Monitoring of the Sympathetic/Vagal Balance Through Multiparametric Analysis of Heart Rate Variability (HRV)

NCT07471802 | Not Yet Recruiting

• 1 other identifier: 27089
• Study Type: observational
• Target: 150
• Locations: 0 countries
• Sites: N/A

Brief Summary

The autonomic nervous system (ANS) plays a crucial role in cardiovascular regulation by modulating heart rate in response to endogenous and environmental stimuli. Heart rate variability (HRV) analysis has been widely used as a non-invasive tool to assess autonomic function and the balance between sympathetic and parasympathetic activity. Although the physiological interpretation of some HRV parameters remains debated-particularly the low-frequency (LF) spectral component as an index of sympathetic activation-HRV remains an important method for evaluating autonomic cardiovascular control. Reduced HRV has been associated with adverse outcomes in several pathological conditions and physiologically declines with aging, mainly due to progressive neuronal loss at central and spinal levels. Among conditions characterized by autonomic dysfunction, cardiovascular autonomic neuropathy (CAN) represents a common complication of diabetes mellitus (DM) and metabolic syndrome. CAN, defined as impairment of autonomic control of the cardiovascular system, develops early in the disease course and is associated with increased mortality and a higher risk of cardiovascular and renal complications. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as glucose-lowering agents, have demonstrated significant cardiovascular and renal protective effects beyond glycemic control. Growing evidence suggests that these drugs exert sympathoinhibitory effects that may be beneficial not only in diabetic patients but also in conditions characterized by sympathetic overactivity. Preclinical and clinical studies have shown that SGLT2i influence autonomic regulation, including sympathetic control of renal function, with reported improvements in 24-hour blood pressure regulation and HRV parameters. Large randomized trials have further confirmed the cardioprotective effects of SGLT2i therapy. Studies such as EMBODY, EMPEROR-Reduced, and EMPEROR-Preserved have demonstrated improvements in HRV indices and significant reductions in cardiovascular death and hospitalization for heart failure, irrespective of diabetic status. Despite these findings, the mechanisms underlying these benefits remain incompletely understood. While reduced sympathetic activity has been proposed as a key mechanism, emerging evidence suggests that SGLT2i may also enhance vagal modulation. Therefore, the present study aims to investigate, in a larger population, the effects of SGLT2i therapy on sympathovagal balance using both spectral HRV parameters and additional indices, including the parasympathetic nervous system index (PNSi), sympathetic nervous system index (SNSi), and the Baevsky Stress Index.

Conditions

Diabete Type 2; Heart Failure; Kidney Disease, Chronic; Cardiorenal Syndrome

Outcome Measures

Primary Outcomes (2)

• Assessment of the sympathetic/vagal balance at baseline

  All outcomes (primary and secondary) will be evaluated at rest, during daily activity and NREM sleep, with short-term (2- and 5-minute) Heart Rate Variability (HRV) analysis from 24-hour Holter recordings, with Kubios Scientific, a gold-standard HRV software tool for research, providing automatic calculation of multiple parameters in the time domain (TD), frequency domain (FD), with non-linear (NL) methods, and automatic time-varying computation of the parasympathetic (PNSi), sympathetic (SNSi), and Baevsky stress (BSTRi) indices, for faster and more comprehensive assessment of cardiac autonomic modulation (the PNS index ranges between -1 and 1 for 68% of the adult population at rest, and similarly scaled SNS index values outside the -1 to 1 range indicate higher or lower than average sympathetic activity) \[1\]. Tables reporting the laboratory's average age-related normal values for all parameters measured in daily activity and NREM sleep are available \[2\]. (Ref. moved to Citations)

  24 hours

• Changes the sympathetic/vagal balance during pharmacological treatment with SGLT2 inhibitors

  Outcome 2 will be assessed with Kubios, measuring the same HRV parameters and indices from the 24-hour follow-up Holter recordings. Changes of the sympathetic/vagal balance will be individually evaluated in each condition (rest, daily activity, and NREM sleep) and compared with the baseline values. No score on a scale will be used.

  24 months

Secondary Outcomes (3)

• Evaluation of diabetic cardiovascular autonomic neuropathy

  24 months

• Correlation between improvement of heart failure or cardiorenal disease

  24 months

• Detection of improvement or normalization of cardiac autonomic balance

  24 months

Interventions

HOLTER ECG monitoring DIAGNOSTIC_TEST

Monitoring of the sympathetic/vagal balance through multiparametric analysis of heart rate variability (HRV) using 24 hours ECG HOLTER

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Outpatient patients with: * Type 2 DM, with or without heart failure and/or chronic kidney disease, with a clinical indication to undergo HOLTER ECG monitoring to exclude or quantify concomitant autonomic dysfunction. * Patients with Cardiomyopathy, with heart failure or cardiorenal syndrome, with a cardiological indication to undergo HOLTER ECG monitoring to exclude or quantify signs attributable to ischemic heart disease and/or cardiac arrhythmias.

You may qualify if:

• Age over 18 years;
• Signed informed consent;
• in Sinus rhythm;
• Patients for whom HOLTER ECG monitoring is clinically indicated, to early identify the possible onset or progression of diabetic autonomic neuropathy, or ischemic changes, or potentially arrhythmogenic electrophysiological alterations;
• On optimized pharmacological treatment according to clinical practice, naïve to SGLT2 inhibitor therapy, prescribed according to the (1A) recommendations of the ESC 2023 guidelines.

You may not qualify if:

• Patients with atrial fibrillation or other arrhythmic burden incompatible with accurate HRV analysis;
• Pacemaker or ICD carriers;
• Immunodeficient patients or patients at risk of developing infections.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Related Publications (5)

• Tarvainen MP, Niskanen JP, Lipponen JA, Ranta-Aho PO, Karjalainen PA. Kubios HRV--heart rate variability analysis software. Comput Methods Programs Biomed. 2014;113(1):210-20. doi: 10.1016/j.cmpb.2013.07.024. Epub 2013 Aug 6.

  PMID: 24054542 BACKGROUND

• Brisinda D, Picerni M, Fenici P, and Fenici R, "Rapid assessment of cardiac autonomic modulation and adaptive stress responses: Automatic calculation of time-varying parasympathetic, sympathetic, and Baevsky stress indexes," Brain & Heart., vol. 2, no. 4, p. 3503, 2024, doi: 10.36922/bh.3503.

  BACKGROUND

• Balcioglu AS, Celik E, Sahin M, Gocer K, Aksu E, Aykan AC. Dapagliflozin Improves Cardiac Autonomic Function Measures in Type 2 Diabetic Patients with Cardiac Autonomic Neuropathy. Anatol J Cardiol. 2022 Nov;26(11):832-840. doi: 10.5152/AnatolJCardiol.2022.1934.

  PMID: 35949125 BACKGROUND

• Zhou L, Niu M, Chen W, Hu Q, Chen Y, Geng X, Gu J. Effects of dapagliflozin on heart rate variability, cardiac function, and short-term prognosis in early-onset post-myocardial infarction heart failure. Front Cardiovasc Med. 2025 Jan 6;11:1490316. doi: 10.3389/fcvm.2024.1490316. eCollection 2024.

  PMID: 39834729 BACKGROUND

• Dimitriadis K, Pitsiori D, Alexiou P, Pyrpyris N, Sakalidis A, Beneki E, Iliakis P, Tatakis F, Theofilis P, Tsioufis P, Konstantinidis D, Aggeli K, Tsioufis K. Modulating Sympathetic Nervous System With the Use of SGLT2 Inhibitors: Where There Is Smoke, There Is Fire? J Cardiovasc Pharmacol. 2025 Jan 1;85(1):12-20. doi: 10.1097/FJC.0000000000001644.

  PMID: 39436317 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Heart Failure; Renal Insufficiency, Chronic; Cardio-Renal Syndrome

Interventions

Electrocardiography, Ambulatory

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Heart Diseases; Cardiovascular Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Electrocardiography; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Diagnostic Techniques and Procedures; Diagnosis; Electrodiagnosis; Monitoring, Ambulatory; Monitoring, Physiologic

Study Officials

• Donatella Brisinda, MD

  Fondazione Policlinico Universitario Agostino Gemelli IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Donatella Brisinda, MD

CONTACT

+390630158195; donatella.brisinda@policlinicogemelli.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2026
• First Posted: March 13, 2026
• Study Start: March 25, 2026
• Primary Completion (Estimated): March 25, 2031
• Study Completion (Estimated): September 1, 2031
• Last Updated: March 24, 2026

Record last verified: 2026-03