Neuropeptide Y (NPY) is an abundant sympathetic co-transmitter, widely found in the central and peripheral nervous systems and with diverse roles in multiple physiological processes. In the cardiovascular system it is found in neurons supplying the vasculature, cardiomyocytes and endocardium, and is involved in physiological processes including vasoconstriction, cardiac remodeling, and angiogenesis. It is increasingly also implicated in cardiovascular disease pathogenesis, including hypertension, atherosclerosis, ischemia/infarction, arrhythmia, and heart failure. This review will focus on the physiological and pathogenic role of NPY in the cardiovascular system. After summarizing the NPY receptors which predominantly mediate cardiovascular actions, along with their signaling pathways, individual disease processes will be considered. A thorough understanding of these roles may allow therapeutic targeting of NPY and its receptors.

Formation of the human heart involves complex biological signals, interactions, specification of myocardial progenitor cells, and heart tube looping. To facilitate survival in the hypoxemic intrauterine environment, the fetus possesses structural, physiological, and functional cardiovascular adaptations that are fundamentally different from the neonate. At birth, upon separation from the placental circulation, the neonatal cardiovascular system takes over responsibility of vital processes for survival. The transition from the fetal to neonatal circulation is considered to be a period of intricate physiological, anatomical, and biochemical changes in the cardiovascular system. With a successful cardiopulmonary transition to the extrauterine environment, the fetal shunts are functionally modified or eliminated, enabling independent life. Investigations using medical imaging tools such as ultrasound and magnetic resonance imaging have helped to define normal and abnormal patterns of cardiac remodeling both in utero and ex utero. This has not only allowed for a better understanding of how congenital cardiac malforma-tions alter the hemodynamic transition to the extrauterine environment but also how other more common complications during pregnancy including intrauterine growth restriction, preeclampsia, and preterm delivery adversely affect offspring cardiac remodeling during this early transitional period. This review article describes key cardiac progenitors involved in embryonic heart development; the cellular, physiological, and anatomical changes during the transition from fetal to neonatal circulation; as well as the unique impact that different pregnancy complications have on cardiac remodeling.

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.

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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.

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.

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BackgroundHypertension prevalence in young adults has increased and is associated with increased incidence of cerebrovascular and cardiovascular events in middle age. However, there is significant debate regards how to effectively manage young adult hypertension with recommendation to target lifestyle intervention. Surprisingly, no trials have investigated whether lifestyle advice developed for blood pressure control in older adults is effective in these younger populations.Methods/DesignTEPHRA is an open label, parallel arm, randomised controlled trial in young adults with high normal and elevated blood pressure. The study will compare a supervised physical activity intervention consisting of 16 weeks structured exercise, physical activity self-monitoring and motivational coaching with a control group receiving usual care/minimal intervention. Two hundred young adults aged 18–35 years, including a subgroup of preterm born participants will be recruited through open recruitment and direct invitation. Participants will be randomised in a ratio of 1:1 to either the exercise intervention group or control group. Primary outcome will be ambulatory blood pressure monitoring at 16 weeks with measure of sustained effect at 12 months. Study measures include multimodal cardiovascular assessments; peripheral vascular measures, blood sampling, microvascular assessment, echocardiography, objective physical activity monitoring and a subgroup will complete multi-organ magnetic resonance imaging.DiscussionThe results of this trial will deliver a novel, randomised control trial that reports the effect of physical activity intervention on blood pressure integrated with detailed cardiovascular phenotyping in young adults. The results will support the development of future research and expand the evidence-based management of blood pressure in young adult populations.Trial RegistrationClinicaltrials.gov registration number NCT02723552, registered on 30 March, 2016.