Joseph Yanni Gerges

Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat.

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate effect of ivabradine, pure heart rate (HR) reducing drug, on ventricular arrhythmias within 24 h after non‐reperfused MI in the rat. ECG was recorded for 24 h after MI in untreated and ivabradine treated rats and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Forty‐five minutes and twenty‐four hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca2+ handling was assessed and expression and function of ion channels were studied. Ivabradine reduced average HR by 17%. Combined VT/VF incidence and arrhythmic mortality were higher in MI versus MI + Ivabradine rats. MI resulted in (1) increase of Ca2+ sensitivity of ryanodine receptors 24 h after MI; (2) increase of HCN4 expression in the left ventricle (LV) and funny current (IF) in LV cardiomyocytes 24 h after MI, and (3) dispersion of MAP duration both 45 min and 24 h after MI. Ivabradine partially prevented all these three potential proarrhythmic effects of MI. Ivabradine is antiarrhythmic in the acute MI in the rat. Potential mechanisms include prevention of: diastolic Ca2+‐leak from sarcoplasmic reticulum, upregulation of IF current in LV and dispersion of cardiac repolarization. Ivabradine could be an attractive antiarrhythmic agent in the setting of acute MI. J. Cell. Physiol. 229: 813–823, 2014.

Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis

Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (n = 8). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation of Cav1.2, HCN4, Kir2.1, RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2+ transient were predicted using computer modelling. Modelling predicted prolongation of the ventricular action potential and an increase in the intracellular Ca2+ transient, both of which would be expected to be arrhythmogenic. Conclusion. High-fat diet causing obesity results in arrhythmogenic cardiac gene expression of ion channels and related molecules.

Decremental conduction in the atrioventricular node and heart block in pulmonary arterial hypertension

cells; they establish 3D vascular structures in vitro and quantifiable vascular networks in vivo Authors: E. Gara1, S.Z. Kiraly1, G. Kiszler2, J. Skopal1, M. Polos1, B. Merkely1, S.E. Harding3, G. Foldes3, 1Semmelweis University, Heart Center -Budapest Hungary, 2Semmelweis University, Department of Pathology and Experimental Cancer Research Budapest Hungary, 3Imperial College London, National Heart and Lung Institute London United Kingdom,Published on behalf of the European Society of Cardiology. All rights reserved.

232 DIFFERENTIAL GENETIC EXPRESSION AND REDUCED LONGITUDINAL FUNCTION IN PATIENTS WITH DIABETES AND SEVERE AORTIC STENSOIS WITH A NORMAL EJECTION FRACTION

Introduction Aortic stenosis and type 2 diabetes mellitus are common conditions and patients with cardiovascular disease and type 2 diabetes tend to have a worse outlook than those with cardiovascular disease alone. We compared patients with severe aortic stenosis and diabetes to patients with severe aortic stenosis but no diabetes. We compared left ventricular (LV) function and expression of key genes in the left ventricle. Methods Two groups of patients with severe aortic stenosis (AVA of 1.0 cm2or less and LV ejection fraction >55%) and with (n=6) or without (n=8) type 2 diabetes were referred for aortic valve replacement. Patients had a full echocardiogram with speckle tracking prior to their operation and had a single apical LV needle biopsy taken just prior to the initiation of cardio-pulmonary bypass. The biopsies were flash frozen for mRNA expression. Expression of 48 mRNAs (responsible for ion channels and involved in energy metabolism and contractile performance in the heart) was measured by qPCR. Expression was normalised to 18S and differences were assessed using Student’s t-test (*P<0.05). Results Mean patient characteristics (with standard deviations) in both groups are shown below: Table 1   Group Age (years) Waist (cm) Weight (kg) BMI (Kg/m2) HbA1c (%) Control 78.8 (8.3) 35.8 (2.7) 79.4 (11.47) 27.8 (2.3) Diabetes 74.9 (12.8) 39.7 (8.8) 84.8 ( 21.4) 31.3 (6.9) 6.9 Mean echocardiogram parameters (with standard deviations) for the two groups are shown below: Table 2   Group LV Septal width (cm) LV End-Diastolic Volume (ml) LV Ejection Fraction (%) LV Longitudinal strain (%) MAPSE(cm) Control 1.6 (0.23) 76.2 (26.5) 63.9 (6.5) 18.3 (3.7) 1.6 (0.23) Diabetes 1.7 (0.48) 89.6 (15.6) 58.2 (2.6) 12.7 (2.5)* 1.1 (0.20)* Of the 48 genetic targets tested on the tissue samples we found an increase in patients with diabetes: NFKB-a proinflammatory transcription factor KIR 2.1 and KIR 3.1- potassium channels NCX 1-sodium-calcium exchanger ANKRD1- a transcription factor We found a decrease in patients with diabetes in: HERG- a potassium channel MTATP 6- a mitochondrial energy production gene NAV 1.5- a sodium channel Discussion We have shown a significant reduction in longitudinal left ventricular function (as evidenced by reduced MAPSE and longitudinal strain) in patients with diabetes mellitus and severe aortic stenosis compared to non diabetic controls. There was no difference in weight, BMI, waist circumference, normal ejection fraction, LV septal thickness and LV end diastolic volume. The left ventricular changes are accompanied by differential expression in several cardiac genes in patients with diabetes and may represent a subclinical cardiomyopathy that could be targeted for primary prevention of symptomatic cardiac disease.