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  1. Schuermans A, den Harink T, Raman B, Smillie RW, Alsharqi M, Mohamed A, et al.
    J Am Heart Assoc, 2022 Dec 06;11(23):e027305.
    PMID: 36453643 DOI: 10.1161/JAHA.122.027305
    Background Preterm birth affects 10% of live births and is associated with an altered left ventricular and right ventricular phenotype and increased cardiovascular disease risk in young adulthood. Because left atrial (LA) and right atrial (RA) volume and function are known independent predictors of cardiovascular outcomes, we investigated whether these were altered in preterm-born young adults. Methods and Results Preterm-born (n=200) and term-born (n=266) adults aged 18 to 39 years underwent cardiovascular magnetic resonance imaging. LA and RA maximal and minimal volumes (absolute, indexed to body surface area, and as a ratio to ventricular volumes) were obtained to study atrial morphology, while LA and RA stroke volume, strain, and strain rate were used to assess atrial function. Secondary analyses consisted of between-group comparisons based on degree of prematurity. Absolute RA volumes and RA volumes indexed to right ventricular volumes were significantly smaller in preterm-born compared with term-born adults. In addition, RA reservoir and booster strain were higher in preterm-born adults, possibly indicating functional compensation for the smaller RA volumes. LA volumes indexed to left ventricular volumes were significantly greater in preterm-born adults as compared with term-born adults, although absolute LA volumes were similar between groups. LA and RA changes were observed across gestational ages in the preterm group but were greatest in those born very-to-extremely preterm. Conclusions Preterm-born adults show changes in LA and RA structure and function, which may indicate subclinical cardiovascular disease. Further research into underlying mechanisms, opportunities for interventions, and their prognostic value is warranted.
  2. Alsharqi M, Huckstep OJ, Lapidaire W, Williamson W, Mohamed A, Tan CMJ, et al.
    Echocardiography, 2021 Aug;38(8):1319-1326.
    PMID: 34185918 DOI: 10.1111/echo.15149
    AIMS: To investigate the left ventricular response to exercise in young adults with hypertension, and identify whether this response can be predicted from changes in left atrial function at rest.

    METHODS: A total of 127 adults aged 18-40 years who completed clinical blood pressure assessment and echocardiography phenotyping at rest and during cardiopulmonary exercise testing, were included. Measurements were compared between participants with suboptimal blood pressure ≥120/80mm Hg (n = 68) and optimal blood pressure <120/80mm Hg (n = 59). Left ventricular systolic function during exercise was obtained from an apical four chamber view, while resting left atrial function was assessed from apical four and two chamber views.

    RESULTS: Participants with suboptimal blood pressure had higher left ventricular mass (p = 0.031) and reduced mitral E velocity (p = 0.02) at rest but no other cardiac differences. During exercise, their rise in left ventricular ejection fraction was reduced (p = 0.001) and they had higher left ventricular end diastolic and systolic volumes (p = 0.001 and p = 0.001, respectively). Resting cardiac size predicted left ventricular volumes during exercise but only left atrial booster pump function predicted the left ventricular ejection fraction response ( β = .29, p = 0.011). This association persisted after adjustment for age, sex, body mass index, and mean arterial pressure.

    CONCLUSION: Young adults with suboptimal blood pressure have a reduced left ventricular systolic response to exercise, which can be predicted by their left atrial booster pump function at rest. Echocardiographic measures of left atrial function may provide an early marker of functionally relevant, subclinical, cardiac remodelling in young adults with hypertension.

  3. Lapidaire W, Forkert ND, Williamson W, Huckstep O, Tan CM, Alsharqi M, et al.
    Neuroimage Clin, 2023;37:103337.
    PMID: 36709637 DOI: 10.1016/j.nicl.2023.103337
    IMPORTANCE: Cerebrovascular changes are already evident in young adults with hypertension and exercise is recommended to reduce cardiovascular risk. To what extent exercise benefits the cerebrovasculature at an early stage of the disease remains unclear.

    OBJECTIVE: To investigate whether structured aerobic exercise increases brain vessel lumen diameter or cerebral blood flow (CBF) and whether lumen diameter is associated with CBF.

    DESIGN: Open, parallel, two-arm superiority randomized controlled (1:1) trial in the TEPHRA study on an intention-to-treat basis. The MRI sub-study was an optional part of the protocol. The outcome assessors remained blinded until the data lock.

    SETTING: Single-centre trial in Oxford, UK.

    PARTICIPANTS: Participants were physically inactive (<150 min/week moderate to vigorous physical activity), 18 to 35 years old, 24-hour ambulatory blood pressure 115/75 mmHg-159/99 mmHg, body mass index below 35 kg/m2 and never been on prescribed hypertension medications. Out of 203 randomized participants, 135 participated in the MRI sub-study. Randomisation was stratified for sex, age (<24, 24-29, 30-35 years) and gestational age at birth (<32, 32-37, >37 weeks).

    INTERVENTION: Study participants were randomised to a 16 week aerobic exercise intervention targeting 3×60 min sessions per week at 60 to 80 % peak heart rate.

    MAIN OUTCOMES AND MEASURES: cerebral blood flow (CBF) maps from ASL MRI scans, internal carotid artery (ICA), middle cerebral artery (MCA) M1 and M2 segments, anterior cerebral artery (ACA), basilar artery (BA), and posterior cerebral artery (PCA) diameters extracted from TOF MRI scans.

    RESULTS: Of the 135 randomized participants (median age 28 years, 58 % women) who had high quality baseline MRI data available, 93 participants also had high quality follow-up data available. The exercise group showed an increase in ICA (0.1 cm, 95 % CI 0.01 to 0.18, p =.03) and MCA M1 (0.05 cm, 95 % CI 0.01 to 0.10, p =.03) vessel diameter compared to the control group. Differences in the MCA M2 (0.03 cm, 95 % CI 0.0 to 0.06, p =.08), ACA (0.04 cm, 95 % CI 0.0 to 0.08, p =.06), BA (0.02 cm, 95 % CI -0.04 to 0.09, p =.48), and PCA (0.03 cm, 95 % CI -0.01 to 0.06, p =.17) diameters or CBF were not statistically significant. The increase in ICA vessel diameter in the exercise group was associated with local increases in CBF.

    CONCLUSIONS AND RELEVANCE: Aerobic exercise induces positive cerebrovascular remodelling in young people with early hypertension, independent of blood pressure. The long-term benefit of these changes requires further study.

    TRIAL REGISTRATION: Clinicaltrials.gov NCT02723552, 30 March 2016.

  4. Tan CMJ, Lewandowski AJ, Williamson W, Huckstep OJ, Yu GZ, Fischer R, et al.
    J Am Heart Assoc, 2021 Aug 03;10(15):e021119.
    PMID: 34275329 DOI: 10.1161/JAHA.121.021119
    Background A subpopulation of endothelial progenitor cells called endothelial colony-forming cells (ECFCs) may offer a platform for cellular assessment in clinical studies because of their remarkable angiogenic and expansion potentials in vitro. Despite endothelial cell function being influenced by cardiovascular risk factors, no studies have yet provided a comprehensive proteomic profile to distinguish functional (ie, more angiogenic and expansive cells) versus dysfunctional circulating ECFCs of young adults. The aim of this study was to provide a detailed proteomic comparison between functional and dysfunctional ECFCs. Methods and Results Peripheral blood ECFCs were isolated from 11 subjects (45% men, aged 27±5 years) using Ficoll density gradient centrifugation. ECFCs expressed endothelial and progenitor surface markers and displayed cobblestone-patterned morphology with clonal and angiogenic capacities in vitro. ECFCs were deemed dysfunctional if <1 closed tube formed during the in vitro tube formation assay and proliferation rate was <20%. Hierarchical functional clustering revealed distinct ECFC proteomic signatures between functional and dysfunctional ECFCs with changes in cellular mechanisms involved in exocytosis, vesicle transport, extracellular matrix organization, cell metabolism, and apoptosis. Targeted antiangiogenic proteins in dysfunctional ECFCs included SPARC (secreted protein acidic and rich in cysteine), CD36 (cluster of differentiation 36), LUM (lumican), and PTX3 (pentraxin-related protein PYX3). Conclusions Circulating ECFCs with impaired angiogenesis and expansion capacities have a distinct proteomic profile and significant phenotype changes compared with highly angiogenic endothelial cells. Impaired angiogenesis in dysfunctional ECFCs may underlie the link between endothelial dysfunction and cardiovascular disease risks in young adults.
  5. Burchert H, Lapidaire W, Williamson W, McCourt A, Dockerill C, Woodward W, et al.
    Am J Respir Crit Care Med, 2023 May 01;207(9):1227-1236.
    PMID: 36459100 DOI: 10.1164/rccm.202205-0858OC
    Rationale: Premature birth is an independent predictor of long-term cardiovascular risk. Individuals affected are reported to have a lower rate of [Formula: see text]o2 at peak exercise intensity ([Formula: see text]o2PEAK) and at the ventilatory anaerobic threshold ([Formula: see text]o2VAT), but little is known about their response to exercise training. Objectives: The primary objective was to determine whether the [Formula: see text]o2PEAK response to exercise training differed between preterm-born and term-born individuals; the secondary objective was to quantify group differences in [Formula: see text]o2VAT response. Methods: Fifty-two preterm-born and 151 term-born participants were randomly assigned (1:1) to 16 weeks of aerobic exercise training (n = 102) or a control group (n = 101). Cardiopulmonary exercise tests were conducted before and after the intervention to measure [Formula: see text]o2PEAK and the [Formula: see text]o2VAT. A prespecified subgroup analysis was conducted by fitting an interaction term for preterm and term birth histories and exercise group allocation. Measurements and Main Results: For term-born participants, [Formula: see text]o2PEAK increased by 3.1 ml/kg/min (95% confidence interval [CI], 1.7 to 4.4), and the [Formula: see text]o2VAT increased by 2.3 ml/kg/min (95% CI, 0.7 to 3.8) in the intervention group versus controls. For preterm-born participants, [Formula: see text]o2PEAK increased by 1.8 ml/kg/min (95% CI, -0.4 to 3.9), and the [Formula: see text]o2VAT increased by 4.6 ml/kg/min (95% CI, 2.1 to 7.0) in the intervention group versus controls. No significant interaction was observed with birth history for [Formula: see text]o2PEAK (P = 0.32) or the [Formula: see text]o2VAT (P = 0.12). Conclusions: The training intervention led to significant improvements in [Formula: see text]o2PEAK and [Formula: see text]o2VAT, with no evidence of a statistically different response based on birth history. Clinical trial registered with www.clinicaltrials.gov (NCT02723552).
  6. Alsharqi M, Lapidaire W, Iturria-Medina Y, Xiong Z, Williamson W, Mohamed A, et al.
    Eur Heart J Imaging Methods Pract, 2023 Sep;1(2):qyad029.
    PMID: 37818310 DOI: 10.1093/ehjimp/qyad029
    AIMS: Accurate staging of hypertension-related cardiac changes, before the development of significant left ventricular hypertrophy, could help guide early prevention advice. We evaluated whether a novel semi-supervised machine learning approach could generate a clinically meaningful summary score of cardiac remodelling in hypertension.

    METHODS AND RESULTS: A contrastive trajectories inference approach was applied to data collected from three UK studies of young adults. Low-dimensional variance was identified in 66 echocardiography variables from participants with hypertension (systolic ≥160 mmHg) relative to a normotensive group (systolic < 120 mmHg) using a contrasted principal component analysis. A minimum spanning tree was constructed to derive a normalized score for each individual reflecting extent of cardiac remodelling between zero (health) and one (disease). Model stability and clinical interpretability were evaluated as well as modifiability in response to a 16-week exercise intervention. A total of 411 young adults (29 ± 6 years) were included in the analysis, and, after contrastive dimensionality reduction, 21 variables characterized >80% of data variance. Repeated scores for an individual in cross-validation were stable (root mean squared deviation = 0.1 ± 0.002) with good differentiation of normotensive and hypertensive individuals (area under the receiver operating characteristics 0.98). The derived score followed expected hypertension-related patterns in individual cardiac parameters at baseline and reduced after exercise, proportional to intervention compliance (P = 0.04) and improvement in ventilatory threshold (P = 0.01).

    CONCLUSION: A quantitative score that summarizes hypertension-related cardiac remodelling in young adults can be generated from a computational model. This score might allow more personalized early prevention advice, but further evaluation of clinical applicability is required.

  7. Williamson W, Lewandowski AJ, Huckstep OJ, Lapidaire W, Ooms A, Tan C, et al.
    EClinicalMedicine, 2022 Jun;48:101445.
    PMID: 35706495 DOI: 10.1016/j.eclinm.2022.101445
    BACKGROUND: Exercise is advised for young adults with elevated blood pressure, but no trials have investigated efficacy at this age. We aimed to determine whether aerobic exercise, self-monitoring and motivational coaching lowers blood pressure in this group.

    METHODS: The study was a single-centre, open, two-arm, parallel superiority randomized clinical trial with open community-based recruitment of physically-inactive 18-35 year old adults with awake 24 h blood pressure 115/75mmHg-159/99 mmHg and BMI<35 kg/m2. The study took place in the Cardiovascular Clinical Research Facility, John Radcliffe Hospital, Oxford, UK. Participants were randomized (1:1) with minimisation factors sex, age (<24, 24-29, 30-35 years) and gestational age at birth (<32, 32-37, >37 weeks) to the intervention group, who received 16-weeks aerobic exercise training (three aerobic training sessions per week of 60 min per session at 60-80% peak heart rate, physical activity self-monitoring with encouragement to do 10,000 steps per day and motivational coaching to maintain physical activity upon completion of the intervention. The control group were sign-posted to educational materials on hypertension and recommended lifestyle behaviours. Investigators performing statistical analyses were blinded to group allocation. The primary outcome was 24 h awake ambulatory blood pressure (systolic and diastolic) change from baseline to 16-weeks on an intention-to-treat basis. Clinicaltrials.gov registered on March 30, 2016 (NCT02723552).

    FINDINGS: Enrolment occurred between 30/06/2016-26/10/2018. Amongst the 203 randomized young adults (n = 102 in the intervention group; n = 101 in the control group), 178 (88%; n = 76 intervention group, n = 84 control group) completed 16-week follow-up and 160 (79%; n = 68 intervention group, n = 69 control group) completed 52-weeks follow-up. There were no group differences in awake systolic (0·0 mmHg [95%CI, -2·9 to 2·8]; P = 0·98) or awake diastolic ambulatory blood pressure (0·6 mmHg [95%CI, -1·4. to 2·6]; P = 0·58). Aerobic training increased peak oxygen uptake (2·8 ml/kg/min [95%CI, 1·6 to 4·0]) and peak wattage (14·2watts [95%CI, 7·6 to 20·9]) at 16-weeks. There were no intervention effects at 52-weeks follow-up.

    INTEPRETATION: These results do not support the exclusive use of moderate to high intensity aerobic exercise training for blood pressure control in young adults.

    FUNDING: Wellcome Trust, British Heart Foundation, National Institute for Health Research, Oxford Biomedical Research Centre.

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