Effects of SGLT2 inhibitors on cardiac autonomic activity and ventricular remodeling in patients with acute myocardial infarction: study protocol for a clinical trial

Effects of SGLT2 inhibitors on cardiac autonomic activity and ventricular remodeling in patients with acute myocardial infarction: study protocol for a clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of SGLT2 inhibitors on cardiac autonomic activity and ventricular remodeling in patients with acute myocardial infarction: study protocol for a clinical trial Jun Wan, Qinglong Zhang, Feng Xu, Xin Jiang, Cai Chen, Xiaodong Pan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5602675/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jul, 2025 Read the published version in Trials → Version 1 posted 6 You are reading this latest preprint version Abstract Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors exhibit significant cardiovascular protective effects in patients with acute myocardial infarction (AMI) complicated with type 2 diabetes mellitus (T2DM), mainly through enhancing cardiac function and reducing malignant arrhythmias. However, evidence supporting their efficacy in non-diabetic AMI patients is limited. Moreover, the relationship between these benefits and improvements in cardiac autonomic function and left ventricular remodeling remains contentious, complicating the understanding of their mechanisms of action. This study aims to fill this knowledge gap regarding dapagliflozin's effects on cardiac autonomic activity and ventricular remodeling in AMI patients. Methods: This study is a prospective, randomized, open-label, assessor-blinded, single-center trial in AMI patients in China. A total of 110 participants will be randomly allocated in a 1:1 ratio to either receive standardized treatment alone or receive standardized treatment along with10 mg of dapagliflozin taken once daily. The primary endpoint is the change from the baseline to 24 weeks in heart rate variability (HRV) and deceleration capacity (DC) measured by 24-h ambulatory Holter monitoring. Secondary endpoints include changes in the left ventricular remodeling index (a relative change of LV end-diastolic volume, LVRI), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic volume (LVESV), and left ventricular ejection fraction (LVEF) from baseline. Changes in various variables from the baseline will also be analyzed, encompassing glucose and lipid levels, blood pressure, body weight, and biomarkers linked to diagnostic and functional parameters of AMI, such as creatine kinase, troponin I (TnI) level, and N terminal pro B type natriuretic peptide (NT-proBNP) level. Discussion: This trial will be the first trial to investigate the effects of dapagliflozin on cardiac autonomic function and ventricular remodeling in AMI patients. Our study aims to enhance understanding of the mechanisms by which dapagliflozin provides cardioprotection, potentially informing future therapeutic strategies for improving outcomes in this population. Trial registration: Clinical trial ID: ChiCTR2400084050. Registration date: May 9, 2024 Dapagliflozin cardiac autonomic activity ventricular remodeling acute myocardial infarction patients Figures Figure 1 Figure 2 Backgroud Following an acute myocardial infarction (AMI), patients are at risk for adverse cardiovascular outcomes due to electrical and ventricular remodeling, which can result in the development of arrhythmias and deterioration of cardiac function. AMI and post-infarction left ventricular systolic dysfunction are identified as the most significant risk factors for sudden cardiac death[ 1][2] . Hence, the principal objective of post-AMI therapy is to mitigate the progression of electrical and cardiac remodeling, consequently decreasing the occurrence of fatal ventricular arrhythmias and enhancing cardiac function. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been found to be effective in decreasing in-hospital arrhythmia burden[ 3] , infarct size[ 4] , mortality, and enhancing long-term outcomes in individuals with AMI[ 5] . However, the exact mechanism remains unclear. Prior researches have indicated that these outcomes are attained through enhancements in cardiac energy metabolism, mitigation of ischemia/reperfusion injury, and augmentation of cardiac systolic function[ 6][7][8][9] . However, recent researches have indicated a potential cardioprotective mechanism for SGLT2 inhibitors, which may involve the inhibition of cardiac sympathetic nerve activity. This suppression of cardiac sympathetic nerve activity not only mitigates cardiac remodeling but also diminishes the incidence of ventricular arrhythmias following AMI[ 10][11] . The EMBODY trial represents the first randomized clinical trial to investigate the effects of SGLT2 inhibitors on cardiac sympathetic and parasympathetic nervous system activity in individuals with both type 2 diabetes (T2DM) and AMI. The findings of this trial indicate that early administration of SGLT2 inhibitors in these patients can lead to significant improvements in cardiac nerve activity, with no reported adverse events[ 12] . It is important to acknowledge that all participants in the EMBODY trial had comorbid diabetes mellitus, potentially complicating the assessment of the genuine efficacy and safety of SGLT2-I therapy specifically in individuals with AMI without diabetes. Given the aforementioned considerations, it is imperative to assess the impact of SGLT2-I on the reduction of cardiac sympathetic activity and the attenuation of ventricular remodeling in patients with AMI. Therefore, a trial was conducted to investigate this matter, and the findings of this study have the potential to shed light on the mechanisms by which SGLT2 inhibitors provide cardioprotective advantages for patients with AMI. Materials and methods This is a prospective, open-label, randomized, assessor-blinded, single-center trial conducted on patients with AMI in the Second Affiliated Hospital of Anhui Medical university. The objective of this trial is to evaluate the effects of SGLT2 inhibitors on cardiac autonomic function and cardiac structure in these high-risk patients. This protocol adheres to the Standard Protocol Items Recommendations outlined in the SPIRIT reporting guidelines (see Fig. 1 and Additional File 1)[ 13] . Approval for the research protocol in this study was obtained from the Ethics Review Committee at the Second Affiliated Hospital of Anhui Medical University (YX2024-041). The research methods adhered to the ethical principles outlined in the Declaration of Helsinki, established by the World Medical Association. This study was conducted in accordance with the specifications of the clinical trial under the coordination and supervision of the Science and Technology Committee and the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University, and a specialized data monitoring and management team was responsible for data management. The trial is registered by the Second Affiliated Hospital of Anhui Medical University (Registration number: ChiCTR2400084050). Inclusion and exclusion criteria Inclusion criteria (1) Adults (aged 18–80 years); (2) Diagnosed with AMI (ST-elevation and non-ST-elevation); (3) Underwent successful percutaneous coronary intervention (PCI) during the acute phase. Exclusion criteria (1) Patients with concomitant diabetes; (2) Patients with persistent atrial fibrillation; (3) Patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m²; (4) Patients who did not undergo successful PCI during the acute phase; (5) Patients who have undergone coronary artery bypass grafting (CABG); (6) Patients receiving cardiac pacemaker therapy; (7) Patients with a history of malignancy; (8) Pregnant patients; (9) Patients who failed to comply with the follow-up protocol. The comprehensive inclusion and exclusion criteria can be found in Table 1 Table 1. Inclusion and exclusion criteria Inclusion criteria Men and women aged 18–80 years Diagnosed with STEMI or NSTEMI Underwent successful PCI during the acute phase Exclusion criteria T1DM and T2DM Persistent atrial fibrillation eGFR below 45 mL/min/1.73 m² Patients who did not undergo successful PCI during the acute phase Patients who have undergone CABG Patients with pacemaker therapy History of malignancy Pregnancy Patients who have taken any SGLT2 inhibitor within the last three months Patients who failed to comply with the follow-up protocol STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; T1DM,Type 1 diabetes mellitus; T2DM,Type 2 diabetes mellitus; eGFR, estimated glomerular filtration rate; CABG, coronary artery bypass grafting; SGLT2, Sodium-glucose co-transporter 2. Trial population and intervention We plan to recruit a total of 110 patients with AMI between May 2024 and June 2025. Detailed inclusion and exclusion criteria are outlined in Table 1. After obtaining written informed consent regarding the study protocol, patients will be randomly assigned to either the dapagliflozin group or the control group. After allocation, patients in the dapagliflozin group will receive dapagliflozin 10 mg daily in addition to standard treatment, while those in the control group will receive standard treatment only to more closely reflect real-world research condition (Figure 2). Standard treatment includes antiplatelet therapy, anticoagulation, lipid-lowering agents, β-blockers, and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). All patients will adhere to the established treatment protocol for 24 weeks, except in cases of severe adverse reactions such as acute drug allergies or acute urinary tract infections. Both groups of patients will not be required to modify their standard care pathways or the aforementioned standardized treatment protocols. we will implement a comprehensive adherence enhancement strategy. This will include patient education about the benefits of the treatment, regular follow-ups to address any concerns. In our study, we will enhance adherence by having patients maintain records of their medication intake, complemented by regular follow-up surveys to monitor their engagement and address any issues. Follow-up assessments will be scheduled at 12 and 24 weeks post-discharge. Randomization and blinding Randomization is achieved by random numbers from a generator for group allocation. Before the trial, a professional generator creates a sequence corresponding to different intervention groups. Eligible subjects are assigned accordingly to minimize selection bias. It's an open - label trial with evaluator blinding. While subjects and researchers know the interventions, evaluators are blind during assessment. Strict measures ensure blinding in data collection and processing to reduce bias and ensure result reliability. Upon confirming eligibility and obtaining informed consent, participants will be allocated to either the dapagliflozin group or the control group (standard treatment) in a 1:1 ratio. The randomization process will be carried out by an independent statistician who is not involved in patient recruitment or treatment. All patients in the dapagliflozin group will be required to take dapagliflozin at a dose of 10 mg daily for 24 weeks. Upon completion of the trial, all patients will have the option to continue dapagliflozin treatment based on their individual circumstances. Study endpoints The primary endpoint is the change from the baseline to 24 weeks in heart rate variability (HRV) and deceleration capacity (DC) measured by 24-h ambulatory Holter monitoring (BI9900, Biomedical Instrument, China). HRV is assessed through both time domain and frequency domain methods. In the time domain analysis, several metrics are evaluated, including the mean RR interval over 24 hours (mean NN), the standard deviation of normal RR intervals (SDNN), the standard deviation of the 5-minute mean normal RR intervals (SDANN), the square root of the mean of the squared differences between successive RR intervals (r-MSSD), and the percentage of adjacent RR intervals differing by more than 50 ms (pNN50). Frequency domain analysis includes total power, high-frequency power (HF) (0.15-0.40 Hz), low-frequency power (LF) (0.04-0.15 Hz), and the LF/HF ratio, which represents the sympathovagal balance. The analysis of heart rate signals utilized the phase-rectified signal averaging (PRSA) algorithm, which effectively removed non-periodic components, including artifacts and arrhythmias. Prolonged heartbeat intervals, in comparison to the preceding intervals, were designated as anchors. Data segments of uniform size surrounding these anchors were selected, and all segments were aligned at the anchors. The following parameters were computed: X(0), representing the mean RR interval across all anchors; X(1), the average RR interval following the anchors; X(-1), the average RR interval preceding the anchors; and X(-2), the average of the second RR intervals prior to the anchors. The DC value was determined using the formula: DC = [X(0) + X(1) - X(-1) - X(-2)] / 4[ 14] . DC ≤ 4.5ms was classified as abnormal[ 15] . The secondary endpoint of this study was the left ventricular remodeling index (LVRI), which was calculated by assessing the percentage change in left ventricular end-diastolic volume (LVEDV) at 12 and 24 weeks compared to the baseline measurement. A positive (LVRI>0%) indicated an increase in LVEDV from baseline to the follow-up assessment[ 16] . Furthermore, pathological LVR (LVRI>20%) was defined as a 20% or greater increase in LVEDV from baseline to follow-up[ 17] . Additionally, changes in various baseline variables will be analyzed, including glucose and lipid levels, blood pressure (BP), body mass index (BMI), and biomarkers associated with the diagnostic and functional parameters of AMI. These biomarkers include creatine kinase, troponin I (TnI) levels, and N terminal pro B type natriuretic peptide (NT-proBNP) levels. Safety events Significant adverse drug reactions such as genitourinary infections, hypoglycemia, hypotension, kidney function impairment, electrolyte disorders and gastrointestinal events will be monitored. Sample size calculation Sample size was calculated for the LF/HF ratio, one of the parameters of the primary end point. Due to the lack of relevant data on the impact of dapagliflozin on cardiac autonomic nerve function in patients with AMI, we could only rely on the pilot study to obtain key information. The pilot study revealed a mean difference in change of -0.4 in the LF/HF ratio between the dapagliflozin and standard treatment from baseline to 24 weeks, with a standard deviation (SD) of 0.7. Using these values, we calculated the required sample size, setting the significance level (α) at 0.05 and the desired power (1-β) at 0.80. Additionally, accounting for a 10% dropout rate based on similar studies, we determined that a total sample size of 110 subjects (55 in each group) is necessary. Recruitment In our single-center trial conducted at the Second Affiliated Hospital of Anhui Medical University, we have established a dedicated chest pain clinic that annually admits a substantial number of eligible AMI patients, significantly exceeding the required sample size for our study. We will implement rigorous verification of the inclusion criteria for patients and conduct a comprehensive assessment of medical reports to accurately identify and recruit participants for the trial. Data management Baseline demographic and clinical characteristics will be collected, including age, gender, medical history, current medications, vital signs, glucose and lipid levels, BMI, liver function tests (including ALT, AST, and bilirubin), renal function tests (including creatinine, blood urea nitrogen, and eGFR), serum electrolytes (sodium, potassium, calcium), thyroid function tests (including TSH, T3 and T4), creatine kinase, cardiac TnI levels, and NT-proBNP levels. Additionally, echocardiographic parameters, HRV parameters (SDNN, SDANN, r-MSSD, pNN50, LF, HF, and LF/HF), and DC will be assessed. These data will be collected through patient interviews and review of medical records. Regular refresher training sessions will be scheduled throughout the study. Where appropriate, duplicate measurements will be taken to minimize variability. All data must be double-checked by the researchers before conducting data analysis. To enhance participant retention and ensure complete follow-up, we will implement regular communication and personalized reminders. For those who discontinue or deviate from the intervention, we will collect data on reasons for discontinuation and relevant clinical outcomes. We will ensure the integrity and security of our data through a process of double data entry by trained personnel, followed by the reconciliation of any discrepancies. Range checks will be employed to validate data values, and access to the secure database will be restricted exclusively to our research team. Data monitoring The Data Monitoring Committee (DMC) for this study will consist of three independent experts: one cardiologist with extensive experience in acute myocardial infarction, one biostatistician with expertise in clinical trials, and one clinical pharmacologist. This diverse background will ensure that the DMC can effectively monitor the integrity, safety, and overall conduct of the study. The trial will be overseen and managed by the Science and Technology Committee of the Second Affiliated Hospital of Anhui Medical University. All serious adverse events, complications, and potential hazards will be promptly reported to and recorded by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University. The DMC will meet at predetermined intervals to review unblinded data, assess any potential safety signals, and provide recommendations regarding the continuation, modification, or termination of the trial based on the gathered data. Protocol amendments Any significant modifications to the study protocol, such as changes to eligibility criteria, outcomes, or analyses, will be communicated promptly to all relevant parties. Written notifications will be sent to investigators, and amendments will be submitted for approval to the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University. Affected trial participants will be informed directly about relevant changes, and updates will be entered into applicable trial registries. Additionally, significant changes will be reported to relevant journals and regulatory authorities to ensure transparency and compliance throughout the trial. Statistical analysis Continuous variables were presented as the mean and standard deviation (SD), and data analysis was performed using Student's t-tests. Categorical variables were displayed as case number (percentage) and evaluated using either the Pearson chi-square test or Fisher exact test. For the comparison of HRV parameters (such as SDNN, SDANN, r-MSSD, pNN50, LF, HF, and LF/HF) and DC value between the two groups at different time points (baseline, 12weeks, 24 weeks), a repeated-measures analysis of variance (ANOVA) will be used. For the assessment of LVRI, as measured by changes of LVEDV, a two-way ANOVA with time and treatment as factors will be employed. Changes in biochemical parameters will be analyzed using paired t-tests for within-group comparisons and independent t-tests for between-group comparisons at each time point. At the end of the trial, appropriate statistical methods will be employed to handle missing data as warranted by the circumstances. Discussion In the current landscape of medical research, the cardiovascular protective effects of SGLT-2 inhibitors have emerged as a significant area of interest. Numerous studies have demonstrated that these agents not only excel in glycemic control but also exhibit substantial potential in improving cardiovascular outcomes. Initially, SGLT-2 inhibitors were found to enhance clinical outcomes in heart failure (HF) patients, reducing mortality rates and hospitalization due to HF, regardless of the presence of diabetes[ 18][19][20] . Subsequent investigations revealed their notable cardioprotective effects in patients with AMI, such as reducing the infarct size and alleviating the burden of arrhythmias[ 21][22] . These findings provide a solid foundation for exploring the application of SGLT-2 inhibitors in the context of AMI. However, the impact of SGLT-2 inhibitors on cardiac autonomic function in AMI patients remains unclear. The EMBODY trial was the first to report that empagliflozin treatment effectively improves cardiac autonomic function in diabetic patients with AMI[ 23] ; however, it remains uncertain whether similar effects are observed in non-diabetic patients experiencing AMI. In patients suffering from AMI, a significant activation of the sympathetic nervous system occurs alongside a suppression of the parasympathetic nervous system. This alteration results in increased sympathetic output and decreased parasympathetic activity, a state commonly referred to as autonomic imbalance[ 24] . Research indicates that following AMI, the autonomic nervous system's function is compromised, which leads to several detrimental effects. Firstly, there is an increase in sympathetic excitability: post-infarction, sympathetic activity is markedly heightened, closely correlating with elevated morbidity and mortality rates among patients[ 25] . The excessive activation of the sympathetic nervous system is considered a major contributor to the development of arrhythmias[ 26] . Secondly, the reduction of parasympathetic activity can result in abnormal tachycardia, which may impair the cardiac electrophysiological stability. This disruption of balance potentially heightens the risk of arrhythmias, particularly during the acute phase of AMI[ 27] . Additionally, the changes in autonomic function induced by AMI have long-term implications on overall cardiac performance[ 28] . Specifically, the electrical properties and contractile function of the heart may be altered due to this autonomic imbalance[ 29] . In the recovery phase following AMI, it is noteworthy that the autonomic nervous system may not fully revert to baseline levels, leading to prolonged sympathetic activation, which can contribute to cardiac remodeling and HF[23][ 30] . Currently, non-invasive methods for assessing cardiac autonomic function primarily rely on HRV. HRV effectively reflects the activity of the sympathetic and vagal nervous systems by analyzing various metrics of inter-beat intervals such as SDNN, SDANN, r-MSSD, pNN50, LF, HF, and LF/HF. Specifically, SDANN, r-MSSD, pNN50, and HF all reflect cardiac parasympathetic nerve activity, while the LF/HF ratio is commonly used to evaluate the relative balance of sympathetic and parasympathetic activity. A higher LF/HF ratio typically indicates increased sympathetic activity[22]. In this study, we employed HRV as our primary assessment tool while also introducing DC as an additional metric to enhance the evaluation of cardiac autonomic function. DC serves as an indicator of parasympathetic nerve activity and is a crucial marker for identifying cardiac autonomic dysfunction[ 31] . Furthermore, it may indicate adverse events and mortality, particularly in patients with AMI[ 32] . By integrating the analyses of HRV and DC, we aim to achieve a more comprehensive understanding of the effects of dapagliflozin on cardiac autonomic function, thereby establishing a stronger theoretical foundation for improving clinical management in AMI patients. The mechanisms by which dapagliflozin improves cardiac autonomic function in patients with AMI remain to be fully elucidated. However, several potential pathways have been proposed. One significant mechanism may involve the hemodynamic effects, where dapagliflozin's ability to induce diuresis and reduce preload leads to improved cardiac output and reduced myocardial workload[ 33] . SGLT2 inhibitors have been shown to reduce blood pressure without accelerating heart rate, suggesting that these medications may be linked to a decrease in sympathetic nervous system activity. Additionally, dapagliflozin is known to positively influence myocardial energy metabolism. By shifting the substrate utilization from glucose to ketones, dapagliflozin may enhance the efficiency of energy production in cardiac myocytes[ 34] . This metabolic shift not only supports better cardiac function but may also reduce the metabolic stress that often accompanies AMI, thereby fostering a more stable autonomic environment. Moreover, dapagliflozin may exert its effects by inhibiting the activation of renal afferent sympathetic nerves[ 35] . The renal effects of SGLT2 inhibitors are considered to be an important mechanism of action, with some cardiovascular benefits arising as a result[ 36] . In addition to its aforementioned cardiovascular protective effects, dapagliflozin has been shown to reduce inflammation[ 37] , prevent ischemia/reperfusion injury[ 38] , and exert anti-fibrotic effects[ 39] . These mechanisms contribute to the improvement of ventricular function and a reduction in cardiac remodeling following AMI. By enhancing cardiac autonomic function and ventricular remodeling, dapagliflozin holds promise for improving clinical outcomes and quality of life in patients who have experienced acute myocardial infarction. Trial limitations This study is the first to investigate the effects of dapagliflozin on cardiac autonomic activity and ventricular remodeling in patients with AMI, yet it has several limitations.. First, its single-center design may limit the generalizability of findings, as outcomes might vary across different regions and populations. The sample size of 110 patients could restrict statistical power, and the open-label nature may introduce bias in reporting and assessment despite an assessor-blinded approach. Additionally, the short follow-up duration of 12 and 24 weeks may not adequately capture long-term effects on cardiovascular health. Recognizing these limitations will enhance our understanding of dapagliflozin's potential role in managing cardiac autonomic dysfunction and left ventricular remodeling in AMI patients and guide future research efforts. Trial status Issue date: 1 Jun 2024 Protocol amendment number: 01 Author: Jun Wan The recruitment start date is May 9, 2024, and the estimated completion date for recruitment is May 2025. The current recruitment status is "ongoing." Abbreviations ACEIs angiotensin-converting enzyme inhibitors AMI acute myocardial infarction ARBs angiotensin receptor blockers BMI body mass index BP blood pressure CABG coronary artery bypass grafting DC deceleration capacity DAPA dapagliflozin eGFR estimated glomerular filtration rate HF heart failure HRV heart rate variability LVESV left ventricular end-diastolic volume LVEF left ventricular ejection fraction LVEDV left ventricular end-diastolic volume LVRI left ventricular remodeling index LF low-frequency power HF high-frequency power NN mean RR interval NT-proBNP N terminal pro B type natriuretic peptide NSTEMI non-ST elevation myocardial infarction PCI percutaneous coronary intervention pNN50 percentage of adjacent RR intervals differing by more than 50 ms RR interval normal RR intervals SGLT2 Sodium-glucose co-transporter 2 SDANN standard deviation of the 5-minute mean normal RR intervals SDNN standard deviation of normal RR intervals STEMI ST-elevation myocardial infarction T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus TnI troponin I r-MSSD square root of the mean of the squared differences between successive RR intervals Declarations Ethics approval and consent to participate Approval for the research protocol in this study was obtained from the Ethics Review Committee at the Second Affiliated Hospital of Anhui Medical University (YX2024-041). All participants provided written informed consent before enrollment, which is retained by the corresponding author HL. Consent for publication There will be no personal identifying information published. Availability of data and materials All primary and secondary results will be published at the conclusion of the trial. Additional data such as participant-level dataset may be requested from the corresponding author for legitimate reasons. Competing interests All authors declared no conflicts of interest. Funding This research was funded by Anhui Medical University through grant number 2023xkj163. The funding organization had no role in the design of this study, the execution of the study, the analysis, the interpretation of the data, or the decision to present the results. Authors' contributions The principal investigator JW conceived the initial study, HL designand and oversaw the overall conduct of the trial. JW is responsible for drafting the manuscript. XDP will take charge of patient recruitment. XJ will participate in the generation of random numbers. QLZ and CC will allocate participants to groups based on the generated numbers, and will also be involved in assessing patient eligibility and data collection. JLC will administer the interventions to the assigned participants. Both FX and JW will contribute to the data analysis and interpretation. Authorship eligibility for this protocol is based on the the guidelines set forth by the International Committee of Medical Journal Editors (ICMJE). Acknowledgements None. Trial Sponsor: Contact name: Jun Wan Address: Department of Emergency Internal Medicine, the Second Affiliated Hospital of Anhui Medical University. No. 678 Furong Road, Economic and Technological Development Zone, Hefei, Anhui230001, China. Telephone: +860551-63869370 References Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med. 2005;352(25):2581-8. Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015;116(12):1887-906. Cesaro A, Gragnano F, Paolisso P, et al. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: Insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022;9:1012220. Paolisso P, Bergamaschi L, Santulli G, et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol. 2022;21(1):77. Paolisso P, Bergamaschi L, Gragnano F, et al. Outcomes in diabetic patients treated with SGLT2-Inhibitors with acute myocardial infarction undergoing PCI: The SGLT2-I AMI PROTECT Registry. Pharmacol Res. 2023;187:106597. Lee MMY, Brooksbank KJM, Wetherall K, et al. Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF). Circulation. 2021;143(6):516-25. Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2021;77(3):243-55. Omar M, Jensen J, Ali M, et al. Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial. JAMA Cardiol. 2021;6(7):836-40. Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020;5(6):632-44. Zhou Z, Liu C, Xu S, et al. Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model. Basic Res Cardiol. 2022;117(1):34. Kasama S, Toyama T, Hatori T, et al. Effects of intravenous atrial natriuretic peptide on cardiac sympathetic nerve activity and left ventricular remodeling in patients with first anterior acute myocardial infarction. J Am Coll Cardiol. 2007;49(6):667-74. Shimizu W, Kubota Y, Hoshika Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020;19(1):148. Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleža-Jerić K, Laupacis A, Moher D. SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials. BMJ. 2013;346:e7586. Buzea CA, Dan GA, Dan AR, et al. Deceleration and Acceleration Capacities in Risk Stratification for Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease. Am J Ther. 2017;24(1): e44-e51. Bauer A, Barthel P, Schneider R, et al. Improved Stratification of Autonomic Regulation for risk prediction in post-infarction patients with preserved left ventricular function (ISAR-Risk). Eur Heart J. 2009;30(5):576-83. Park Y, Koh JS, Lee JH, et al. Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI). JACC Cardiovasc Interv. 2020;13(19):2220-34. Bolognese L, Neskovic AN, Parodi G, et al. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation. 2002;106(18):2351-7. Packer M, Anker SD, Butler J, et al. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation. 2021;143(4):326-36. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008. Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2021;77(3):243-55. Paolisso P, Bergamaschi L, Santulli G, et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol. 2022;21(1):77. Cesaro A, Gragnano F, Paolisso P, et al. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: Insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022;9:1012220. Shimizu W, Kubota Y, Hoshika Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020;19(1):148. Elia A, Fossati S. Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimer's disease. Front Physiol. 2023;14:1060666. Graham LN,Smith PA,Huggett RJ, et al. Sympathetic drive in anterior and inferior uncomplicated acute myocardial infarction. Circulation. 2004;109 (19):2285-9. Goldberger JJ, Arora R, Buckley U, Shivkumar K. Autonomic Nervous System Dysfunction: JACC Focus Seminar. J Am Coll Cardiol. 2019;73(10):1189-206. Schismenos V, Tzanis AA, Papadopoulos GE, Nikas D, Koniari I, Kolettis TM. Autonomic Responses During Acute Anterior Versus Inferior Myocardial Infarction: A Systematic Review and Meta-Analysis. Cureus. 2023;15(11):e48893. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. 2014;114(6):1004-21. Jing Y,Ding Y,Fu H, et al. Empagliflozin ameliorates ventricular arrhythmias by inhibiting sympathetic remodeling via nerve growth factor/tyrosine kinase receptor A pathway inhibition. J Cardiovasc Med (Hagerstown). 2024;25 (9):664-73. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114(11):1815-26. Buzea CA, Dan GA, Dan AR, et al. Deceleration and Acceleration Capacities in Risk Stratification for Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease. Am J Ther. 2017;24(1): e44-e51. Bauer A, Kantelhardt JW, Barthel P, et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet. 2006;367(9523):1674-81. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrates utilization in response to sodiumglucose co-transporter-2 inhibition in nondiabetic subjects and type 2 diabetic patients. Diabetes 2016;65:1190-5. Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71(5):471-6. Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020;5(6):632-44. Kim SR, Lee SG, Kim SH, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020;11(1):2127. Nikolaou PE, Mylonas N, Makridakis M, et al. Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?. Basic Res Cardiol. 2022;117(1):27. Kang S, Verma S, Hassanabad AF, et al. Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results. Can J Cardiol. 2020;36(4):543-53. Supplementary Files SPIRITchecklist.docx SPIRITFigure.doc Cite Share Download PDF Status: Published Journal Publication published 14 Jul, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 05 Apr, 2025 Reviewers agreed at journal 22 Mar, 2025 Reviewers invited by journal 22 Mar, 2025 Editor invited by journal 07 Mar, 2025 Editor assigned by journal 31 Jan, 2025 First submitted to journal 08 Dec, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5602675","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":432433291,"identity":"fd180a4c-7bd0-4930-98de-84cfa8c68731","order_by":0,"name":"Jun Wan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYHACwwcVSDw5Nvb2A4S0GBucQebx8ZxJIKTFTAJZS+I8CQcDvOr5ZyRvkDjYZhPNL3384uOCmsPpbRIMCQw/Krbh1CJxI63A4GBbWu7Mvpxi4xnHDue2STceYOw5cxu3NTdyDJI/th3O3XCGJ02atwGoReZAAjNjG24t8kAtBw62/c/df4Yn/TdQSzqbRIIBXi0GN3IMGw62HcjdwMN+jBmoJYGgFsMzz4oZDpxLzp1xhodZmudYumEbMJAP4vOL3PHk7T8OlNnl9vewP/zMU2MtL9/efvDBjwo83hdIYGBgZAOxeEDR0QwWPIBbPRDwg6T/gFjsD4BEHV7Fo2AUjIJRMDIBAIunYSrdJRuGAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1545-6556","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jun","middleName":"","lastName":"Wan","suffix":""},{"id":432433292,"identity":"7b29c27f-c756-45f2-ab7a-760aaadd9709","order_by":1,"name":"Qinglong Zhang","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qinglong","middleName":"","lastName":"Zhang","suffix":""},{"id":432433293,"identity":"5c6c92ba-e5e6-4c3d-8c40-9e1e7f4ae587","order_by":2,"name":"Feng Xu","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Xu","suffix":""},{"id":432433294,"identity":"21ae1ff3-3701-4542-a85d-f551dd6185c6","order_by":3,"name":"Xin Jiang","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Jiang","suffix":""},{"id":432433295,"identity":"9845fa69-629a-4bfe-a103-0f2efead9015","order_by":4,"name":"Cai Chen","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Cai","middleName":"","lastName":"Chen","suffix":""},{"id":432433296,"identity":"8fbbb046-4ab3-4102-83f5-16ccb2003e6a","order_by":5,"name":"Xiaodong Pan","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Pan","suffix":""},{"id":432433297,"identity":"d88276de-50d5-461d-8289-fbcb0d6333a6","order_by":6,"name":"Jinglin Cheng","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinglin","middleName":"","lastName":"Cheng","suffix":""},{"id":432433298,"identity":"aa5abf59-8cd9-4068-a7d2-f8c87a395a40","order_by":7,"name":"He Li","email":"","orcid":"","institution":"Second Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-12-08 11:37:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5602675/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5602675/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-08956-x","type":"published","date":"2025-07-14T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79663577,"identity":"eb07df0e-f983-4d21-8b00-caee41f665aa","added_by":"auto","created_at":"2025-04-01 09:54:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":50387,"visible":true,"origin":"","legend":"\u003cp\u003eThe schedule and timing of intervention and assessments. −t1, 1 day pre-allocation; t0, allocation; t1,1 day after allocation; t2, 12 weeks after allocation; t3, 24 weeks after allocation; DAPA group, dapagliflozin 10 mg daily in addition to standard treatment; Control group, standard treatment only;\u003c/p\u003e\n\u003cp\u003eLaboratory data1: C-reactive protein, Haemoglobin A1c, creatine kinase, troponin I, and N terminal pro B type natriuretic peptide levels. Laboratory data2: Laboratory data1 plus serum hemoglobin, alanine transaminase, aspartate transaminase, bilirubin, uric acid, cholesterol, sodium, potassium, creatinine and urea. HRV: heart rate variability; DC, deceleration capacity; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-diastolic volume; LVRI, left ventricular remodeling index.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5602675/v1/b5d97255d4e112a4c1140fdd.png"},{"id":79666354,"identity":"d9261dcf-aa08-461e-aaff-cbeb20a30ea7","added_by":"auto","created_at":"2025-04-01 10:18:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":339003,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePCI, percutaneous coronary intervention; T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; eGFR, estimated glomerular filtration rate; CABG, coronary artery bypass grafting; DAPA, dapagliflozin; HRV, heart rate variability; DC, deceleration capacity; LVRI, left ventricular remodeling index.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5602675/v1/16f99f4d33a71bc2c3800b51.png"},{"id":87219466,"identity":"0dd6bd6d-be7d-455c-a86b-30b1ce1ba336","added_by":"auto","created_at":"2025-07-21 16:05:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":997627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5602675/v1/daeb1f39-f9d3-420e-8bdb-183824081e75.pdf"},{"id":79663589,"identity":"805287b7-6460-41f8-9acb-abf767c19cde","added_by":"auto","created_at":"2025-04-01 09:54:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35820,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-5602675/v1/27a0137ca28069d013833263.docx"},{"id":79663587,"identity":"becea1cb-f262-4cd1-a04c-81f190cd3011","added_by":"auto","created_at":"2025-04-01 09:54:52","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":37888,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFigure.doc","url":"https://assets-eu.researchsquare.com/files/rs-5602675/v1/4036c098430904f5f08c3161.doc"}],"financialInterests":"","formattedTitle":"Effects of SGLT2 inhibitors on cardiac autonomic activity and ventricular remodeling in patients with acute myocardial infarction: study protocol for a clinical trial","fulltext":[{"header":"Backgroud","content":"\u003cp\u003eFollowing an acute myocardial infarction (AMI), patients are at risk for adverse cardiovascular outcomes due to electrical and ventricular remodeling, which can result in the development of arrhythmias and deterioration of cardiac function. AMI and post-infarction left ventricular systolic dysfunction are identified as the most significant risk factors for sudden cardiac death[\u003csup\u003e1][2]\u003c/sup\u003e. Hence, the principal objective of post-AMI therapy is to mitigate the progression of electrical and cardiac remodeling, consequently decreasing the occurrence of fatal ventricular arrhythmias and enhancing cardiac function.\u003c/p\u003e\n\u003cp\u003eSodium-glucose co-transporter 2 (SGLT2) inhibitors have been found to be effective in decreasing in-hospital arrhythmia burden[\u003csup\u003e3]\u003c/sup\u003e, infarct size[\u003csup\u003e4]\u003c/sup\u003e, mortality, and enhancing long-term outcomes in individuals with AMI[\u003csup\u003e5]\u003c/sup\u003e. However, the exact mechanism remains unclear. Prior researches have indicated that these outcomes are attained through enhancements in cardiac energy metabolism, mitigation of ischemia/reperfusion injury, and augmentation of cardiac systolic function[\u003csup\u003e6][7][8][9]\u003c/sup\u003e. However, recent researches have indicated a potential cardioprotective mechanism for SGLT2 inhibitors, which may involve the inhibition of cardiac sympathetic nerve activity. This suppression of cardiac sympathetic nerve activity not only mitigates cardiac remodeling but also diminishes the incidence of ventricular arrhythmias following AMI[\u003csup\u003e10][11]\u003c/sup\u003e. The EMBODY trial represents the first randomized clinical trial to investigate the effects of SGLT2 inhibitors on cardiac sympathetic and parasympathetic nervous system activity in individuals with both type 2 diabetes (T2DM) and AMI. The findings of this trial indicate that early administration of SGLT2 inhibitors in these patients can lead to significant improvements in cardiac nerve activity, with no reported adverse events[\u003csup\u003e12]\u003c/sup\u003e. It is important to acknowledge that all participants in the EMBODY trial had comorbid diabetes mellitus, potentially complicating the assessment of the genuine efficacy and safety of SGLT2-I therapy specifically in individuals with AMI without diabetes.\u003c/p\u003e\n\u003cp\u003eGiven the aforementioned considerations, it is imperative to assess the impact of \u0026nbsp;SGLT2-I on the reduction of cardiac sympathetic activity and the attenuation of ventricular remodeling in patients with AMI. Therefore, a trial was conducted to investigate this matter, and the findings of this study have the potential to shed light on the mechanisms by which SGLT2 inhibitors provide cardioprotective advantages for patients with AMI.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThis is a prospective, open-label, randomized, assessor-blinded, single-center trial conducted on patients with AMI in the Second Affiliated Hospital of Anhui Medical university. The objective of this trial is to evaluate the effects of SGLT2 inhibitors on cardiac autonomic function and cardiac structure in these high-risk patients. This protocol adheres to the Standard Protocol Items Recommendations outlined in the SPIRIT reporting guidelines (see Fig. 1 and Additional File 1)[\u003csup\u003e13]\u003c/sup\u003e. Approval for the research protocol in this study was obtained from the Ethics Review Committee at the Second Affiliated Hospital of Anhui Medical University (YX2024-041). The research methods adhered to the ethical principles outlined in the Declaration of Helsinki, established by the World Medical Association. This study was conducted in accordance with the specifications of the clinical trial under the coordination and supervision of the Science and Technology Committee and the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University, and a specialized data monitoring and management team was responsible for data management. The trial is registered by the Second Affiliated Hospital of Anhui Medical University (Registration number: ChiCTR2400084050).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and exclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) Adults (aged 18\u0026ndash;80 years); \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(2) Diagnosed with AMI (ST-elevation and non-ST-elevation); \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(3) Underwent successful percutaneous coronary intervention (PCI) during the acute phase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) Patients with concomitant diabetes; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(2) Patients with persistent atrial fibrillation; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(3) Patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m\u0026sup2;; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(4) Patients who did not undergo successful PCI during the acute phase; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(5) Patients who have undergone coronary artery bypass grafting (CABG); \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(6) Patients receiving cardiac pacemaker therapy; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(7) Patients with a history of malignancy; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(8) Pregnant patients;\u003c/p\u003e\n\u003cp\u003e(9) Patients who failed to comply with the follow-up protocol.\u003c/p\u003e\n\u003cp\u003eThe comprehensive inclusion and exclusion criteria can be found in Table 1\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Inclusion and exclusion criteria\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col\u003e\n \u003cli\u003eMen and women aged 18\u0026ndash;80 years\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"2\"\u003e\n \u003cli\u003eDiagnosed with STEMI or NSTEMI\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"3\"\u003e\n \u003cli\u003eUnderwent successful PCI during the acute phase\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col\u003e\n \u003cli\u003eT1DM and T2DM\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"2\"\u003e\n \u003cli\u003ePersistent atrial fibrillation\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"3\"\u003e\n \u003cli\u003eeGFR below 45 mL/min/1.73 m\u0026sup2;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"4\"\u003e\n \u003cli\u003ePatients who did not undergo successful PCI during the acute phase\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"5\"\u003e\n \u003cli\u003ePatients who have undergone CABG\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"6\"\u003e\n \u003cli\u003ePatients with pacemaker therapy\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"7\"\u003e\n \u003cli\u003eHistory of malignancy\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"8\"\u003e\n \u003cli\u003ePregnancy\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"9\"\u003e\n \u003cli\u003ePatients who have taken any SGLT2 inhibitor within the last three months\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 568px;\"\u003e\n \u003col start=\"10\"\u003e\n \u003cli\u003ePatients who failed to comply with the follow-up protocol\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSTEMI, ST-elevation myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; T1DM,Type 1 diabetes mellitus; T2DM,Type 2 diabetes mellitus; eGFR, estimated glomerular filtration rate; CABG, \u0026nbsp;coronary artery bypass grafting; SGLT2, Sodium-glucose co-transporter 2. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial population and intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe plan to recruit a total of 110 patients with AMI between May 2024 and June 2025. Detailed inclusion and exclusion criteria are outlined in Table 1. After obtaining written informed consent regarding the study protocol, patients will be randomly assigned to either the dapagliflozin group or the control group. After allocation, patients in the dapagliflozin group will receive dapagliflozin 10 mg daily in addition to standard treatment, while those in the control group will receive standard treatment only to more closely reflect real-world research condition (Figure 2). Standard treatment includes antiplatelet therapy, anticoagulation, lipid-lowering agents, \u0026beta;-blockers, and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). All patients will adhere to the established treatment protocol for 24 weeks, except in cases of severe adverse reactions such as acute drug allergies or acute urinary tract infections. Both groups of patients will not be required to modify their standard care pathways or the aforementioned standardized treatment protocols. we will implement a comprehensive adherence enhancement strategy. This will include patient education about the benefits of the treatment, regular follow-ups to address any concerns. In our study, we will enhance adherence by having patients maintain records of their medication intake, complemented by regular follow-up surveys to monitor their engagement and address any issues. Follow-up assessments will be scheduled at 12 and 24 weeks post-discharge.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and blinding \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomization is achieved by random numbers from a generator for group allocation. Before the trial, a professional generator creates a sequence corresponding to different intervention groups. Eligible subjects are assigned accordingly to minimize selection bias. It\u0026apos;s an open - label trial with evaluator blinding. While subjects and researchers know the interventions, evaluators are blind during assessment. Strict measures ensure blinding in data collection and processing to reduce bias and ensure result reliability. Upon confirming eligibility and obtaining informed consent, participants will be allocated to either the dapagliflozin group or the control group (standard treatment) in a 1:1 ratio. The randomization process will be carried out by an independent statistician who is not involved in patient recruitment or treatment. All patients in the dapagliflozin group will be required to take dapagliflozin at a dose of 10 mg daily for 24 weeks. Upon completion of the trial, all patients will have the option to continue dapagliflozin treatment based on their individual circumstances. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is the change from the baseline to 24 weeks in heart rate variability (HRV) and deceleration capacity (DC) measured by 24-h ambulatory Holter monitoring (BI9900, Biomedical Instrument, China). HRV is assessed through both time domain and frequency domain methods. In the time domain analysis, several metrics are evaluated, including the mean RR interval over 24 hours (mean NN), the standard deviation of normal RR intervals (SDNN), the standard deviation of the 5-minute mean normal RR intervals (SDANN), the square root of the mean of the squared differences between successive RR intervals (r-MSSD), and the percentage of adjacent RR intervals differing by more than 50 ms (pNN50). Frequency domain analysis includes total power, high-frequency power (HF) (0.15-0.40 Hz), low-frequency power (LF) (0.04-0.15 Hz), and the LF/HF ratio, which represents the \u0026nbsp;sympathovagal balance. The analysis of heart rate signals utilized the phase-rectified signal averaging (PRSA) algorithm, which effectively removed non-periodic components, including artifacts and arrhythmias. Prolonged heartbeat intervals, in comparison to the preceding intervals, were designated as anchors. Data segments of uniform size surrounding these anchors were selected, and all segments were aligned at the anchors. The following parameters were computed: X(0), representing the mean RR interval across all anchors; X(1), the average RR interval following the anchors; X(-1), the average RR interval preceding the anchors; and X(-2), the average of the second RR intervals prior to the anchors. The DC value was determined using the formula: DC = [X(0) + X(1) - X(-1) - X(-2)] / 4[\u003csup\u003e14]\u003c/sup\u003e. DC\u0026nbsp;\u0026le;\u0026nbsp;4.5ms was classified as abnormal[\u003csup\u003e15]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe secondary endpoint of this study was the left ventricular remodeling index (LVRI), which was calculated by assessing the percentage change in left ventricular end-diastolic volume (LVEDV) at 12 and 24 weeks compared to the baseline measurement. A positive (LVRI\u0026gt;0%) indicated an increase in LVEDV from baseline to the follow-up assessment[\u003csup\u003e16]\u003c/sup\u003e. Furthermore, pathological LVR (LVRI\u0026gt;20%) was defined as a 20% or greater increase in LVEDV from baseline to follow-up[\u003csup\u003e17]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAdditionally, changes in various baseline variables will be analyzed, including glucose and lipid levels, blood pressure (BP), body mass index (BMI), and biomarkers associated with the diagnostic and functional parameters of AMI. These biomarkers include creatine kinase, troponin I (TnI) levels, and N terminal pro B type natriuretic peptide (NT-proBNP) levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant adverse drug reactions such as genitourinary infections, hypoglycemia, hypotension, kidney function impairment, electrolyte disorders and gastrointestinal events will be monitored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample size was calculated for the LF/HF ratio, one of the parameters of the primary end point. Due to the lack of relevant data on the impact of dapagliflozin on cardiac autonomic nerve function in patients with AMI, we could only rely on the pilot study to obtain key information. The pilot study revealed a mean difference in change of -0.4 in the LF/HF ratio between the dapagliflozin and standard treatment from baseline to 24 weeks, with a standard deviation (SD) of 0.7. Using these values, we calculated the required sample size, setting the significance level (\u0026alpha;) at 0.05 and the desired power (1-\u0026beta;) at 0.80. Additionally, accounting for a 10% dropout rate based on similar studies, we determined that a total sample size of 110 subjects (55 in each group) is necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our single-center trial conducted at the Second Affiliated Hospital of Anhui Medical University, we have established a dedicated chest pain clinic that annually admits a substantial number of eligible AMI patients, significantly exceeding the required sample size for our study. We will implement rigorous verification of the inclusion criteria for patients and conduct a comprehensive assessment of medical reports to accurately identify and recruit participants for the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline demographic and clinical characteristics will be collected, including age, gender, medical history, current medications, vital signs, glucose and lipid levels, BMI, liver function tests (including ALT, AST, and bilirubin), renal function tests (including creatinine, blood urea nitrogen, and eGFR), serum electrolytes (sodium, potassium, calcium), thyroid function tests (including TSH, T3 and T4), creatine kinase, cardiac TnI levels, and NT-proBNP levels. Additionally, echocardiographic parameters, HRV parameters (SDNN, SDANN, r-MSSD, pNN50, LF, HF, and LF/HF), and DC will be assessed. These data will be collected through patient interviews and review of medical records. Regular refresher training sessions will be scheduled throughout the study. Where appropriate, duplicate measurements will be taken to minimize variability. All data must be double-checked by the researchers before conducting data analysis. To enhance participant retention and ensure complete follow-up, we will implement regular communication and personalized reminders. For those who discontinue or deviate from the intervention, we will collect data on reasons for discontinuation and relevant clinical outcomes. We will ensure the integrity and security of our data through a process of double data entry by trained personnel, followed by the reconciliation of any discrepancies. Range checks will be employed to validate data values, and access to the secure database will be restricted exclusively to our research team.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Data Monitoring Committee (DMC) for this study will consist of three independent experts: one cardiologist with extensive experience in acute myocardial infarction, one biostatistician with expertise in clinical trials, and one clinical pharmacologist. This diverse background will ensure that the DMC can effectively monitor the integrity, safety, and overall conduct of the study. The trial will be overseen and managed by the Science and Technology Committee of the Second Affiliated Hospital of Anhui Medical University. All serious adverse events, complications, and potential hazards will be promptly reported to and recorded by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University. The DMC will meet at predetermined intervals to review unblinded data, assess any potential safety signals, and provide recommendations regarding the continuation, modification, or termination of the trial based on the gathered data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol amendments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny significant modifications to the study protocol, such as changes to eligibility criteria, outcomes, or analyses, will be communicated promptly to all relevant parties. Written notifications will be sent to investigators, and amendments will be submitted for approval to the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University. Affected trial participants will be informed directly about relevant changes, and updates will be entered into applicable trial registries. Additionally, significant changes will be reported to relevant journals and regulatory authorities to ensure transparency and compliance throughout the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were presented as the mean and standard deviation (SD), and data analysis was performed using Student\u0026apos;s t-tests. Categorical variables were displayed as case number (percentage) and evaluated using either the Pearson chi-square test or Fisher exact test. For the comparison of HRV parameters (such as SDNN, SDANN, r-MSSD, pNN50, LF, HF, and LF/HF) and DC value between the two groups at different time points (baseline, 12weeks, 24 weeks), a repeated-measures analysis of variance (ANOVA) will be used. For the assessment of LVRI, as measured by changes of LVEDV, a two-way ANOVA with time and treatment as factors will be employed. Changes in biochemical parameters will be analyzed using paired t-tests for within-group comparisons and independent t-tests for between-group comparisons at each time point. At the end of the trial, appropriate statistical methods will be employed to handle missing data as warranted by the circumstances.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the current landscape of medical research, the cardiovascular protective effects of SGLT-2 inhibitors have emerged as a significant area of interest. Numerous studies have demonstrated that these agents not only excel in glycemic control but also exhibit substantial potential in improving cardiovascular outcomes. Initially, SGLT-2 inhibitors were found to enhance clinical outcomes in heart failure (HF) patients, reducing mortality rates and hospitalization due to HF, regardless of the presence of diabetes[\u003csup\u003e18][19][20]\u003c/sup\u003e. Subsequent investigations revealed their notable cardioprotective effects in patients with AMI, such as reducing the infarct size and alleviating the burden of arrhythmias[\u003csup\u003e21][22]\u003c/sup\u003e. These findings provide a solid foundation for exploring the application of SGLT-2 inhibitors in the context of AMI. However, the impact of SGLT-2 inhibitors on cardiac autonomic function in AMI patients remains unclear. The EMBODY trial was the first to report that empagliflozin treatment effectively improves cardiac autonomic function in diabetic patients with AMI[\u003csup\u003e23]\u003c/sup\u003e; however, it remains uncertain whether similar effects are observed in non-diabetic patients experiencing AMI.\u003c/p\u003e\n\u003cp\u003eIn patients suffering from AMI, a significant activation of the sympathetic nervous system occurs alongside a suppression of the parasympathetic nervous system. This alteration results in increased sympathetic output and decreased parasympathetic activity, a state commonly referred to as autonomic imbalance[\u003csup\u003e24]\u003c/sup\u003e. Research indicates that following AMI, the autonomic nervous system\u0026apos;s function is compromised, which leads to several detrimental effects. Firstly, there is an increase in sympathetic excitability: post-infarction, sympathetic activity is markedly heightened, closely correlating with elevated morbidity and mortality rates among patients[\u003csup\u003e25]\u003c/sup\u003e. The excessive activation of the sympathetic nervous system is considered a major contributor to the development of arrhythmias[\u003csup\u003e26]\u003c/sup\u003e. Secondly, the reduction of parasympathetic activity can result in abnormal tachycardia, which may impair the cardiac electrophysiological stability. This disruption of balance potentially heightens the risk of arrhythmias, particularly during the acute phase of AMI[\u003csup\u003e27]\u003c/sup\u003e. Additionally, the changes in autonomic function induced by AMI have long-term implications on overall cardiac performance[\u003csup\u003e28]\u003c/sup\u003e. Specifically, the electrical properties and contractile function of the heart may be altered due to this autonomic imbalance[\u003csup\u003e29]\u003c/sup\u003e. In the recovery phase following AMI, it is noteworthy that the autonomic nervous system may not fully revert to baseline levels, leading to prolonged sympathetic activation, which can contribute to cardiac remodeling and HF[23][\u003csup\u003e30]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCurrently, non-invasive methods for assessing cardiac autonomic function primarily rely on HRV. HRV effectively reflects the activity of the sympathetic and vagal nervous systems by analyzing various metrics of inter-beat intervals such as SDNN, SDANN, r-MSSD, pNN50, LF, HF, and LF/HF. Specifically, SDANN, r-MSSD, pNN50, and HF all reflect cardiac parasympathetic nerve activity, while the LF/HF ratio is commonly used to evaluate the relative balance of sympathetic and parasympathetic activity. A higher LF/HF ratio typically indicates increased sympathetic activity[22]. In this study, we employed HRV as our primary assessment tool while also introducing DC as an additional metric to enhance the evaluation of cardiac autonomic function. DC serves as an indicator of parasympathetic nerve activity and is a crucial marker for identifying cardiac autonomic dysfunction[\u003csup\u003e31]\u003c/sup\u003e. Furthermore, it may indicate adverse events and mortality, particularly in patients with AMI[\u003csup\u003e32]\u003c/sup\u003e. By integrating the analyses of HRV and DC, we aim to achieve a more comprehensive understanding of the effects of dapagliflozin on cardiac autonomic function, thereby establishing a stronger theoretical foundation for improving clinical management in AMI patients.\u003c/p\u003e\n\u003cp\u003eThe mechanisms by which dapagliflozin improves cardiac autonomic function in patients with AMI remain to be fully elucidated. However, several potential pathways have been proposed. One significant mechanism may involve the hemodynamic effects, where dapagliflozin\u0026apos;s ability to induce diuresis and reduce preload leads to improved cardiac output and reduced myocardial workload[\u003csup\u003e33]\u003c/sup\u003e. SGLT2 inhibitors have been shown to reduce blood pressure without accelerating heart rate, suggesting that these medications may be linked to a decrease in sympathetic nervous system activity. Additionally, dapagliflozin is known to positively influence myocardial energy metabolism. By shifting the substrate utilization from glucose to ketones, dapagliflozin may enhance the efficiency of energy production in cardiac myocytes[\u003csup\u003e34]\u003c/sup\u003e. This metabolic shift not only supports better cardiac function but may also reduce the metabolic stress that often accompanies AMI, thereby fostering a more stable autonomic environment. Moreover, dapagliflozin may exert its effects by inhibiting the activation of renal afferent sympathetic nerves[\u003csup\u003e35]\u003c/sup\u003e. The renal effects of SGLT2 inhibitors are considered to be an important mechanism of action, with some cardiovascular benefits arising as a result[\u003csup\u003e36]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn addition to its aforementioned cardiovascular protective effects, dapagliflozin has been shown to reduce inflammation[\u003csup\u003e37]\u003c/sup\u003e, prevent ischemia/reperfusion injury[\u003csup\u003e38]\u003c/sup\u003e, and exert anti-fibrotic effects[\u003csup\u003e39]\u003c/sup\u003e. These mechanisms contribute to the improvement of ventricular function and a reduction in cardiac remodeling following AMI. By enhancing cardiac autonomic function and ventricular remodeling, dapagliflozin holds promise for improving clinical outcomes and quality of life in patients who have experienced acute myocardial infarction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is the first to investigate the effects of dapagliflozin on cardiac autonomic activity and ventricular remodeling in patients with AMI, yet it has several limitations.. First, its single-center design may limit the generalizability of findings, as outcomes might vary across different regions and populations. The sample size of 110 patients could restrict statistical power, and the open-label nature may introduce bias in reporting and assessment despite an assessor-blinded approach. Additionally, the short follow-up duration of 12 and 24 weeks may not adequately capture long-term effects on cardiovascular health. Recognizing these limitations will enhance our understanding of dapagliflozin\u0026apos;s potential role in managing cardiac autonomic dysfunction and left ventricular remodeling in AMI patients and guide future research efforts.\u003c/p\u003e\n\u003ch2\u003eTrial status\u003c/h2\u003e\n\u003cp\u003eIssue date: 1 Jun 2024\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eProtocol amendment number: 01\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor: Jun Wan\u003c/p\u003e\n\u003cp\u003eThe recruitment start date is May 9, 2024, and the estimated completion date for recruitment is May 2025. The current recruitment status is \u0026quot;ongoing.\u0026quot;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACEIs angiotensin-converting enzyme inhibitors \u003c/p\u003e\n\u003cp\u003eAMI acute myocardial infarction \u003c/p\u003e\n\u003cp\u003eARBs angiotensin receptor blockers \u003c/p\u003e\n\u003cp\u003eBMI body mass index \u003c/p\u003e\n\u003cp\u003eBP blood pressure \u003c/p\u003e\n\u003cp\u003eCABG coronary artery bypass grafting \u003c/p\u003e\n\u003cp\u003eDC deceleration capacity \u003c/p\u003e\n\u003cp\u003eDAPA dapagliflozin \u003c/p\u003e\n\u003cp\u003eeGFR estimated glomerular filtration rate \u003c/p\u003e\n\u003cp\u003eHF heart failure \u003c/p\u003e\n\u003cp\u003eHRV heart rate variability \u003c/p\u003e\n\u003cp\u003eLVESV left ventricular end-diastolic volume\u003c/p\u003e\n\u003cp\u003eLVEF left ventricular ejection fraction\u003c/p\u003e\n\u003cp\u003eLVEDV left ventricular end-diastolic volume \u003c/p\u003e\n\u003cp\u003eLVRI left ventricular remodeling index \u003c/p\u003e\n\u003cp\u003eLF low-frequency power \u003c/p\u003e\n\u003cp\u003eHF high-frequency power \u003c/p\u003e\n\u003cp\u003eNN mean RR interval \u003c/p\u003e\n\u003cp\u003eNT-proBNP N terminal pro B type natriuretic peptide \u003c/p\u003e\n\u003cp\u003eNSTEMI non-ST elevation myocardial infarction \u003c/p\u003e\n\u003cp\u003ePCI percutaneous coronary intervention \u003c/p\u003e\n\u003cp\u003epNN50 percentage of adjacent RR intervals differing by more than 50 ms \u003c/p\u003e\n\u003cp\u003eRR interval normal RR intervals \u003c/p\u003e\n\u003cp\u003eSGLT2 Sodium-glucose co-transporter 2 \u003c/p\u003e\n\u003cp\u003eSDANN standard deviation of the 5-minute mean normal RR intervals \u003c/p\u003e\n\u003cp\u003eSDNN standard deviation of normal RR intervals \u003c/p\u003e\n\u003cp\u003eSTEMI ST-elevation myocardial infarction \u003c/p\u003e\n\u003cp\u003eT1DM Type 1 diabetes mellitus \u003c/p\u003e\n\u003cp\u003eT2DM Type 2 diabetes mellitus \u003c/p\u003e\n\u003cp\u003eTnI troponin I \u003c/p\u003e\n\u003cp\u003er-MSSD square root of the mean of the squared differences between successive RR intervals \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval for the research protocol in this study was obtained from the Ethics Review Committee at the Second Affiliated Hospital of Anhui Medical University (YX2024-041). All participants provided written informed consent before enrollment, which is retained by the corresponding author HL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere will be no personal identifying information published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll primary and secondary results will be published at the conclusion of the trial. Additional data such as participant-level dataset may be requested from the corresponding author for legitimate reasons.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declared no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by Anhui Medical University through grant number 2023xkj163. The funding organization had no role in the design of this study, the execution of the study, the analysis, the interpretation of the data, or the decision to present the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe principal investigator JW conceived the initial study, HL designand and oversaw the overall conduct of the trial. JW is responsible for drafting the manuscript. XDP will take charge of patient recruitment. XJ will participate in the generation of random numbers. QLZ and CC will allocate participants to groups based on the generated numbers, and will also be involved in assessing patient eligibility and data collection. JLC will administer the interventions to the assigned participants. Both FX and JW will contribute to the data analysis and interpretation. Authorship eligibility for this protocol is based on the the guidelines set forth by the International Committee of Medical Journal Editors (ICMJE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Sponsor:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContact name: Jun Wan\u003c/p\u003e\n\u003cp\u003eAddress: Department of Emergency Internal Medicine, the Second Affiliated Hospital of Anhui Medical University. No. 678 Furong Road, Economic and Technological Development Zone, Hefei, Anhui230001, China.\u003c/p\u003e\n\u003cp\u003eTelephone: +860551-63869370\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med. 2005;352(25):2581-8. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015;116(12):1887-906. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Cesaro A, Gragnano F, Paolisso P, et al. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: Insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022;9:1012220. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Paolisso P, Bergamaschi L, Santulli G, et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol. 2022;21(1):77. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Paolisso P, Bergamaschi L, Gragnano F, et al. Outcomes in diabetic patients treated with SGLT2-Inhibitors with acute myocardial infarction undergoing PCI: The SGLT2-I AMI PROTECT Registry. Pharmacol Res. 2023;187:106597. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Lee MMY, Brooksbank KJM, Wetherall K, et al. Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF). Circulation. 2021;143(6):516-25.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2021;77(3):243-55. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Omar M, Jensen J, Ali M, et al. Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial. JAMA Cardiol. 2021;6(7):836-40. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020;5(6):632-44. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Zhou Z, Liu C, Xu S, et al. Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model. Basic Res Cardiol. 2022;117(1):34. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Kasama S, Toyama T, Hatori T, et al. Effects of intravenous atrial natriuretic peptide on cardiac sympathetic nerve activity and left ventricular remodeling in patients with first anterior acute myocardial infarction. J Am Coll Cardiol. 2007;49(6):667-74. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Shimizu W, Kubota Y, Hoshika Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020;19(1):148. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Chan A-W, Tetzlaff JM, G\u0026oslash;tzsche PC, Altman DG, Mann H, Berlin J, Dickersin K, Hr\u0026oacute;bjartsson A, Schulz KF, Parulekar WR, Krleža-Jerić K, Laupacis A, Moher D. SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials. BMJ. 2013;346:e7586.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Buzea CA, Dan GA, Dan AR, et al. Deceleration and Acceleration Capacities in Risk Stratification for Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease. Am J Ther. 2017;24(1): e44-e51. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Bauer A, Barthel P, Schneider R, et al. Improved Stratification of Autonomic Regulation for risk prediction in post-infarction patients with preserved left ventricular function (ISAR-Risk). Eur Heart J. 2009;30(5):576-83. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Park Y, Koh JS, Lee JH, et al. Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI). JACC Cardiovasc Interv. 2020;13(19):2220-34.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Bolognese L, Neskovic AN, Parodi G, et al. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation. 2002;106(18):2351-7.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Packer M, Anker SD, Butler J, et al. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation. 2021;143(4):326-36.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2021;77(3):243-55. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Paolisso P, Bergamaschi L, Santulli G, et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol. 2022;21(1):77. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Cesaro A, Gragnano F, Paolisso P, et al. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: Insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022;9:1012220. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Shimizu W, Kubota Y, Hoshika Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020;19(1):148. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Elia A, Fossati S. Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimer\u0026apos;s disease. Front Physiol. 2023;14:1060666. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Graham LN,Smith PA,Huggett RJ, et al. Sympathetic drive in anterior and inferior uncomplicated acute myocardial infarction. Circulation. 2004;109 (19):2285-9. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Goldberger JJ, Arora R, Buckley U, Shivkumar K. Autonomic Nervous System Dysfunction: JACC Focus Seminar. J Am Coll Cardiol. 2019;73(10):1189-206. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Schismenos V, Tzanis AA, Papadopoulos GE, Nikas D, Koniari I, Kolettis TM. Autonomic Responses During Acute Anterior Versus Inferior Myocardial Infarction: A Systematic Review and Meta-Analysis. Cureus. 2023;15(11):e48893. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. 2014;114(6):1004-21. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Jing Y,Ding Y,Fu H, et al. Empagliflozin ameliorates ventricular arrhythmias by inhibiting sympathetic remodeling via nerve growth factor/tyrosine kinase receptor A pathway inhibition. J Cardiovasc Med (Hagerstown). 2024;25 (9):664-73. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003eFlorea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114(11):1815-26.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Buzea CA, Dan GA, Dan AR, et al. Deceleration and Acceleration Capacities in Risk Stratification for Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease. Am J Ther. 2017;24(1): e44-e51.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Bauer A, Kantelhardt JW, Barthel P, et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet. 2006;367(9523):1674-81. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrates utilization in response to sodiumglucose co-transporter-2 inhibition in nondiabetic subjects and type 2 diabetic patients. Diabetes 2016;65:1190-5.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71(5):471-6. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020;5(6):632-44.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Kim SR, Lee SG, Kim SH, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020;11(1):2127.\u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Nikolaou PE, Mylonas N, Makridakis M, et al. Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?. Basic Res Cardiol. 2022;117(1):27. \u003c/strong\u003e\u003c/li\u003e\n\u003cli\u003e Kang S, Verma S, Hassanabad AF, et al. Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results. Can J Cardiol. 2020;36(4):543-53. \u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dapagliflozin, cardiac autonomic activity, ventricular remodeling, acute myocardial infarction patients","lastPublishedDoi":"10.21203/rs.3.rs-5602675/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5602675/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSodium-glucose co-transporter 2 (SGLT2) inhibitors exhibit significant cardiovascular protective effects in patients with acute myocardial infarction (AMI) complicated with type 2 diabetes mellitus (T2DM), mainly through enhancing cardiac function and reducing malignant arrhythmias. However, evidence supporting their efficacy in non-diabetic AMI patients is limited. Moreover, the relationship between these benefits and improvements in cardiac autonomic function and left ventricular remodeling remains contentious, complicating the understanding of their mechanisms of action. This study aims to fill this knowledge gap regarding dapagliflozin's effects on cardiac autonomic activity and ventricular remodeling in AMI patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis study is a prospective, randomized, open-label, assessor-blinded, single-center trial in AMI patients in China. A total of 110 participants will be randomly allocated in a 1:1 ratio to either receive standardized treatment alone or receive standardized treatment along with10 mg of dapagliflozin taken once daily. The primary endpoint is the change from the baseline to 24 weeks in heart rate variability (HRV) and deceleration capacity (DC) measured by 24-h ambulatory Holter monitoring. Secondary endpoints include changes in the left ventricular remodeling index (a relative change of LV end-diastolic volume, LVRI), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic volume (LVESV), and left ventricular ejection fraction (LVEF) from baseline. Changes in various variables from the baseline will also be analyzed, encompassing glucose and lipid levels, blood pressure, body weight, and biomarkers linked to diagnostic and functional parameters of AMI, such as creatine kinase, troponin I (TnI) level, and N terminal pro B type natriuretic peptide (NT-proBNP) level.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThis trial will be the first trial to investigate the effects of dapagliflozin on cardiac autonomic function and ventricular remodeling in AMI patients. Our study aims to enhance understanding of the mechanisms by which dapagliflozin provides cardioprotection, potentially informing future therapeutic strategies for improving outcomes in this population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003eClinical trial ID: ChiCTR2400084050. 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