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Premature birth is an independent predictor of long-term cardiovascular risk. Individuals affected are reported to have a lower rate of oxygen consumption at peak exercise intensity and at ventilatory anaerobic threshold, but little is known about their response to exercise training.To explore if peak exercise oxygen consumption and ventilatory anaerobic threshold responses to exercise training differ between preterm-born and term-born individuals.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 oxygen consumption at peak exercise intensity and the ventilatory anaerobic threshold. A prespecified subgroup analysis was conducted by fitting an interaction term for preterm and term birth history and exercise group allocation.Within term-born participants, peak exercise oxygen consumption increased by 3.1 (95% confidence interval: 1.7 to 4.4)ml/kg/min and ventilatory anaerobic threshold increased by 2.3 (95% confidence interval: 0.7 to 3.8)ml/kg/min in the intervention group versus controls. Within preterm-born participants, peak exercise oxygen consumption increased by 1.8 (95% confidence interval: -0.4 to 3.9)ml/kg/min and ventilatory anaerobic threshold increased by 4.6 (95% confidence interval: 2.1 to 7.0)ml/kg/min in the intervention group versus controls. No significant interaction was observed for peak exercise oxygen consumption (p=0.32) or ventilatory anaerobic threshold (p=0.12).The training intervention led to significant improvements in peak exercise oxygen consumption and ventilatory anaerobic threshold, with no evidence of a statistically different response based on birth history. Clinical trial registration available at www.gov, ID: NCT02723552. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

What is the topic of this review? Studies using cardiovascular magnetic resonance imaging and echocardiography to investigate cardiac alterations at rest and during exercise-induced physiological stress in adults born preterm. What advances does it highlight? People born preterm have a greater long-term cardiovascular risk, which may be explained in part by their cardiac structural and functional alterations. They have potentially adverse alterations in left and right ventricular structure and function that worsens with blood pressure elevation; an impaired myocardial functional reserve; and an increase in diffuse myocardial fibrosis that may drive their lower diastolic function.Preterm birth accounts for more than 10% of births worldwide and associates with a long-term increase in cardiovascular disease risk. The period around preterm birth is a rapid and critical phase of cardiovascular development, which might explain why changes in multiple components of the cardiovascular system have been observed in individuals born preterm. These alterations include reduced microvascular density, increased macrovascular stiffness, and higher systolic and diastolic blood pressure. Cardiac alterations have been observed in people born preterm as early as neonatal life and infancy, with potentially adverse changes in both left and right ventricular structure and function extending into adulthood. Indeed, studies using cardiovascular magnetic resonance imaging and echocardiography have demonstrated that preterm-born individuals have structural cardiac changes and functional impairments. Furthermore, myocardial tissue characterization by cardiovascular magnetic resonance imaging has demonstrated an increase in left ventricular diffuse myocardial fibrosis in young adults born preterm, and under acute physiological stress, their myocardial functional reserve assessed by echocardiography is reduced. The preterm heart is also more susceptible to chronic systolic blood pressure elevation, with a significantly greater increase in left ventricular mass as systolic blood pressure rises observed in preterm-born compared to term-born young adults. Given these known, potentially adverse acute and chronic cardiac adaptations in the preterm-born population, primary prevention strategies are needed to reduce long-term cardiovascular disease risk in this subgroup of the population.

BackgroundAdults who were born prematurely (MethodsMultilevel models were used to compare trajectories from early childhood (ranging from birth to 9 years) to age 25 years of BMI, fat mass, lean mass, systolic and diastolic blood pressure (BP), lipids, glucose and insulin, between participants born preterm (N=311-733, range 25-36 completed weeks gestation) and term (N=5365-12097) in a contemporary UK birth cohort study. We also investigated gestational age as a continuum.ResultsIn children born preterm (versus term), systolic and diastolic BP were higher at age 7 (mean predicted differences 0.6mmHg; 95%CI -0.3, 1.5 and 0.6mmHg; 95%CI 0.03, 1.3, respectively). By age 25 years, the difference in SBP persisted (1.4, 95%CI -0.1, 2.9 mmHg) and in DBP (−0.2, 95%CI -1.3, 0.9 mmHg) disappeared. Participants born preterm (versus term) had lower BMI between 7 and 18 years, but by age 25, there was no difference. Lean mass and fat mass (measured from age 9 only) trajectories were consistent with BMI. HDL-c was higher, and triglycerides lower at birth in those born preterm, but this difference also disappeared by 25 years. There was no evidence of differences in glucose and insulin between participants born preterm compared to term.ConclusionsThere were few, modest differences in cardiometabolic health measures during early life in those born preterm versus term. All disappeared by age 25, except the small difference in SBP. Longer follow-up is needed to establish if and when trajectories of measures of cardiometabolic health in term and preterm born people diverge.Clinical perspectiveWhat is new?Whether life course trajectories of commonly assessed cardiovascular disease (CVD) risk factors such as blood pressure, are different in people born preterm vs those born at term, is unknown.By age 25, we generally found no evidence of differences between people born preterm and term on measures of cardiometabolic health except that systolic blood pressure was modestly higher in those born preterm. We also observed more favourable outcomes with lower adiposity measures between ages 9 and 18 years.Clinical implicationsThe reported increased risk of CVD in people born preterm is not apparent in early adulthood.Whilst it may emerge in later life, our results suggest no justification for CVD screening using ‘classic’ risk factors in young adults based on their gestational age.Further work to replicate these findings in other independent cohorts and studies with follow-up into mid life are required to examine when associations emerge.

Progressive improvements in perinatal care and respiratory management of preterm infants has resulted in increased survival of extremely low gestational age newborns over the past few decades. However, the incidence of bronchopulmonary dysplasia (BPD), the chronic lung disease after preterm birth, has not changed. Studies of the long-term follow-up of adults born preterm have shown persistent abnormalities of respiratory, cardiovascular, and cardiopulmonary function possibly leading to a lesser exercise capacity. The underlying causes of these abnormalities are incompletely known, but we hypothesize that dysanapsis, i.e., discordant growth and development, in the respiratory and cardiovascular systems is a central structural feature that leads to the lesser exercise capacity in young adults born preterm compared to those born at term. We discuss how the hypothesized system dysanapsis underscores the observed respiratory, cardiovascular, and cardiopulmonary limitations. Specifically, adults born preterm have 1) normal lung volumes but smaller airways that causes expiratory airflow limitation and abnormal respiratory mechanics but without impacts on pulmonary gas exchange efficiency; 2) normal total cardiac size but smaller cardiac chambers, and 3) in some cases, evidence of pulmonary hypertension particularly during exercise, suggesting a reduced pulmonary vascular capacity despite reduced cardiac output. We speculate that these underlying developmental abnormalities may accelerate the normal age-associated decline in exercise capacity, via an accelerated decline in respiratory, cardiovascular, and cardiopulmonary function. Finally, we suggest areas of future research, especially the need for longitudinal and interventional studies from infancy into adulthood to better understand how preterm birth alters exercise capacity across the lifespan.

Supplemental Digital Content is available in the text., Women with hypertensive pregnancies are 4× more likely to develop chronic hypertension. Previously, we showed a short period of blood pressure (BP) self-management following hypertensive pregnancy resulted in persistently lower BP after 6 months. We now report the impact on long-term BP control. Women who participated in the postpartum randomized controlled trial, SNAP-HT (Self-Management of Postnatal Hypertension; NCT02333240), were invited for 24-hour ambulatory and clinic BP measures. Height and weight were measured by calibrated scales and standardized tape measures, activity by 7-day wrist-worn accelerometer, and dietary factors assessed by questionnaire. Sixty-one of 70 eligible women were followed up 3.6±0.4 years after their original pregnancy. Twenty-four–hour diastolic BP was 7.0 mm Hg lower in those originally randomized to postpartum BP self-management instead of usual care. This difference remained significant after adjustment for either BP at the time of delivery (−7.4 mm Hg [95% CI, −10.7 to −4.2]; P

Supplemental Digital Content is available in the text., Hypertensive pregnancy is associated with increased maternal cardiovascular risk in later life. A range of cardiovascular adaptations after pregnancy have been reported to partly explain this risk. We used multimodality imaging to identify whether, by midlife, any pregnancy-associated phenotypes were still identifiable and to what extent they could be explained by blood pressure. Participants were identified by review of hospital maternity records 5 to 10 years after pregnancy and invited to a single visit for detailed cardiovascular imaging phenotyping. One hundred seventy-three women (age, 42±5 years, 70 after normotensive and 103 after hypertensive pregnancy) underwent magnetic resonance imaging of the heart and aorta, echocardiography, and vascular assessment, including capillaroscopy. Women with a history of hypertensive pregnancy had a distinct cardiac geometry with higher left ventricular mass index (49.9±7.1 versus 46.0±6.5 g/m2; P=0.001) and ejection fraction (65.6±5.4% versus 63.7±4.3%; P=0.03) but lower global longitudinal strain (−18.31±4.46% versus −19.94±3.59%; P=0.02). Left atrial volume index was also increased (40.4±9.2 versus 37.3±7.3 mL/m2; P=0.03) and E:A reduced (1.34±0.35 versus 1.52±0.45; P=0.003). Aortic compliance (0.240±0.053 versus 0.258±0.063; P=0.046) and functional capillary density (105.4±23.0 versus 115.2±20.9 capillaries/mm2; P=0.01) were reduced. Only differences in functional capillary density, left ventricular mass, and atrial volume indices remained after adjustment for blood pressure (P

Aims We tested the hypothesis that the known reduction in myocardial functional reserve in preterm-born young adults is an independent predictor of exercise capacity (peak VO2) and heart rate recovery (HRR). Methods and results We recruited 101 normotensive young adults (n = 47 born preterm; 32.8 ± 3.2 weeks’ gestation and n = 54 term-born controls). Peak VO2 was determined by cardiopulmonary exercise testing (CPET), and lung function assessed using spirometry. Percentage predicted values were then calculated. HRR was defined as the decrease from peak HR to 1 min (HRR1) and 2 min of recovery (HRR2). Four-chamber echocardiography views were acquired at rest and exercise at 40% and 60% of CPET peak power. Change in left ventricular ejection fraction from rest to each work intensity was calculated (EFΔ40% and EFΔ60%) to estimate myocardial functional reserve. Peak VO2 and per cent of predicted peak VO2 were lower in preterm-born young adults compared with controls (33.6 ± 8.6 vs. 40.1 ± 9.0 mL/kg/min, P = 0.003 and 94% ± 20% vs. 108% ± 25%, P = 0.001). HRR1 was similar between groups. HRR2 decreased less in preterm-born young adults compared with controls (−36 ± 13 vs. −43 ± 11 b.p.m., P = 0.039). In young adults born preterm, but not in controls, EFΔ40% and EFΔ60% correlated with per cent of predicted peak VO2 (r2 = 0.430, P = 0.015 and r2 = 0.345, P = 0.021). Similarly, EFΔ60% correlated with HRR1 and HRR2 only in those born preterm (r2 = 0.611, P = 0.002 and r2 = 0.663, P = 0.001). Conclusions Impaired myocardial functional reserve underlies reductions in peak VO2 and HRR in young adults born moderately preterm. Peak VO2 and HRR may aid risk stratification and treatment monitoring in this population.

Background: Approximately 10% of infants are born preterm. Preterm birth leads to short and long-term changes in cardiac shape and function. By using a rat model of neonatal high-oxygen (80%O 2 ) exposure, mimicking the premature hyperoxic transition to the extrauterine environment, we revealed a major role of the renin-angiotensin system peptide Angio II (angiotensin II) and its receptor AT1 (angiotensin receptor type 1) on neonatal O 2 -induced cardiomyopathy. Here, we tested whether treatment with either orally active compounds of the peptides Angio-(1–7) or alamandine included in cyclodextrin could prevent postnatal cardiac remodeling and the programming of cardiomyopathy induced by neonatal high-O 2 exposure. Methods: Sprague-Dawley pups were exposed to room air or 80% O 2 from postnatal day 3 (P3) to P10. Neonatal rats were treated orally from P3 to P10 and assessed at P10 and P28. Left ventricular (LV) shapes were characterized by tridimensional computational atlases of ultrasound images in addition to histomorphometry. Results: At P10, high O 2 -exposed rats presented a smaller, globular and hypertrophied LV shape versus controls. Treatment with cyclodextrin–Angio-(1–7) significantly improved LV function in the O 2 -exposed neonatal rats and slightly changed LV shape. Cyclodextrin-alamandine and cyclodextrin–Angio-(1–7) treatments similarly reduced hypertrophy at P10 as well as LV remodeling and dysfunction at P28. Both treatments upregulated cardiac angiotensin-converting enzyme 2 in O 2 -exposed rats at P10 and P28. Conclusions: Our findings demonstrate LV remodeling changes induced by O 2 -stress and the potential benefits of treatments targeting the cardioprotective renin-angiotensin system axis, supporting the neonatal period as an important window for interventions aiming at preventing cardiomyopathy in people born preterm.

Background The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19. Methods Fifty-eight patients and thirty matched controls (single visit), recruited between 14th March - 25th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months. • View related content for this article Findings At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T1 (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O2) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m2, P=0·005) decreased and RV ejection fraction (+3·2%, P=0·0003) increased. Native T1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O2, although better, were abnormal in patients versus controls. 31% had reduced pV̇O2 secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures. Interpretation In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health. Funding The authors’ work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107.

OBJECTIVE: To assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process. STUDY DESIGN: Data from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14 months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6 years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship. RESULTS: Of the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14 months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6 years, with an almost linear increase in the observed risk as gestational age decreased below 37 weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight. CONCLUSIONS: Preterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome. ispartof: J Pediatr vol:255 pages:198-206.e4 ispartof: location:United States status: published

IntroductionNew-onset hypertension affects approximately 10% of pregnancies and is associated with a significant increase in risk of cardiovascular disease in later life, with blood pressure measured 6 weeks postpartum predictive of blood pressure 5–10 years later. A pilot trial has demonstrated that improved blood pressure control, achevied via self-management during the puerperium, was associated with lower blood pressure 3-4 years postpartum. Physician Optimised Post-partum Hypertension Treatment (POP-HT) will formally evaluate whether improved blood pressure control in the puerperium results in lower blood pressure at 6 months post partum, and improvements in cardiovascular and cerebrovascular phenotypes.Methods and analysisPOP-HT is an open-label, parallel arm, randomised controlled trial involving 200 women aged 18 years or over, with a diagnosis of pre-eclampsia or gestational hypertension, and requiring antihypertensive medication at discharge. Women are recruited by open recruitment and direct invitation around time of delivery and randomised 1:1 to, either an intervention comprising physician-optimised self-management of postpartum blood pressure or, usual care. Women in the intervention group upload blood pressure readings to a ‘smartphone’ app that provides algorithm-driven individualised medication-titration. Medication changes are approved by physicians, who review blood pressure readings remotely. Women in the control arm follow assessment and medication adjustment by their usual healthcare team. The primary outcome is 24-hour average ambulatory diastolic blood pressure at 6–9 months post partum. Secondary outcomes include: additional blood pressure parameters at baseline, week 1 and week 6; multimodal cardiovascular assessments (CMR and echocardiography); parameters derived from multiorgan MRI including brain and kidneys; peripheral macrovascular and microvascular measures; angiogenic profile measures taken from blood samples and levels of endothelial circulating and cellular biomarkers; and objective physical activity monitoring and exercise assessment. An additional 20 women will be recruited after a normotensive pregnancy as a comparator group for endothelial cellular biomarkers.Ethics and disseminationIRAS PROJECT ID 273353. This trial has received a favourable opinion from the London—Surrey Research Ethics Committee and HRA (REC Reference 19/LO/1901). The investigator will ensure that this trial is conducted in accordance with the principles of the Declaration of Helsinki and follow good clinical practice guidelines. The investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising from the study. Authors will acknowledge that the study was funded by the British Heart Foundation Clinical Research Training Fellowship (BHF Grant number FS/19/7/34148). Authorship will be determined in accordance with the ICMJE guidelines and other contributors will be acknowledged.Trial registration numberNCT04273854.

Globally, preterm birth affects more than one in every 10 live births. Although the short-term cardiopulmonary complications of prematurity are well known, long-term health effects are only now becoming apparent. Indeed, preterm birth has been associated with elevated cardiovascular morbidity and mortality in adulthood. Experimental animal models and observational human studies point toward changes in heart morphology and function from birth to adulthood in people born preterm that may contribute to known long-term risks. Moreover, recent data support the notion of a heterogeneous cardiac phenotype of prematurity, which is likely driven by various maternal, early, and late life factors. This review aims to describe the early fetal-to-neonatal transition in preterm birth, the different structural and functional changes of the preterm human heart across developmental stages, as well as potential factors contributing to the cardiac phenotype of prematurity.

Supplemental Digital Content is available in the text., Abnormal uteroplacental remodeling leads to placental hypoperfusion, causing fetal growth restriction and pregnancy-related hypertension, which are associated with endothelial dysfunction and markers of reduced vascular NO bioavailability and oxidative stress. Tetrahydrobiopterin (BH4) is a redox cofactor for eNOS (endothelial NO synthase) with a required role in NO generation. Using mice models and human samples, we investigated the physiological requirement for endothelial cell BH4 in uteroplacental vascular adaptation and blood pressure regulation to pregnancy. In pregnant mice, selective maternal endothelial BH4 deficiency resulting from targeted deletion of Gch1 caused progressive hypertension during pregnancy and fetal growth restriction. Maternal endothelial cell Gch1 deletion caused defective functional and structural remodeling in uterine arteries and in spiral arteries, leading to placental insufficiency. Using primary endothelial cells isolated from either normal or hypertensive pregnancies, we found that hypertensive pregnancies are associated with reduced endothelial cell BH4 levels, impaired eNOS activity, and reduced endothelial cell proliferation, mediated by reduced GTPCH (GTP cyclohydrolase 1) protein. In rescue experiments, high blood pressure and fetal growth restriction in pregnant endothelial cell Gch1 deficient mice was not rescued by oral BH4 supplementation, due to systemic oxidation of BH4 to dihydrobiopterin. However, the fully reduced folate, 5-methyltetrahydrofolate prevented BH4 oxidation, reduced blood pressure to normal levels, and normalized fetal growth. We identify a critical requirement for maternal endothelial cell BH4 biosynthesis in uteroplacental vascular remodeling in pregnancy. Restoration of endothelial cell BH4 with reduced folates identifies a novel therapeutic target for the prevention and treatment of pregnancy-related hypertension such as preeclampsia.

Simpson's biplane rule (SBR) is considered the gold standard method for left ventricle (LV) volume quantification from echocardiography but relies on a summation-of-disks approach that makes assumptions about LV orientation and cross-sectional shape. We aim to identify key limiting factors in SBR and to develop a new robust standard for volume quantification. Three methods for computing LV volume were studied: (i) SBR, (ii) addition of a truncated basal cone (TBC) to SBR and (iii) a novel method of basal-oriented disks (BODs). Three retrospective cohorts representative of the young, adult healthy and heart failure populations were used to study the impact of anatomical variations in volume computations. Results reveal how basal slanting can cause over- and underestimation of volume, with errors by SBR and TBC10 mL for slanting angles6°. Only the BOD method correctly accounted for basal slanting, reducing relative volume errors by SBR from -2.23 ± 2.21% to -0.70 ± 1.91% in the adult population and similar qualitative performance in the other two cohorts. In conclusion, the summation of basal oriented disks, a novel interpretation of SBR, is a more accurate and precise method for estimating LV volume.

Background Cardiac magnetic resonance (CMR) and cardiopulmonary exercise testing (CPET) have provided important insights into the prevalence of early cardiopulmonary abnormalities in COVID-19 patients. It is currently unknown whether such abnormalities persist over time and relate to ongoing symptoms. Purpose To describe the longitudinal trajectory of cardiopulmonary abnormalities on CMR and CPET in moderate to severe COVID-19 patients and assess their relationship with ongoing symptoms. Methods Fifty-eight previously hospitalised COVID-19 patients and 30 age, sex, body mass index, comorbidity-matched controls underwent CMR, CPET and a symptom-based questionnaire at 2–3 months (2–3m). Repeat assessments (including gas transfer) were performed in 46 patients at 6 months (6m). Results During admission, 1/3rd of patients needed ventilation or intensive care (Table 1) and three (5%) had a raised troponin. On CMR, patients had preserved left (LV) and right ventricular (RV) volumes and function at 2–3m from infection. By 6m, LV function did not change but RV end diastolic volume decreased (mean difference −4.3 mls/m2, p=0.005) and RV function increased (mean difference +3.2%, p Patients had higher native T1 (a marker of fibroinflammation) at 2–3m compared to controls (Table 1, Fig. 1B), which normalised by 6m. Extracellular volume was normal and improved by 6m. Native T2, a marker of myocardial oedema, did not differ between patients and controls on serial CMR. At 2–3m, late gadolinium enhancement (LGE) was higher in patients (p=0.023) but became comparable to controls by 6m (p=0.62). Six (12%) patients had LGE in a myocarditis pattern and one (2%) had myocardial infarction. None had active myocarditis using the Modified Lake Louise Criteria. Lung imaging (T2-weighted) revealed parenchymal abnormalities in 2/3rds of patients at 2–3 and 6 months. The extent of abnormalities improved on serial imaging (Table 1). Gas transfer (DLco) was worse in those with lung abnormalities (77% vs 91% of predicted, p=0.009). CPET revealed reduced peak oxygen consumption (pVO2) in patients at 2–3m, which normalised by 6m (80.5% to 93.3% of predicted, p=0.001) (Table 1, Fig. 1C). At 2–3m, 49% of patients had submaximal tests (respiratory exchange ratio Cardiac symptoms (chest pain, dyspnoea, palpitations, dizziness or syncope) were present in 83% of patients at 2–3m, reducing to 52% by 6m (p Conclusions Cardiopulmonary parameters (on CMR and CPET) improved in moderate-severe COVID-19 patients from 2–3 to 6 months post infection. Despite this, patients continued to experience cardiac symptoms which had no relationship with measured parameters. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): 1. NIHR Oxford and Oxford Health Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust2. Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107 Table 1Figure 1

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 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.

Background: Breathlessness is common in patients post-COVID-19, yet its association with objective measures of cardiopulmonary health is unknown. We sought to 1) describe the natural history of breathlessness and cardiopulmonary abnormalities & 2) evaluate their relationship post-COVID-19. Methods: Fifty-eight previously hospitalised COVID-19 patients & 30 controls underwent cardiopulmonary MRI (CMR), lung function testing & CPET at 2-3 & 6 months (m) from symptom-onset. Results: At 2-3m persistent breathlessness (MRC grade>1) was reported by 64% of patients, reducing to 57% by 6m, vs 10% of controls. On CMR, patients had preserved cardiac volumes & function at both 2-3m & 6m. Myocardial native T1, a marker of inflammation, was raised in 26% at 2-3m, but normalised by 6m, with no signs of active myocarditis (Fig1A). 60% of patients had lung parenchymal abnormalities at 2-3m, improving in extent by 6m. Patients had reduced FEV1 & FVC on spirometry at 2-3m. At 6m, FEV1 normalised, FVC remained slightly reduced & gas transfer was impaired in 52%. CPET revealed reduced peak VO2 & abnormal VE/VCO2 slope (marker of lung efficiency) in patients at 2-3m, which improved by 6m (Fig1B). There was no relationship between persistent breathlessness & CMR, CPET or spirometry measures at 6m (Fig1C). Conclusions: Despite improvement in objective measures of cardiopulmonary health, over half the patients post-COVID-19 continue to experience breathlessness at 6m.

Background Preterm birth is associated with increased cardiovascular disease risk, but it is unclear when this risk emerges. We compared life course trajectories from birth to adulthood of multiple cardiometabolic health measures in adults born preterm compared with term. Methods Multilevel models were used to compare trajectories from birth to age 25 years of BMI, fat mass, lean mass, systolic and diastolic blood pressure (BP), lipids, glucose and insulin, between participants born preterm (N = 311-560) and term (N = 5365-9262) in a contemporary UK birth cohort study. We also investigated gestational age as a continuum. Results Systolic and diastolic BP were higher at age 7 (mean predicted differences 0.8mmHg; 95%CI -0.1, 1.7 and 0.7mmHg; 95%CI 0.03, 1.3, respectively). The difference in SBP persisted and in DBP disappeared by 25 years. Preterm participants had lower BMI between 7 and 18 years, but by age 25, there was no difference. Lean mass and fat mass (measured from age 9 only) trajectories were consistent with BMI. HDL-c was higher, and triglycerides lower at birth in those born preterm, but this difference disappeared by 25 years. No other differences were found. Conclusions There were few, modest differences in cardiometabolic health measures during early life in those born preterm versus term. All disappeared by age 25, except SBP. Longer follow-up is needed to establish if and when trajectories diverge. Key messages By age 25, there were no differences in measures of cardiometabolic health between people born preterm and term except for a higher SBP in those born preterm.

ObjectiveTo examine associations of birth weight with clinical and imaging indicators of cardiovascular health and evaluate mechanistic pathways in the UK Biobank.MethodsCompeting risk regression was used to estimate associations of birth weight with incident myocardial infarction (MI) and mortality (all-cause, cardiovascular disease, ischaemic heart disease, MI), over 7–12 years of longitudinal follow-up, adjusting for age, sex, deprivation, maternal smoking/hypertension and maternal/paternal diabetes. Mediation analysis was used to evaluate the role of childhood growth, adulthood obesity, cardiometabolic diseases and blood biomarkers in mediating the birth weight–MI relationship. Linear regression was used to estimate associations of birth weight with left ventricular (LV) mass-to-volume ratio, LV stroke volume, global longitudinal strain, LV global function index and left atrial ejection fraction.Results258 787 participants from white ethnicities (61% women, median age 56 (49, 62) years) were studied. Birth weight had a non-linear relationship with incident MI, with a significant inverse association below an optimal threshold of 3.2 kg (subdistribution HR: 1.15 (1.08 to 1.22), p=6.0×10–5) and attenuation to the null above this threshold. The birth weight–MI effect was mediated through hypertension (8.4%), glycated haemoglobin (7.0%), C reactive protein (6.4%), high-density lipoprotein (5.2%) and high cholesterol (4.1%). Birth weight–mortality associations were statistically non-significant after Bonferroni correction. In participants with cardiovascular magnetic resonance (n=19 314), lower birth weight was associated with adverse LV remodelling (greater concentricity, poorer function).ConclusionsLower birth weight was associated with greater risk of incident MI and unhealthy LV phenotypes; effects were partially mediated through cardiometabolic disease and systemic inflammation. These findings support consideration of birth weight in risk prediction and highlight actionable areas for disease prevention.

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 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 (urn:x-wiley:07422822:media:echo15149:echo15149-math-0001= .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.

Preterm-born individuals have higher blood pressure with an increased risk of hypertension by young adulthood, as well as potentially adverse cardiac remodeling even when normotensive. To what extent blood pressure elevation affects left ventricular (LV) structure and function in adults born preterm is currently unknown.To investigate whether changes observed in LV structure and function in preterm-born adults make them more susceptible to cardiac remodeling in association with blood pressure elevation.This cross-sectional cohort study, conducted at the Oxford Cardiovascular Clinical Research Facility and Oxford Centre for Clinical Magnetic Resonance Research, included 468 adults aged 18 to 40 years. Of these, 200 were born preterm (37 weeks' gestation) and 268 were born at term (≥37 weeks' gestation). Cardiac magnetic resonance imaging was used to characterize LV structure and function, with clinical blood pressure readings measured to assess hypertension status. Demographic and anthropometric data, as well as birth history and family medical history information, were collected. Data were analyzed between January 2012 and February 2021.Cardiac magnetic resonance measures of LV structure and function in response to systolic blood pressure elevation.The cohort was primarily White (95%) with a balanced sex distribution (51.5% women and 48.5% men). Preterm-born adults with and without hypertension had higher LV mass index, reduced LV function, and smaller LV volumes compared with term-born individuals both with and without hypertension. In regression analyses of systolic blood pressure with LV mass index and LV mass to end-diastolic volume ratio, there was a leftward shift in the slopes in preterm-born compared with term-born adults. Compared with term-born adults, there was a 2.5-fold greater LV mass index per 1-mm Hg elevation in systolic blood pressure in very and extremely preterm-born adults (32 weeks' gestation) (0.394 g/m2 vs 0.157 g/m2 per 1 mm Hg; P .001) and a 1.6-fold greater LV mass index per 1-mm Hg elevation in systolic blood pressure in moderately preterm-born adults (32 to 36 weeks' gestation) (0.250 g/m2 vs 0.157 g/m2 per 1 mm Hg; P .001). The LV mass to end-diastolic volume ratio per 1-mm Hg elevation in systolic blood pressure in the very and extremely preterm-born adults was 3.4-fold greater compared with those born moderately preterm (3.56 × 10-3 vs 1.04 × 10-3 g/mL per 1 mm Hg; P .001) and 3.3-fold greater compared with those born at term (3.56 × 10-3 vs 1.08 × 10-3 g/mL per 1 mm Hg; P .001).Preterm-born adults have a unique LV structure and function that worsens with systolic blood pressure elevation. Additional primary prevention strategies specifically targeting cardiovascular risk reduction in this population may be warranted.

Background Preterm birth affects about 10% of live births worldwide and is associated with cardiac alterations. Animal models of preterm birth suggest that left ventricular functional impairment may be due to an up-regulation of myocardial fibrosis. Objectives The aim of this study was to determine whether diffuse left ventricular fibrosis is evident in young adults born preterm. Methods One hundred one normotensive young adults born preterm (n = 47, mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) were included from YACHT (Young Adult Cardiovascular Health sTudy). Left ventricular structure and function were quantified by cardiovascular magnetic resonance and echocardiography. Intravenous administration of a gadolinium-based contrast agent during cardiovascular magnetic resonance was used to quantify focal myocardial fibrosis on the basis of late gadolinium enhancement and, in combination with T1 mapping, to quantify diffuse myocardial fibrosis on the basis of assessment of myocardial extracellular volume fraction. Results Adults born preterm had smaller left ventricular end-diastolic and stroke volumes, with greater left ventricular mass and wall thickness (P < 0.001). In addition, longitudinal peak systolic strain and diastolic strain rate by both cardiovascular magnetic resonance and echocardiography, and E/A ratio measured by echocardiography, were lower in preterm-born compared to term-born adults (P < 0.05). Extracellular volume fraction was greater in preterm-born compared with term-born adults (27.81% ± 1.69% vs 25.48% ± 1.41%; P < 0.001) and was a significant mediator in the relationship between gestational age and both longitudinal peak diastolic strain rate and E/A ratio. Conclusions Preterm-born young adults have greater extracellular volume fraction in the left ventricle that is inversely related with gestational age and may underlie their diastolic functional impairments.

People born preterm are at risk of developing both cardiac and brain abnormalities. We aimed to investigate whether cardiovascular physiology may directly affect brain structure in young adulthood and whether cardiac changes are associated with modifiable biomarkers. Forty-eight people born preterm, followed since birth, underwent cardiac MRI at age 25.1 ± 1.4 years and brain MRI at age 33.4 ± 1.0 years. Term born controls were recruited at both time points for comparison. Cardiac left and right ventricular stroke volume, left and right ventricular end diastolic volume and right ventricular ejection fraction were significantly different between preterm and term born controls and associated with subcortical brain volumes and fractional anisotropy in the corpus callosum in the preterm group. This suggests that cardiovascular abnormalities in young adults born preterm are associated with potentially adverse future brain health. Associations between left ventricular stroke volume indexed to body surface area and right putamen volumes, as well as left ventricular end diastolic length and left thalamus volumes, remained significant when adjusting for early life factors related to prematurity. Although no significant associations were found between modifiable biomarkers and cardiac physiology, this highlights that cardiovascular health interventions may also be important for brain health in preterm born adults.

Background Left atrial (LA) size and function are known predictors of new onset atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients. Components of LA deformation including reservoir, conduit, and booster function provide additional information on atrial mechanics. Whether or not LA deformation can augment our ability to predict the risk of new onset AF in HCM patients beyond standard measurements is unknown. Methods We assessed LA size, function, and deformation on cardiovascular magnetic resonance (CMR) in 238 genotyped HCM patients and compared this with twenty age, sex, blood pressure and body mass index matched control subjects. We further evaluated the determinants of new onset AF in HCM patients. Results Compared to control subjects, HCM patients had higher LA antero-posterior diameter, lower LA ejection fraction and lower LA reservoir (19.9 [17.1, 22.2], 21.6 [19.9, 22.9], P = 0.047) and conduit strain (10.6 ± 4.4, 13.7 ± 3.3, P = 0.002). LA booster strain did not differ between healthy controls and HCM patients, but HCM patients who developed new onset AF (n = 33) had lower booster strain (7.6 ± 3.3, 9.5 ± 3.0, P = 0.001) than those that did not (n = 205). In separate multivariate models, age, LA ejection fraction, and LA booster and reservoir strain were each independent determinants of AF. Age ≥ 55 years was the strongest determinant (HR 6.62, 95% CI 2.79–15.70), followed by LA booster strain ≤ 8% (HR 3.69, 95% CI 1.81–7.52) and LA reservoir strain ≤ 18% (HR 2.56, 95% CI 1.24–5.27). Conventional markers of HCM phenotypic severity, age and sudden death risk factors were associated with LA strain components. Conclusions LA strain components are impaired in HCM and, together with age, independently predicted the risk of new onset AF. Increasing age and phenotypic severity were associated with LA strain abnormalities. Our findings suggest that the routine assessment of LA strain components and consideration of age could augment LA size in predicting risk of AF, and potentially guide prophylactic anticoagulation use in HCM.

Background The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Methods Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. Findings At 2–3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p Interpretation A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. Funding NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

Background Previous studies have shown that prematurity leads to altered right ventricular (RV) geometry and performance with persistent impairments in RV systolic function in young adulthood. It is unknown to what extent pulmonary physiology impacts these findings. Purpose To better quantify known alterations in RV morphology and function in preterm-born young adults and to determine to what extent these changes are influenced by the pulmonary circulation. Methods A total of 101 normotensive preterm-born (n=47, mean gestational age 32.8±3.2 weeks) and term-born (n=54) young adults were recruited. Echocardiography and cardiovascular magnetic resonance (CMR) imaging were performed to characterise RV morphology, RV function, pulmonary hemodynamics and RV-pulmonary arterial vascular (PA) coupling. CMR cine images were used to create a 3D computational atlas of the RV geometry and principal component analysis was undertaken to identify the key modes of shape variation. Spirometry was performed to assess lung function. Results RV CMR revealed a higher absolute and indexed RV mass (P Conclusions Multimodality cardiac imaging demonstrated that moderately preterm-born young adults exhibit structural and functional RV alterations, independent of lung physiology. Their RV remains hemodynamically coupled to its pulmonary circulation despite higher RV afterload, lower RV function and altered morphology. Figure 1. Statistical shape model of the RV Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

BackgroundThe medium-term effects of Coronavirus disease (COVID-19) on multiple organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.MethodsFifty-eight COVID-19 patients post-hospital discharge and 30 comorbidity-matched controls were prospectively enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.FindingsAt 2-3 months from disease-onset, 64% of patients experienced persistent breathlessness and 55% complained of significant fatigue. On MRI, tissue signal abnormalities were seen in the lungs (60%), heart (26%), liver (10%) and kidneys (29%) of patients. COVID-19 patients also exhibited tissue changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domain relative to controls. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance (405±118m vs 517±106m in controls, pInterpretationA significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of breathlessness, fatigue, anxiety, depression and exercise limitation at 2-3 months from disease-onset. Persistent lung and extra-pulmonary organ MRI findings are common. In COVID-19 survivors, chronic inflammation may underlie multiorgan abnormalities and contribute to impaired quality of life.FundingNIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

Preterm birth accounts for over 15 million global births per year. Perinatal interventions introduced since the early 1980s, such as antenatal glucocorticoids, surfactant, and invasive ventilation strategies, have dramatically improved survival of even the smallest, most vulnerable neonates. As a result, a new generation of preterm-born individuals has now reached early adulthood, and they are at increased risk of cardiovascular diseases. To better understand the sequelae of preterm birth, cardiovascular follow-up studies in adolescents and young adults born preterm have focused on characterizing changes in cardiac, vascular, and pulmonary structure and function. Being born preterm associates with a reduced cardiac reserve and smaller left and right ventricular volumes, as well as decreased vascularity, increased vascular stiffness, and higher pressure of both the pulmonary and systemic vasculature. The purpose of this review is to present major epidemiological evidence linking preterm birth with cardiovascular disease; to discuss findings from clinical studies showing a long-term impact of preterm birth on cardiac remodeling, as well as the systemic and pulmonary vascular systems; to discuss differences across gestational ages; and to consider possible driving mechanisms and therapeutic approaches for reducing cardiovascular burden in individuals born preterm.

Background Pregnancy complications such as preterm birth and fetal growth restriction are associated with altered prenatal and postnatal cardiac development. We studied whether there were changes related specifically to pregnancy hypertension. Methods and Results Left and right ventricular volumes, mass, and function were assessed at birth and 3 months of age by echocardiography in 134 term‐born infants. Fifty‐four had been born to mothers who had normotensive pregnancy and 80 had a diagnosis of preeclampsia or pregnancy‐induced hypertension. Differences between groups were interpreted, taking into account severity of pregnancy disorder, sex, body size, and blood pressure. Left and right ventricular mass indexed to body surface area ( LVMI and RVMI ) were similar in both groups at birth ( LVMI 20.9±3.7 versus 20.6±4.0 g/m 2 , P =0.64, RVMI 17.5±3.7 versus 18.1±4.7 g/m 2 , P =0.57). However, right ventricular end diastolic volume index was significantly smaller in those born to hypertensive pregnancy (16.8±5.3 versus 12.7±4.7 mL/m 2 , P =0.001), persisting at 3 months of age (16.4±3.2 versus 14.4±4.8 mL/m 2 , P =0.04). By 3 months of age these infants also had significantly greater LVMI and RVMI ( LVMI 24.9±4.6 versus 26.8±4.9 g/m 2 , P =0.04; RVMI 17.1±4.2 versus 21.1±3.9 g/m 2 , P RVMI and right ventricular end diastolic volume index at 3 months, but not left ventricular measures, correlated with severity of the hypertensive disorder. No differences in systolic or diastolic function were evident. Conclusions Infants born at term to a hypertensive pregnancy have evidence of both prenatal and postnatal differences in cardiac development, with right ventricular changes proportional to the severity of the pregnancy disorder. Whether differences persist long term as well as their underlying cause and relationship to increased cardiovascular risk requires further study.

CONTEXT: Preterm birth is associated with incident heart failure in children and young adults. OBJECTIVE: To determine the effect size of preterm birth on cardiac remodeling from birth to young adulthood. DATA SOURCES: Data sources include Medline, Embase, Scopus, Cochrane databases, and clinical trial registries (inception to March 25, 2020). STUDY SELECTION: Studies in which cardiac phenotype was compared between preterm individuals born at DATA EXTRACTION: Random-effects models were used to calculate weighted mean differences with corresponding 95% confidence intervals. RESULTS: Thirty-two observational studies were included (preterm = 1471; term = 1665). All measures of left ventricular (LV) and right ventricular (RV) systolic function were lower in preterm neonates, including LV ejection fraction (P = .01). Preterm LV ejection fraction was similar from infancy, although LV stroke volume index was lower in young adulthood. Preterm LV peak early diastolic tissue velocity was lower throughout development, although preterm diastolic function worsened with higher estimated filling pressures from infancy. RV longitudinal strain was lower in preterm-born individuals of all ages, proportional to the degree of prematurity (R2 = 0.64; P = .002). Preterm-born individuals had persistently smaller LV internal dimensions, lower indexed LV end-diastolic volume in young adulthood, and an increase in indexed LV mass, compared with controls, of 0.71 g/m2 per year from childhood (P = .007). LIMITATIONS: The influence of preterm-related complications on cardiac phenotype could not be fully explored. CONCLUSIONS: Preterm-born individuals have morphologic and functional cardiac impairments across developmental stages. These changes may make the preterm heart more vulnerable to secondary insults, potentially underlying their increased risk of early heart failure.

Preterm-born individuals have altered right-ventricular (RV) structure and function in young adulthood ([1][1]). To what extent the pulmonary circulation impacts these findings remains largely unknown. However, unlike RV changes that are apparent across gestational ages of prematurity, acute and