Influence of Perivascular Adipose Tissue on Microcirculation: A Link Between Hypertension and Obesity.

Alterations in microcirculation play a crucial role in the pathogenesis of cardiovascular and metabolic disorders such as obesity and hypertension. The small resistance arteries of these patients show a typical remodeling, as indicated by an increase of media or total wall thickness to lumen diameter ratio that impairs organ flow reserve. The majority of blood vessels are surrounded by a fat depot which is termed perivascular adipose tissue (PVAT). In recent years, data from several studies have indicated that PVAT is an endocrine organ that can produce a variety of adipokines and cytokines, which may participate in the regulation of vascular tone, and the secretory profile varies with adipocyte phenotype and disease status. The PVAT of lean humans largely secretes the vasodilator adiponectin, which will act in a paracrine fashion to reduce peripheral resistance and improve nutrient uptake into tissues, thereby protecting against the development of hypertension and diabetes. In obesity, PVAT becomes enlarged and inflamed, and the bioavailability of adiponectin is reduced. The inevitable consequence is a rise in peripheral resistance with higher blood pressure. The interrelationship between obesity and hypertension could be explained, at least in part, by a cross-talk between microcirculation and PVAT. In this article, we propose an integrated pathophysiological approach of this relationship, in order to better clarify its role in obesity and hypertension, as the basis for effective and specific prevention and treatment.

Metacognitive therapy home-based self-help for anxiety and depression in cardiovascular disease patients in the UK: A single-blind randomised controlled trial.

BACKGROUND: Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT). METHODS AND FINDINGS: We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR (n = 118, 49.2%) or usual CR alone (n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = -2.64 [-4.49 to -0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data. CONCLUSION: Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients. TRIAL REGISTRATION: NCT03999359.

Perivascular Adipose Tissue Anticontractile Function Is Mediated by Both Endothelial and Neuronal Nitric Oxide Synthase Isoforms.

BACKGROUND: The mechanism of the perivascular adipose tissue (PVAT) anticontractile effect is well characterized in rodent visceral vascular beds; however, little is known about the mechanism of PVAT anticontractile function in subcutaneous vessels. In addition, we have previously shown that PVAT anticontractile function is nitric oxide synthase (NOS) dependent but have not investigated the roles of NOS isoforms. OBJECTIVE: Here, we examined PVAT anticontractile function in the mouse gracilis artery, a subcutaneous fat depot, in lean control and obese mice and investigated the mechanism in comparison to a visceral depot. METHOD: Using the wire myograph, we generated responses to noradrenaline and electrical field stimulation in the presence of pharmacological tools targeting components of the known PVAT anticontractile mechanism. In addition, we performed ex vivo "fat transplants" in the organ bath. RESULTS: The mechanism of PVAT anticontractile function is similar between subcutaneous and visceral PVAT depots. Both endothelial and neuronal NOS isoforms mediated the PVAT anticontractile effect. Loss of PVAT anticontractile function in obesity is independent of impaired vasoreactivity, and function can be restored in visceral PVAT by NOS activation. CONCLUSIONS: Targeting NOS isoforms may be useful in restoring PVAT anticontractile function in obesity, ameliorating increased vascular tone, and disease.

Evaluating Metacognitive Therapy to Improve Treatment of Anxiety and Depression in Cardiovascular Disease: The NIHR Funded PATHWAY Research Programme.

Background: Anxiety and depression contribute to poorer physical and mental health outcomes in cardiac patients. Psychological treatments are not routinely offered in cardiac care and have mixed and small effects. We conducted a series of studies under the PATHWAY research programme aimed at understanding and improving mental health outcomes for patients undergoing cardiac rehabilitation (CR) through provision of metacognitive therapy (MCT). Methods: PATHWAY was a series of feasibility trials, single-blind, multicenter, randomized controlled trials (RCTs), qualitative, stated preferences for therapy and health economics studies. Findings: Patients felt their psychological needs were not met in CR and their narratives of distress could be parsimoniously explained by the metacognitive model. Patients reported they would prefer therapy over no therapy as part of CR, which included delivery by a cardiac professional. Two feasibility studies demonstrated that RCTs of group-based and self-help MCT were acceptable, could be embedded in CR services, and that RCTs of these interventions were feasible. A definitive RCT of group-MCT within CR (n = 332) demonstrated significantly greater reductions in the severity of anxiety and depression, exceeding CR alone, with gains maintained at 12 month follow-up (SMD HADS total score = 0.52 at 4 months and 0.33 at 12 months). A definitive trial of self-help MCT is ongoing. Conclusion: There is a need to better meet the psychological needs of CR patients. Embedding MCT into CR demonstrated high acceptability and improved efficacy on psychological outcomes. Results support roll-out of MCT in CR with evaluation of national implementation. Registration: URL: NCT02420431; ISRCTN74643496; NCT03129282.

Metacognitive therapy self-help for anxiety-depression: Single-blind randomized feasibility trial in cardiovascular disease.

BACKGROUND: One in three cardiovascular disease (CVD) patients experience significant anxiety and depression. Current psychological interventions have limited efficacy in reducing such symptoms and are offered as a face-to-face intervention that may be a barrier to accessing treatment. We evaluated the feasibility and acceptability of delivering assisted home-based self-help metacognitive therapy (home-MCT) to cardiac rehabilitation (CR) patients experiencing anxiety and depression. METHOD: One hundred eight CR patients with elevated anxiety and/or depression were recruited to a single-blind randomized feasibility trial across two United Kingdom National Health Service Trusts and were randomized to usual CR or usual CR plus home-MCT. The feasibility and acceptability of adding home-MCT to CR was based on credibility or expectancy ratings, recruitment rate, drop-outs, number of CR and home-MCT modules completed, and ability of outcome measures to discriminate between patients. The study was used to refine the sample size estimate for a full-scale trial. The quality of telephone support calls delivered by CR staff trained in MCT was assessed. RESULTS: Home-MCT was found to be feasible and acceptable for the current CR patients with anxiety and depression. Recruitment and retention of participants was high, and attendance at CR was similar for both groups. Completion of home-MCT was high, but the quality of telephone support calls delivered was lower than expected. CONCLUSIONS: Home-MCT was acceptable and feasible to deliver to CR patients experiencing anxiety and depression, and the feasibility of conducting a full-scale trial of the intervention was established. Home-MCT may provide additional treatment options for cardiac patients experiencing psychological distress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Long-term cardiovascular risk prediction in the emergency department: a mixed-methods study protocol.

INTRODUCTION: Cardiovascular disease (CVD) remains one of the leading causes of preventable death in Europe, therefore any opportunity to intervene and improve care should be maximised. Known CVD risk factors are routinely collected in the emergency department (ED), yet they are often not acted on. If the risk factors have prognostic value and a pathway can be created, then this would provide more holistic care for patients and reduce health system inefficiency. METHODS AND ANALYSIS: In this mixed-methods study, we will use quantitative methods to investigate the prognostic characteristics of routinely collected data for long-term CVD outcomes, and qualitative methods to investigate how to use and implement this knowledge. The quantitative arm will use a database of approximately 21 000 chest pain patient episodes with a mean follow-up of 7.3 years. We will use Cox regression to evaluate the prognostic characteristics of routinely collected ED data for long-term CVD outcomes. We will also use a series of semi-structured interviews to co-design a prototype care pathway with stakeholders via thematic analysis. To enable the development of prototypes, themes will be structured into a logic model consisting of situation, inputs, outputs and mechanism. ETHICS AND DISSEMINATION: This work has been approved by Research Ethics Committee (Wales REC7) and the Human Research Authority under reference 19/WA/0312 and 19/WA/0311. It has also been approved by the Confidentiality Advisory Group reference 19/CAG/0209. Dissent recorded in the NHS' opt-out scheme will be applied to the dataset by NHS Digital. This work will be disseminated through peer-review publication, conference presentation and a public dissemination strategy. TRIAL REGISTRATION NUMBER: ISRCTN41008456. PROTOCOL VERSION: V.1.0-7 June 2021.

The prognostic value of emergency department measured hypertension: A systematic review and meta-analysis.

OBJECTIVES: The objective was to assess the prognostic value of hypertension detected in the emergency department (ED). METHODS: The ED presents a unique opportunity to predict long-term cardiovascular disease (CVD) outcomes with its potential for high-footfall, and large-scale routine data collection applied to underserved patient populations. A systematic review and meta-analyses were conducted to assess the prognostic performance and feasibility of ED-measured hypertension as a risk factor for long-term CVD outcomes. We searched MEDLINE and Embase databases and gray literature sources. The target populations were undifferentiated ED patients. The prognostic factor of interest was hypertension. Feasibility outcomes included prevalence, reliability, and follow-up attendance. Meta-analyses were performed for feasibility using a random effect and exact likelihood. RESULTS: The searches identified 1072 studies after title and abstract review, 53 studies had their full text assessed for eligibility, and 26 studies were included. Significant heterogeneity was identified, likely due to the international populations and differing study design. The meta-analyses estimate of prevalence for ED-measured hypertension was 0.31 (95% confidence interval  0.25-0.37). ED hypertension was persistent outside the ED (FE estimate of 0.50). The proportion of patients attending follow-up was low with an exact likelihood estimate of 0.41. Three studies examined the prognostic performance of hypertension and demonstrated an increased risk of long-term CVD outcomes. CONCLUSION: Hypertension can be measured feasibly in the ED and consequently used in a long-term cardiovascular risk prediction model. There is an opportunity to intervene in targeted individuals, using routinely collected data.

Advanced cardiovascular risk prediction in the emergency department: updating a clinical prediction model - a large database study protocol.

BACKGROUND: Patients presenting with chest pain represent a large proportion of attendances to emergency departments. In these patients clinicians often consider the diagnosis of acute myocardial infarction (AMI), the timely recognition and treatment of which is clinically important. Clinical prediction models (CPMs) have been used to enhance early diagnosis of AMI. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid is currently in clinical use across Greater Manchester. CPMs have been shown to deteriorate over time through calibration drift. We aim to assess potential calibration drift with T-MACS and compare methods for updating the model. METHODS: We will use routinely collected electronic data from patients who were treated using TMACS at two large NHS hospitals. This is estimated to include approximately 14,000 patient episodes spanning June 2016 to October 2020. The primary outcome of acute myocardial infarction will be sourced from NHS Digital's admitted patient care dataset. We will assess the calibration drift of the existing model and the benefit of updating the CPM by model recalibration, model extension and dynamic updating. These models will be validated by bootstrapping and one step ahead prequential testing. We will evaluate predictive performance using calibrations plots and c-statistics. We will also examine the reclassification of predicted probability with the updated TMACS model. DISCUSSION: CPMs are widely used in modern medicine, but are vulnerable to deteriorating calibration over time. Ongoing refinement using routinely collected electronic data will inevitably be more efficient than deriving and validating new models. In this analysis we will seek to exemplify methods for updating CPMs to protect the initial investment of time and effort. If successful, the updating methods could be used to continually refine the algorithm used within TMACS, maintaining or even improving predictive performance over time. TRIAL REGISTRATION: ISRCTN number: ISRCTN41008456.

Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation: PATHWAY-A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy.

BACKGROUND: Depression and anxiety in cardiovascular disease are significant, contributing to poor prognosis. Unfortunately, current psychological treatments offer mixed, usually small improvements in these symptoms. The present trial tested for the first time the effects of group metacognitive therapy (MCT; 6 sessions) on anxiety and depressive symptoms when delivered alongside cardiac rehabilitation (CR). METHODS: A total of 332 CR patients recruited from 5 National Health Service Trusts across the North-West of England were randomly allocated to MCT+CR (n=163, 49.1%) or usual CR alone (n=169, 50.9%). Randomization was 1:1 via minimization balancing arms on sex and Hospital Anxiety and Depression Scale scores within hospital site. The primary outcome was Hospital Anxiety and Depression Scale total after treatment (4-month follow-up). Secondary outcomes were individual Hospital Anxiety and Depression Scales, traumatic stress symptoms, and psychological mechanisms including metacognitive beliefs and repetitive negative thinking. Analysis was intention to treat. RESULTS: The adjusted group difference on the primary outcome, Hospital Anxiety and Depression Scale total score at 4 months, significantly favored the MCT+CR arm (-3.24 [95% CI, -4.67 to -1.81], P<0.001; standardized effect size, 0.52 [95% CI, 0.291 to 0.750]). The significant difference was maintained at 12 months (-2.19 [95% CI, -3.72 to -0.66], P=0.005; standardized effect size, 0.33 [95% CI, 0.101 to 0.568]). The intervention improved outcomes significantly for both depression and anxiety symptoms when assessed separately compared with usual care. Sensitivity analysis using multiple imputation of missing values supported these findings. Most secondary outcomes favored MCT+CR, with medium to high effect sizes for psychological mechanisms of metacognitive beliefs and repetitive negative thinking. No adverse treatment-related events were reported. CONCLUSIONS: Group MCT+CR significantly improved depression and anxiety compared with usual care and led to greater reductions in unhelpful metacognitions and repetitive negative thinking. Most gains remained significant at 12 months. Study strengths include a large sample, a theory-based intervention, use of longer-term follow-up, broad inclusion criteria, and involvement of a trials unit. Limitations include no control for additional contact as part of MCT to estimate nonspecific effects, and the trial was not intended to assess cardiac outcomes. Nonetheless, results demonstrated that addition of the MCT intervention had broad and significant beneficial effects on mental health symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ISRCTN74643496.

Covid-19, Lockdown and Self-Isolation: Evaluation of Deliberate Self-Harm Admissions.

Background: COVID 19 is still presenting a clear and dynamic global threat. The United Kingdom remains one of the hardest hit countries from the pandemic. In January 2021 parliament announced that the UK will be entering a full national lockdown. This paper explores what effect lockdown measures had on rates of deliberate self-harm presentations to one NHS trust in Manchester UK. Methods: This paper compared the number of cases of deliberate self-harm which presented to the emergency department of Manchester Royal Infirmary for March-May in 2018, 2019 and 2020. This was achieved by utilising coding from emergency department data and reviewing hospital records surrounding each case. Results: 2018 recorded a total of 101 admissions as a result of DSH with all causes admissions of 8,514 making the proportions of admissions due to self-harm 1.19%. In 2019, 9,038 patients were admitted, of these, 130 (1.44%) were identified as DSH. In 2020 the total number of admissions fell to 5,676 with 118 admitted due to self-harm, representing 2.08% of admissions. The absolute number of admissions remained stable however the proportion of admissions due to self-harm was significantly higher in 2020 (p < 0.001). Other significant findings include a higher proportion of male admissions compared to females in 2020 (58.5%) and a decrease in the normal of cases relating to paracetamol overdose in 2020. Discussion: The findings demonstrated by this study do not indicate that lockdown is an absolute risk for DSH behaviours however it does illustrate the stable nature of these cases despite and dramatic decline in all cause admissions. The rate of increase of deliberate self-harm accelerated significantly between March and May in 2020. Steps must be taken to avoid a similar situation following the 2021 lockdown and beyond - focus on improving access to certain virtual services may help to achieve this goal.

Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise.

PURPOSE: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and ß3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function. METHODS: Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of ß3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT. RESULTS: High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via ß3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing ß3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored. CONCLUSION: Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Interleukin-33 rescues perivascular adipose tissue anticontractile function in obesity.

Perivascular adipose tissue (PVAT) depots are metabolically active and play a major vasodilator role in healthy lean individuals. In obesity, they become inflamed and eosinophil-depleted and the anticontractile function is lost with the development of diabetes and hypertension. Moreover, eosinophil-deficient ΔdblGATA-1 mice lack PVAT anticontractile function and exhibit hypertension. Here, we have investigated the effects of inducing eosinophilia on PVAT function in health and obesity. Control, obese, and ΔdblGATA-1 mice were administered intraperitoneal injections of interleukin-33 (IL-33) for 5 days. Conscious restrained blood pressure was measured, and blood was collected for glucose and plasma measurements. Wire myography was used to assess the contractility of mesenteric resistance arteries. IL-33 injections induced a hypereosinophilic phenotype. Obese animals had significant elevations in blood pressure, blood glucose, and plasma insulin, which were normalized with IL-33. Blood glucose and insulin levels were also lowered in lean treated mice. In arteries from control mice, PVAT exerted an anticontractile effect on the vessels, which was enhanced with IL-33 treatment. In obese mice, loss of PVAT anticontractile function was rescued by IL-33. Exogenous application of IL-33 to isolated arteries induced a rapidly decaying endothelium-dependent vasodilation. The therapeutic effects were not seen in IL-33-treated ΔdblGATA-1 mice, thereby confirming that the eosinophil is crucial. In conclusion, IL-33 treatment restored PVAT anticontractile function in obesity and reversed development of hypertension, hyperglycemia, and hyperinsulinemia. These data suggest that targeting eosinophil numbers in PVAT offers a novel approach to the treatment of hypertension and type 2 diabetes in obesity.NEW & NOTEWORTHY In this study, we have shown that administering IL-33 to obese mice will restore PVAT anticontractile function, and this is accompanied by normalized blood pressure, blood glucose, and plasma insulin. Moreover, the PVAT effect is enhanced in control mice given IL-33. IL-33 induced a hypereosinophilic phenotype in our mice, and the effects of IL-33 on PVAT function, blood pressure, and blood glucose are absent in eosinophil-deficient mice, suggesting that the effects of IL-33 are mediated via eosinophils.