Multi-Organ Phenotypes of Offspring Born Following Hypertensive Disorders of Pregnancy: A Systematic Review.

BACKGROUND: Hypertensive pregnancies are associated with an increased risk of cardiovascular and neurological diseases in the offspring during later life. However, less is known about the potential impact on multi-organ phenotypes in offspring before disease symptoms occur. The objective of this systematic review was to determine the associations of fetal exposure to maternal hypertensive pregnancy with multi-organ phenotypes across developmental stages. METHODS AND RESULTS: Ovid MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), WoS, Scopus, CINAHL, and ClinicalTrials.gov were systematically searched until February 2024. Records were independently screened by 2 authors. Studies reporting on the structure or function of the heart, blood vessels, brain, liver, and kidneys in offspring of hypertensive pregnancies compared with a normotensive control population were included. Risk of bias was assessed using the Newcastle-Ottawa Scale. Extracted data were presented using harvest plots. Seventy-three studies including 7091 offspring of hypertensive pregnancies and 42 164 controls were identified that met the inclusion criteria. Thirty-two studies were investigations in fetuses, 24 in neonates and infants, 12 in children, 2 in adolescents, and 3 in adults. Offspring of hypertensive pregnancies had structural and functional changes in the heart compared with controls in some studies across developmental stages. Offspring of hypertensive pregnancies also had smaller occipital and parietal vessels, higher aortic intima-media thickness, and lower retinal arteriolar-to-venular ratio. Some conflicting evidence existed for other phenotypical alterations. CONCLUSIONS: There is still inconsistent evidence of multi-organ structural and functional differences in offspring of hypertensive pregnancies. The evidence base could therefore be further strengthened through well-designed and conducted prospective studies. REGISTRATION INFORMATION: www.crd.york.ac.uk. Unique Identifier: CRD42023387550.

A compound-target pairs dataset: differences between drugs, clinical candidates and other bioactive compounds.

Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases.

Can heart failure phenotypes be predicted by cardiac remodelling peripartum or postpartum?

Hypertension during pregnancy affects up to 10% of pregnancies and is associated with significant cardiovascular morbidity and mortality. In the short-term it can result in pre-eclampsia, haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, or even hypertension associated acute heart failure, all of which may necessitate pre-term delivery to prevent maternal or neonatal death. In the long term, a history of gestational hypertension and pre-eclampsia significantly increases the risk of future cardiovascular disease including chronic hypertension, coronary artery disease, heart failure and stroke. This review explores our current level of knowledge of the phenotypes of heart failure, paying particular attention to those specific to women, and the role of pregnancy and non-pregnancy related risk factors in the development of this condition. We discuss why women with hypertensive pregnancy may be disproportionately affected by heart failure with preserved ejection fraction (HFpEF) and whether a unique phenotype of heart failure unique to hypertensive pregnancy exists. Finally, we explore how future cardiovascular risk may be predicted based on cardiac remodelling during or after pregnancy and suggest potential areas of further research in the field.

Occurrence of "Natural Selection" in Successful Small Molecule Drug Discovery.

Published compounds from ChEMBL version 32 are used to seek evidence for the occurrence of "natural selection" in drug discovery. Three measures of natural product (NP) character were applied, to compare time- and target-matched compounds reaching the clinic (clinical compounds in phase 1-3 development and approved drugs) with background compounds (reference compounds). Pseudo-NPs (PNPs), containing NP fragments combined in ways inaccessible by nature, are increasing over time, reaching 67% of clinical compounds first disclosed since 2010. PNPs are 54% more likely to be found in post-2008 clinical versus reference compounds. The majority of target classes show increased clinical compound NP character versus their reference compounds. Only 176 NP fragments appear in >1000 clinical compounds published since 2008, yet these make up on average 63% of the clinical compound's core scaffolds. There is untapped potential awaiting exploitation, by applying nature's building blocks─"natural intelligence"─to drug design.

Novel Role of 5-Methyl-(6S)-Tetrahydrofolate in Mediating Endothelial Cell Tetrahydrobiopterin in Pregnancy and Implications for Gestational Hypertension.

BACKGROUND: Folate intake during pregnancy is essential for fetal development and maternal health. However, the specific effects of folic acid (FA) and 5-methyl-(6S)-tetrahydrofolate (5-MTHF) on the prevention and treatment of hypertensive disorders of pregnancy remain unclear. We investigated whether FA and 5-MTHF have different effects on endothelial cell tetrahydrobiopterin (BH4) metabolism in pregnancy and the possible consequences for endothelial NO generation, maternal blood pressure, and fetal growth. METHODS: We analyzed the maternal blood pressure in pregnant wild-type (Gch1fl/fl) and Gch1fl/fl Tie2cre mice treated with either FA or 5-MTHF starting before pregnancy, mid-pregnancy or late pregnancy. BH4, superoxide, and NO bioavailability were determined in mouse and human models of endothelial cell BH4 deficiency by high-performance liquid chromatography. RESULTS: In vitro studies in mouse and human endothelial cells showed that treatment with 5-MTHF, but not FA, elevated BH4 levels, reduced superoxide production, and increased NO synthase activity. In primary endothelial cells isolated from women with hypertensive pregnancies, exposure to 5-MTHF, but not FA, restored the reduction in BH4 levels and NO synthase activity. In vivo studies in mice revealed that oral treatment with 5-MTHF, but not FA, prevented and treated hypertension in pregnancy when administered either before or during pregnancy, respectively, and normalized placental and fetal growth restriction if administered from mid-gestation onward. CONCLUSIONS: Collectively, these studies identify a critical role for 5-MTHF in endothelial cell function in pregnancy, related to endothelial cell BH4 availability and NO synthase activity. Thus, 5-MTHF represents a novel therapeutic agent that may potentially improve endothelial function in hypertensive disorders of pregnancy by targeting endothelial cell BH4.

Left Atrial Mechanics Following Preeclamptic Pregnancy.

BACKGROUND: Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension, cardiac dysfunction or both. METHODS: In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. RESULTS: At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). CONCLUSIONS: LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

Isometric Exercise Training and Arterial Hypertension: An Updated Review.

Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research.

The role of exercise training on cardiovascular risk factors and heart disease in patients with chronic kidney disease G3-G5 and G5D: a Clinical Consensus Statement of the European Association of Preventive Cardiology of the ESC and the European Association of Rehabilitation in Chronic Kidney Disease.

Cardiovascular (CV) morbidity and mortality is high in patients with chronic kidney disease (CKD). Most patients reveal a high prevalence of CV risk factors such as diabetes or arterial hypertension and many have manifest cardiovascular disease (CVD), such as coronary artery disease and chronic heart failure with an increased risk of clinical events including sudden cardiac death. Diabetes mellitus and hypertension contribute to the development of CKD and the prevalence of CKD is in the range of 20-65% in diabetic and 30-50% in hypertensive patients. Therefore, prevention and optimal treatment of CV risk factors and comorbidities are key strategies to reduce CV risk and improve survival in CKD. Beyond common CV risk factors, patients with CKD are often physically inactive and have low physical function leading to subsequent frailty with muscle fatigue and weakness, sarcopenia and increased risk of falling. Consequently, the economic health burden of CKD is high, requiring feasible strategies to counteract this vicious cycle. Regular physical activity and exercise training (ET) have been shown to be effective in improving risk factors, reducing CVD and reducing frailty and falls. Nonetheless, combining ET and a healthy lifestyle with pharmacological treatment is not frequently applied in clinical practice. For that reason, this Clinical Consensus Statement reviews the current literature and provides evidence-based data regarding the role of ET in reducing CV and overall burden in patients with CKD. The aim is to increase awareness among cardiologists, nephrologists, and healthcare professionals of the potential of exercise therapy in order to encourage implementation of ET in clinical practice, eventually reducing CV risk and disease, as well as reducing frailty in patients with CKD G3-G5D.

Accelerometer-based sedentary time, light physical activity, and moderate-to-vigorous physical activity from childhood with arterial stiffness and carotid IMT progression: A 13-year longitudinal study of 1339 children.

AIMS: We examined the longitudinal associations of sedentary time (ST), light physical activity (LPA), and moderate-to-vigorous PA (MVPA) from childhood with carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness and carotid intima-media thickness (cIMT). METHODS: We studied 1339 children, aged 11 years from Avon Longitudinal Study of Parents and Children, UK, followed up for 13 years. Accelerometer-based ST, LPA, and MVPA were assessed at ages 11, 15, and 24 years clinic visits. cfPWV and cIMT were measured with Vicorder and ultrasound, respectively, at ages 17 and 24 years. RESULTS: Among 1339 [56.4% female] participants, mean ST increased from ages 11 through 24 years, while mean LPA and MVPA decreased. Persistently high ST tertile from childhood was associated with increased cfPWV progression, effect estimate 0.047 m/s; [(95% CI 0.005 to 0.090); p = 0.030], but not cIMT progression. Persistently high LPA tertile category was associated with decreased cfPWV progression in males -0.022 m/s; [(-0.028 to -0.017); p < 0.001] and females -0.027 m/s; [(-0.044 to -0.010); p < 0.001]. Cumulative LPA exposure decreased the odds of progressively worsening cfPWV [Odds ratio 0.994 (0.994-0.995); p < 0.0001] and cIMT. Persistent exposure to ≥60 min/day of MVPA was paradoxically associated with increased cfPWV progression in males 0.053 m/s; [(0.030 to 0.077); p < 0.001] and females 0.012 m/s; [(0.002 to 0.022); p = 0.016]. Persistent exposure to ≥60 min/day of MVPA was inversely associated with cIMT progression in females -0.017 mm; [(-0.026 to -0.009); p < 0.001]. CONCLUSION: LPA >3 h/day from childhood may attenuate progressively worsening vascular damage associated with increased ST in youth.

Beliefs, experiences and concerns of using artificial intelligence in healthcare: A qualitative synthesis.

Objective: Artificial intelligence (AI) is a developing field in the context of healthcare. As this technology continues to be implemented in patient care, there is a growing need to understand the thoughts and experiences of stakeholders in this area to ensure that future AI development and implementation is successful. The aim of this study was to conduct a literature search of qualitative studies exploring the opinions of stakeholders such as clinicians, patients, and technology experts in order to establish the most common themes and ideas that have been presented in this research. Methods: A literature search was conducted of existing qualitative research on stakeholder beliefs about the use of AI use in healthcare. Twenty-one papers were selected and analysed resulting in the development of four key themes relating to patient care, patient-doctor relationships, lack of education and resources, and the need for regulations. Results: Overall, patients and healthcare workers are open to the use of AI in care and appear positive about potential benefits. However, concerns were raised relating to the lack of empathy in interactions of AI tools, and potential risks that may arise from the data collection needed for AI use and development. Stakeholders in the healthcare, technology, and business sectors all stressed that there was a lack of appropriate education, funding, and guidelines surrounding AI, and these concerns needed to be addressed to ensure future implementation is safe and suitable for patient care. Conclusion: Ultimately, the results found in this study highlighted that there was a need for communication between stakeholder in order for these concerns to be addressed, mitigate potential risks, and maximise benefits for patients and clinicians alike. The results also identified a need for further qualitative research in this area to further understand stakeholder experiences as AI use continues to develop.

Self-monitoring blood pressure in Pregnancy: Evaluation of health professional experiences of the BUMP trials.

BACKGROUND: The BUMP trials evaluated a self-monitoring of blood pressure intervention in addition to usual care, testing whether they improved detection or control of hypertension for women at risk of hypertension or with hypertension during pregnancy. This process evaluation aimed to understand healthcare professionals' perspectives and experiences of the BUMP trials of self-monitoring of blood pressure during pregnancy. METHODS: Twenty-two in-depth qualitative interviews and an online survey with 328 healthcare professionals providing care for pregnant people in the BUMP trials were carried out across five maternity units in England. RESULTS: Analysis used Normalisation Process Theory to identify factors required for successful implementation and integration into routine practice. Healthcare professionals felt self-monitoring of blood pressure did not over-medicalise pregnancy for women with, or at risk of, hypertension. Most said self-monitored readings positively affected their clinical encounters and professional roles, provided additive information on which to base decisions and enriched their relationships with pregnant people. Self-monitoring of blood pressure shifts responsibilities. Some healthcare professionals felt women having responsibility to decide on timing of monitoring and whether to act on self-monitored readings was unduly burdensome, and resulted in healthcare professionals taking additional responsibility for supporting them. CONCLUSIONS: Despite healthcare professionals' early concerns that self-monitoring of blood pressure might over-medicalise pregnancy, our analysis shows the opposite was the case when used in the care of pregnant people with, or at higher risk of, hypertension. While professionals retained ultimate clinical responsibility, they viewed self-monitoring of blood pressure as a means of sharing responsibility and empowering women to understand their bodies, to make judgements and decisions, and to contribute to their care.

Temporal patterns of pre- and post-natal target organ damage associated with hypertensive pregnancy: a systematic review.

AIMS: Hypertensive pregnancy is associated with increased risks of developing a range of vascular disorders in later life. Understanding when hypertensive target organ damage first emerges could guide optimal timing of preventive interventions. This review identifies evidence of hypertensive target organ damage across cardiac, vascular, cerebral, and renal systems at different time points from pregnancy to postpartum. METHODS AND RESULTS: Systematic review of Ovid/MEDLINE, EMBASE, and ClinicalTrials.gov up to and including February 2023 including review of reference lists. Identified articles underwent evaluation via a synthesis without meta-analysis using a vote-counting approach based on direction of effect, regardless of statistical significance. Risk of bias was assessed for each outcome domain, and only higher quality studies were used for final analysis. From 7644 articles, 76 studies, including data from 1 742 698 pregnancies, were identified of high quality that reported either blood pressure trajectories or target organ damage during or after a hypertensive pregnancy. Left ventricular hypertrophy, white matter lesions, proteinuria, and retinal microvasculature changes were first evident in women during a hypertensive pregnancy. Cardiac, cerebral, and retinal changes were also reported in studies performed during the early and late post-partum period despite reduction in blood pressure early postpartum. Cognitive dysfunction was first reported late postpartum. CONCLUSION: The majority of target organ damage reported during a hypertensive pregnancy remains evident throughout the early and late post-partum period despite variation in blood pressure. Early peri-partum strategies may be required to prevent or reverse target organ damage in women who have had a hypertensive pregnancy.

This review identifies evidence of damage to the heart, brain, and blood vessels during and after hypertensive disorders of pregnancy and compares the pattern of changes that occur to blood pressure variations. Changes in the heart, brain, and blood vessels are first found in women during a hypertensive pregnancy and are also reported early after pregnancy. The majority of target organ damage reported remains evident long after pregnancy despite variation in blood pressure levels.

Cardiac Remodeling After Hypertensive Pregnancy Following Physician-Optimized Blood Pressure Self-Management: The POP-HT Randomized Clinical Trial Imaging Substudy.

BACKGROUND: Hypertensive pregnancy disorders are associated with adverse cardiac remodeling, which can fail to reverse in the postpartum period in some women. The Physician-Optimized Postpartum Hypertension Treatment trial demonstrated that improved blood pressure control while the cardiovascular system recovers postpartum associates with persistently reduced blood pressure. We now report the effect on cardiac remodeling. METHODS: In this prospective, randomized, open-label, blinded end point trial, in a single UK hospital, 220 women were randomly assigned 1:1 to self-monitoring with research physician-optimized antihypertensive titration or usual postnatal care from a primary care physician and midwife. Participants were 18 years of age or older, with preeclampsia or gestational hypertension, requiring antihypertensives on hospital discharge postnatally. Prespecified secondary cardiac imaging outcomes were recorded by echocardiography around delivery, and again at blood pressure primary outcome assessment, around 9 months postpartum, when cardiovascular magnetic resonance was also performed. RESULTS: A total of 187 women (101 intervention; 86 usual care) underwent echocardiography at baseline and follow-up, at a mean 258±14.6 days postpartum, of which 174 (93 intervention; 81 usual care) also had cardiovascular magnetic resonance at follow-up. Relative wall thickness by echocardiography was 0.06 (95% CI, 0.07-0.05; P<0.001) lower in the intervention group between baseline and follow-up, and cardiovascular magnetic resonance at follow-up demonstrated a lower left ventricular mass (-6.37 g/m2; 95% CI, -7.99 to -4.74; P<0.001), end-diastolic volume (-3.87 mL/m2; 95% CI, -6.77 to -0.98; P=0.009), and end-systolic volume (-3.25 mL/m2; 95% CI, 4.87 to -1.63; P<0.001) and higher left and right ventricular ejection fraction by 2.6% (95% CI, 1.3-3.9; P<0.001) and 2.8% (95% CI, 1.4-4.1; P<0.001), respectively. Echocardiography-assessed left ventricular diastolic function demonstrated a mean difference in average E/E' of 0.52 (95% CI, -0.97 to -0.07; P=0.024) and a reduction in left atrial volumes of -4.33 mL/m2 (95% CI, -5.52 to -3.21; P<0.001) between baseline and follow-up when adjusted for baseline differences in measures. CONCLUSIONS: Short-term postnatal optimization of blood pressure control after hypertensive pregnancy, through self-monitoring and physician-guided antihypertensive titration, associates with long-term changes in cardiovascular structure and function, in a pattern associated with more favorable cardiovascular outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04273854.

Experiences of using artificial intelligence in healthcare: a qualitative study of UK clinician and key stakeholder perspectives.

OBJECTIVES: Artificial intelligence (AI) is a rapidly developing field in healthcare, with tools being developed across various specialties to support healthcare professionals and reduce workloads. It is important to understand the experiences of professionals working in healthcare to ensure that future AI tools are acceptable and effectively implemented. The aim of this study was to gain an in-depth understanding of the experiences and perceptions of UK healthcare workers and other key stakeholders about the use of AI in the National Health Service (NHS). DESIGN: A qualitative study using semistructured interviews conducted remotely via MS Teams. Thematic analysis was carried out. SETTING: NHS and UK higher education institutes. PARTICIPANTS: Thirteen participants were recruited, including clinical and non-clinical participants working for the NHS and researchers working to develop AI tools for healthcare settings. RESULTS: Four core themes were identified: positive perceptions of AI; potential barriers to using AI in healthcare; concerns regarding AI use and steps needed to ensure the acceptability of future AI tools. Overall, we found that those working in healthcare were generally open to the use of AI and expected it to have many benefits for patients and facilitate access to care. However, concerns were raised regarding the security of patient data, the potential for misdiagnosis and that AI could increase the burden on already strained healthcare staff. CONCLUSION: This study found that healthcare staff are willing to engage with AI research and incorporate AI tools into care pathways. Going forward, the NHS and AI developers will need to collaborate closely to ensure that future tools are suitable for their intended use and do not negatively impact workloads or patient trust. Future AI studies should continue to incorporate the views of key stakeholders to improve tool acceptability. TRIAL REGISTRATION NUMBER: NCT05028179; ISRCTN15113915; IRAS ref: 293515.

Contrast echocardiography: a practical guideline from the British Society of Echocardiography.

Ultrasound contrast agents (UCAs) have a well-established role in clinical cardiology. Contrast echocardiography has evolved into a routine technique through the establishment of contrast protocols, an excellent safety profile, and clinical guidelines which highlight the incremental prognostic utility of contrast enhanced echocardiography. This document aims to provide practical guidance on the safe and effective use of contrast; reviews the role of individual staff groups; and training requirements to facilitate its routine use in the echocardiography laboratory.