(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

Mechanisms of Electrical Activation and Conduction in the Gastrointestinal System: Lessons from Cardiac Electrophysiology.

This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fphys.2016.00182The gastrointestinal (GI) tract is an electrically excitable organ system containing multiple cell types, which coordinate electrical activity propagating through this tract. Disruption in its normal electrophysiology is observed in a number of GI motility disorders. However, this is not well characterized and the field of GI electrophysiology is much less developed compared to the cardiac field. The aim of this article is to use the established knowledge of cardiac electrophysiology to shed light on the mechanisms of electrical activation and propagation along the GI tract, and how abnormalities in these processes lead to motility disorders and suggest better treatment options based on this improved understanding. In the first part of the article, the ionic contributions to the generation of GI slow wave and the cardiac action potential (AP) are reviewed. Propagation of these electrical signals can be described by the core conductor theory in both systems. However, specifically for the GI tract, the following unique properties are observed: changes in slow wave frequency along its length, periods of quiescence, synchronization in short distances and desynchronization over long distances. These are best described by a coupled oscillator theory. Other differences include the diminished role of gap junctions in mediating this conduction in the GI tract compared to the heart. The electrophysiology of conditions such as gastroesophageal reflux disease and gastroparesis, and functional problems such as irritable bowel syndrome are discussed in detail, with reference to ion channel abnormalities and potential therapeutic targets. A deeper understanding of the molecular basis and physiological mechanisms underlying GI motility disorders will enable the development of better diagnostic and therapeutic tools and the advancement of this field.Croucher Foundatio

ST-Segment Depression in Leads I and aVL: Artifactual or Pathophysiological Findings?

The 12-lead electrocardiogram (ECG) is a routinely performed test but is susceptible to misinterpretation even by experienced physicians. We report a case of a 72-year-old lady with no prior cardiac history presented to our hospital with atypical chest pain. Her initial electrocardiogram shows an initial ST depression followed by positive deflections leads I and aVL. Non-physiological ST segment and T-wave changes are also observed in the precordial leads V2 to V6. By contrast, these abnormalities are notably absent in lead II. A repeat of the ECG taken 30 minutes later reveals the resolution of most abnormalities seen in the initial ECG on a background of high-frequency noise in the limb leads. She was referred to the cardiology department for further management. An urgent echocardiogram revealed no regional wall motion abnormalities with preserved ejection fraction, and her coronary angiogram revealed no significant coronary stenosis. This case illustrates the importance of understanding different factors that can cause ST segment abnormalities, notably artifactual changes that can mimic ST segment myocardial infarction. </p