Table 1.

TEPHRA trial objectives, outcome measures and measurement time-points

Objectives	Measures	Time-points
Benefits of Exercise
• Short term Blood Pressure Response: The primary objective is to compare the effect of aerobic exercise intervention and physical activity self-monitoring versus usual care/minimal intervention on ambulatory blood pressure levels in young adults with high normal and elevated blood pressure.	– Systolic and diastolic blood pressure measured during ambulatory blood pressure monitoring	Measured at baseline and at 16 week follow-up
• Sustained blood pressure response: To compare the sustained effect of aerobic exercise intervention with continued physical activity self-monitoring and motivational coaching versus usual care/minimal intervention on awake blood pressure levels in young adults with high normal and elevated blood pressure.	– Systolic and diastolic blood pressure measured during ambulatory blood pressure monitoring	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Cardiovascular Fitness: To compare the effect of aerobic exercise intervention and physical activity self-monitoring versus usual care/minimal intervention on cardiovascular performance and stress response in young adults with high normal and elevated blood pressure.	– Cardiopulmonary exercise testing - Oxygen uptake and carbon dioxide exchange kinetics across submaximal and peak exercise – Dynamic central and peripheral cardiovascular response to exercise stress – Circulating plasma stress biomarkers collected pre and post exercise. – Haemodynamic response to exercise: blood pressure, heart rate, measures of cardiac performance during cardiopulmonary exercise testing. – Exercise stress echocardiography (subgroup)	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Physical Function: Compare the 16-week and sustained effect of intervention on objectively measured walking gait, walking cadence and global physical function.	– Objective measure of physical activity (7 day wear of activity monitor) – Objective gait analysis – Questionnaire	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Cardiac Remodelling: Investigate cardiac adaptation and remodelling following intervention, with reference to gestational age and baseline cardiovascular phenotypes.	Cardiac echocardiography measures Cardiac MRI measures (subgroup) – Cardiac mass – Left and right ventricular structure and function – 3D-shape and functional analysis	– baseline – 16 weeks follow-up – 52 weeks follow-up (echocardiography only)
• Cerebrovascular Remodelling: Investigate cerebrovascular adaptation and remodelling following intervention, with reference to gestational age and baseline cerebrovascular phenotypes.	Brain MRI (subgroup) – White and grey matter volumes – Subcortical nuclei volumes – Cortical thickness – White matter integrity – White matter hyperintensities – White matter connectivity – Brain vessel morphology – Brain vascular resistance – Brain blood flow and arrival time	– baseline – 16 week follow-up
• Hepatic Remodelling: To investigate hepatic remodelling and mean change in hepatic adiposity pre and post exercise intervention compared to control.	Liver MRI (subgroup) – Structure and volume – Intra-hepatic lipid content – Steatohepatitis – Hepatic fibrosis – Hepatic Iron Load	– baseline – 16 weeks follow-up
• Metabolic Function: Compare the effects of intervention on the fasting metabolic profile.	– Fasting glucose profile – Fasting insulin profile – Fasting lipid profile	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Retinal and Dermal microvascular structure: Compare the effect of intervention on retinal and dermal vascular structures.	– Retinal imaging arteriolar and venular indices – Dermal capillary density	– baseline – 16 weeks follow-up – 52 weeks follow-up
Mediators of Exercise Adaptation and Blood Pressure Response
• Physical activity behaviours: Compare the 16-week and sustained effect of intervention on objectively measured ambulatory physical activity and sedentary behaviour in young adults with high normal and elevated blood pressure.	– Objective measure of physical activity (7 day wear of activity monitor)	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Molecular endothelial and angiogenic function: Compare the effect of aerobic exercise intervention versus usual care/minimal intervention on circulatory markers of angiogenesis and endothelial colony-forming cells (ECFC) function and association with change in blood pressure and cardiovascular fitness.	– Circulatory markers of angiogenic function. – ECFC colony growth (before or after 15 days in culture) – ECFC function: ECFC proliferation rate and number of branches and closed tubes formed on matrigel – Systolic and diastolic blood pressure measured during ambulatory blood pressure monitoring – Cardiopulmonary exercise testing	– baseline – 16 weeks follow-up
• Vascular remodelling: Compare the effect of aerobic exercise intervention and physical activity self-monitoring versus usual care/minimal intervention on central blood pressures, vascular stiffness and vascular structures.	– Pulse wave velocity – Augmentation index – Central blood pressure – Retinal imaging arteriolar and venular indices – Dermal capillary density	– baseline – 16 weeks follow-up – 52 weeks follow-up
Predictors of Response to Exercise and Blood Pressure Change
• Perceptions of the study and intervention compliance: Track compliance with the intervention and characterize participants’ subjective and qualitative experience of intervention and correlate with intervention effects on blood pressure and cardiovascular fitness to assess efficacy of the intervention.	– Exercise log and Fitbit step counts via Fitabase – Structured interview of participants	– 0–16 weeks training log – 16–52 weeks step count – End of trial period
• Physical activity beliefs: Investigate the correlation between physical activity behaviour change and participants’ cognitive and psycho-social determinants of exercise including self-efficacy to exercise, motivations to exercise.	– Objective measure of physical activity (7 day wear of activity monitor) – Self-reported questionnaire responses, including self-reported physical activity questionnaires, cognitive and psycho-social questionnaire items and self-efficacy measures.	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Baseline cardiovascular phenotypes: Investigate the associations between baseline cardiovascular phenotypes including the preterm born phenotype and response to exercise intervention across outcomes.	– Systolic and diastolic blood pressure measured during ambulatory blood pressure monitoring – Cardiopulmonary exercise testing - Oxygen uptake and carbon dioxide exchange kinetics across submaximal and peak exercise – Cardiac remodelling: echocardiography and cardiac MRI	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Baseline cerebrovascular phenotypes: Investigate the associations between baseline cerebrovascular structures; white matter connectome, subcortical volumes (caudate, thalamus and hippocampus) and cortical thickness (across insular, precuneus and posterior cingualate) and responsiveness to exercise intervention across outcomes.	– Systolic and diastolic blood pressure measured during ambulatory blood pressure monitoring – Cardiopulmonary exercise testing - Oxygen uptake and carbon dioxide exchange kinetics across submaximal and peak exercise – Cardiac remodelling echocardiography and cardiac MRI	– baseline – 16 weeks follow-up – 52 weeks follow-up
• Tertiles of blood pressure and cardiovascular risk: Investigate differences in response to exercise intervention across outcomes in associations with baseline tertiles of the study population blood pressure and cardiovascular risk scores.	– Systolic and diastolic blood pressure measured during ambulatory blood pressure monitoring – Cardiopulmonary exercise testing - Oxygen uptake and carbon dioxide exchange kinetics across submaximal and peak exercise – Cardiac remodelling echocardiography and cardiac MRI	– baseline – 16 weeks follow-up – 52 weeks follow-up
• ECFC function: Investigate if baseline molecular and cellular mechanisms in ECFC predict response to exercise intervention across outcomes.	– ECFC proteomics – ECFC molecular and cellular responses to in vitro shear and metabolic stresses. – Systolic and diastolic blood pressure measured during ambulatory blood pressure – Oxygen uptake and carbon dioxide exchange kinetics across submaximal and peak exercise – Whole, plasma, and serum blood samples at rest. – Retinal imaging arteriolar	– baseline – 16 weeks follow-up