Inherited Thoracic Aortic Disease: New Insights and Translational Targets.

Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter.

Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: A systematic review.

The accurate identification of peripheral artery disease (PAD) in patients with diabetes and foot ulceration is important, in order to inform timely management and to plan intervention including revascularisation. A variety of non-invasive tests are available to diagnose PAD at the bedside, but there is no consensus as to the most useful test, or the accuracy of these bedside investigations when compared to reference imaging tests such as magnetic resonance angiography, computed tomography angiography, digital subtraction angiography or colour duplex ultrasound. Members of the International Working Group of the Diabetic Foot updated our previous systematic review, to include all eligible studies published between 1980 and 2018.

Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: A systematic review.

Clinical outcomes of patients with diabetes, foot ulceration, and peripheral artery disease (PAD) are difficult to predict. The prediction of important clinical outcomes, such as wound healing and major amputation, would be a valuable tool to help guide management and target interventions for limb salvage. Despite the existence of a number of classification tools, no consensus exists as to the most useful bedside tests with which to predict outcome.

Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: A systematic review.

In patients with diabetes, foot ulceration and peripheral artery disease (PAD), it is often difficult to determine whether, when and how to revascularise the affected lower extremity. The presence of PAD is a major risk factor for non-healing and yet clinical outcomes of revascularisation are not necessarily related to technical success. The International Working Group of the Diabetic Foot updated systematic review on the effectiveness of revascularisation of the ulcerated foot in patients with diabetes and PAD is comprised of 64 studies describing >13 000 patients.

Study protocol for the groin wound infection after vascular exposure (GIVE) audit and multicentre cohort study.

Introduction: Surgical site infections (SSIs) following groin incision for arterial exposure are commonplace and a significant cause of morbidity and mortality following major arterial surgery. Published incidence varies considerably. The primary aim of GIVE will be to compare individual units' practice with established guidelines from The National Institute for Health and Care Excellence (NICE).

Plasma Desmosine and Abdominal Aortic Aneurysm Disease.

Background It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the breakdown of elastin within the aortic tunica media, leading to aortic dilatation and rupture. The aim of this study was to investigate the association of plasma desmosine (pDES), an elastin-specific degradation product, with disease severity and clinical outcome in patients with AAA.

Urinary estrogens as a non-invasive biomarker of viable pregnancy in the giant panda (Ailuropoda melanoleuca).

Female giant pandas show complex reproductive traits, being seasonally monoestrus, displaying a variable length embryonic diapause and exhibiting pseudopregnancy. Currently, there is no confirmatory non-invasive biomarker of blastocyst implantation or pregnancy. This study aimed to monitor urinary estrogens across gestation in pregnancy (n = 4), pseudopregnancy (n = 4) and non-birth cycles (n = 5) in the giant panda.

Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome.

Context: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists.

Objectives: To evaluate an analytic approach to IAS and responses to different treatments.

Non-invasive assessment of liver disease in rats using multiparametric magnetic resonance imaging: a feasibility study.

Non-invasive quantitation of liver disease using multiparametric magnetic resonance imaging (MRI) could refine clinical care pathways, trial design and preclinical drug development. The aim of this study was to evaluate the use of multiparametric MRI in experimental models of liver disease. Liver injury was induced in rats using 4 or 12 weeks of carbon tetrachloride (CCl) intoxication and 4 or 8 weeks on a methionine and choline deficient (MCD) diet.

Multiparametric magnetic resonance imaging for quantitation of liver disease: a two-centre cross-sectional observational study.

LiverMultiScan is an emerging diagnostic tool using multiparametric MRI to quantify liver disease. In a two-centre prospective validation study, 161 consecutive adult patients who had clinically-indicated liver biopsies underwent contemporaneous non-contrast multiparametric MRI at 3.0 tesla (proton density fat fraction (PDFF), T1 and T2* mapping), transient elastography (TE) and Enhanced Liver Fibrosis (ELF) test.

Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension.

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr)apelin-13 and matched saline placebo during invasive right heart catheterization.

Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models.

Aims/hypothesis: Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies.

Secretome Analysis of Hypoxia-Induced 3T3-L1 Adipocytes Uncovers Novel Proteins Potentially Involved in Obesity.

In the obese state, as adipose tissue expands, adipocytes become hypoxic and dysfunctional, leading to changes in the pattern of adipocyte-secreted proteins. To better understand the role of hypoxia in the mechanisms linked to obesity, we comparatively analyzed the secretome of murine differentiated 3T3-L1 adipocytes exposed to normoxia or hypoxia for 24 h. Proteins secreted into the culture media were precipitated by trichloroacetic acid and then digested with trypsin.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

Background: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).

Methods: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.

Mechanisms and Therapeutic Targets of Cardiac Regeneration: Closing the Age Gap.

While a regenerative response is limited in the mammalian adult heart, it has been recently shown that the neonatal mammalian heart possesses a marked but transient capacity for regeneration after cardiac injury, including myocardial infarction. These findings evidence that the mammalian heart still retains a regenerative capacity and highlights the concept that the expression of distinct molecular switches (that activate or inhibit cellular mechanisms regulating tissue development and regeneration) vary during different stages of life, indicating that cardiac regeneration is an age-dependent process. Thus, understanding the mechanisms underpinning regeneration in the neonatal-infarcted heart is crucial to develop new treatments aimed at improving cardiovascular regeneration in the adult.

In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis.

The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1.

Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution: Part 3 of a 3-Part Series.

Oxidative stress occurs whenever the release of reactive oxygen species (ROS) exceeds endogenous antioxidant capacity. In this paper, we review the specific role of several cardiovascular risk factors in promoting oxidative stress: diabetes, obesity, smoking, and excessive pollution. Specifically, the risk of developing heart failure is higher in patients with diabetes or obesity, even with optimal medical treatment, and the increased release of ROS from cardiac mitochondria and other sources likely contributes to the development of cardiac dysfunction in this setting.

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

Background: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers.

Iterative reconstruction can permit the use of lower X-ray tube current in CT coronary artery calcium scoring.

Objective:: CT coronary artery calcium scoring (CACS) is additive to traditional risk factors for predicting future cardiac events but is associated with relatively high radiation doses. We assessed the feasibility of CACS radiation dose reduction using a lower tube current and iterative reconstruction (IR).

Methods:: Artificial noise was added to the raw data from 27 CACS studies from patients who were symptomatic to simulate lower tube current scanning (75, 50 and 25% original current).

Smooth Muscle Enriched Long Noncoding RNA (SMILR) Regulates Cell Proliferation.

Background: Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology.

Protein corona formation in bronchoalveolar fluid enhances diesel exhaust nanoparticle uptake and pro-inflammatory responses in macrophages.

In biological fluids nanoparticles bind a range of molecules, particularly proteins, on their surface. The resulting protein corona influences biological activity and fate of nanoparticle in vivo. Corona composition is often determined by the biological milieu encountered at the entry portal into the body, and, can therefore, depend on the route of exposure to the nanoparticle.

Diagnostic Strategies for the Evaluation of Chest Pain: Clinical Implications From SCOT-HEART and PROMISE.

SCOT-HEART (Scottish COmputed Tomography of the HEART) and PROMISE (PROspective Multicenter Imaging Study for Evaluation of chest pain) represent the 2 largest and most comprehensive cardiovascular imaging outcome trials in patients with stable chest pain and provide significant insights into patient diagnosis, management, and outcomes. These trials are particularly timely, given the well-recognized knowledge gaps and widespread use of noninvasive imaging. The overall goal of this review is to distill the data generated from these 2 pivotal trials to better inform the practicing clinician in the selection of noninvasive testing for stable chest pain.

Perioperative elafin for ischaemia-reperfusion injury during coronary artery bypass graft surgery: a randomised-controlled trial.

Background: Elafin is a potent endogenous neutrophil elastase inhibitor that protects against myocardial inflammation and injury in preclinical models of ischaemic-reperfusion injury. We investigated whether elafin could inhibit myocardial ischaemia-reperfusion injury induced during coronary artery bypass graft (CABG) surgery.

Methods And Results: In a randomised double-blind placebo-controlled parallel group clinical trial, 87 patients undergoing CABG surgery were randomised 1:1 to intravenous elafin 200 mg or saline placebo administered after induction of anaesthesia and prior to sternotomy.

Calcification in Aortic Stenosis: The Skeleton Key.

Aortic stenosis is a common, potentially fatal condition that is set to become an increasing public health burden. Once symptoms develop, there is an inexorable deterioration with a poor prognosis. Despite this, there are no medical therapies capable of modifying disease progression, and the only available treatment is aortic valve replacement, to which not all patients are suited.

MRI using ultrasmall superparamagnetic particles of iron oxide in patients under surveillance for abdominal aortic aneurysms to predict rupture or surgical repair: MRI for abdominal aortic aneurysms to predict rupture or surgery-the MA(3)RS study.

Introduction: Population screening for abdominal aortic aneurysms (AAA) halves the associated mortality and has led to the establishment of national screening programmes. Prediction of aneurysm growth and rupture is challenging and currently relies on serial diameter measurements with ultrasound. Recently, a novel MRI-based technique using ultrasmall superparamagnetic particles of iron oxide (USPIO) has demonstrated considerable promise as a method of identifying aneurysm inflammation and expansion.