Exercise Prescription in Cardiac Rehabilitation Mediated by Autonomic Function

NCT07288840 | Enrolling By Invitation DMC

• 1 other identifier: FCT 2024.04320.BD
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 2

Brief Summary

Cardiac rehabilitation (CR) is an essential secondary prevention component in the treatment of cardiovascular diseases and one of the most cost- effective clinical interventions. Exercise training (ET) in CR programs (CRP) has unequivocal benefits in the reduction of cardiovascular adverse events, by decreasing the overactivated sympathetic tone. This ET added value can be measured by variables that express autonomic control using indirect (standard) or direct (experimental) methodologies. Direct autonomic assessment (ex. Microneurography) is accurate but unusable in daily practice, whereas standard indirect autonomic assessment using clinical parameters is imprecise, resulting in underprescription to safeguard patient safety, with less benefit to the patients. In this project, we aim to apply Machine Learning models to a set of indirect and direct variables, to make a multivariate correlation analysis and so define a normalization factor for exercise prescription.

Conditions

Cardiac Rehabilitation; Exercise Therapy; Autonomic Nervous System Imbalance; Treatment Outcomes

Keywords

Cardiac Rehabilitation; Exercise prescription; Autonomic funtion; microneurography; cardiopulmonary exercise testing

Outcome Measures

Primary Outcomes (1)

• Normalization Factor for Sympathetic Activation Derived from Multimodal Autonomic Assessment

  A composite autonomic normalization factor will be generated using Principal Component Analysis (PCA) applied to multimodal autonomic and metabolic biomarkers (including microneurography-derived MSNA, heart rate variability indices from 24-hour Holter, CPET first-minute heart rate recovery, and serum/urinary catecholamines). This factor will quantify the individual degree of sympathetic activation and will serve as the basis for personalized exercise training prescription (Units of mesaure: unitless)

  Baseline (before initiation of cardiac rehabilitation program)

Secondary Outcomes (12)

• Basal Sympathetic Nervous System Activity (MSNA burst frequency)

  Baseline

• SDNN (Heart Rate Variability) obtained from 24-hour Holter ECG and long-duration ECG

  Baseline

• RMSSD (Heart Rate Variability) obtained from 24-hour Holter ECG and long duration ECG

  Baseline

• LF Power (Heart Rate Variability) Low-frequency spectral power obtained from 24-hour Holter ECG

  Baseline

• LF/HF Ratio (Heart Rate Variability) obtained from 24-hour Holter ECG

  Baseline

Study Arms (2)

Patients with Coronary artery disease without Heart Failure (CADnonHF)

This group with clearly demonstrated Autonomic Simpathetic System overactivation will have a detailed evaluation of the autonomic nervous system by performing an echocardiogram, 24-hour Holter monitoring, cardiopulmonary exercise test, long-term electrocardiogram, microneurography, and serum and urinary determination of catecholamine levels

Patients with non- ischemic Heart Failure with reduced ejection fraction (NIHFrEF)

This group, that also has clearly demonstrated Autonomic Simpathetic System overactivation, will, in the same way, have a detailed evaluation of the autonomic nervous system by performing an echocardiogram, 24-hour Holter monitoring, cardiopulmonary exercise test, long-term electrocardiogram, microneurography, and serum and urinary determination of catecholamine levels

Eligibility Criteria

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

Study Population

Adult patients diagnosed with non-ischemic heart failure with reduced ejection fraction (NIHFrEF) or stable coronary artery disease without heart failure (CADnonHF), consecutively enrolled in the Cardiac Rehabilitation Program at Centro Hospitalar de Leiria, and undergoing comprehensive autonomic and metabolic assessment."

You may qualify if:

• Patients with Coronary artery disease and no heart failure criteria
• Patients with non ischaemic heart failure and reduced left ventricle ejection fraction

You may not qualify if:

• patients with ongoing acute coronary syndrome
• patients with ongoing acute decompensated heart failure
• Severe valvular heart disease that might confound the relationship between exercise and autonomic function.
• Severe arrhythmias (e.g., sustained ventricular tachycardia, atrial fibrillation with a rapid ventricular rate) that are symptomatic or untreated
• Severe uncontrolled hypertension (e.g., systolic BP \> 180 mmHg or diastolic BP \> 110 mmHg)
• Active infectious diseases or other significant acute medical illnesses (e.g., sepsis, active malignancy, acute kidney injury)
• Pregnancy or lactation (to ensure safety during exercise interventions)
• Significant cognitive impairment or mental illness (e.g., dementia, schizophrenia) that would impair the ability to follow exercise protocols or understand study instructions
• nability to comply with study procedures due to any reason (e.g., language barriers, lack of informed consent)
• Chronically immunocompromised states (e.g., HIV with CD4 count \< 200 cells/µL or on immunosuppressive therapy)
• Presence of significant comorbidities such as advanced chronic obstructive pulmonary disease (COPD), kidney disease (e.g., stage 4-5 chronic kidney disease), or uncontrolled diabetes that would make exercise unsafe or confound the study outcomes
• Critical limb ischemia, or severely symptomatic peripheral artery disease or claudication limiting functional capacity and response to exercise
• Advanced chronic kidney disease (stage 4 or 5), due to contraindications with exercise
• Severe anemia (hemoglobin \< 8 g/dL) or other blood disorders that affect exercise capacity
• Inability to tolerate exercise due to other comorbidities or debility

Sponsors & Collaborators

• Universidade do Minho - ICVS: collaborator
• Hospital Santo André - Centro Hospitalar de Leiria: collaborator
• Fundação para a Ciência e a Tecnologia (FCT): collaborator
• Instituto Politécnico de Leiria: lead

Study Sites (2)

ciTechCare - Center for Innovative Care and Health Technology

Leiria, Leiria District, 2414-016, Portugal

Location

ICVS - Life and Health Sciences Research Institute, Minho University Medical School

Braga, Minho, 4710-057, Portugal

Location

Related Publications (13)

• Anderson L, Thompson DR, Oldridge N, Zwisler AD, Rees K, Martin N, Taylor RS. Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2016 Jan 5;2016(1):CD001800. doi: 10.1002/14651858.CD001800.pub3.

  PMID: 26730878 BACKGROUND

• Watson AM, Hood SG, May CN. Mechanisms of sympathetic activation in heart failure. Clin Exp Pharmacol Physiol. 2006 Dec;33(12):1269-74. doi: 10.1111/j.1440-1681.2006.04523.x.

  PMID: 17184514 BACKGROUND

• Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016 Nov 7;37(42):3232-3245. doi: 10.1093/eurheartj/ehw334. Epub 2016 Aug 14. No abstract available.

  PMID: 27523477 BACKGROUND

• Bento L, Fonseca-Pinto R, Povoa P. Autonomic nervous system monitoring in intensive care as a prognostic tool. Systematic review. Rev Bras Ter Intensiva. 2017 Oct-Dec;29(4):481-489. doi: 10.5935/0103-507X.20170072.

  PMID: 29340538 BACKGROUND

• Sacramento JF, Ribeiro MJ, Rodrigues T, Olea E, Melo BF, Guarino MP, Fonseca-Pinto R, Ferreira CR, Coelho J, Obeso A, Seica R, Matafome P, Conde SV. Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver. Diabetologia. 2017 Jan;60(1):158-168. doi: 10.1007/s00125-016-4133-y. Epub 2016 Oct 16.

  PMID: 27744526 BACKGROUND

• Sandesara PB, Lambert CT, Gordon NF, Fletcher GF, Franklin BA, Wenger NK, Sperling L. Cardiac rehabilitation and risk reduction: time to "rebrand and reinvigorate". J Am Coll Cardiol. 2015 Feb 3;65(4):389-395. doi: 10.1016/j.jacc.2014.10.059.

  PMID: 25634839 BACKGROUND

• Adler AJ, Martin N, Mariani J, Tajer CD, Owolabi OO, Free C, Serrano NC, Casas JP, Perel P. Mobile phone text messaging to improve medication adherence in secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017 Apr 29;4(4):CD011851. doi: 10.1002/14651858.CD011851.pub2.

  PMID: 28455948 BACKGROUND

• Besnier F, Labrunee M, Pathak A, Pavy-Le Traon A, Gales C, Senard JM, Guiraud T. Exercise training-induced modification in autonomic nervous system: An update for cardiac patients. Ann Phys Rehabil Med. 2017 Jan;60(1):27-35. doi: 10.1016/j.rehab.2016.07.002. Epub 2016 Aug 16.

  PMID: 27542313 BACKGROUND

• Long L, Anderson L, He J, Gandhi M, Dewhirst A, Bridges C, Taylor R. Exercise-based cardiac rehabilitation for stable angina: systematic review and meta-analysis. Open Heart. 2019 Jun 5;6(1):e000989. doi: 10.1136/openhrt-2018-000989. eCollection 2019.

  PMID: 31245012 BACKGROUND

• Alter DA, Zagorski B, Marzolini S, Forhan M, Oh PI. On-site programmatic attendance to cardiac rehabilitation and the healthy-adherer effect. Eur J Prev Cardiol. 2015 Oct;22(10):1232-46. doi: 10.1177/2047487314544084. Epub 2014 Jul 30.

  PMID: 25079239 BACKGROUND

• Andrade N, Alves E, Costa AR, Moura-Ferreira P, Azevedo A, Lunet N. Knowledge about cardiovascular disease in Portugal. Rev Port Cardiol (Engl Ed). 2018 Aug;37(8):669-677. doi: 10.1016/j.repc.2017.10.017. Epub 2018 Jul 25. English, Portuguese.

  PMID: 30055948 BACKGROUND

• Abreu A, Mendes M, Dores H, Silveira C, Fontes P, Teixeira M, Santa Clara H, Morais J. Mandatory criteria for cardiac rehabilitation programs: 2018 guidelines from the Portuguese Society of Cardiology. Rev Port Cardiol (Engl Ed). 2018 May;37(5):363-373. doi: 10.1016/j.repc.2018.02.006. Epub 2018 Apr 30. English, Portuguese.

  PMID: 29724635 BACKGROUND

• Atlas Writing Group; ESC Atlas of Cardiology is a compendium of cardiovascular statistics compiled by the European Heart Agency, a department of the European Society of Cardiology.; Developed in collaboration with the national societies of the European Society of Cardiology member countries; Timmis A, Townsend N, Gale CP, Torbica A, Lettino M, Petersen SE, Mossialos EA, Maggioni AP, Kazakiewicz D, May HT, De Smedt D, Flather M, Zuhlke L, Beltrame JF, Huculeci R, Tavazzi L, Hindricks G, Bax J, Casadei B, Achenbach S, Wright L, Vardas P. European Society of Cardiology: Cardiovascular Disease Statistics 2019 (Executive Summary). Eur Heart J Qual Care Clin Outcomes. 2020 Jan 1;6(1):7-9. doi: 10.1093/ehjqcco/qcz065. No abstract available.

  PMID: 31957796 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood samples for serum catecholamine measurement and urine samples for urinary catecholamine analysis

Study Officials

• Vitor Hugo Eira Pereira, MD, PhD

  ICVS - Life and Health Sciences Research Institute, Minho University Medical School

  STUDY DIRECTOR

• Rui Manuel Fonseca Pinto, MD, PhD

  ciTechCare - Center for Innovative Care and Health Technology, Polytechnic University of Leiria

  STUDY DIRECTOR

• João Carlos Araújo Morais, MD,PhD

  ciTechCare - Center for Innovative Care and Health Technology

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Doctor (MD), Cardiologist, Coordinator of the Cardiac Rehabilitation Unit of Hospital Santo André

Study Record Dates

• First Submitted: November 24, 2025
• First Posted: December 17, 2025
• Study Start: January 2, 2024
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: December 17, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

PT (2)