Reducing Heart Failure Risk in Late-Life With Physical Activity

Hypertension Clinical Trial

Official title:

Reducing Heart Failure Risk in Late-Life With Physical Activity: Impact on Cardiac Structure and Function and Proteomic Signatures

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06247774
• Other study ID #: 2023p002781
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 2024
• Est. completion date: May 2029

Study information

• Verified date: January 2024
• Source: Brigham and Women's Hospital
• Contact: Sheila Hegde, MD
• Phone: 6177325500
• Email: shegde[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to learn about the molecular pathways associated with the benefit of a regular exercise program in patients with high blood pressure and who don't already participate in regular exercise.

The main question it aims to answer is to identify protein signatures associated with the benefits of a cardiac rehabilitation exercise program.

The trial will enroll 42 participants, who will be randomized to a 12 week cardiac rehabilitation exercise program versus control arm and asked to participate in the following at the beginning and end of study:

• Cardiopulmonary exercise test (CPET)

• Echocardiogram

• Physical function test

• 6-minute walk test

• Hand grip strength

• Quality of life questionnaire

• Blood draws

Researchers will compare results between those who do and don't participate in the exercise program.

Description:

Lifestyle modification with physical activity (PA) appears to be protective of several age-related cardiovascular (CV) outcomes, including heart failure (HF), in a dose-dependent manner. While many studies with exercise training have demonstrated improvement in quality of life and cardiorespiratory fitness, findings have not been consistent with regards to the potential for exercise to preserve or even improve cardiac function in adults with HF. There remains incomplete understanding of the molecular pathways by which PA mitigates HF risk. Furthermore, exercise studies often exclude older adults, who are disproportionately affected by HF, though our preliminary data suggest the protective effects of PA extend to late-life. Older adults are at particularly heightened risk for HF with preserved ejection fraction (HFpEF), which is characterized by impaired left ventricular (LV) diastolic function and impaired systolic deformation despite preserved LV ejection fraction (LVEF). Unlike with HF with reduced ejection fraction (HFrEF), effective pharmacologic therapies or interventions to improve cardiac function among individuals with preserved LVEF are limited. Thus, there is a critical need to define the cardiovascular mechanisms by which PA impacts HF risk in older adults that may enable the identification of novel therapeutic targets to prevent HF and HFpEF in particular.

As proteins orchestrate and carry out cellular functions in health and in diseases, one method of characterizing changes in CV function is to investigate cell signaling by studying the circulating proteome. Proteomic approaches have previously been used to identify pathways relevant to myocardial infarction and have also been used to investigate molecular pathways characterizing PA and CV disease. A recent study demonstrated upregulation of inflammation-related proteins in HFpEF patients (n=228) compared to controls, and their association with worse indices of cardiac function. Specific proteomic patterns have also been associated with aerobic exercise, with 2 proteomic modules that were specifically preserved with aging in habitual exercisers. Data from Swedish cohorts has also shown an association of leisure-time PA with 28 CV-specific proteins involved in atherosclerotic processes. Serial multi-omic measures (including proteomics) have been used to demonstrate marked intra-individual changes in circulating proteins with acute exercise. More recently, high-throughput proteomic profiling has been successfully employed in younger adults to identify baseline protein levels associated with change in cardiorespiratory fitness following an exercise intervention. However, to-date, limited data exist regarding intervention-related changes in the proteome in older adults at risk for HF and the extent to which these changes correlate with changes in cardiorespiratory fitness.

Supervised exercise-training with cardiac rehabilitation (CR) has been well established as an effective method to improve maximal oxygen consumption (VO2 max), a measure of cardiorespiratory fitness. Improvement in VO2 max has also been demonstrated with exercise training in sedentary older adults over 65 years of age.

The objective of this proposal is to identify protein signatures characterizing the known benefits of a structured CR program on VO2 max. Our working hypotheses is that proteomic approaches will identify novel biomarkers that uniquely characterize molecular pathways associated with exercise training and CR-related changes in proteins will correlate with changes in VO2 max. Successful completion of this aim will identify possible novel protein signatures underlying the protective biological pathways mediated by a structured CR program that may be used as preliminary data for future grant proposals.

Aim: Identify molecular pathways underlying the beneficial effect of a structured PA intervention on functional capacity with the use of plasma proteomics in older sedentary adults at high risk of HF. (BWH-based cohort). Hypotheses: (1) Randomization to participation in a cardiac rehabilitation (CR) program will result in improvement in circulating levels of 4 plasma proteins associated with change in VO2max, a measure of cardiorespiratory fitness, and with genetic evidence supporting a causal effect on HF and cardiac structure (ATF6, STC1, JAG1, PTK7). The investigators will randomize 42 sedentary adults at high risk of HF (stage B HF) to participation in a CR program and perform proteomic analysis, cardiopulmonary exercise testing, and echocardiography at baseline and 12 weeks.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 42
• Est. completion date: May 2029
• Est. primary completion date: January 2029
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 65 Years to 99 Years

Eligibility

Inclusion Criteria:

• Hypertension (controlled on stable medication regimen)

• Structural heart abnormality (LVH or LA enlargement)

• LVEF > 50%

• Sedentary

• BMI <30

Exclusion Criteria:

• Diabetes

• Unable to exercise

• Supplemental oxygen use

• Pulmonary hypertension

• Sleep apnea

• Regular exercise training

• Devices that limit ability to achieve target heart rate

• Moderate to severe valve disease

• Recent (within 3 months) major CV event or planned procedures (within 6 months)

• Terminal illness, life expectancy <6 months

• Inability or unwillingness to comply with study requirements

• No access to smart phone/tablet

Related Conditions & MeSH terms

• Cardiac Rehabilitation
• Exercise Training
• Heart Failure
• Hypertension
• Proteomics

Intervention

Behavioral:
• Cardiac Rehabilitation
Participation in a 12-week cardiac rehabilitation program
• Attention Control
Participants will receive regular phone calls in place of cardiac rehabilitation visits

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Brigham and Women's Hospital

References & Publications (17)

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Hieda M, Sarma S, Hearon CM Jr, Dias KA, Martinez J, Samels M, Everding B, Palmer D, Livingston S, Morris M, Howden E, Levine BD. Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection Fraction. Circulation. 2020 Jan 14;141(2):115-123. doi: 10.1161/CIRCULATIONAHA.119.040332. Epub 2019 Dec 23. — View Citation

Hieda M, Sarma S, Hearon CM Jr, MacNamara JP, Dias KA, Samels M, Palmer D, Livingston S, Morris M, Levine BD. One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction. Circulation. 2021 Sep 21;144(12):934-946. doi: 10.1161/CIRCULATIONAHA.121.054117. Epub 2021 Sep 20. — View Citation

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Keteyian SJ, Ades PA, Beatty AL, Gavic-Ott A, Hines S, Lui K, Schopfer DW, Thomas RJ, Sperling LS. A Review of the Design and Implementation of a Hybrid Cardiac Rehabilitation Program: AN EXPANDING OPPORTUNITY FOR OPTIMIZING CARDIOVASCULAR CARE. J Cardiopulm Rehabil Prev. 2022 Jan 1;42(1):1-9. doi: 10.1097/HCR.0000000000000634. — View Citation

Ngo D, Sinha S, Shen D, Kuhn EW, Keyes MJ, Shi X, Benson MD, O'Sullivan JF, Keshishian H, Farrell LA, Fifer MA, Vasan RS, Sabatine MS, Larson MG, Carr SA, Wang TJ, Gerszten RE. Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease. Circulation. 2016 Jul 26;134(4):270-85. doi: 10.1161/CIRCULATIONAHA.116.021803. — View Citation

O'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Miller NH, Fleg JL, Schulman KA, McKelvie RS, Zannad F, Pina IL; HF-ACTION Investigators. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 2009 Apr 8;301(14):1439-50. doi: 10.1001/jama.2009.454. — View Citation

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Shah AM, Claggett B, Loehr LR, Chang PP, Matsushita K, Kitzman D, Konety S, Kucharska-Newton A, Sueta CA, Mosley TH, Wright JD, Coresh J, Heiss G, Folsom AR, Solomon SD. Heart Failure Stages Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study. Circulation. 2017 Jan 17;135(3):224-240. doi: 10.1161/CIRCULATIONAHA.116.023361. Epub 2016 Nov 23. — View Citation

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* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Impact of Cardiac Rehabilitation training on single protein changes	Change in protein levels assessed by blood draws and measured by Somascan assay. ANCOVA analysis adjusting for baseline protein levels with intention to treat group assignment	12 weeks
Secondary	Correlation of change in proteins with change in VO2 max	Correlation of single protein changes associated with change in VO2 max	12 weeks
Secondary	Correlation of change in proteins with change in LV global longitudinal strain	Correlation of single protein changes associated with change in LV global longitudinal strain	12 weeks
Secondary	Correlation of change in proteins with change in LV diastolic function	Correlation of single protein changes associated with change in LV diastolic function	12 weeks
Secondary	Correlation of change in proteins with change in VE/VCO2	Correlation of single protein changes associated with change in VE/VCO2	12 weeks
Secondary	Correlation of change in proteins with change in Short Physical Performance Battery (SPPB)	Correlation of single protein changes associated with change in Short Physical Performance Battery (SPPB)	12 weeks
Secondary	Correlation of change in proteins with change in 6-minute walk test	Correlation of single protein changes associated with change in 6-minute walk test	12 weeks
Secondary	Correlation of change in proteins with change in grip strength	Correlation of single protein changes associated with change in grip strength	12 weeks
Secondary	Correlation of change in proteins with change in EQ-5D (QOL)	Correlation of single protein changes associated with change in EQ-5D (QOL)	12 weeks
Secondary	Correlation of change in proteins with change in step counts	Correlation of single protein changes associated with change in step counts	12 weeks
Secondary	Correlation of baseline proteins with change in VO2 max	Correlation of baseline proteins with change in VO2 max	12 weeks
Secondary	Correlation of baseline proteins with change in LV global longitudinal strain	Correlation of baseline proteins with change in LV global longitudinal strain	12 weeks
Secondary	Correlation of baseline proteins with change in LV diastolic function	Correlation of baseline proteins with change in LV diastolic function	12 weeks
Secondary	Correlation of baseline proteins with change in VE/VCO2	Correlation of baseline proteins with change in VE/VCO2	12 weeks
Secondary	Correlation of baseline proteins with change in SPPB	Correlation of baseline proteins with change in SPPB	12 weeks
Secondary	Correlation of baseline proteins with change in 6-minute walk test	Correlation of baseline proteins with change in 6-minute walk test	12 weeks
Secondary	Correlation of baseline proteins with change in grip strength	Correlation of baseline proteins with change in grip strength	12 weeks
Secondary	Correlation of baseline proteins with change in EQ-5D (QOL)	Correlation of baseline proteins with change in EQ-5D (QOL)	12 weeks
Secondary	Correlation of baseline proteins with change in step counts	Correlation of baseline proteins with change in step counts	12 weeks