Updates on sphingolipids: Spotlight on retinopathy.

The sphingolipids ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine (Sph), and sphingosine-1-phosphate (S1P)) are key signaling molecules that regulate many patho-biological processes. During the last decade, they have gained increasing attention since they may participate in important and numerous retinal processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Cer for instance has emerged as a key mediator of inflammation and death of neuronal and retinal pigment epithelium cells in experimental models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. S1P may have opposite biological actions, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1- phosphate may also contribute to uveitis. Furthermore, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), have been shown to preserve neuronal viability and retinal function. Collectively, the expanding role for these sphingolipids in the modulation of vital processes in retina cell types and in their dysregulation in retinal degenerations makes them attractive therapeutic targets.

A comparison of characteristics and outcomes of patients with community-acquired and hospital-acquired COVID-19 in the United Kingdom: An observational study.

BACKGROUND AND OBJECTIVES: Reports comparing the characteristics of patients and their clinical outcomes between community-acquired (CA) and hospital-acquired (HA) COVID-19 have not yet been reported in the literature. We aimed to characterise and compare clinical, biochemical and haematological features, in addition to clinical outcomes, between these patients. METHODS: This multi-centre, retrospective, observational study enrolled 488 SARS-CoV-2 positive patients - 339 with CA infection and 149 with HA infection. All patients were admitted to a hospital within the University Hospitals of Morecambe Bay NHS Foundation Trust between March 7th and May 18th, 2020. RESULTS: The CA cohort comprised of a significantly younger population, median age 75 years, versus 80 years in the HA cohort (P = 0·0002). Significantly less patients in the HA group experienced fever (P = 0·03) and breathlessness (P < 0·0001). Furthermore, significantly more patients had anaemia and hypoalbuminaemia in the HA group, compared to the CA group (P < 0·0001 for both). Hypertension and a lower median BMI were also significantly more pronounced in the HA cohort (P = 0·03 and P = 0·0001, respectively). The mortality rate was not significantly different between the two cohorts (34% in the CA group and 32% in the HA group, P = 0·64). However, the CA group required significantly greater ICU care (10% versus 3% in the HA group, P = 0·009). CONCLUSION: Hospital-acquired and community-acquired COVID-19 display similar rates of mortality despite significant differences in baseline characteristics of the respective patient populations. Delineation of community- and hospital-acquired COVID-19 in future studies on COVID-19 may allow for more accurate interpretation of results.

Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes.

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.

The therapeutic effect of B-type natriuretic peptides in acute decompensated heart failure.

B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.

The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases.

The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin-converting enzyme (ACE) comprises the classical RAS. The non-classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1-7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non-classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

TRP channels in gastric cancer: New hopes and clinical perspectives.

Gastric cancer is a multifactorial disease associated with a combination of and environmental factors. Each year, one million new gastric cancer cases are diagnosed worldwide and two-thirds end up losing the battle with this devastating disease. Currently, surgery represents the only effective treatment option for patients with early stage tumors. However, the asymptomatic phenotype of this disease during the early stages poses as a significant limiting factor to diagnosis and often renders treatments ineffective. To address these issues, scientists are focusing on personalized medicine and discovering new ways to treat cancer patients. Emerging therapeutic options include the transient receptor potential (TRP) channels. Since their discovery, TRP channels have been shown to contribute significantly to the pathophysiology of various cancers, including gastric cancer. This review will summarize the current knowledge about gastric cancer and provide a synopsis of recent advancements on the role and involvement of TRP channels in gastric cancer as well as a discussion of the benefits of targeting TPR channel in the clinical management of gastric cancer.

NPR-C (Natriuretic Peptide Receptor-C) Modulates the Progression of Angiotensin II-Mediated Atrial Fibrillation and Atrial Remodeling in Mice.

BACKGROUND: Atrial fibrillation (AF) commonly occurs in hypertension and in association with elevated Ang II (angiotensin II) levels. The specific mechanisms underlying Ang II-mediated AF are unclear, and interventions to prevent the effects of Ang II are lacking. NPs (natriuretic peptides), which elicit their effects through specific NP receptors, including NPR-C (natriuretic peptide receptor-C), are cardioprotective hormones that affect cardiac structure and function. METHODS: This study used wild-type and NPR-C knockout (NPR-C-/-) mice to investigate the effects of Ang II (3 mg/kg per day for 3 weeks) on AF susceptibility and atrial function using in vivo electrophysiology, high-resolution optical mapping, patch clamping, and molecular biology. In some experiments, wild-type mice were cotreated with Ang II and the NPR-C agonist cANF (0.07-0.14 mg/kg per day) for 3 weeks. RESULTS: In wild-type mice, Ang II increased susceptibility to AF in association with a prolongation of P-wave duration, increased atrial refractory period, and slowed atrial conduction. These effects were exacerbated in Ang II-treated NPR-C-/- mice. Ang II prolonged action potential duration and reduced action potential upstroke velocity (Vmax). These effects were greater in left atrial myocytes from Ang II-treated NPR-C-/- mice. Ang II also increased fibrosis in both atria in wild-type mice, whereas Ang II-treated NPR-C-/- mice exhibited substantially higher fibrosis throughout the atria. Fibrotic responses were associated with changes in expression of profibrotic genes, including TGFß and TIMP1. Cotreating wild-type mice with Ang II and the NPR-C agonist cANF dose dependently reduced AF inducibility by preventing some of the Ang II-induced changes in atrial myocyte electrophysiology and preventing fibrosis throughout the atria. CONCLUSIONS: NPR-C may represent a new target for the prevention of Ang II-induced AF via protective effects on atrial electrical and structural remodeling.

Is the prescription right? A review of non-vitamin K antagonist anticoagulant (NOAC) prescriptions in patients with non-valvular atrial fibrillation. Safe prescribing in atrial fibrillation and evaluation of non-vitamin K oral anticoagulants in stroke prevention (SAFE-NOACS) group.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are a major advance for stroke prevention in atrial fibrillation (AF). Use of the vitamin K antagonist (VKA), warfarin, has dropped 40% since 2010 in our institution. There is limited Irish hospital data on NOAC prescribing for stroke prevention. METHOD: Single centre, retrospective observational cohort study of consecutive AF patients at increased risk of stroke and/or awaiting electrical cardioversion. Data on prescribed NOACs from February 2010 till July 2015 was collected from the electronic inpatient record. Appropriateness of prescriptions was based on CHA2DS2-VASC score and accuracy on individual NOAC SPCs. Potential drug interactions and bleeding risk were also quantified. RESULTS: A total of 348 patients AF and increased risk of stroke (CHA2DS2-VASC score > 1 for men and > 2 for women) were studied. Forty-eight percent were female with a mean age 71 ± 18.6 years, 52% of whom were > 75. Mean CHA2DS2-Vasc and HAS-BLED scores were 4.1 ± 1.8 and 1.4 ± 0.8, respectively. Rivaroxaban, dabigatran and apixaban were prescribed to 154 (54.2%), 106 (34.3%) and 41 (13.2%) patients, respectively. 20.4% had inaccurate prescriptions; 92.9% (n = 65) underdosed and 7.1% (n = 5) on inappropriately higher doses. Neither choice of NOAC, age, history of anaemia, previous bleeding or co-prescribed antiplatelets influenced the accuracy of prescription (p = NS), but decreased renal function appeared to do so (p = 0.05). CONCLUSION: Our study highlights significant inaccuracies in NOAC prescribing. Patients commenced on NOACs should be assessed and followed up in a multidisciplinary AF clinic to ensure safe and effective prescribing and stroke prevention.

Evolving use of natriuretic peptide receptor type-C as part of strategies for the treatment of pulmonary hypertension due to left ventricle heart failure.

Pulmonary hypertension (PH) due to left ventricular heart failure (LV-HF) is a disabling and life-threatening disease for which there is currently no single marketed pharmacological agent approved. Despite recent advances in the pathophysiological understanding, there is as yet no prospect of cure, and the majority of patients continue to progress to right ventricular failure and die. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent or reverse the increase in pulmonary artery pressures while enhancing cardiac performance in PH due to LV-HF. In the present article, we first focused on the Natriuretic Peptide Receptor type C (NPR-C) based therapeutic strategies aimed at lowering pulmonary artery pressure. Second, we reviewed potential NPR-C therapeutic strategies to reverse or least halt the detrimental effects of diastolic dysfunction and impaired nitic oxide signalling pathways, as well as possibilities for neurohumoral modulation.

Markers of Atherosclerosis: Part 1 - Serological Markers.

Atherosclerosis is a major contributor to morbidity and mortality worldwide. With therapeutic consequences in mind, several risk scores are being used to differentiate individuals with low, intermediate or high cardiovascular (CV) event risk. The most appropriate management of intermediate risk individuals is still not known, therefore, novel biomarkers are being sought to help re-stratify them as low or high risk. This narrative review is presented in two parts. Here, in Part 1, we summarise current knowledge on serum (serological) biomarkers of atherosclerosis. Among novel biomarkers, high sensitivity C-reactive protein (hsCRP) has emerged as the most promising in chronic situations, others need further clinical studies. However, it seems that a combination of serum biomarkers offers more to risk stratification than either biomarker alone. In Part 2, we address genetic and imaging markers of atherosclerosis, as well as other developments relevant to risk prediction.

Markers of Atherosclerosis: Part 2 - Genetic and Imaging Markers.

This is Part 2 of a two-part review summarising current knowledge on biomarkers of atherosclerosis. Part 1 addressed serological biomarkers. Here, in part 2 we address genetic and imaging markers, and other developments in predicting risk. Further improvements in risk stratification are expected with the addition of genetic risk scores. In addition to single nucleotide polymorphisms (SNPs), recent advances in epigenetics offer DNA methylation profiles, histone chemical modifications, and micro-RNAs as other promising indicators of atherosclerosis. Imaging biomarkers are better studied and already have a higher degree of clinical applicability in cardiovascular (CV) event prediction and detection of preclinical atherosclerosis. With new methodologies, such as proteomics and metabolomics, discoveries of new clinically applicable biomarkers are expected.

Distinct patterns of atrial electrical and structural remodeling in angiotensin II mediated atrial fibrillation.

Atrial fibrillation (AF) is prevalent in hypertension and elevated angiotensin II (Ang II); however, the mechanisms by which Ang II leads to AF are poorly understood. Here, we investigated the basis for this in mice treated with Ang II or saline for 3 weeks. Ang II treatment increased susceptibility to AF compared to saline controls in association with increases in P wave duration and atrial effective refractory period, as well as reductions in right and left atrial conduction velocity. Patch-clamp studies demonstrate that action potential (AP) duration was prolonged in right atrial myocytes from Ang II treated mice in association with a reduction in repolarizing K+ currents. In contrast, APs in left atrial myocytes from Ang II treated mice showed reductions in upstroke velocity and overshoot, as well as greater prolongations in AP duration. Ang II reduced Na+ current (INa) in the left, but not the right atrium. This reduction in INa was reversible following inhibition of protein kinase C (PKC) and PKCα expression was increased selectively in the left atrium in Ang II treated mice. The transient outward K+ current (Ito) showed larger reductions in the left atrium in association with a shift in the voltage dependence of activation. Finally, Ang II caused fibrosis throughout the atria in association with changes in collagen expression and regulators of the extracellular matrix. This study demonstrates that hypertension and elevated Ang II cause distinct patterns of electrical and structural remodeling in the right and left atria that collectively create a substrate for AF.

Natriuretic Peptide Receptor-C Protects Against Angiotensin II-Mediated Sinoatrial Node Disease in Mice.

Sinoatrial node (SAN) disease mechanisms are poorly understood, and therapeutic options are limited. Natriuretic peptide(s) (NP) are cardioprotective hormones whose effects can be mediated partly by the NP receptor C (NPR-C). We investigated the role of NPR-C in angiotensin II (Ang II)-mediated SAN disease in mice. Ang II caused SAN disease due to impaired electrical activity in SAN myocytes and increased SAN fibrosis. Strikingly, Ang II treatment in NPR-C-/- mice worsened SAN disease, whereas co-treatment of wild-type mice with Ang II and a selective NPR-C agonist (cANF) prevented SAN dysfunction. NPR-C may represent a new target to protect against the development of Ang II-induced SAN disease.

Dynamic changes of the composition of plasma HDL particles in patients with cardiac disease: Spotlight on sphingosine-1-phosphate/serum amyloid A ratio.

Several epidemiological studies reported an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease (ASCVD). However, therapeutic interventions targeted at raising HDL-cholesterol failed to improve cardiovascular outcomes, suggesting that HDL components distinct from cholesterol may account for the anti-atherothrombotic effects attributed to this lipoprotein. Sphingosine-1-phosphate (S1P) and the acute phase protein serum amyloid A (SAA) have been identified as integral constituents of HDL particles. Evidence suggests that S1P and SAA levels within HDL particles may be affected by inflammation and oxidative stress, which are coexisting processes underlying ASCVD. Because SAA, an inflammation-related marker, and S1P, an anti-atherothrombotic marker, have relatively clear opposite characteristics among the HDL-associated proteins, the approach of assessing the two markers simultaneously may provide new insights in clinical practice (S1P/SAA Index). This review focuses on evidence in support of the concept that the S1P/SAA Index may affect the HDL atheroprotective properties and may, therefore represent a potential target for therapeutic interventions.

Time to redefine body mass index categories in chronic diseases? Spotlight on obesity paradox.

Obesity is a complex condition classically characterised by excessive body fat accumulation and represents one of the most important public health problems worldwide. Although several epidemiological studies have shown that elevated BMI is associated with higher morbidity, and with increased rate of death from all causes and from cardiovascular disease, accumulating evidence suggests that being overweight or obese may be protective (the so-called obesity paradox), at least in chronic diseases. These observations, not only question the validity of the BMI system, but also raise the intriguing question of whether we should redefine what the normal range of BMI is in individuals suffering from a chronic disease. In the present article, we review the available information on the association between elevated BMI and increased morbidity and mortality including obesity-related paradoxes, explore key aspects of the role and limitations of BMI as a measure of increased adiposity and outline potential solutions to address the current controversies regarding the impact of obesity on human health.

Is there a way out for the 2014 Ebola outbreak in Western Africa?

The 2014 Ebola outbreak in West Africa, primarily affecting Guinea, Sierra Leone, and Liberia, has exceeded all previous Ebola outbreaks in the number of cases and in international response. Although infections only occur frequently in Western Africa, the virus has the potential to spread globally and is classified as a category A pathogen that could be misused as a bioterrorism agent. This review aims (i) to discuss the latest data to aid our current recommendations for the prevention and control of the Ebola virus infection, (ii) to review its pathophysiology as well as offering insights on the most current data available about Ebola vaccine progress and potential use.