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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

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 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.

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.

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: 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.

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.

Hypertensive disorders of pregnancy, including preeclampsia, affect nearly 10% of all pregnancies and are associated with significant long-term detrimental effects on both maternal and offspring cardiovascular health. Current management of preeclampsia involves timely delivery with the more severe form of disease requiring iatrogenic preterm birth. The effects on the maternal cardiovascular system have been studied extensively; however, less is known about the short- and long-term impacts on offspring cardiovascular health. There is a growing body of evidence suggesting that the offspring of pre-eclamptic pregnancies have an altered cardiac structure and function, along with a unique vascular physiology driven by lower endothelial function. Many of these changes can also be seen in those born preterm even in the absence of pregnancy hypertension. It is difficult to determine the relative contribution of pre-maturity and preeclampsia to the cardiovascular phenotype of those exposed to these pregnancy complications as they are, in many cases, inextricably linked. This review, therefore, focuses specifically on the evidence from clinical studies showing a negative cardiovascular impact of preeclampsia in preterm-born offspring, investigating phenotypic similarities and differences between offspring born preterm to normotensive vs. pre-eclamptic pregnancies. We explore the unique cardiac and vascular alterations in pre-eclamptic offspring born preterm, highlighting knowledge gaps, and potential areas of further research in the field.

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

Funding Acknowledgements British Heart Foundation (BHF) grants (PG/13/58/30397) Background Young adults with mildly elevated blood pressure are less likely to engage with physical activity. This may be because early hypertension alters myocardial response to moderate exercise, leading to greater perceived exertion and lower levels of enjoyment. As atrial and ventricular function are closely coupled we investigated whether subclinical atrial changes at rest may identify this myocardial response. Purpose To identify whether subclinical changes in left atrial function at rest predict response to exercise by performing left atrial deep-phenotyping in a cohort of young adults with a range of blood pressures. Methods Seventy-one full-term born young adults (25.25 ± 5.13 years) were enrolled in the Young Adult Cardiovascular Health sTudy (YACHT) to undergo baseline clinical and cardiovascular phenotyping including detailed blood pressure measurement. Cardiopulmonary exercise testing combined with echocardiography imaging was performed to assess the myocardial response to physical exercise at 40%, 60% and 80% of peak exercise load for all participants. Left ventricular ejection fraction and global longitudinal strain were measured from an apical four chamber view at each exercise load, and resting left atrial phasic function was assessed by conventional and speckle tracking echocardiography from apical four and two chamber views (figure 1). Results In this young cohort with a range of blood pressure (120.9 ± 12.96/70.85 ± 9.78 mmHg), resting left atrial reservoir and conduit function, but not left atrial structural measures, showed good correlation with left ventricular ejection fraction and global longitudinal strain during 40%, 60% and 80% of peak exercise. The association between resting left atrial conduit with left ventricular deformation at 60% of peak exercise intensity remained significant when adjusted for age, sex and mean arterial pressure (P = 0.007). Conclusion Left atrial phasic function at rest predicts left ventricular responses to physical exercise in this cohort of young adults, which may relate to early subclinical left atrial remodelling in early hypertension. These findings require validation in other cohorts and investigation of whether this exercise limitation can be overcome in young hypertensives. Abstract P374 Figure 1

Cardiovascular health of premature infants reaching early adulthood is an area of ongoing research. There is emerging evidence delineating the challenges faced by those individuals. Young adults born premature demonstrate a unique cardiac phenotype characterized by reduced biventricular volume, relatively lower systolic and diastolic function, and a disproportionate increase in muscle mass. This may clinically manifest by an increased risk of cardiovascular incidents, hypertension, and reduced exercise tolerance. Those consequences appear to result from early postnatal cardiac remodeling due to premature birth and associated co-morbidities. Recent evidence suggests that early exposure to breast milk slows down or even arrests those pathophysiological changes, thereby mitigating the long-term adverse effects of premature birth on cardiovascular health. In this review article, we discuss the role of breast milk in preventing early adulthood cardiovascular disease in infants born premature. We explore the emerging evidence and examine the possible mechanistic pathways mediating this phenomenon. Furthermore, we aim to demonstrate the vital role of early breast milk exposure in preventing cardiovascular disease in preterm infants.

Introduction Cardiovascular disease (CVD) is more common in women who have had pregnancy complications such as spontaneous pregnancy loss. We used cross-sectional data from the UK Biobank Imaging Enhancement Study to determine whether pregnancy loss is associated with cardiac or vascular remodelling in later life, which might contribute to this increased risk. Methods Pregnancy history was reported by women participating in UK Biobank between 2006 and 2010 at age 40–69 years using a self-completed touch-screen questionnaire. Self-reported pregnancy loss was related to cardiovascular measures collected in those women who had participated in the Imaging Enhancement Study up to the end of 2015. Cardiac structure and function were assessed by magnetic resonance (CMR) steady-state free precession imaging at 1.5 Tesla. Three long axes cines (horizontal, vertical and LV outflow tract) and a complete short axis stack were acquired, covering both ventricles. Tagging was used to measure myocardial strain in basal, midventricular and apical short axes views. Carotid intima-media thickness (CIMT) measurements were taken for both common carotid arteries using a CardioHealth Station. Statistical associations with CMR and carotid measures were adjusted for age, BMI and other cardiovascular risk factors. Results Data were available on 2660 women of whom 113 were excluded because of pre-existing CVD and 8 had no pregnancy information available. Of the remaining 2539, 466 were nulligravid and 2073 had a history of pregnancies, of whom 622 reported at least one pregnancy loss (92% miscarriages and 8% stillbirths) and 1451 reported no pregnancy loss. No significant differences in cardiac or carotid parameters were evident in women who reported pregnancy loss compared to other groups (Table 1). CMR cardiac geometry & CIMT measurements Variable Pregnancy History Adjusted Means ± SE Effect Size (%) 95% CI P LVEDV (ml) Pregnancy Loss 122.2±1.0 0 – – No Pregnancy 124.1±1.4 1.58 (−0.83, 4.05) 0.20 Pregnancy (no loss) 122.2±0.8 0.2 (−1.42, 1.48) 0.97 LVESV (ml) Pregnancy Loss 47.8±0.6 0 – – No Pregnancy 48.0±0.8 0.45 (−3.19, 4.22) 0.81 Pregnancy (no loss) 47.3±0.5 −1.01 (−3.19, 1.22) 0.37 VEF (%) Pregnancy Loss 60.6±0.3 0 – – No Pregnancy 61.0±0.4 0.42 (−0.50, 1.35) 0.37 Pregnancy (no loss) 61.0±0.2 0.43 (−0.14, 0.99) 0.14 LVM (g) Pregnancy Loss 70.6±0.6 0 – – No Pregnancy 70.5±0.8 −0.15 (−2.68, 2.44) 0.91 Pregnancy (no loss) 70.4±0.5 −0.26 (−1.81, 1.30) 0.74 CIMT (μm) Pregnancy Loss 633.3±6.5 0 – – No Pregnancy 619.3±8.4 −2.22 (−5.04, 0.68) 0.13 Pregnancy (no loss) 627.1±4.9 −0.99 (−2.75, 0.81) 0.28 Conclusion Women who self-report pregnancy loss do not have significant differences in cardiac or carotid structure in later life to explain past epidemiological findings of increased cardiovascular risk in this population. This may be because this risk operates through other disease mechanisms or that self-report is not a sufficiently reliable way to identify pregnancy loss, and thereby allocate women into risk groups.

Hypertensive disorders of pregnancy affect up to 10% of pregnancies worldwide, which includes the 3%–5% of all pregnancies complicated by preeclampsia. Preeclampsia is defined as new onset hypertension after 20 weeks’ gestation with evidence of maternal organ or uteroplacental dysfunction or proteinuria. Despite its prevalence, the risk factors that have been identified lack accuracy in predicting its onset and preventative therapies only moderately reduce a woman’s risk of preeclampsia. Preeclampsia is a major cause of maternal morbidity and is associated with adverse foetal outcomes including intra-uterine growth restriction, preterm birth, placental abruption, foetal distress, and foetal death in utero. At present, national guidelines for foetal surveillance in preeclamptic pregnancies are inconsistent, due to a lack of evidence detailing the most appropriate assessment modalities as well as the timing and frequency at which assessments should be conducted. Current management of the foetus in preeclampsia involves timely delivery and prevention of adverse effects of prematurity with antenatal corticosteroids and/or magnesium sulphate depending on gestation. Alongside the risks to the foetus during pregnancy, there is also growing evidence that preeclampsia has long-term adverse effects on the offspring. In particular, preeclampsia has been associated with cardiovascular sequelae in the offspring including hypertension and altered vascular function.

Key Points Question What are the associations of exposure to mother’s own milk on cardiac performance during the first year of age in preterm infants? Findings This cross-sectional study of 80 preterm infants found that those with higher exposure to mother’s own milk had enhanced cardiac function and morphology on echocardiographic examination at age 1 year, with values approaching those of full-term infants in the control group. Meaning These findings suggest that there is a favorable association between consumption of maternal breast milk and cardiac performance at age 1 year in preterm infants., This cross-sectional study investigates the association between consumption of maternal breast milk and cardiac performance at age 1 year among individuals born preterm., Importance There is a beneficial association between human breast milk exposure in the neonatal period and cardiac mechanics in adults who were born preterm. It is unknown whether this benefit is apparent in infants in the first year of age. Objective To test the hypothesis that higher consumption of mother’s own milk in preterm infants is associated with enhanced cardiac performance during the first year of age. Design, Setting, and Participants This cross-sectional study of cardiac and nutritional data at an academic medical center included 80 individuals born preterm and 100 individuals in the control group born full-term. All births were between 2011 and 2013. Two-dimensional echocardiograms were performed at 32 weeks’ and 36 weeks’ postmenstrual age and at 1 year’s corrected age in individuals born preterm and at 1 month and 1 year of age in individuals born full-term. Statistical analysis was performed from January to May 2021. Exposures Consumption of mother’s own milk. Main Outcomes and Measures Main study outcomes included echocardiography measures of right and left ventricle longitudinal strain (function), left ventricle mass index and right ventricular areas (morphology), and pulmonary vascular resistance (pulmonary hemodynamics) at age 1 year. Results Of 180 infants included in the study, 97 (54%) were Black infants and 89 (49%) were female infants. Among the 80 infants born in the preterm cohort, 43 (54%) were female infants and 43 (54%) were Black infants. The median gestational age at birth of the preterm infants was 27.0 weeks (interquartile range, 26.0-28.0 weeks) and the median birth weight was 960 g (interquartile range, 800–1138). For each week of exposure to mother’s own milk, preterm infants had greater magnitudes of right ventricular strain (eg, right longitudinal strain: β, 0.021; 95% CI, 0.002-0.041; P

Purpose of reviewAround 10% of the global population is born preterm (Recent findings Being born between 28 and 31 weeks’ gestation results in a 4-fold higher risk of heart failure in childhood and adolescence and 17-fold increased risk when born less than 28 weeks’ gestation. In support of this being due to a reduction in myocardial functional reserve, preterm-born young adults have an impaired left ventricular cardiac systolic response to moderate and high intensity physiological stress, despite having a preserved resting left ventricular ejection fraction. Similar impairments under physiological stress were also recently reported regarding the right ventricle in young adults born preterm.Summary Preterm birth relates to a unique cardiac phenotype with an impaired response to stress conditions. These data, combined with the work in animal models, suggest that being born preterm may lead to a novel form of cardiomyopathy. Understanding the driving mechanisms leading to this unique cardiac phenotype is important to reduce risk of future heart failure and cardiovascular events.

IntroductionCardiovascular disease (CVD) is more common in women who have had pregnancy complications such as spontaneous pregnancy loss. We used cross-sectional data from the UK Biobank Imaging Enhancement Study to determine whether pregnancy loss is associated with cardiac or vascular remodelling in later life, which might contribute to this increased risk.MethodsPregnancy history was reported by women participating in UK Biobank between 2006 and 2010 at age 40-69 years using a self-completed touch-screen questionnaire. Associations between self-reported spontaneous pregnancy loss and cardiovascular measures, collected in women who participated in the Imaging Enhancement Study up to the end of 2015, were examined. Cardiac structure and function were assessed by magnetic resonance (CMR) steady-state free precession imaging at 1.5 Tesla. Carotid intima-media thickness (CIMT) measurements were taken for both common carotid arteries using a CardioHealth Station. Statistical associations with CMR and carotid measures were adjusted for age, BMI and other cardiovascular risk factors.ResultsData were available on 2660 women of whom 111 were excluded because of pre-existing cardiovascular disease and 30 had no pregnancy information available. Of the remaining 2519, 446 were nulligravid and 2073 had a history of pregnancies, of whom 622 reported at least one pregnancy loss (92% miscarriages and 8% stillbirths) and 1451 reported no pregnancy loss. No significant differences in any cardiac or carotid parameters were evident in women who reported pregnancy loss compared to other groups (Table 1).ConclusionWomen who self-report pregnancy loss do not have significant differences in cardiac structure, cardiac function, or carotid structure in later life to explain their increased cardiovascular risk. This suggests any cardiovascular risks associated with pregnancy loss operate through other disease mechanisms. Alternatively, other characteristics of pregnancy loss, which we were not able to take account of, such as timing and number of pregnancy losses may be required to identify those at greatest cardiovascular risk.

Importance: Risk of stroke and brain atrophy in later life relate to levels of cardiovascular risk in early adulthood. However, it is unknown whether cerebrovascular changes are present in young adults. Objective: To examine relationships between modifiable cardiovascular risk factors and cerebrovascular structure, function, and white matter integrity in young adults. Design, Setting, and Participants: A cross-sectional observational study of 125 young adults (aged 18-40 years) without clinical evidence of cerebrovascular disease. Data collection was completed between August 2014 and May 2016 at the University of Oxford, United Kingdom. Final data collection was completed on May 31, 2016. Exposures: The number of modifiable cardiovascular risk factors at recommended levels, based on the following criteria: body mass index (BMI) 6 months; blood pressure on awake ambulatory monitoring Main Outcomes and Measures: Cerebral vessel density, caliber and tortuosity, brain white matter hyperintensity lesion count. In a subgroup (n = 52), brain blood arrival time and cerebral blood flow assessed by brain magnetic resonance imaging (MRI). Results: A total of 125 participants, mean (SD) age 25 (5) years, 49% women, with a mean (SD) score of 6.0 (1.4) modifiable cardiovascular risk factors at recommended levels, completed the cardiovascular risk assessment and brain MRI protocol. Cardiovascular risk factors were correlated with cerebrovascular morphology and white matter hyperintensity count in multivariable models. For each additional modifiable risk factor categorized as healthy, vessel density was greater by 0.3 vessels/cm3 (95% CI, 0.1-0.5; P = .003), vessel caliber was greater by 8 μm (95% CI, 3-13; P = .01), and white matter hyperintensity lesions were fewer by 1.6 lesions (95% CI, −3.0 to −0.5; P = .006). Among the 52 participants with available data, cerebral blood flow varied with vessel density and was 2.5 mL/100 g/min higher for each healthier category of a modifiable risk factor (95% CI, 0.16-4.89; P = .03). Conclusions and Relevance: In this preliminary study involving young adults without clinical evidence of cerebrovascular disease, a greater number of modifiable cardiovascular risk factors at recommended levels was associated with higher cerebral vessel density and caliber, higher cerebral blood flow, and fewer white matter hyperintensities. Further research is needed to verify these findings and determine their clinical importance.

Objectives To study whether young adults with elevated blood pressure have an altered left ventricular stress response and whether this is determined by cardiac structure. Methods We recruited 148 young adults (mean age 27±5 years) with a range of blood pressures for cardiovascular phenotyping at rest with cardiac magnetic resonance. A subgroup (n=49) then underwent exercise stress echocardiography while exercising at 40%, 60%, and 80% of peak exercise capacity. Myocardial stress response was assessed from changes in ejection fraction and biochemistry (post-exercise copeptin release). Results were compared in participants with systolic or diastolic BP e 120/80 mm Hg (n=62, mean BP 129/77 mm Hg) vs. those with systolic and diastolic BP Results Resting left ventricular ejection fraction was similar between groups with higher or lower blood pressure. However, during physical exercise, despite similar achieved work load, higher blood pressure was associated with lower ejection fraction at 40% and 60% exercise load (73.9±3.25 vs. 80.0±4.54%, p Conclusions x0013_Young adults with modest blood pressure elevation have a significantly lower systolic response to exercise. The association between this altered stress response and daily functional limitations in young adulthood, as well as cardiovascular disease progression and event risk, requires further study.

Preterm-born individuals have elevated blood pressure. We tested the hypothesis that this associates with an enhanced antiangiogenic circulating profile and that this association is mediated by variations in capillary density. We studied 204 adults aged 25 years (range, 20–30 years), of which 102 had been followed up prospectively since very preterm birth (mean gestational age, 30.3±2.5 weeks) and 102 were born term to uncomplicated pregnancies. A panel of circulating biomarkers, including soluble endoglin and soluble fms-like tyrosine kinase-1, were compared between groups and related to perinatal history and adult cardiovascular risk. Associations with cardiovascular phenotype were studied in 90 individuals who had undergone detailed assessment of microvascular, macrovascular, and cardiac structure and function. Preterm-born individuals had elevations in soluble endoglin (5.64±1.03 versus 4.06±0.85 ng/mL; P P P P =0.002). Other circulating biomarkers, including those of inflammation and endothelial activation, were not related to blood pressure. There was a specific graded association between soluble endoglin and degree of functional and structural capillary rarefaction ( P =0.002 and P

Background Heart rate variability (HRV) has emerged as a predictor of later cardiac risk. This study tested whether pregnancy complications that may have long-term offspring cardiac sequelae are associated with differences in HRV at birth, and whether these HRV differences identify abnormal cardiovascular development in the postnatal period. Methods Ninety-eight sleeping neonates had 5-min electrocardiogram recordings at birth. Standard time and frequency domain parameters were calculated and related to cardiovascular measures at birth and 3 months of age. Results Increasing prematurity, but not maternal hypertension or growth restriction, was associated with decreased HRV at birth, as demonstrated by a lower root mean square of the difference between adjacent NN intervals (rMSSD) and low (LF) and high-frequency power (HF), with decreasing gestational age (p Conclusions Altered cardiac autonomic function at birth relates to prematurity rather than other pregnancy complications and does not predict cardiovascular developmental patterns during the first 3 months post birth. Long-term studies will be needed to understand the relevance to cardiovascular risk.

Background: Hypertension or pre-hypertension in young adults is unusual and more often linked with an adverse family or pregnancy history, such as preterm birth, than hypertension which develops later in life1–4. Surprisingly, no trials have investigated whether lifestyle advice developed for blood pressure control in older adults is effective in these young populations5. Methods: TEPHRA is a randomised control trial of a 16 week physical activity intervention including behaviour change and structured exercise in young adults with pre- and stage 1 hypertension. On-line recruitment is used with targeting to ensure inclusion of a proportion born preterm. Primary outcome is 24 hr ambulatory blood pressure at 4 months. Subjects undergo additional multimodal assessments including vascular stiffness, blood sampling, microvascular assessment, echocardiography, remote activity monitoring and multi-organ magnetic resonance imaging to identify potential predictors of blood pressure change. Results: Recruitment started in April 2016 and currently (June 2017) 344 potential participants have been screened with 103 progressing to a baseline visit, of which 91 have been randomized. Two participants have completed their 12 month follow up. Recruitment is predicted to be completed by February 2018 with data reporting of four months outcomes in late 2018. Conclusion: TEPHRA aims to deliver the most in-depth investigation to date on the effects of physical exercise on the cardiovascular system and health of young adults at risk of early hypertension and cardiovascular disease.

Background: Two-dimensional (2D) ultrasound quality has improved in recent years. Quantification of cardiac dimensions is important to screen and monitor certain fetal conditions. We assessed the feasibility and reproducibility of fetal ventricular measures using 2D echocardiography, reported normal ranges in our cohort, and compared estimates to other modalities. Methods: Mass and end-diastolic volume were estimated by manual contouring in the four-chamber view using TomTec Image Arena 4.6 in end diastole. Nomograms were created from smoothed centiles of measures, constructed using fractional polynomials after log transformation. The results were compared to those of previous studies using other modalities. Results: A total of 294 scans from 146 fetuses from 15+0 to 41+6 weeks of gestation were included. Seven percent of scans were unanalysable and intraobserver variability was good (intraclass correlation coefficients for left and right ventricular mass 0.97 [0.87-0.99] and 0.99 [0.95-1.0], respectively). Mass and volume increased exponentially, showing good agreement with 3D mass estimates up to 28 weeks of gestation, after which our measurements were in better agreement with neonatal cardiac magnetic resonance imaging. There was good agreement with 4D volume estimates for the left ventricle. Conclusion: Current state-of-the-art 2D echocardiography platforms provide accurate, feasible, and reproducible fetal ventricular measures across gestation, and in certain circumstances may be the modality of choice.

Background Ultrasound imaging is able to quantify carotid arterial wall structure for the assessment of cerebral and cardiovascular disease risks. We describe a protocol and quality assurance process to enable carotid imaging at large scale that has been developed for the UK Biobank Imaging Enhancement Study of 100,000 individuals. Design An imaging protocol was developed to allow measurement of carotid intima-media thickness from the far wall of both common carotid arteries. Six quality assurance criteria were defined and a web-based interface (Intelligent Ultrasound) was developed to facilitate rapid assessment of images against each criterion. Results and conclusions Excellent inter and intra-observer agreements were obtained for image quality evaluations on a test dataset from 100 individuals. The image quality criteria then were applied in the UK Biobank Imaging Enhancement Study. Data from 2560 participants were evaluated. Feedback of results to the imaging team led to improvement in quality assurance, with quality assurance failures falling from 16.2% in the first two-month period examined to 6.4% in the last. Eighty per cent had all carotid intima-media thickness images graded as of acceptable quality, with at least one image acceptable for 98% of participants. Carotid intima-media thickness measures showed expected associations with increasing age and gender. Carotid imaging can be performed consistently, with semi-automated quality assurance of all scans, in a limited timeframe within a large scale multimodality imaging assessment. Routine feedback of quality control metrics to operators can improve the quality of the data collection.

BACKGROUND: It is essential that we are able to assess variations in blood flow in order to fully understand cardiovascular function in disease pathologies and for identification of individuals at long-term risk of cardiovascular disease development. Qualitative and quantitative assessments of blood flow by imaging modalities have been limited, and much of the accurate quantification has relied on invasive measures. METHODS: This review discusses how four-dimensional velocity cardiovascular magnetic resonance (4D flow CMR) offers increasing potential for the non-invasive assessment of blood flow in the heart and major blood vessels such as the aorta. 4D flow CMR refers to phase contrast CMR with flow encoding in all three spatial directions that is resolved relative to all three dimensions of space and to the dimension of time throughout the cardiac cycle. RESULTS: It has been demonstrated that 4D flow CMR can be used to assess parameters such as flow, pressure, velocity, wall shear stress and turbulent kinetic energy throughout the heart and major vessels of the cardiovascular system. It has been possible to gain new insights into cardiovascular pathologies such as, but not limited to, hypertrophic cardiomyopathy, dilated cardiomyopathy, Marfan syndrome and aortic bicuspid valve disease. CONCLUSION: Future work to standardize 4D flow CMR scan acquisition parameters is required, similarly as the development of automated analysis tools and standardized reporting of quantitative metrics to increase capacity for larger studies and translation to clinical practice. In doing so, the potential for 4D flow CMR to disentangle complex questions related to cardiovascular function will be maximized.

Introduction: Women with a history of preeclampsia have a two-fold higher risk of acute ischemic stroke even after controlling for classic cardiovascular risk factors. We determined whether specific patterns in cerebral damage are present after preeclampsia that may explain this risk. Methods: We performed brain magnetic resonance imaging in women between 5 and 15 years after either a preeclamptic or normotensive pregnancy. Analysis of white matter structure was undertaken using voxel-based segmentation of fluid attenuation inversion recovery sequences to assess white matter lesion volume and diffusion tensor imaging to measure microstructural integrity. Voxel-based analysis of grey matter volumes was performed in T1 weighted sequences with adjustment for skull size. Cardiovascular, obstetric profiles were assessed. Results: Thirty-four previously preeclamptic women (aged 42.8 ± 5.1 years, mean ± SD) and 49 controls were included. Previously preeclamptic women had reduced cortical grey matter volume (523.2 ± 30.1 vs 544.4 ± 44.7 ml, p-6 mm 2 /sec, p Conclusions: A history of preeclampsia is associated with temporal lobe white matter damage and cortical atrophy in young women, which is out of proportion to their classic cardiovascular risk profile and increases with time from pregnancy, consistent with ongoing susceptibility and cumulative brain damage.

Human clinical studies as well as laboratory animal studies demonstrate that offspring of pregnancies affected by common complications, such as preeclampsia and preterm birth, display developmental phenotypes that relate distinctly to the pregnancy disorder. Several studies have now found microvascular differences in offspring of hypertensive pregnancies, and there is interest in whether these may underlie epidemiologic associations between gestational hypertension and a higher risk of hypertension and stroke in the offspring. The retinal circulation provides a unique window into microvascular structure, of likely relevance to both the cerebrovasculature and broader cardiovascular risk. Yesil et al. (Am J Epidemiol. 2016;184(9):605–615) report in this issue of the Journal that maternal gestational blood pressure elevation is associated with reduced retinal vascular caliber in offspring at 6 years of age, providing a link between variation in pregnancy characteristics and childhood vascular development. Further work to understand the longitudinal association between pregnancy, emergence of microvascular changes, and cardiovascular risk may identify opportunities for future preventive interventions.

Right ventricular strain assessment by feature tracking from cine images shows acceptable levels of agreement with echocardiography

Background— As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy. Methods and Results— Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3–59.2 kg/m 2 ) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P P R =0.04; P =0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R =0.41; women, R =0.51; both P R =−0.43; women, R =−0.44; both P R =−0.37; women, R =−0.35; both P Conclusions— A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling.

Cardiovascular death is the leading cause of mortality in women. Low physical fitness and sedentary behaviour are recognized as major risk factors and increased physical activity is therefore promoted as a strategy to reduce cardiovascular risk. Recommendations advise at least 150 minutes of moderate to vigorous activity per week and, when possible, reduced sitting time, with cardiovascular benefits gained from as little as 15 minutes of exercise per day. The same recommendations apply to patients with a history of cardiovascular disease, such as myocardial infarction or chronic heart failure, and systematic review evidence supports the use of aerobic exercise and resistance training in other chronic disease management settings, including blood pressure control. A major challenge for the health care community is the delivery of affordable interventions, which maintain increased physical activity behaviour in the long term, to sustain the health benefits. Environmental and lifestyle modifications across a range of domains – including transport, leisure, home and education – provide an important opportunity to increase activity within a population. Workplacebased physical activity interventions in particular have been identified as a way to provide effective risk reduction and, reassuringly, the reported incidence of serious adverse events in randomized control trials and within disease populations undergoing cardiac rehabilitation programmes is low. However, despite this volume of evidence that physical activity is good, it is possible that cardiovascular risk is increased in some people during certain types of exercise. Physical activity increases blood pressure, with heavy resistance exercise being associated with the most extreme transient changes in systolic levels. This type of static exercise reduces venous return and increases the cardiac afterload as well as strain. The presence of disease may further exacerbate these increases in blood pressure as people at risk of hypertension are known to have an exaggerated blood pressure response to exercise. People who exhibit this response are at increased risk of stroke and cardiovascular death. Similar transient physiological stresses to those observed in resistance exercise programmes may occur in occupational settings where people lift or manoeuvre heavy loads. Allesoe et al. have reported a prospective cohort study that explores the association between questionnaire-reported workplace physical activity and incident ischaemic heart disease retrieved from a national register of hospital discharges. They found that, in an occupational setting, self-reported high physical activity levels in women with hypertension were associated with a three-fold greater risk of future ischaemic heart disease than that seen in normotensive women who reported moderate physical activity at work. This is a novel finding in a population of over 12,000 women monitored prospectively for nearly 15 years. Previous occupation-based studies have tended to focus on male employees and therefore the authors should be commended for addressing this relevant question in a female population. There are distinct features of cardiovascular disease specific to women, such as the development of early hypertension related to pregnancy, as well as unique patterns of aortic and cardiac remodelling that may be relevant to their blood pressure response and warrant tailored primary prevention advice. The type of occupation may need to be part of this advice, but, equally, occupation may be important because it offers a setting and

© 2016 American Heart Association, Inc. Previous studies report benefits of exercise for blood pressure control in middle age and older adults, but longer-term effectiveness in younger adults is not well established. We performed a systematic review and meta-analysis of published randomized control trials with meta-regression of potential effect modifiers. An information specialist completed a comprehensive search of available data sources, including studies published up to June 2015. Authors applied strict inclusion and exclusion criteria to screen 9524 titles. Eligible studies recruited younger adults with a cardiovascular risk factor (with at least 25% of cohort aged 18-40 years); the intervention had a defined physical activity strategy and reported blood pressure as primary or secondary outcome. Meta-analysis included 14 studies randomizing 3614 participants, mean age 42.2±6.3 (SD) years. At 3 to 6 months, exercise was associated with a reduction in systolic blood pressure of -4.40 mm Hg (95% confidence interval, -5.78 to -3.01) and in diastolic blood pressure of -4.17 mm Hg (95% confidence interval, -5.42 to -2.93). Intervention effect was not significantly influenced by baseline blood pressure, body weight, or subsequent weight loss. Observed intervention effect was lost after 12 months of follow-up with no reported benefit over control, mean difference in systolic blood pressure -1.02 mm Hg (95% confidence interval, -2.34 to 0.29), and in diastolic blood pressure -0.91 mm Hg (95% confidence interval, -1.85 to 0.02). Current exercise guidance provided to reduce blood pressure in younger adults is unlikely to benefit long-term cardiovascular risk. There is need for continued research to improve age-specific strategies and recommendations for hypertension prevention and management in young adults.

Arterial stiffness: using simple surrogate measures to make sense of a biologically complex phenomenon

Investigations into how perinatal growth and intrauterine environment may 'programme' risk of later cardiovascular disease have been ongoing for over two decades. One of the more recent outcomes of these studies is the observation that certain pregnancy-related conditions, such as preterm birth, have an unusually large impact on the long-term cardiovascular health of the offspring. In the present paper, we review the current literature of how preterm birth affects the long-term cardiovascular structure and function of the offspring, considering three major areas of investigation: firstly, outlining the long-term cardiovascular phenotypic changes in preterm-born individuals; secondly, investigating factors related to preterm birth that may be modifying cardiovascular phenotype, such as preeclampsia, perinatal interventions, and physiological disturbances; and thirdly, the expected clinical relevance of these cardiovascular changes. This review discusses the importance of continued research focused on the mechanistic understanding of these cardiovascular alterations in order to develop specific primary prevention strategies.

Background— Young adults born preterm have distinct differences in left ventricular mass, function, and geometry. Animal studies suggest that cardiomyocyte changes are evident in both ventricles after preterm birth; therefore, we investigated whether these young adults also have differences in their right ventricular structure and function. Methods and Results— We studied 102 preterm-born young adults followed up prospectively since birth and 132 term-born control subjects born to uncomplicated pregnancies. We quantified right ventricular structure and function by cardiovascular magnetic resonance on a 1.5-T Siemens scanner using Argus and TomTec postprocessing software. Preterm birth was associated with a small right ventricle (end diastolic volume, 79.8±13.2 versus 88.5±11.8 mL/m 2 ; P 2 ; P r =−0.47, P P =0.006). Indeed, 21% had values below the lower limit observed in the term-born adults and 6% had mild systolic dysfunction ( Conclusions— Preterm birth is associated with global myocardial structural and functional differences in adult life, including smaller right ventricular size and greater mass. The changes are greater in the right ventricle than previously observed in the left ventricle, with potentially clinically significant impairment in right ventricular systolic function.

BACKGROUND AND OBJECTIVES: Preterm birth relates to long-term alterations in cardiac morphology and function. Understanding whether preterm postnatal life is a tractable period of cardiovascular development that can be positively altered by nutrition is relevant to long-term outcomes. We hypothesized that being fed human breast milk during early postnatal life is beneficial to long-term cardiac structure and function in preterm-born individuals compared with infant formulas. METHODS: A total of 926 preterm-born infants originally took part in a randomized controlled trial of postnatal milk-feeding regimens between 1982 and 1985 across 5 different UK centers. Preterm-born individuals were randomly assigned to either breast milk donated by unrelated lactating women or nutrient-enriched formulas. We followed 102 individuals from this cohort: 30 of whom had been randomized to being fed exclusively human milk and 16 to being fed exclusively formula. As a comparison group, we recruited an additional 102 individuals born term to uncomplicated pregnancies. Cardiac morphology and function were assessed by MRI. RESULTS: Preterm-born individuals fed exclusively human milk as infants had increased left and right ventricular end-diastolic volume index (+9.73%, P = .04 and +18.2%, P < .001) and stroke volume index (+9.79%, P = .05 and +22.1%, P = .01) compared with preterm-born individuals who were exclusively formula fed as infants. CONCLUSIONS: This study provides the first evidence of a beneficial association between breast milk and cardiac morphology and function in adult life in those born preterm and supports promotion of human milk for the care of preterm infants to reduce long-term cardiovascular risk.