(Tpeak-Tend)/QRS and (Tpeak-Tend)/(QT x QRS): novel markers for predicting arrhythmic risk in Brugada syndrome

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Oxford University Press

Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, Langendorff-perfused mouse hearts.

This is the final version of the article. It first appeared from Spandidos Publications via http://dx.doi.org/10.3892/br.2016.577Ventricular arrhythmic and electrophysiological properties were examined during normokalaemia (5.2 mM [K+]), hypokalaemia (3 mM [K+]) or hypokalaemia in the presence of 0.1 or 2 mM heptanol in Langendorff-perfused mouse hearts. Left ventricular epicardial or endocardial monophasic action potential recordings were obtained during right ventricular pacing. Hypokalaemia induced ventricular premature beats (VPBs) in 5 of 7 and ventricular tachycardia (VT) in 6 of 7 hearts (P0.05), reducing excitation wavelengths (λ, CV × VERP) from 7.9±1.1 to 5.1±0.3 mm (P0.001). Heptanol (0.1 mM) prevented VT, restored effective refractory period (ERP) to 45.2±2.9 msec without altering CV or APD, returning λ to control values (P>0.05) and CI to 8.4±3.8 msec (P0.05), returning λ and CI to control values (P>0.05). Anti-arrhythmic effects of heptanol during hypokalaemia were explicable by ERP changes, scaling λ and CI.GT was supported by a Wellcome Trust Vacation Scholarship, Trinity Hall, Cambridge, a Biotechnology and Biological Sciences Research Council (BBSRC) CASE Studentship and Xention Discovery. The experiments were conducted in the laboratory of Dr. Andrew Grace and Prof. Christopher Huang at the University of Cambridge, whose funding was provided by the British Heart Foundation, the Medical Research Council, the Wellcome Trust and the BBSRC

A Patient with Atezolizumab-Induced Autoimmune Diabetes Mellitus Presenting with Diabetic Ketoacidosis

Background: Atezolizumab, an immune checkpoint inhibitor, is a humanized monoclonal, anti-programmed death ligand 1 (PD-L1) antibody used for the treatment of metastatic urothelial carcinoma that has progressed after chemotherapy. Case Presentation: We describe a patient with a known history of urothelial carcinoma who presented with diabetic ketoacidosis 6 weeks following his second cycle of atezolizumab. His serum lactate level was slightly elevated (2 mM) and his β-hydroxybutyrate level was elevated (3.9 mM). High anion gap metabolic acidosis secondary to diabetic ketoacidosis was diagnosed. Subsequent testing demonstrated hemoglobin A 1c level of 9.9%, positivity for anti-glutamic acid decarboxylase antibody (0.03 nM, reference range <0.02 nM), and suppressed C-peptide level (0.1 μg/L, reference range 0.9–7.1 μg/L) in the absence of detectable anti-islet antigen 2 (IA-2) or anti-insulin antibodies. His initial management included cessation of atezolizumab treatment, intravenous sodium chloride administration, and insulin pump infusion, after which metabolic acidosis gradually resolved. The insulin pump was subsequently switched to Protaphane at 18 units before breakfast and 8 units before dinner, together with metformin at 1000 mg twice daily. Four weeks later his medication was changed to human isophane insulin plus neutral insulin (70%/30%; Mixtard 30 HM; 26 units/4 units). Linagliptin at 5 mg was added 1 month later. His hemoglobin A 1c level declined to 8.1% 1 year later. Conclusions: PD-L1 inhibitors can induce type 1 diabetes, and patients can present with diabetic ketoacidosis. Blood glucose levels should be regularly monitored in patients who are prescribed these medications

Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions.

This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ijcha.2015.10.003Ventricular arrhythmias arise from disruptions in the normal orderly sequence of electrical activation and recovery of the heart. They can be categorized into disorders affecting predominantly cellular depolarization or repolarization, or those involving action potential (AP) conduction. This article briefly discusses the factors causing conduction abnormalities in the form of unidirectional conduction block and reduced conduction velocity (CV). It then examines the roles that sodium channels and gap junctions play in AP conduction. Finally, it synthesizes experimental results to illustrate molecular mechanisms of how abnormalities in these proteins contribute to such conduction abnormalities and hence ventricular arrhythmogenesis, in acquired pathologies such as acute ischaemia and heart failure, as well as inherited arrhythmic syndromes.GT received a BBSRC Doctoral CASE Studentship at the Department of Biochemistry, University of Cambridge, in conjunction with Xention Discovery, for his Ph.D. studies. This manuscript is based, in part, on the doctoral thesis of GT. GT thanks Dr. Antony Workman of University of Glasgow, and Prof. Sarah Lummis, of University of Cambridge, for their helpful comments on an earlier draft of his thesis. We also thank two anonymous expert reviewers who have provided insightful comments and helpful suggestions which we have used to improve our original manuscript

Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus.

This is the final version of the article. It first appeared from Hindawi via https://doi.org/10.1155/2016/2848759Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population.GT was awarded a BBSRC Doctoral Training Award at the University of Cambridge for his PhD

Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts.

This is the final version of the article. It first appeared from Spandidos via https://doi.org/ 10.3892/mmr.2016.5738In the current study, arrhythmogenic effects of the gap junction inhibitor heptanol (0.05 mM) were examined in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricular epicardium during right ventricular pacing. Regular activity was observed both prior and subsequent to application of heptanol in all of the 12 hearts studied during 8 Hz pacing. By contrast, induced ventricular tachycardia (VT) was observed after heptanol treatment in 6/12 hearts using a S1S2 protocol (Fisher's exact test; P0.05). Consequently, excitation wavelengths (λ; CV x ERP) were reduced from 9.1±0.6 to 6.5±0.6 mm (P0.05). Together, these observations demonstrate for the first time, to the best of our knowledge, that inhibition of gap junctions alone using a low heptanol concentration (0.05 mM) was able to reduce CV, which alone was sufficient to permit the induction of VT using premature stimulation by reducing λ, which therefore appears central in the determination of arrhythmic tendency.GT was awarded a BBSRC Doctoral Training Award at the University of Cambridge

Flow in Rotating Serpentine Coolant Passages With Skewed Trip Strips

Laser velocimetry was utilized to map the velocity field in serpentine turbine blade cooling passages with skewed trip strips. The measurements were obtained at Reynolds and Rotation numbers of 25,000 and 0.24 to assess the influence of trips, passage curvature and Coriolis force on the flow field. The interaction of the secondary flows induced by skewed trips with the passage rotation produces a swirling vortex and a corner recirculation zone. With trips skewed at +45 deg, the secondary flows remain unaltered as the cross-flow proceeds from the passage to the turn. However, the flow characteristics at these locations differ when trips are skewed at -45 deg. Changes in the flow structure are expected to augment heat transfer, in agreement with the heat transfer measurements of Johnson, et al. The present results show that trips are skewed at -45 deg in the outward flow passage and trips are skewed at +45 deg in the inward flow passage maximize heat transfer. Details of the present measurements were related to the heat transfer measurements of Johnson, et al. to relate fluid flow and heat transfer measurements

Atrial anti-arrhythmic effects of heptanol in Langendorff-perfused mouse hearts

This is the author accepted manuscript. It is currently embargoed pending publication.Acute effects of heptanol (0.1 to 2 mM) on atrial electrophysiology were explored in Langendorff-perfused mouse hearts. Left atrial bipolar electrogram or monophasic action potential recordings were obtained during right atrial stimulation. Regular pacing at 8 Hz elicited atrial activity in 11 out of 11 hearts without inducing atrial arrhythmias. Programmed electrical stimulation using a S1S2 protocol provoked atrial tachy-arrhythmias in 9 of 17 hearts. In the initially arrhythmic group, 2 mM heptanol exerted anti-arrhythmic effects (Fisher’s exact test, P 0.05), which led to increases in excitation wavelength (CV x ERP) from 4.3 ± 0.4 to 6.2 ± 0.5 mm (P 0.05), leaving both excitation wavelength (6.3 ± 0.9 vs. 5.6 ± 0.6; P > 0.05) and ERP/APD₉₀ ratio (2.0 ± 0.2 vs. 2.1 ± 0.1; P > 0.05) unaltered. Lower heptanol concentrations (0.1, 0.5 and 1 mM) did not alter arrhythmogenicity or the above parameters. The present findings contrast with known ventricular pro-arrhythmic effects of heptanol associated with decreased ventricular wavelength, despite increased ERP/APD ratio observed in both the atria and ventricles.The author was supported by a i) Wellcome Trust Vacation Scholarship, ii) Trinity Hall, Cambridge and iii) a Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral CASE Studentship at the Department of Biochemistry, University of Cambridge, in conjunction with Xention Discovery, for his Ph.D. studies. The experiments were conducted in the laboratory of Dr. Andrew Grace and Prof. Christopher Huang at the University of Cambridge, whose funding was provided by the British Heart Foundation, the Medical Research Council, the Wellcome Trust and the BBSRC

Association of inflammatory markers based on routine blood with prognosis in patients underwent percutaneous coronary intervention

Inflammation contributes to the pathophysiological processes of coronary artery disease. We evaluated the association between inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW), systemic inflammatory index, platelet-lymphocyte ratio, and 1-year all-cause mortality in patients underwent percutaneous coronary intervention (PCI). In this retrospective cohort, we consecutively enrolled 4651 patients who underwent PCI. Baseline demographic details, clinical data, and laboratory parameters on admission were analyzed. The primary outcome was 1-year all-cause mortality after PCI. We performed Cox regression and restricted cubic spline analysis to assessed the association between the inflammatory biomarkers and the clinical outcome. The area under the curve from receiver operating characteristic analysis was determined for the ability to classify mortality outcomes. A total of 4651 patients were included. Of these, 198 (4.26%) died on follow-up. Univariate Cox regression showed that NLR (heart rate [HR]: 1.070, 95% confidence interval [CI]: 1.060–1.082, P &lt; .001), RDW (HR: 1.441, 95% CI 1.368–1.518, P &lt; .001), systemic inflammatory index (HR: 1.000, 95% CI 1.000–3.180, P &lt; .001), platelet-lymphocyte ratio (HR: 3.812, 95% CI 1.901–3.364, P &lt; .001) were significant predictors of 1-year all-cause mortality. After adjusting for other confounders in multivariate analysis, NLR (HR: 01.038, 95% CI 1.022–1.054, P &lt; .001) and RDW (HR: 1.437, 95% CI 1.346–1.535, P &lt; .001) remained significant predictors. Restricted cubic spline analysis showed the relationship between RDW, NLR, and 1-year all-cause mortality was linear after adjusting for the covariables (P for non-linearity &lt; 0.001). The multivariable adjusted model led to improvement in the area under the curve to 0.83 (P &lt; .05). Nomogram was created to predict the probability of 1 year mortality. Among the laboratory indices, RDW and NLR showed the best performance for mortality risk prediction. Multivariate predictive models significantly improved risk stratification

A narrative review on prediabetes or diabetes and atrial fibrillation: From molecular mechanisms to clinical practice

Based on glucose levels, people fall into three groups, normal individuals, prediabetic patients, and diabetic mellitus (DM) patients. Prediabetes (pre-DM) is an intermediate condition that exists between normal glucose levels and DM. Atrial fibrillation (AF), one of the most prevalent cardiac arrhythmias in medical practice, contributes to a considerable morbidity and mortality rate. In this review, we looked at the clinical symptoms, pathological alterations, molecular mechanisms, and associated risk factors of pre-DM, type 2 DM (T2DM), and AF. In clinical practice, pre-DM can increase the prevalence of AF. In the hyperglycemic state, oxidative stress, inflammation, and endoplasmic reticulum stress can cause alterations in atrial cell or cardiac fibroblast function through tumor necrosis factor-α/nuclear factor-κB (NF-κB)/transforming growth factor-β, mitogen-activated protein kinase-matrix metalloproteinase-9 and PARP-1 is poly (ADP-ribose) polymerase 1. IκB kinase-α/NF-κB pathways, and further cause atria undergo structural, electrical, and neural remodeling which lead to the occurrence and persistence of AF. In addition, pre-DM and T2DM may worsen as a result of obesity, obstructive sleep apnea, and arterial hypertension. Furthermore, clinical researches have demonstrated that lifestyle interventions and/or pharmacotherapy in pre-DM patients can effectively delay the progresssion of pre-DM to T2DM. Individualized glycemic management and AF management should be provided to AF patients with pre-DM or DM