{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:45:22Z","timestamp":1760060722395,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Center for Complementary &amp; Integrative Health of the National Institutes of Health","award":["R33AT010680"],"award-info":[{"award-number":["R33AT010680"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Vascular endothelial function is closely related to brain health, especially in individuals with cardiovascular risk factors. In a randomized, crossover clinical trial (NCT04121741), we have previously shown that 30 min of singing improves microvascular endothelial function in older adults with coronary artery disease. Here, we report on secondary and exploratory analyses, including (1) changes in cortisol and cytokine levels and their impact on vascular endothelial function, and (2) the impact of personal music experience on vascular function. Methods: Participants had three study visits separated by 2\u20137 days, according to a randomized, researcher-blinded, crossover, controlled design: (1) a 30-min period of live singing with an in-person music therapist, (2) a 30-min period of singing along to an instructional video and (3) a 30-min rest (control). Primary outcomes included macrovascular endothelial function assessed by brachial artery flow-mediated dilation (BA FMD%) and microvascular function assessed by peripheral arterial tonometry [Framingham reactive hyperemia index (fRHI) and reactive hyperemia index (RHI)]. Exploratory outcomes included (log) changes in salivary cortisol and cytokine (IL-6, TNF-\u03b1, IL-1\u03b2, IL-8) levels. Participants were asked to complete the Brief Music Experience Questionnaire (BMEQ), a 53-item validated self-report questionnaire designed to measure an individual\u2019s overall experience with music. The BMEQ assesses how people perceive, react to, and engage with music in various aspects of their lives. Results: Sixty-five subjects (mean age 67.7 \u00b1 6.6 years, 40% female) completed the study. Compared to those subjects completing the BMEQ (n = 31), there were no significant differences in age, sex, race, or presence of diabetes mellitus, hypertension, high cholesterol, heart failure, chronic kidney disease, or chronic respiratory disease in subjects who did not complete the BMEQ (n = 34). Total BMEQ score did not impact changes in BA FMD% (\u22123.49 \u00b1 2.00, p = 0.086), changes in fRHI (0.58 \u00b1 0.93, p = 0.535), or changes in RHI (0.73 \u00b1 0.65, p = 0.262). When we decompose the sum of squares based on intervention, sex, race, and age, the BMEQ score does not predict changes in vascular function measures. In cross-over analyses, there were no acute changes in salivary cortisol or cytokine levels with 30 min of singing compared to control. Changes in IL-8 were directly related to changes in microvascular endothelial function (0.470 \u00b1 0.184, p = 0.012 for RHI and 0.780 \u00b1 0.248, p = 0.002 for fRHI). Changes in TNF-\u03b1 were inversely related to changes in fRHI (\u22120.547 \u00b1 0.263, p = 0.040). Changes in cortisol concentrations were not related to measures of vascular function. Conclusions: The beneficial changes in microvascular endothelial function are not modified by personal music experience in older subjects with known coronary artery disease. There were no changes in salivary cortisol or cytokine levels after 30 min of singing compared to control.<\/jats:p>","DOI":"10.3390\/brainsci15090996","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T10:06:25Z","timestamp":1758017185000},"page":"996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Does Music Experience Impact the Vascular Endothelial Response to Singing?"],"prefix":"10.3390","volume":"15","author":[{"given":"Mehri","family":"Bagherimohamadipour","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Hammad","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Visotcky","sequence":"additional","affiliation":[{"name":"CIBMTR<sup>\u00ae<\/sup> (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7780-6825","authenticated-orcid":false,"given":"Rodney","family":"Sparapani","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-7197","authenticated-orcid":false,"given":"Jacquelyn","family":"Kulinski","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Rodgers, J.L., Jones, J., Bolleddu, S.I., Vanthenapalli, S., Rodgers, L.E., Shah, K., Karia, K., and Panguluri, S.K. (2019). Cardiovascular Risks Associated with Gender and Aging. J. Cardiovasc. Dev. Dis., 6.","key":"ref_1","DOI":"10.3390\/jcdd6020019"},{"doi-asserted-by":"crossref","unstructured":"Bai, T., Yu, S., and Feng, J. (2022). Advances in the Role of Endothelial Cells in Cerebral Small Vessel Disease. Front. Neurol., 13.","key":"ref_2","DOI":"10.3389\/fneur.2022.861714"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"H2","DOI":"10.1152\/ajpheart.00471.2010","article-title":"Assessment of flow-mediated dilation in humans: A methodological and physiological guideline","volume":"300","author":"Thijssen","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e002270","DOI":"10.1161\/JAHA.115.002270","article-title":"Prognostic Value of Flow-Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis","volume":"4","author":"Matsuzawa","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0002-9149(02)02433-5","article-title":"Effect of exercise on upper and lower extremity endothelial function in patients with coronary artery disease","volume":"90","author":"Gokce","year":"2002","journal-title":"Am. J. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.jpeds.2004.02.027","article-title":"Effects of exercise training on vascular function in obese children","volume":"144","author":"Watts","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/clc.23096","article-title":"Association between ideal cardiovascular health and markers of subclinical cardiovascular disease","volume":"41","author":"Shpilsky","year":"2018","journal-title":"Clin. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.tcm.2021.06.004","article-title":"Effects of music on the cardiovascular system","volume":"32","author":"Kulinski","year":"2021","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1080\/17437199.2019.1627897","article-title":"Effects of music interventions on stress-related outcomes: A systematic review and two meta-analyses","volume":"14","author":"Spruit","year":"2020","journal-title":"Health Psychol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jvoice.2017.07.008","article-title":"A Review of the Physiological Effects and Mechanisms of Singing","volume":"32","author":"Kang","year":"2018","journal-title":"J. Voice"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e000959","DOI":"10.1136\/bmjresp-2021-000959","article-title":"Physiological demands of singing for lung health compared with treadmill walking","volume":"8","author":"Philip","year":"2021","journal-title":"BMJ Open Respir. Res."},{"doi-asserted-by":"crossref","unstructured":"Bagherimohamadipour, M., Hammad, M., Visotcky, A., Sparapani, R., and Kulinski, J. (2025). Effects of singing on vascular health in older adults with coronary artery disease: A randomized, crossover trial. Front. Cardiovasc. Med., 12.","key":"ref_12","DOI":"10.3389\/fcvm.2025.1546462"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100374","DOI":"10.1016\/j.bbih.2021.100374","article-title":"Music, mental health, and immunity","volume":"18","author":"Rebecchini","year":"2021","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1177\/1943862111420539","article-title":"Reporting Guidelines for Music-based Interventions","volume":"3","author":"Robb","year":"2011","journal-title":"Music Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101566","DOI":"10.1016\/j.smrv.2021.101566","article-title":"Peripheral arterial tonometry-PAT technology","volume":"61","author":"Schnall","year":"2022","journal-title":"Sleep Med. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1161\/CIRCULATIONAHA.107.748574","article-title":"Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study","volume":"117","author":"Hamburg","year":"2008","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0735-1097(01)01746-6","article-title":"Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force","volume":"39","author":"Corretti","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0301-5629(02)00709-3","article-title":"Within-subject variability of flow-mediated vasodilation of the brachial artery in healthy men and women: Implications for experimental studies","volume":"29","author":"Bots","year":"2003","journal-title":"Ultrasound Med. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1097\/HJH.0b013e328353f222","article-title":"Assessment of flow-mediated dilation reproducibility: A nationwide multicenter study","volume":"30","author":"Ghiadoni","year":"2012","journal-title":"J. Hypertens."},{"doi-asserted-by":"crossref","unstructured":"Ryznar, R., Wong, C., Onat, E., Towne, F., LaPorta, A., and Payton, M. (2022). Principal component analysis of salivary cytokines and hormones in the acute stress response. Front. Psychiatry, 13.","key":"ref_20","DOI":"10.3389\/fpsyt.2022.957545"},{"doi-asserted-by":"crossref","unstructured":"Sanada, K., Montero-Marin, J., Alda Diez, M., Salas-Valero, M., Perez-Yus, M.C., Morillo, H., Demarzo, M.M., Garcia-Toro, M., and Garcia-Campayo, J. (2016). Effects of Mindfulness-Based Interventions on Salivary Cortisol in Healthy Adults: A Meta-Analytical Review. Front. Physiol., 7.","key":"ref_21","DOI":"10.3389\/fphys.2016.00471"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s40279-013-0139-5","article-title":"Prediction of maximal or peak oxygen uptake from ratings of perceived exertion","volume":"44","author":"Coquart","year":"2014","journal-title":"Sports Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.apmr.2004.10.043","article-title":"Borg\u2019s rating of perceived exertion scales: Do the verbal anchors mean the same for different clinical groups?","volume":"86","author":"Dawes","year":"2005","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3200\/JRLP.140.4.329-345","article-title":"The Music Experience Questionnaire: Development and correlates","volume":"140","author":"Werner","year":"2006","journal-title":"J. Psychol."},{"doi-asserted-by":"crossref","unstructured":"Jones, B., and Kenward, M.G. (1989). Design and analysis for three or more treatments. Design and Analysis of Cross-Over Trials, Chapman & Hall.","key":"ref_25","DOI":"10.4324\/9780203009277"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e60387","DOI":"10.2196\/60387","article-title":"United Voices Group-Singing Intervention to Address Loneliness and Social Isolation Among Older People with HIV During the COVID-19 Pandemic: Intervention Adaption Study","volume":"8","author":"Hill","year":"2024","journal-title":"JMIR Form. Res."},{"doi-asserted-by":"crossref","unstructured":"Tragantzopoulou, P., and Giannouli, V. (2025). A Song for the Mind: A Literature Review on Singing and Cognitive Health in Aging Populations. Brain Sci., 15.","key":"ref_27","DOI":"10.3390\/brainsci15030227"},{"key":"ref_28","first-page":"100533","article-title":"Predictors of improvement in cardiovascular biomarkers with singing","volume":"53","author":"Somasundaram","year":"2025","journal-title":"Am. Heart J. Plus"},{"doi-asserted-by":"crossref","unstructured":"Sakano, K., Ryo, K., Tamaki, Y., Nakayama, R., Hasaka, A., Takahashi, A., Ebihara, S., Tozuka, K., and Saito, I. (2014). Possible benefits of singing to the mental and physical condition of the elderly. Biopsychosoc. Med., 8.","key":"ref_29","DOI":"10.1186\/1751-0759-8-11"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/BF03345606","article-title":"Exercise and circulating cortisol levels: The intensity threshold effect","volume":"31","author":"Hill","year":"2008","journal-title":"J. Endocrinol. Investig."},{"doi-asserted-by":"crossref","unstructured":"Breit, S., Kupferberg, A., Rogler, G., and Hasler, G. (2018). Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Front. Psychiatry, 9.","key":"ref_31","DOI":"10.3389\/fpsyt.2018.00044"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"631","DOI":"10.3332\/ecancer.2016.631","article-title":"Singing modulates mood, stress, cortisol, cytokine and neuropeptide activity in cancer patients and carers","volume":"10","author":"Fancourt","year":"2016","journal-title":"Ecancermedicalscience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jneuroim.2018.02.011","article-title":"Circulating cytokine levels are associated with symptoms of depression and anxiety among people with alcohol and drug use disorders","volume":"318","author":"Martinez","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ctim.2016.03.017","article-title":"A mixed-method systematic review to investigate the effect of group singing on health related quality of life","volume":"27","author":"Reagon","year":"2016","journal-title":"Complement. Ther. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25302","DOI":"10.31083\/RCM25302","article-title":"Physiological Mechanisms Driving Microcirculatory Enhancement: The Impact of Physical Activity","volume":"26","author":"Li","year":"2025","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.21037\/atm-22-5763","article-title":"Exercise training combined with alprostadil improves myocardial infarction and coronary microcirculation disorder in aged rats by inhibiting mitogen-activated protein kinase (MAPK) signaling pathway activation","volume":"10","author":"Zhang","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1161\/HYPERTENSIONAHA.108.119883","article-title":"Assessment of sympathetic cardiovascular drive in human hypertension: Achievements and perspectives","volume":"54","author":"Grassi","year":"2009","journal-title":"Hypertension"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3400\/avd.ra.14-00048","article-title":"The Relationship between Vascular Function and the Autonomic Nervous System","volume":"7","author":"Amiya","year":"2014","journal-title":"Ann. Vasc. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1161\/01.CIR.101.13.1519","article-title":"IL-8 is an angiogenic factor in human coronary atherectomy tissue","volume":"101","author":"Simonini","year":"2000","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1042\/CS20080196","article-title":"Role of TNF-alpha in vascular dysfunction","volume":"116","author":"Zhang","year":"2009","journal-title":"Clin. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100504","DOI":"10.1016\/j.bbih.2022.100504","article-title":"The inflammatory immune system after wake up in healthy male individuals: A highly standardized and controlled study","volume":"25","author":"Petrowski","year":"2022","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.tics.2013.02.007","article-title":"The neurochemistry of music","volume":"17","author":"Chanda","year":"2013","journal-title":"Trends Cogn. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.bbi.2017.01.011","article-title":"The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis","volume":"64","author":"Marsland","year":"2017","journal-title":"Brain Behav. Immun."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/9\/996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:15Z","timestamp":1760035575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/9\/996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["brainsci15090996"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15090996","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}