{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T22:54:10Z","timestamp":1776207250181,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T00:00:00Z","timestamp":1688515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Entropy"],"abstract":"<jats:p>Cardiovascular diseases are the leading cause of morbidity and mortality in adults worldwide. There is one common pathophysiological aspect present in all cardiovascular diseases\u2014dysfunctional heart rhythm regulation. Taking this aspect into consideration for cardiovascular risk predictions opens important research perspectives, allowing for the development of preventive treatment techniques. The aim of this study was to find out whether certain pathologically appearing signs in the heart rate variability (HRV) of an apparently healthy person, even with high HRV, can be defined as biomarkers for a disturbed cardiac regulation and whether this can be treated preventively by a drug-free method. This multi-phase study included 218 healthy subjects of either sex, who consecutively visited the physician at Gesundheit clinic because of arterial hypertension, depression, headache, psycho-emotional stress, extreme weakness, disturbed night sleep, heart palpitations, or chest pain. In study phase A, baseline measurement to identify individuals with cardiovascular risks was done. Therefore, standard HRV, as well as the new cardiorhythmogram (CRG) method, were applied to all subjects. The new CRG analysis used here is based on the recently introduced LF drops and HF counter-regulation. Regarding the mechanisms of why these appear in a steady-state cardiorhythmmogram, they represent non-linear event-based dynamical HRV biomarkers. The next phase of the study, phase B, tested whether the pathologically appearing signs identified via CRG in phase A could be clinically influenced by drug-free treatment. In order to validate the new CRG method, it was supported by non-linear HRV analysis in both phase A and in phase B. Out of 218 subjects, the pathologically appearing signs could be detected in 130 cases (60%), p &lt; 0.01, by the new CRG method, and by the standard HRV analysis in 40 cases (18%), p &lt; 0.05. Thus, the CRG method was able to detect 42% more cases with pathologically appearing cardiac regulation. In addition, the comparative CRG analysis before and after treatment showed that the pathologically appearing signs could be clinically influenced without the use of medication. After treatment, the risk group decreased eight-fold\u2014from 130 people to 16 (p &lt; 0.01). Therefore, progression of the detected pathological signs to structural cardiac pathology or arrhythmia could be prevented in most of the cases. However, in the remaining risk group of 16 apparently healthy subjects, 8 people died due to all-cause mortality. In contrast, no other subject in this study has died so far. The non-linear parameter which is able to quantify the changes in CRGs before versus after treatment is FWRENYI4 (symbolic dynamic feature); it decreased from 2.85 to 2.53 (p &lt; 0.001). In summary, signs of pathological cardiac regulation can be identified by the CRG analysis of apparently healthy subjects in the early stages of development of cardiac pathology. Thus, our method offers a sensitive biomarker for cardiovascular risks. The latter can be influenced by non-drug treatments (acupuncture) to stop the progression into structural cardiac pathologies or arrhythmias in most but not all of the patients. Therefore, this could be a real and easy-to-use supplemental method, contributing to primary prevention in cardiology.<\/jats:p>","DOI":"10.3390\/e25071023","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:34:30Z","timestamp":1688603670000},"page":"1023","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pathological Heart Rate Regulation in Apparently Healthy Individuals"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0382-4542","authenticated-orcid":false,"given":"Ludmila","family":"Sidorenko","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, State University of Medicine and Pharmacy, \u201cNicolae Testemitanu\u201d, Stefan cel Mare Str. 165, MD-2004 Chisinau, Moldova"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Sidorenko","sequence":"additional","affiliation":[{"name":"Medical Center \u201cGesundheit\u201d, Mihai Kogalniceanu Str. 45\/2, MD-2009 Chisinau, Moldova"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrej","family":"Gapelyuk","sequence":"additional","affiliation":[{"name":"Cardiovascular Physics, Humboldt-Universit\u00e4t zu Berlin, D-10099 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0922-9971","authenticated-orcid":false,"given":"Niels","family":"Wessel","sequence":"additional","affiliation":[{"name":"Cardiovascular Physics, Humboldt-Universit\u00e4t zu Berlin, D-10099 Berlin, Germany"},{"name":"MSB Medical School Berlin GmbH, D-14197 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.ecl.2022.02.005","article-title":"Assessment of Cardiovascular Disease Risk: A 2022 Update","volume":"51","author":"Goldsborough","year":"2022","journal-title":"Endocrinol. 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