Exercise and brain health in patients with coronary artery disease: study protocol for the HEART-BRAIN randomized controlled trial

Introduction Patients with coronary artery disease (CAD), also called coronary heart disease, have a higher risk of developing cognitive impairment and mental health disorders compared to the general population. There is a need to identify effective and sustainable strategies to improve brain health in individuals with CAD, in which physical exercise could play a major role. The overall goal of the HEART-BRAIN randomized controlled trial (RCT) is to investigate the effects of exercise, including different types, on brain health outcomes in patients with CAD, and the underlying mechanisms. Methods This three-arm, single-blinded RCT will include 90 adults with CAD, aged 50-75 years. The participants will be randomized into: 1) control group - usual care (n=30), including periodic medical visits and medication management, 2) aerobic high-intensity interval training (HIIT) (n=30), or 3) aerobic HIIT combined with resistance exercise training (n=30). The intervention will last 12 weeks, offering 3 sessions (45min each) per week to the exercise groups, and the study outcomes will be assessed at baseline and after the intervention. The primary outcome of the study is to determine changes in global and regional cerebral blood flow assessed by magnetic resonance imaging. Secondary outcomes include changes in brain vascularization, cognitive measures (i.e., general cognition, executive function and episodic memory), and cardiorespiratory fitness. Additional health-related outcomes will be evaluated, and several potential mediators and moderators will be investigated (i.e., brain structure and function, cardiovascular and brain-based biomarkers, hemodynamics, physical function, body composition, mental health, and lifestyle behavior). Conclusions The HEART-BRAIN RCT will provide novel insights on how exercise can impact brain health in patients with CAD and the potential mechanisms explaining the heart-brain connection, such as changes in cerebral blood flow. The results might have important clinical implications by increasing the evidence on the effectiveness of exercise-based preventive strategies that could delay cognitive decline in this high-risk CAD population. Our findings will be relevant for patients with CAD, researchers and healthcare providers involved in CAD-related clinical care. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT06214624 ### Funding Statement The HEART-BRAIN Project is supported with the Grant PID2020-120249RB-I00 funded by MCIN/AEI/10.13039/501100011033. Additional support was obtained from the Andalusian Government (Junta de Andalucia, Plan Andaluz de Investigacion, ref. P20\_00124) and the CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Granada, Spain. Moreover, EAB has received funding from the European Union s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No [101064851]. AT has received funding from the Junta de Andalucia, Spain, under the Postdoctoral Research Fellows (Ref. POSTDOC\_21_00745). PS-U is supported by a Margarita Salas grant from the Spanish Ministry Universities. IEC is supported by RYC2019-027287-I grant funded by MCIN/AEI/10.13039/501100011033/ and ESF Investing in your future. IMF is supported by the Spanish Ministry of Science, Innovation and Universities (JDC2022-049642-I). AC was funded by postdoctoral research grants from the Swedish Heart-Lung Foundation (grant number 20230343), the County Council of Ostergotland, Sweden (grant number RO-990967), the Swedish Society of Cardiology, and the Swedish Society of Clinical Physiology. BFG is supported by the Spanish Ministry of Education, Culture and Sport (PID2022-137399OB-I00) funded by MCIN/AEI/10.13039/501100011033 and FSE+. MOR, LSA and JFO are supported by the Spanish Ministry of Science, Innovation and Universities (FPU 22/02476, FPU 21/06192 and FPU 22/03052, respectively). JHM is supported by the Spanish Ministry of Science, Innovation and Universities under Beatriz Galindo 2022 fellowship program (BG22/00075). JSM is supported by the National Agency for Research and Development (ANID)/Scholarship Program/DOCTORADO BECAS CHILE/2022 (Grant No.72220164). SVA is supported by a Health and Behavior International Collaborative Award by the Society of Behavioral Medicine. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial protocol is in accordance with the principles of the Declaration of Helsinki and was approved by the Research Ethics Board of the Andalusian Health Service (CEIM/CEI Provincial de Granada; #1776-N-21 on December 21st, 2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors