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| ID | Type | Description | Link |
|---|---|---|---|
| BRWEP2024W014090204 | Other Grant/Funding Number | Beijing Municipal Health Commission | |
| 2025ZD0546100 | Other Grant/Funding Number | National Health Commission of the People's Republic of China |
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| Name | Class |
|---|---|
| Beijing Municipal Health Commission | OTHER_GOV |
| National Health Commission of the People's Republic of China | UNKNOWN |
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Cardiovascular-Kidney-Metabolic (CKM) Syndrome is a continuous clinical disease spectrum integrating cardiovascular, renal, and metabolic disorders. Heart failure with preserved ejection fraction (HFpEF) is considered Stage 4 of CKM syndrome, characterized primarily by impairment of cardiac structure and function. Numerous studies have confirmed that exercise intervention is effective in improving metabolic profiles and inflammatory status in Stages 0-3 of CKM syndrome (e.g., obesity, metabolic syndrome, hypertension, and diabetes), and significantly improves clinical outcomes. However, for Stage 4 CKM syndrome, especially in patients with HFpEF, conventional exercise prescription faces significant challenges in balancing safety and efficacy. Moreover, traditional "one-size-fits-all" exercise rehabilitation strategies have failed to significantly improve clinical outcomes due to the lack of individualized precision approaches.
To address this gap, this study proposes to adopt a multicenter, randomized, controlled design, enrolling patients with HFpEF at Stage 4 of CKM syndrome and randomly assigning them to either a personalized high-intensity interval training (HIIT) intervention group or a standard care control group. The **primary endpoint** of this study is the change in peak oxygen consumption (peak VO₂) from baseline after 24 weeks of intervention. In addition, a series of **secondary endpoints** have been established for comprehensive evaluation, including inflammatory biomarkers, cardiac structure and function, quality of life, and composite clinical events. These endpoints aim to comprehensively assess the intervention effects from the perspectives of cardiopulmonary function, metabolism and inflammation, quality of life, and clinical outcomes, as well as to explore the underlying mechanisms.
This study is expected to validate the beneficial effects of personalized exercise on peak VO₂ and various secondary endpoints in patients with Stage 4 CKM syndrome. It will not only provide high-level evidence-based support for exercise therapy in HFpEF but also deepen the understanding of the role of exercise intervention in the full-course management of CKM syndrome, offering key scientific support for the development of precision prevention and treatment strategies across all stages.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| HIIT intervention group | Experimental | Subjects in the intervention group will undergo a 24-week personalized high-intensity interval training (HIIT) program, four times per week, with the exercise protocol tailored based on cardiopulmonary exercise testing (CPET). In addition, they will receive guideline-directed healthy lifestyle recommendations and optimal medical therapy (GDMT) |
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| Standard care control group | No Intervention | Control group subjects will receive guideline-directed optimal medical therapy (GDMT) , identical to that provided to the intervention group. In addition, they will receive a single, standardized health education session focused on HFpEF and obesity management, covering general recommendations regarding diet, weight management, and regular physical activity. No structured or supervised exercise prescription or program will be offered to the control group. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| High-intensity interval training | Behavioral | Subjects in the intervention group will receive a personalized high-intensity interval training (HIIT) protocol based on cardiopulmonary exercise testing (CPET) and will undergo a 24-week HIIT intervention, four times per week.The exercise protocol consisted of a 5-minute warm-up at 30-40 watts, followed by 8 cycles of high-intensity exercise performed at 80-90% of peak VO₂ for 30 seconds, each interspersed with a 60-second active recovery period of low-intensity exercise at 50-60% of peak VO₂ , and concluded with a 5-minute cool-down at 30-40 watts. |
| Measure | Description | Time Frame |
|---|---|---|
| Peak VO2 | Peak VO2 is assessed through CPET, using a maximal graded treadmill test based on the Chinese expert consensus on the standardized clinical application of CPET. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Measure | Description | Time Frame |
|---|---|---|
| Blood specimen | Lab tests include cytokines | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Blood specimen | Lab tests include high-sensitivity C-reactive protein (hs-CRP) |
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Inclusion Criteria:
Men and women aged 35-70 years;
Physical inactivity / sedentary lifestyle defined as:
Sedentary behavior: average daily sitting time > 6 hours over the past 6 months; AND/OR Insufficient physical activity: average weekly moderate-intensity physical activity < 150 minutes or vigorous-intensity physical activity < 75 minutes as assessed by the International Physical Activity Questionnaire (IPAQ);
Patients with HFpEF at Stage 4 of CKM syndrome who have been clinically stable within the past month (New York Heart Association [NYHA] functional class II-III);
Willingness to improve health status through appropriate exercise.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yida Tang, MD,PhD | Contact | 010-82265996 | tangyida@bjmu.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Yida Tang, MD,PhD | Peking University Third Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Chao-Yang Hospital, Capital Medical University | Beijing | China |
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Only blinding is maintained for data management personnel, laboratory testing personnel, and data analysts, while not applied to subjects and clinical investigators in the clinical trial.
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| Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Blood specimen | Lab tests include adipokines | Baseline（week 0），End of study（week 24 ） |
| Blood specimen | Lab tests include N-terminal pro-B-type natriuretic peptide (NT-proBNP) | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Blood specimen | Lab tests include cardiac troponin | Baseline（week 0），End of study（week 24 ） |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered, disease-specific instrument that assesses physical limitations, symptoms (frequency, severity, and change), self-efficacy, social function, and quality of life in patients with heart failure. It has demonstrated high reliability and validity. Scores are transformed to a range of 0 to 100, with higher scores reflecting better health-related quality of life. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| The New York Heart Association (NYHA) Functional Classification | The New York Heart Association (NYHA) Functional Classification is a commonly used tool by clinicians to quantify the severity of symptoms and physical activity limitations in patients with heart failure. The classification places patients into one of four categories: Class I (no limitation of physical activity), Class II (slight limitation, ordinary activity causes symptoms), Class III (marked limitation, less than ordinary activity causes symptoms), and Class IV (unable to carry on any physical activity without discomfort, symptoms may be present at rest). | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Montreal Cognitive Assessment (MoCA) | The Montreal Cognitive Assessment (MoCA) is a standardized 30-point screening tool used to detect cognitive impairment. It assesses multiple cognitive domains including visuospatial/executive function, naming, memory, attention, language, abstraction, delayed recall, and orientation. The test takes approximately 10 minutes to administer. Scores range from 0 to 30, with higher scores reflecting better cognitive function. A score of 26 or above is generally considered normal; 18-25 indicates mild cognitive impairment; 10-17 indicates moderate cognitive impairment; and below 10 indicates severe cognitive impairment. One point is added to the raw score for individuals with 12 or fewer years of education. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Hospital Anxiety and Depression Scale (HADS) | The Hospital Anxiety and Depression Scale (HADS) is a 14-item, self-administered screening tool designed to assess symptoms of anxiety and depression. It comprises two independent subscales: anxiety (HADS-A) and depression (HADS-D), each containing 7 items. Each item is scored from 0 to 3, yielding a subscale total score ranging from 0 to 21, with higher scores indicating greater symptom severity. Based on established cutoffs, scores of 0-7 are considered normal, 8-10 indicate borderline abnormal (mild), and 11-21 indicate abnormal (moderate to severe). | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Pittsburgh Sleep Quality Index (PSQI) | The Pittsburgh Sleep Quality Index (PSQI) is a 19-item, self-rated questionnaire that assesses sleep quality over a 1-month time interval. It comprises seven component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 to 3, and the sum of these seven components yields a global PSQI score ranging from 0 to 21, with higher scores indicating poorer sleep quality. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| International Physical Activity Questionnaire (IPAQ) | The International Physical Activity Questionnaire (IPAQ) Long Form is a 27-item, self-administered questionnaire that assesses physical activity over the past 7 days across five life domains: work-related activity, transportation-related activity, domestic and gardening activity, leisure-time activity, and sitting time. Metabolic equivalent (MET) values assigned are: walking = 3.3 METs, moderate-intensity activity = 4.0 METs, and vigorous-intensity activity = 8.0 METs. Activity volume for each domain is calculated as MET-minutes per week (MET-min/week) using the formula: MET value × days per week × minutes per day. Total physical activity is derived by summing MET-min/week across all domains. Based on total MET-min/week, participants are classified into three levels: low (< 600 MET-min/week), moderate (600-3000 MET-min/week), and high (≥ 3000 MET-min/week) | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Peak O₂ pulse | Peak O₂ pulse will be assessed by cardiopulmonary exercise testing (CPET) . | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Anaerobic Threshold (AT) | Anaerobic Threshold (AT) will be assessed by cardiopulmonary exercise testing (CPET) . | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| VE/VCO₂ slope | VE/VCO₂ slope will be assessed by cardiopulmonary exercise testing (CPET) . Ventilation (VE) and carbon dioxide output (VCO₂) will be measured breath-by-breath throughout the test. The VE/VCO₂ slope will be calculated by linear regression analysis of VE versus VCO₂ using data from the beginning of exercise up to the respiratory compensation point (RCP). | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| left atrial volume index (LAVI) assessed by echocardiography | Left atrial volume index (LAVI) will be assessed using echocardiography. LAVI is calculated as left atrial volume indexed to body surface area (BSA), and will be reported in mL/m². | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| left atrial volume index (LAVI) assessed by cardiac magnetic resonance(CMR) | Left atrial volume index (LAVI) will be measured by cardiac magnetic resonance(CMR). LAVI is calculated as left atrial volume indexed to body surface area (BSA) and reported in mL/m². | Baseline（week 0），End of study（week 24 ） |
| Left ventricular mass index (LVMI) assessed by echocardiography | Left ventricular mass index (LVMI) will be measured by echocardiography. LVMI is derived by indexing LVM to body surface area (BSA) and reported in g/m². | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Left ventricular mass index (LVMI) assessed by cardiac magnetic resonance(CMR) | Left ventricular mass index (LVMI) will be measured by cardiac magnetic resonance(CMR). LVMI is derived by indexing LVM to body surface area (BSA) and reported in g/m². | Baseline（week 0），End of study（week 24） |
| left atrial volume (LAV) | Left atrial volume (LAV) will be assessed using echocardiography , and will be reported in mL. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| left atrial area (LAA) | Left atrial area (LAA) will be measured by echocardiography . Left atrial area index (LAAI) will be calculated as LAA max divided by body surface area (BSA) and reported in cm²/m². | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| left atrial diameter (LAD) | Left atrial diameter (LAD) will be measured by echocardiography and reported in mm. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Diastolic function index (E/e' ratio) | Diastolic function index (E/e' ratio) will be measured by echocardiography. The E/e' ratio is a noninvasive surrogate marker for estimating left ventricular filling pressure and is central to the grading of diastolic dysfunction. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Global longitudinal strain (GLS) | Global longitudinal strain (GLS) will be measured by echocardiography and reported in %. GLS is expressed as a negative value, with more negative values indicating better left ventricular systolic function. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Left ventricular myocardial work (MW) | Left ventricular myocardial work (MW) will be assessed by echocardiography and reported in mmHg%. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Left atrial strain (LAS) | Left atrial strain (LAS) will be measured by echocardiography and reported in %. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Epicardial adipose tissue volume (EATV) | Epicardial adipose tissue volume (EATV) will be quantified using cardiac magnetic resonance (CMR) and reported in mL. | Baseline（week 0），End of study（week 24 ） |
| Pericardial adipose tissue volume | Pericardial adipose tissue volume will be quantified using cardiac magnetic resonance (CMR) and reported in mL | Baseline（week 0），End of study（week 24 ） |
| Liver fat content (LFC) | Liver fat content (LFC) will be quantified using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) and expressed as a percentage (%) | Baseline（week 0），End of study（week 24 ） |
| Liver Stiffness Measurement（LSM）assessed by magnetic resonance elastography (MRE) | Liver stiffness measurement (LSM) will be assessed by magnetic resonance elastography (MRE) and reported in kilopascals (kPa), with higher values indicating more severe liver fibrosis | Baseline（week 0），End of study（week 24 ） |
| Liver Stiffness Measurement（LSM）assessed by FibroTouch transient elastography | Liver stiffness measurement (LSM) will be assessed using the FibroTouch transient elastography system and reported in kilopascals (kPa). | Baseline（week 0），End of study（week 24 ） |
| Visceral adipose tissue area (VATA) | Visceral adipose tissue area (VATA) will be measured using non-contrast chest CT and reported in cm² | Baseline（week 0），End of study（week 24 ） |
| BMI | Weight (kg) is measured with digital weighing scale. Height (cm) is measured with a portable stadiometer. BMI is calculated as weight in kilograms divided by the square of height in meters | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Waist-to-height ratio (WHtR) | Waist-to-height ratio (WHtR) will be calculated using standard anthropometric measurements. Waist circumference will be measured at the midpoint between the lower costal margin and the iliac crest at the mid-axillary line at the end of expiration. WHtR is calculated as waist circumference divided by height. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| Waist-to-hip ratio (WHR) | Waist-to-hip ratio (WHR) will be calculated using standard anthropometric measurements. Waist circumference will be measured at the midpoint between the lower costal margin and the iliac crest at the mid-axillary line at the end of expiration; hip circumference will be measured at the maximal gluteal protuberance. WHR as waist circumference divided by hip circumference. | Baseline（week 0），Mid-term（week 12），End of study（week 24 ） |
| All-Cause Death | All-cause death is defined as death from any cause occurring from baseline to the end of follow-up. Death information will be ascertained through regular follow-up, medical record review, and family reports. For participants lost to follow-up, vital status will be confirmed by cross-referencing with the local population death registry. This study will report the incidence of all-cause death from randomization to the end of study. | Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 |
| Heart failure rehospitalization | Heart failure rehospitalization is defined as an unplanned hospitalization (≥24 hours) due to decompensated heart failure, requiring at least one of the following intravenous therapies during the hospital stay: (1) intravenous diuretics; (2) intravenous vasodilators; or (3) intravenous inotropic agents. This study will report the incidence of heart failure rehospitalization from baseline to the end of the study. | Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 |
| Exercise intervention-related adverse events | Exercise intervention-related adverse events are defined as any adverse medical events occurring during participation in the exercise intervention protocol or within post-exercise, judged by the investigator to have a possible, probable, or definite causal relationship with the study exercise intervention. These include, but are not limited to, exercise-induced arrhythmias, angina, hypotensive/hypertensive crises, and musculoskeletal injuries requiring medical intervention. The overall incidence of exercise-related adverse events will be reported from baseline to the end of the study. | Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 |
| Clinical deterioration | Clinical deterioration is defined as any of the following events due to worsening heart failure that do not meet hospitalization criteria: (1) unscheduled clinic visit for worsening HF symptoms (dyspnea, edema, fatigue) requiring therapy intensification; (2) emergency department observation (<24 hours) for decompensated HF; (3) outpatient/day-care intravenous diuretics or vasodilators; or (4) significant upward titration of oral diuretics (e.g., dose doubling or new agent), confirmed by the investigator. Events progressing to hospitalization will be captured under "HF rehospitalization" and excluded here. Incidence will be reported as proportion of participants from baseline to the end of the study. | Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 |
| Fecal specimens | Fecal specimens will be collected at baseline and Week 24 for gut microbiome profiling. | Baseline（week 0），End of study（week 24 ） |
| Beijing Hospital | Beijing | China |
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| Beijing Xiaotangshan Hospital | Beijing | China |
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| Beijing Zhongguancun Hospital | Beijing | China |
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| Community Health Station of the Party School of the Central Committee of C.P.C | Beijing | China |
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| Jimenli Community Health Service Center | Beijing | China |
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| Peking University First Hospital | Beijing | China |
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| Peking University Third Hospital | Beijing | China |
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| Xueyuanlu Community Health Service Center | Beijing | China |
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| Shanghai East Hospital | Shanghai | China |
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| Wuhan Asia Heart Hospital | Wuhan | China |
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| ID | Term |
|---|---|
| D009043 | Motor Activity |
| ID | Term |
|---|---|
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D000072696 | High-Intensity Interval Training |
| ID | Term |
|---|---|
| D064797 | Physical Conditioning, Human |
| D015444 | Exercise |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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