnostics, 15.","DOI":"10.3390\/diagnostics15212780"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107901","DOI":"10.1016\/j.rmed.2024.107901","article-title":"Hypersensitivity pneumonitis radiologic features in interstitial lung diseases","volume":"236","author":"Shalmon","year":"2025","journal-title":"Respir. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.echo.2018.06.004","article-title":"Guidelines for Performing a Comprehensive Transthoracic Echocardiographic Examination in Adults: Recommendations from the American Society of Echocardiography","volume":"32","author":"Mitchell","year":"2019","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.echo.2016.01.011","article-title":"Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging","volume":"29","author":"Nagueh","year":"2016","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"180071","DOI":"10.1183\/16000617.0071-2018","article-title":"Acute exacerbations of progressive-fibrosing interstitial lung diseases","volume":"27","author":"Kolb","year":"2018","journal-title":"Eur. Respir. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17534666251335774","DOI":"10.1177\/17534666251335774","article-title":"Treatable traits in interstitial lung disease: A narrative review","volume":"19","author":"Harrison","year":"2025","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"495","DOI":"10.3899\/jrheum.2023-0801","article-title":"Contribution of Left Ventricular Diastolic Dysfunction to Survival and Breathlessness in Systemic Sclerosis\u2013Associated Interstitial Lung Disease","volume":"51","author":"Fairley","year":"2024","journal-title":"J. Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Stumpf, M.J., Wirtz, M.M.L., Fleddermann, M.F., Biener, L., Weinhold, L., Weber, M., Schaefer, C.A., Nickenig, G., Skowasch, D., and Pizarro, C. (2024). Impact of interstitial lung disease on left ventricular myocardial function. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0286423"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in Heart Failure with a Preserved Ejection Fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1056\/NEJMoa1313731","article-title":"Spironolactone for Heart Failure with Preserved Ejection Fraction","volume":"370","author":"Pitt","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1056\/NEJMoa1908655","article-title":"Angiotensin\u2013Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction","volume":"381","author":"Solomon","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/ajh.2009.173","article-title":"Blood Pressure Control Determines Improvement in Diastolic Dysfunction in Early Hypertension","volume":"22","author":"Almuntaser","year":"2009","journal-title":"Am. J. Hypertens."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.echo.2025.03.011","article-title":"Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography and for Heart Failure With Preserved Ejection Fraction Diagnosis: An Update from the American Society of Echocardiography","volume":"38","author":"Nagueh","year":"2025","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1136\/hrt.2005.080150","article-title":"Characteristics of left ventricular diastolic dysfunction in the community: An echocardiographic survey","volume":"92","author":"Abhayaratna","year":"2006","journal-title":"Heart"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1093\/aje\/kww214","article-title":"Prevalence and Predictors of Diastolic Dysfunction According to Different Classification Criteria: The Coronary Artery Risk Development in Young in Adults Study","volume":"185","author":"Colangelo","year":"2017","journal-title":"Am. J. Epidemiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1001\/archinte.164.5.551","article-title":"Association Between Pulmonary Fibrosis and Coronary Artery Disease","volume":"164","author":"Kizer","year":"2004","journal-title":"Arch. Intern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e033596","DOI":"10.1161\/JAHA.123.033596","article-title":"Impact of Coronary Microvascular Dysfunction on Functional Left Ventricular Remodeling and Diastolic Dysfunction","volume":"13","author":"Aldujeli","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.amjmed.2024.02.034","article-title":"Smoking and respiratory diseases in patients with coronary microvascular dysfunction","volume":"137","author":"Freund","year":"2024","journal-title":"Am. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.jcmg.2022.12.027","article-title":"Relation of Left Ventricular Diastolic Function to Global Fibrosis Burden: Implications for Heart Failure Risk Stratification","volume":"16","author":"Lewandowski","year":"2023","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3899\/jrheum.2024-0154","article-title":"The Scleroderma Tango: Unraveling the Delicate Dance of Diastolic Dysfunction and Interstitial Lung Disease","volume":"51","author":"Jani","year":"2024","journal-title":"J. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1056\/NEJMoa1402582","article-title":"A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis","volume":"370","author":"King","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1038\/s41591-021-01452-0","article-title":"Pirfenidone in heart failure with preserved ejection fraction: A randomized phase 2 trial","volume":"27","author":"Lewis","year":"2021","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1513\/AnnalsATS.201903-198RL","article-title":"Angiotensin Receptor Blockers and Subclinical Interstitial Lung Disease: The MESA Study","volume":"16","author":"Gannon","year":"2019","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.chest.2019.04.015","article-title":"Association of Angiotensin Modulators with the Course of Idiopathic Pulmonary Fibrosis","volume":"156","author":"Kreuter","year":"2019","journal-title":"CHEST"}],"container-title":["Advances in Respiratory Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2543-6031\/94\/4\/57\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:18:41Z","timestamp":1785921521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2543-6031\/94\/4\/57"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["arm94040057"],"URL":"https:\/\/doi.org\/10.3390\/arm94040057","relation":{},"ISSN":["2543-6031"],"issn-type":[{"value":"2543-6031","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}