How Could Sensor-Based Measurement of Physical Activity Be Used in Cardiovascular Healthcare?

Physical activity and cardiovascular disease (CVD) are intimately linked. Low levels of physical activity increase the risk of CVDs, including myocardial infarction and stroke. Conversely, when CVD develops, it often reduces the ability to be physically active. Despite these largely understood relationships, the objective measurement of physical activity is rarely performed in routine healthcare. The ability to use sensor-based approaches to accurately measure aspects of physical activity has the potential to improve many aspects of cardiovascular healthcare across the spectrum of healthcare, from prediction, prevention, diagnosis, and treatment to disease monitoring. This review discusses the potential of sensor-based measurement of physical activity to augment current cardiovascular healthcare. We highlight many factors that should be considered to maximise the benefit and reduce the risks of such an approach. Because the widespread use of such devices in society is already a reality, it is important that scientists, clinicians, and healthcare providers are aware of these considerations.

Using the Non-Adoption, Abandonment, Scale-Up, Spread, and Sustainability (NASSS) Framework to Identify Barriers and Facilitators for the Implementation of Digital Twins in Cardiovascular Medicine.

A digital twin is a computer-based "virtual" representation of a complex system, updated using data from the "real" twin. Digital twins are established in product manufacturing, aviation, and infrastructure and are attracting significant attention in medicine. In medicine, digital twins hold great promise to improve prevention of cardiovascular diseases and enable personalised health care through a range of Internet of Things (IoT) devices which collect patient data in real-time. However, the promise of such new technology is often met with many technical, scientific, social, and ethical challenges that need to be overcome-if these challenges are not met, the technology is therefore less likely on balance to be adopted by stakeholders. The purpose of this work is to identify the facilitators and barriers to the implementation of digital twins in cardiovascular medicine. Using, the Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework, we conducted a document analysis of policy reports, industry websites, online magazines, and academic publications on digital twins in cardiovascular medicine, identifying potential facilitators and barriers to adoption. Our results show key facilitating factors for implementation: preventing cardiovascular disease, in silico simulation and experimentation, and personalised care. Key barriers to implementation included: establishing real-time data exchange, perceived specialist skills required, high demand for patient data, and ethical risks related to privacy and surveillance. Furthermore, the lack of empirical research on the attributes of digital twins by different research groups, the characteristics and behaviour of adopters, and the nature and extent of social, regulatory, economic, and political contexts in the planning and development process of these technologies is perceived as a major hindering factor to future implementation.

Continuous Monitoring of Health and Mobility Indicators in Patients with Cardiovascular Disease: A Review of Recent Technologies.

Cardiovascular diseases kill 18 million people each year. Currently, a patient's health is assessed only during clinical visits, which are often infrequent and provide little information on the person's health during daily life. Advances in mobile health technologies have allowed for the continuous monitoring of indicators of health and mobility during daily life by wearable and other devices. The ability to obtain such longitudinal, clinically relevant measurements could enhance the prevention, detection and treatment of cardiovascular diseases. This review discusses the advantages and disadvantages of various methods for monitoring patients with cardiovascular disease during daily life using wearable devices. We specifically discuss three distinct monitoring domains: physical activity monitoring, indoor home monitoring and physiological parameter monitoring.

Wearable technology and the cardiovascular system: the future of patient assessment.

The past decade has seen a dramatic rise in consumer technologies able to monitor a variety of cardiovascular parameters. Such devices initially recorded markers of exercise, but now include physiological and health-care focused measurements. The public are keen to adopt these devices in the belief that they are useful to identify and monitor cardiovascular disease. Clinicians are therefore often presented with health app data accompanied by a diverse range of concerns and queries. Herein, we assess whether these devices are accurate, their outputs validated, and whether they are suitable for professionals to make management decisions. We review underpinning methods and technologies and explore the evidence supporting the use of these devices as diagnostic and monitoring tools in hypertension, arrhythmia, heart failure, coronary artery disease, pulmonary hypertension, and valvular heart disease. Used correctly, they might improve health care and support research.

Therapeutic targeting of vascular malformation in a zebrafish model of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) causes arteriovenous malformations (AVMs) in multiple organs to cause bleeding, neurological and other complications. HHT is caused by mutations in the BMP co-receptor endoglin. We characterised a range of vascular phenotypes in embryonic and adult endoglin mutant zebrafish and the effect of inhibiting different pathways downstream of Vegf signalling. Adult endoglin mutant zebrafish developed skin AVMs, retinal vascular abnormalities and cardiac enlargement. Embryonic endoglin mutants developed an enlarged basilar artery (similar to the previously described enlarged aorta and cardinal vein) and larger numbers of endothelial membrane cysts (kugeln) on cerebral vessels. Vegf inhibition prevented these embryonic phenotypes, leading us to investigate specific Vegf signalling pathways. Inhibiting mTOR or MEK pathways prevented abnormal trunk and cerebral vasculature phenotypes, whereas inhibiting Nos or Mapk pathways had no effect. Combined subtherapeutic mTOR and MEK inhibition prevented vascular abnormalities, confirming synergy between these pathways in HHT. These results indicate that the HHT-like phenotype in zebrafish endoglin mutants can be mitigated through modulation of Vegf signalling. Combined low-dose MEK and mTOR pathway inhibition could represent a novel therapeutic strategy in HHT.

EVA1A (Eva-1 Homolog A) Promotes Endothelial Apoptosis and Inflammatory Activation Under Disturbed Flow Via Regulation of Autophagy.

BACKGROUND: Hemodynamic wall shear stress (WSS) exerted on the endothelium by flowing blood determines the spatial distribution of atherosclerotic lesions. Disturbed flow (DF) with a low WSS magnitude and reversing direction promotes atherosclerosis by regulating endothelial cell (EC) viability and function, whereas un-DF which is unidirectional and of high WSS magnitude is atheroprotective. Here, we study the role of EVA1A (eva-1 homolog A), a lysosome and endoplasmic reticulum-associated protein linked to autophagy and apoptosis, in WSS-regulated EC dysfunction. METHODS: The effect of WSS on EVA1A expression was studied using porcine and mouse aortas and cultured human ECs exposed to flow. EVA1A was silenced in vitro in human ECs and in vivo in zebrafish using siRNA (small interfering RNA) and morpholinos, respectively. RESULTS: EVA1A was induced by proatherogenic DF at both mRNA and protein levels. EVA1A silencing resulted in decreased EC apoptosis, permeability, and expression of inflammatory markers under DF. Assessment of autophagic flux using the autolysosome inhibitor, bafilomycin coupled to the autophagy markers LC3-II (microtubule-associated protein 1 light chain 3-II) and p62, revealed that EVA1A knockdown promotes autophagy when ECs are exposed to DF, but not un-DF . Blocking autophagic flux led to increased EC apoptosis in EVA1A-knockdown cells exposed to DF, suggesting that autophagy mediates the effects of DF on EC dysfunction. Mechanistically, EVA1A expression was regulated by flow direction via TWIST1 (twist basic helix-loop-helix transcription factor 1). In vivo, knockdown of EVA1A orthologue in zebrafish resulted in reduced EC apoptosis, confirming the proapoptotic role of EVA1A in the endothelium. CONCLUSIONS: We identified EVA1A as a novel flow-sensitive gene that mediates the effects of proatherogenic DF on EC dysfunction by regulating autophagy.

Applying Artificial Intelligence to Wearable Sensor Data to Diagnose and Predict Cardiovascular Disease: A Review.

Cardiovascular disease (CVD) is the world's leading cause of mortality. There is significant interest in using Artificial Intelligence (AI) to analyse data from novel sensors such as wearables to provide an earlier and more accurate prediction and diagnosis of heart disease. Digital health technologies that fuse AI and sensing devices may help disease prevention and reduce the substantial morbidity and mortality caused by CVD worldwide. In this review, we identify and describe recent developments in the application of digital health for CVD, focusing on AI approaches for CVD detection, diagnosis, and prediction through AI models driven by data collected from wearables. We summarise the literature on the use of wearables and AI in cardiovascular disease diagnosis, followed by a detailed description of the dominant AI approaches applied for modelling and prediction using data acquired from sensors such as wearables. We discuss the AI algorithms and models and clinical applications and find that AI and machine-learning-based approaches are superior to traditional or conventional statistical methods for predicting cardiovascular events. However, further studies evaluating the applicability of such algorithms in the real world are needed. In addition, improvements in wearable device data accuracy and better management of their application are required. Lastly, we discuss the challenges that the introduction of such technologies into routine healthcare may face.

Analytical Approaches for the Segmentation of the Zebrafish Brain Vasculature.

With advancements in imaging techniques, data visualization allows new insights into fundamental biological processes of development and disease. However, although biomedical science is heavily reliant on imaging data, interpretation of datasets is still often based on subjective visual assessment rather than rigorous quantitation. This overview presents steps to validate image processing and segmentation using the zebrafish brain vasculature data acquired with light sheet fluorescence microscopy as a use case. Blood vessels are of particular interest to both medical and biomedical science. Specific image enhancement filters have been developed that enhance blood vessels in imaging data prior to segmentation. Using the Sato enhancement filter as an example, we discuss how filter application can be evaluated and optimized. Approaches from the medical field such as simulated, experimental, and augmented datasets can be used to gain the most out of the data at hand. Using such datasets, we provide an overview of how biologists and data analysts can assess the accuracy, sensitivity, and robustness of their segmentation approaches that allow extraction of objects from images. Importantly, even after optimization and testing of a segmentation workflow (e.g., from a particular reporter line to another or between immunostaining processes), its generalizability is often limited, and this can be tested using double-transgenic reporter lines. Lastly, due to the increasing importance of deep learning networks, a comparative approach can be adopted to study their applicability to biological datasets. In summary, we present a broad methodological overview ranging from image enhancement to segmentation with a mixed approach of experimental, simulated, and augmented datasets to assess and validate vascular segmentation using the zebrafish brain vasculature as an example. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. HIGHLIGHTS: Simulated, experimental, and augmented datasets provide an alternative to overcome the lack of segmentation gold standards and phantom models for zebrafish cerebrovascular segmentation. Direct generalization of a segmentation approach to the data for which it was not optimized (e.g., different transgenics or antibody stainings) should be treated with caution. Comparison of different deep learning segmentation methods can be used to assess their applicability to data. Here, we show that the zebrafish cerebral vasculature can be segmented with U-Net-based architectures, which outperform SegNet architectures.

Asymmetric Hapln1a drives regionalized cardiac ECM expansion and promotes heart morphogenesis in zebrafish development.

AIMS: Vertebrate heart development requires the complex morphogenesis of a linear tube to form the mature organ, a process essential for correct cardiac form and function, requiring coordination of embryonic laterality, cardiac growth, and regionalized cellular changes. While previous studies have demonstrated broad requirements for extracellular matrix (ECM) components in cardiac morphogenesis, we hypothesized that ECM regionalization may fine tune cardiac shape during heart development. METHODS AND RESULTS: Using live in vivo light sheet imaging of zebrafish embryos, we describe a left-sided expansion of the ECM between the myocardium and endocardium prior to the onset of heart looping and chamber ballooning. Analysis using an ECM sensor revealed the cardiac ECM is further regionalized along the atrioventricular axis. Spatial transcriptomic analysis of gene expression in the heart tube identified candidate genes that may drive ECM expansion. This approach identified regionalized expression of hapln1a, encoding an ECM cross-linking protein. Validation of transcriptomic data by in situ hybridization confirmed regionalized hapln1a expression in the heart, with highest levels of expression in the future atrium and on the left side of the tube, overlapping with the observed ECM expansion. Analysis of CRISPR-Cas9-generated hapln1a mutants revealed a reduction in atrial size and reduced chamber ballooning. Loss-of-function analysis demonstrated that ECM expansion is dependent upon Hapln1a, together supporting a role for Hapln1a in regionalized ECM modulation and cardiac morphogenesis. Analysis of hapln1a expression in zebrafish mutants with randomized or absent embryonic left-right asymmetry revealed that laterality cues position hapln1a-expressing cells asymmetrically in the left side of the heart tube. CONCLUSION: We identify a regionalized ECM expansion in the heart tube which promotes correct heart development, and propose a novel model whereby embryonic laterality cues orient the axis of ECM asymmetry in the heart, suggesting these two pathways interact to promote robust cardiac morphogenesis.

Cerebrovascular development: mechanisms and experimental approaches.

The cerebral vasculature plays a central role in human health and disease and possesses several unique anatomic, functional and molecular characteristics. Despite their importance, the mechanisms that determine cerebrovascular development are less well studied than other vascular territories. This is in part due to limitations of existing models and techniques for visualisation and manipulation of the cerebral vasculature. In this review we summarise the experimental approaches used to study the cerebral vessels and the mechanisms that contribute to their development.

Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions.

Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies.

The cardiac complications of COVID-19: many publications, multiple uncertainties.

Since the first description of COVID-19 in December 2019, more than 63,000 publications have described its virology, clinical course, management, treatment and prevention. Most physicians are now encountering, or will soon encounter, patients with COVID-19 and must attempt to simultaneously assimilate this avalanche of information while managing an entirely novel disease with few guiding precedents. It is increasingly clear that, although primarily a respiratory illness, COVID-19 is associated with cardiovascular complications. However, the true incidence of direct cardiac complications remains unclear, as all complications thus far reported can also occur in patients without COVID-19. In this review, we briefly summarise and critically appraise the data on cardiac complications associated with COVID-19 and describe some cases from our own experience. We identify unresolved questions and highlight the many uncertainties in this developing field.

Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes.

Flowing blood generates a frictional force called shear stress that has major effects on vascular function. Branches and bends of arteries are exposed to complex blood flow patterns that exert low or low oscillatory shear stress, a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress is protective. Endothelial cells are critical sensors of shear stress but the mechanisms by which they decode complex shear stress environments to regulate physiological and pathophysiological responses remain incompletely understood. Several laboratories have advanced this field by integrating specialized shear-stress models with systems biology approaches, including transcriptome, methylome and proteome profiling and functional screening platforms, for unbiased identification of novel mechanosensitive signalling pathways in arteries. In this Review, we describe these studies, which reveal that shear stress regulates diverse processes and demonstrate that multiple pathways classically known to be involved in embryonic development, such as BMP-TGFß, WNT, Notch, HIF1α, TWIST1 and HOX family genes, are regulated by shear stress in arteries in adults. We propose that mechanical activation of these pathways evolved to orchestrate vascular development but also drives atherosclerosis in low shear stress regions of adult arteries.

Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish.

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood and currently no treatment exists to prevent these negative effects. We previously found that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish, and the ability of SNP to prevent these. We incubated 4-days post-fertilisation (dpf) zebrafish embryos in 20 mM glucose or mannitol for 5 days until 9 dpf, with or without 0.1 mM SNP co-treatment for 24 h (8-9 dpf), and quantified vascular NO reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and transient receptor potential cation channel subfamily V member 4 (TRPV4), as well as spontaneous neuronal activation at 9 dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced NO reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour, we found that glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype and function of the optic tectum, and on whole-organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.This article has an associated First Person interview with the first author of the paper.

The role of endothelial cilia in postembryonic vascular development.

BACKGROUND: Cilia are essential for morphogenesis and maintenance of many tissues. Loss-of-function of cilia in early Zebrafish development causes a range of vascular defects, including cerebral hemorrhage and reduced arterial vascular mural cell coverage. In contrast, loss of endothelial cilia in mice has little effect on vascular development. We therefore used a conditional rescue approach to induce endothelial cilia ablation after early embryonic development and examined the effect on vascular development and mural cell development in postembryonic, juvenile, and adult Zebrafish. RESULTS: ift54(elipsa)-mutant Zebrafish are unable to form cilia. We rescued cilia formation and ameliorated the phenotype of ift54 mutants using a novel Tg(ubi:loxP-ift54-loxP-myr-mcherry,myl7:EGFP)sh488 transgene expressing wild-type ift54 flanked by recombinase sites, then used a Tg(kdrl:cre)s898 transgene to induce endothelial-specific inactivation of ift54 at postembryonic ages. Fish without endothelial ift54 function could survive to adulthood and exhibited no vascular defects. Endothelial inactivation of ift54 did not affect development of tagln-positive vascular mural cells around either the aorta or the caudal fin vessels, or formation of vessels after tail fin resection in adult animals. CONCLUSIONS: Endothelial cilia are not essential for development and remodeling of the vasculature in juvenile and adult Zebrafish when inactivated after embryogenesis.

tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis.

Angiogenesis requires co-ordination of multiple signalling inputs to regulate the behaviour of endothelial cells (ECs) as they form vascular networks. Vascular endothelial growth factor (VEGF) is essential for angiogenesis and induces downstream signalling pathways including increased cytosolic calcium levels. Here we show that transmembrane protein 33 (tmem33), which has no known function in multicellular organisms, is essential to mediate effects of VEGF in both zebrafish and human ECs. We find that tmem33 localises to the endoplasmic reticulum in zebrafish ECs and is required for cytosolic calcium oscillations in response to Vegfa. tmem33-mediated endothelial calcium oscillations are critical for formation of endothelial tip cell filopodia and EC migration. Global or endothelial-cell-specific knockdown of tmem33 impairs multiple downstream effects of VEGF including ERK phosphorylation, Notch signalling and embryonic vascular development. These studies reveal a hitherto unsuspected role for tmem33 and calcium oscillations in the regulation of vascular development.

An integrated in utero MR method for assessing structural brain abnormalities and measuring intracranial volumes in fetuses with congenital heart disease: results of a prospective case-control feasibility study.

PURPOSE: To refine methods that assess structural brain abnormalities and calculate intracranial volumes in fetuses with congenital heart diseases (CHD) using in utero MR (iuMR) imaging. Our secondary objective was to assess the prevalence of brain abnormalities in this high-risk cohort and compare the brain volumes with normative values. METHODS: We performed iuMR on 16 pregnant women carrying a fetus with CHD and gestational age ≥ 28-week gestation and no brain abnormality on ultrasonography. All cases had fetal echocardiography by a pediatric cardiologist. Structural brain abnormalities on iuMR were recorded. Intracranial volumes were made from 3D FIESTA acquisitions following manual segmentation and the use of 3D Slicer software and were compared with normal fetuses. Z scores were calculated, and regression analyses were performed to look for differences between the normal and CHD fetuses. RESULTS: Successful 2D and 3D volume imaging was obtained in all 16 cases within a 30-min scan. Despite normal ultrasonography, 5/16 fetuses (31%) had structural brain abnormalities detected by iuMR (3 with ventriculomegaly, 2 with vermian hypoplasia). Brain volume, extra-axial volume, and total intracranial volume were statistically significantly reduced, while ventricular volumes were increased in the CHD cohort. CONCLUSION: We have shown that it is possible to perform detailed 2D and 3D studies using iuMR that allow thorough investigation of all intracranial compartments in fetuses with CHD in a clinically appropriate scan time. Those fetuses have a high risk of structural brain abnormalities and smaller brain volumes even when brain ultrasonography is normal.

The triune of intestinal microbiome, genetics and inflammatory status and its impact on the healing of lower gastrointestinal anastomoses.

Gastrointestinal resections are a common operation and most involve an anastomosis to rejoin the ends of the remaining bowel to restore gastrointestinal (GIT) continuity. While most joins heal uneventfully, in up to 26% of patients healing fails and an anastomotic leak (AL) develops. Despite advances in surgical technology and techniques, the rate of anastomotic leaks has not decreased over the last few decades raising the possibility that perhaps we do not yet fully understand the phenomenon of AL and are thus ill-equipped to prevent it. As in all complex conditions, it is necessary to isolate each different aspect of disease for interrogation of its specific role, but, as we hope to demonstrate in this article, it is a dangerous oversimplification to consider any single aspect as the full answer to the problem. Instead, consideration of important individual observations in parallel could illuminate the way forward towards a possibly simple solution amidst the complexity. This article details three aspects that we believe intertwine, and therefore should be considered together in wound healing within the GIT during postsurgical recovery: the microbiome, the host genetic make-up and their relationship to the perioperative inflammatory status. Each of these, alone or in combination, has been linked with various states of health and disease, and in combining these three aspects in the case of postoperative recovery from bowel resection, we may be nearer an answer to preventing anastomotic leaks than might have been thought just a few years ago.