{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:11:32Z","timestamp":1791447092256,"version":"4.3.3"},"reference-count":48,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Calcific aortic stenosis (CAS) is a newly emerging pandemic in elderly individuals due to the aging of the population in the world. Surgical Aortic Valve Replacement (SAVR) and Transcatheter Aortic Valve Replacement (TAVR) are the cornerstone of the management of severe aortic stenosis accompanied by one or more symptoms. Moreover, an appropriate interventional treatment of CAS, in elderly patients, is a very complex decision for heart teams, to avoid bad outcomes such as operative mortality, cardiovascular and all-cause death, hospitalization for heart failure, worsening of quality of life. In fact, CAS in the elderly is not only a focal valve disease, but a very complex clinical picture with different risk factors and etiologies, differing underlying pathophysiology, large phenotypic heterogeneity in a context of subjective biological, phenotypic and functional aging until frailty and disability. In this review, we analyzed separately and in a more integrated manner, the natural and prognostic histories of the progression of aortic stenosis, the phenotypes of myocardial damage and heart failure, within the metrics and aging trajectory. The aim is to suggest, during the clinical timing of valve disease, the best interval time for an appropriate and effective interventional treatment in each older patient, beyond subjective symptoms by integration of clinical, geriatric, chemical, and advanced imaging biomarkers.<\/jats:p>","DOI":"10.3390\/jcm14155560","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T08:33:06Z","timestamp":1754555586000},"page":"5560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Calcific Aortic Valve Stenosis: A Focal Disease in Older and Complex Patients\u2014What Could Be the Best Time for an Appropriate Interventional Treatment?"],"prefix":"10.3390","volume":"14","author":[{"given":"Annamaria","family":"Mazzone","sequence":"first","affiliation":[{"name":"Fondazione Toscana Gabriele Monasterio Massa, 54100 Massa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-200X","authenticated-orcid":false,"given":"Augusto","family":"Esposito","sequence":"additional","affiliation":[{"name":"Fondazione Toscana Gabriele Monasterio Massa, 54100 Massa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4604-0871","authenticated-orcid":false,"given":"Ilenia","family":"Foffa","sequence":"additional","affiliation":[{"name":"Fondazione Toscana Gabriele Monasterio Massa, 54100 Massa, Italy"},{"name":"Istituto di Fisiologia Clinica, Consiglio Nazionale delle Ricerche, 54100 Massa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5244-0556","authenticated-orcid":false,"given":"Sergio","family":"Berti","sequence":"additional","affiliation":[{"name":"Fondazione Toscana Gabriele Monasterio Massa, 54100 Massa, Italy"},{"name":"Istituto di Fisiologia Clinica, Consiglio Nazionale delle Ricerche, 54100 Massa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0140-6736(06)69208-8","article-title":"Burden of valvular heart diseases: A population-based study","volume":"368","author":"Nkomo","year":"2006","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1161\/01.CIR.38.1S5.V-61","article-title":"Aortic stenosis","volume":"38","author":"Ross","year":"1968","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1001\/jama.2024.16477","article-title":"Calcific Aortic Stenosis: A Review","volume":"332","author":"Otto","year":"2024","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Damluji, A.A., Bernacki, G., Afilalo, J., Lyubarova, R., Orkaby, A.R., Kwak, M.J., Hummel, S., Kirkpatrick, J.N., Maurer, M.S., and Wenger, N. (2024). TAVR in Older Adults: Mowing Towards a Comprehensive Geriatric Assessment and Away from Chronological Age: JACC Family Series. JACC Adv., 3.","DOI":"10.1016\/j.jacadv.2024.100877"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mazzone, A., Del Turco, S., Trianni, G., Quadrelli, P., Marotta, M., Bastiani, L., Gasbarri, T., D\u2019Agostino, A., Mariani, M., and Basta, G. (2023). The Positive Impact of Early Frailty Levels on Mortality in Elderly Patients with Severe Aortic Stenosis Undergoing Transcatheter\/Surgical Aortic Valve Replacement. J. Cardiovasc. Dev. Dis., 10.","DOI":"10.3390\/jcdd10050212"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1016\/j.jacc.2021.09.1367","article-title":"Evaluating Medical Therapy for Calcific Aortic Stenosis: JACC State-of the-Art Review","volume":"78","author":"Lindman","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.jacc.2020.11.035","article-title":"2020 ACC\/AHA guideline for the management of patients with valvular heart disease: Executive summary: A report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"77","author":"Otto","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/eurheartj\/ehab395","article-title":"2021 ESC\/EACTS guidelines for the management of valvular heart disease","volume":"43","author":"Vahanian","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.jacc.2024.11.006","article-title":"Aortic Valve Replacement vs Clinical Sureveillance in Asymptomatic Severe Aortic Valve Replacement: A Systematic review and Meta-Analysis","volume":"85","author":"Banovic","year":"2025","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gilmanov, D., Mazzone, A., Berti, S., and Glauber, M. (2011). Is comorbidity equivalent to symptoms in asymptomatic AS?. Nat. Rev. Cardiol., 8.","DOI":"10.1038\/nrcardio.2011.203-c1"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Halapas, A., and Cokkinos, D.V. (2025). Aortic Stenosis Progression Is a New Cardiovascular Paradigm Coming of Age?. J. Clin. Med., 14.","DOI":"10.3390\/jcm14030903"},{"key":"ref_12","first-page":"481","article-title":"Management of Asymptomatic Severe Aortic Stenosis: Evolving Concepts in Timing of Valve Replacement","volume":"13","author":"Lindman","year":"2020","journal-title":"Cardiovasc. Imaging"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Du, Y., G\u00f6ssl, M., Garcia, S., Enriquez-Sarano, M., Cavalcante, J.L., Bae, R., Hashimoto, G., Fukui, M., Lopes, B., and Ahmed, A. (2021). Natural history observations in moderate aortic stenosis. BMC Cardiovasc. Disord., 21.","DOI":"10.1186\/s12872-021-01901-1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1161\/CIRCULATIONAHA.111.079368","article-title":"Should severe aortic stenosis be operated on before symptom onset? Severe aortic stenosis should not be operated on before symptom onset","volume":"126","author":"Shah","year":"2012","journal-title":"Circulation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.hfc.2023.02.005","article-title":"Aortic Valvular Stenosis and Heart Failure: Advances in Diagnostic, Management, and Intervention","volume":"19","author":"Jean","year":"2023","journal-title":"Heart Fail. Clin."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mihatov, N., and Pibarot, P. (2024). Moderate Aortic Stenosis with Cardiac Damage: A New Type of Severe Aortic Stenosis. Struct. Heart, 8.","DOI":"10.1016\/j.shj.2024.100336"},{"key":"ref_17","first-page":"43","article-title":"Asymptomatic Severe Aortic Stenosis in the Elderly","volume":"10","author":"Zilberszac","year":"2017","journal-title":"Cardiovasc. Imaging"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Greenhalgh, T., A\u2019Court, C., and Shaw, S. (2017). Understanding heart failure: Explaining telehealth\u2014A hermeneutic systematic review. BMC Cardiovasc. Disord., 17.","DOI":"10.1186\/s12872-017-0594-2"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.amjcard.2020.12.046","article-title":"Transcatheter Aortic Valve Implantation in Patients with Acute Severe Aortic Stenosis Hospitalized with Acute Heart Failure","volume":"144","author":"Kaewkes","year":"2021","journal-title":"Am. J. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Esposito, A., Foffa, I., Vecoli, C., Bastiani, L., Berti, S., and Mazzone, A. (2024). The impact of Acute Heart Failure on Frailty Degree and Outcomes in Elderly Patients with Severe Aortic Stenosis and Chronic Heart Failure with Preserved Ejection Fraction. J. Cardiovasc. Dev. Dis., 11.","DOI":"10.3390\/jcdd11050150"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1001\/jamacardio.2024.3486","article-title":"Aortic Stenosis, Heart Failure, and Aortic Valve Replacement","volume":"9","author":"Mengi","year":"2024","journal-title":"JAMA Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ijcard.2016.09.020","article-title":"The frailty syndrome and mortality among very old patients with symptomatic severe aortic stenosis under different treatments","volume":"224","author":"Parajes","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.recesp.2019.11.015","article-title":"Asymptomatic aortic stenosis in a geriatric population: The role of frailty and comorbidity in mortality","volume":"74","author":"Ramos","year":"2021","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1056\/NEJMra2301292","article-title":"Frailty in Older Adults","volume":"391","author":"Kim","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.36628\/ijhf.2023.0064","article-title":"Heart Failure with Preserved Ejection Fraction and Frailty: From Young to Superaged Coexisting HFpEF and Frailty","volume":"6","author":"Fukui","year":"2024","journal-title":"Int. J. Heart Fail."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zamudio-Rodr\u00edguez, A., Avila-Funes, J.A., Tabue-Teguo, M., Dartigues, J.F., Amieva, H., and P\u00e9r\u00e8s, K. (2022). Towards an approach of disability along a continuum from robustness, pre-frailty, frailty to disability. Age Ageing, 51.","DOI":"10.1093\/ageing\/afac025"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., Monti, D., Capri, M., and Salvioli, S. (2018). The Continuum of Aging and Age-Related Diseases:Common Mechanisms but Different Rates. Front. Med., 5.","DOI":"10.3389\/fmed.2018.00061"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1161\/CIRCRESAHA.118.312816","article-title":"Time and Metric of Aging","volume":"123","author":"Ferrucci","year":"2018","journal-title":"Circ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.jcin.2024.01.284","article-title":"Cronological vs Biological Age in Interventional Cardiology: A Comprehensive Approach to Care for Older Adults: JACC Family Series","volume":"17","author":"Damluji","year":"2024","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Brunetti, E., Luc\u00e0, F., Presta, R., Marchionni, N., Boccanelli, A., Ungar, A., Rao, C.M., Ingianni, N., Lettino, M., and Del Sindaco, D. (2024). A Comprehensive Geriatric Workup and Frailty Assessment in Older Patients with Severe Aortic Stenosis. J. Clin. Med., 13.","DOI":"10.3390\/jcm13144169"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1056\/NEJMoa2405880","article-title":"Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis","volume":"392","author":"Schwartz","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1001\/jama.2024.22730","article-title":"Early Intervention in Patients with Asymptomatic Severe Aortic Stenosis and Myocardial Fibrosis: The EVOLVED Randomized Clinical Trial","volume":"333","author":"Loganath","year":"2025","journal-title":"JAMA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1161\/CIRCULATIONAHA.121.057639","article-title":"Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial","volume":"145","author":"Banovic","year":"2022","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJMoa1912846","article-title":"Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis","volume":"382","author":"Kang","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jacquemyn, X., S\u00e1, M.P., Mar\u00edn-Cuartas, M., Bax, J.J., Borger, M.A., Clavel, M.A., Pibarot, P., G\u00e9n\u00e9reux, P., and Sultan, I. (2025). Early aortic valve replacement versus conservative management in asymptomatic severe aortic stenosis: Meta-analysis of time-to-event data of randomized controlled trials. Int. J. Cardiol., 432.","DOI":"10.1016\/j.ijcard.2025.133269"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.jacc.2013.09.038","article-title":"Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population","volume":"63","author":"Kamstrup","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1093\/ehjcvp\/pvae092","article-title":"Lipid-lowering therapies for aortic stenosis: A drug-target Mendelian randomization study","volume":"11","author":"Ciofani","year":"2025","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1093\/eurheartj\/ehp158","article-title":"Association of fetuin-A levels with the progression of aortic valve calcification in non-dialyzed patients","volume":"30","author":"Koos","year":"2009","journal-title":"Eur. Heart J."},{"key":"ref_39","first-page":"384","article-title":"B-type natriuretic peptide in patients with asymptomatic severe aortic stenosis","volume":"105","author":"Nakatsuma","year":"2019","journal-title":"Heart"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Stein, E.J., Fearon, W.F., Elmariah, S., Kim, J.B., Kapadia, S., Kumbhani, D.J., Gillam, L., Whisenant, B., Quader, N., and Zajarias, A. (2022). Left Ventricular Hypertrophy and Biomarkers of Cardiac Damage and Stress in Aortic Stenosis. J. Am. Heart Assoc., 11.","DOI":"10.1161\/JAHA.121.023466"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1161\/CIRCULATIONAHA.125.074425","article-title":"Cardiac biomarkers in patients with asymptomatic severe aortic stenosis: Analysis from the EARLY TAVR trial","volume":"151","author":"Lindman","year":"2025","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, M., Chen, H., and Li, H. (2022). Prognostic Value of Global Longitudinal Strain in Asymptomatic Aortic Stenosis: A Systematic Review and Meta-Analysis. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.778027"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1093\/ehjci\/jeae040","article-title":"Peak atrial longitudinal strain and risk stratification in moderate and severe aortic stenosis","volume":"25","author":"Springhetti","year":"2024","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.jacc.2017.12.035","article-title":"Reverse Myocardial Remodeling Following Valve Replacement in Patients with Aortic Stenosis","volume":"71","author":"Treibel","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1093\/eurheartj\/ehx353","article-title":"Reappraising myocardial fibrosis in severe aortic stenosis: An invasive and non-invasive study in 133 patients","volume":"39","author":"Treibel","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.jacc.2011.03.064","article-title":"Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis","volume":"58","author":"Dweck","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.jcmg.2024.03.001","article-title":"Techniques for Tracking Biological Aging of the Cardiovascular System: JACC Family Series","volume":"17","author":"Szabo","year":"2024","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Karakasis, P., Theofilis, P., Patoulias, D., Vlachakis, P.K., Pamporis, K., Sagris, M., Ktenopoulos, N., Kassimis, G., Antoniadis, A.P., and Fragakis, N. (2025). Sodium-Glucose Cotransporter 2 Inhibitors in Aortic Stenosis: Toward a Comprehensive Cardiometabolic Approach. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26104494"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/15\/5560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:25:13Z","timestamp":1760034313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/15\/5560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,7]]},"references-count":48,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["jcm14155560"],"URL":"https:\/\/doi.org\/10.3390\/jcm14155560","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,7]]}}}