{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:43Z","timestamp":1760060683297,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Education, Science, and Technological Development of Serbia","award":["TP-32040","III 45003"],"award-info":[{"award-number":["TP-32040","III 45003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Syncope is a common clinical problem often requiring pharmacological treatment, yet evidence-based therapies remain limited. Midodrine, a vasopressor agent, is frequently used, though its autonomic effects over time remain unclear. This study aimed to assess autonomic nervous system changes and blood pressure response in syncope patients treated with Midodrine, placebo, or their combination. Additionally, the structural properties of the Midodrine placebo were analyzed using nanotechnological methods. Methods: A total of 67 patients with syncope were randomized to receive Midodrine, sucrose placebo, or their combination over three weeks. All participants underwent 24 h Holter ECG with heart rate variability (HRV) analysis and ambulatory blood pressure monitoring before and after therapy. Structural analysis of Midodrine tablets, sucrose, and Midodrine placebo was performed using Raman spectroscopy and X-ray diffraction (XRD). Results: Patients receiving the Midodrine\u2013placebo combination showed a significant reduction in HRV markers of parasympathetic activity (RMSSD, pNN50, HF) and an increase in sympathetic dominance (LF\/HF ratio) compared to the other groups. Only this group showed a statistically significant rise in average systolic and diastolic blood pressure. Raman and XRD analyses revealed structural alterations in the sucrose-based placebo compared to its original form, indicating subtle changes in crystalline structure. Conclusions: In this exploratory study, the combination of Midodrine and placebo was associated with autonomic imbalance and modest increases in blood pressure, which may indicate a potential effect in patients with hypotensive syncope phenotypes. These preliminary findings should be interpreted with caution, and the structural modifications observed in the placebo formulation are presented as hypotheses requiring further investigation rather than established mechanisms.<\/jats:p>","DOI":"10.3390\/jcm14186386","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T12:04:55Z","timestamp":1757505895000},"page":"6386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Programmed Placebo Effect in Patients with Syncope: Preliminary Clinical and Nanostructural Insights with a Hypothetical Quantum-Level Interpretation"],"prefix":"10.3390","volume":"14","author":[{"given":"Branka","family":"Had\u017ei\u0107","sequence":"first","affiliation":[{"name":"Institute of Physics, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neboj\u0161a","family":"Rom\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Physics, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5090-6029","authenticated-orcid":false,"given":"Nikola","family":"Markovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-8449","authenticated-orcid":false,"given":"Ma\u0161a","family":"Petrovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milovan","family":"Boji\u0107","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"},{"name":"School of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Branislav","family":"Milovanovi\u0107","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Diseases \u201cDedinje\u201d, 11000 Belgrade, Serbia"},{"name":"School of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1093\/eurheartj\/ehy037","article-title":"2018 ESC Guidelines for the Diagnosis and Management of Syncope","volume":"39","author":"Brignole","year":"2018","journal-title":"Eur. 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