Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC162

Poster Communications

Two pathways to sinoatrial node dysfunction in heart failure

J. Yanni1, X. J. Cai2, T. Yamanushi3, J. O. Tellez1, C. Jones2, R. Hutcheon2, O. Monfredi1, G. Hao1, U. Mackiewicz4, M. Maczewski4, A. Beresewicz4, J. Jahraus2, H. Dobrzynski1, M. Boyett1

1. Cardiovascular Medicine, University of Manchester, Manchester, United Kingdom. 2. Liverpool University, Liverpool, United Kingdom. 3. Kagawa Prefectural College of Health Sciences, Kagawa, Japan. 4. Medical Center of Postgraduate Education, Warsaw, Poland.


The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction is associated with heart failure (HF), and bradyarrhythmias are responsible for a substantial proportion of deaths of HF patients. Ion channels and their associated subunits are key to the pacemaker function of the SAN, and we investigated whether there are changes in ion channel gene expression in the SAN in HF. Three animal models were studied: (i) a rabbit model of volume and pressure overload (caused by destruction of the aortic valve and banding of the aorta under ketamine HCL (50 mg/kg body weight, i.m.) anaesthesia, followed by temgesic (15 m/kg) s.c.); (ii) a rat model of pulmonary hypertension (PHT; caused by subcutaneous injection of monocrotaline (produced by a single injection of 60 mg/kg monocrotaline (MCT) solution s.c. into the interscapular region and killed under sodium pentobarbiturate (45mg/kg) anesthesia)); and (iii) a rat model of myocardial infarction (MI; caused by ligation of the proximal left coronary artery under ketamine HCL and Xylazine (100mg/5mg/kg body weight, i.p.) anaesthesia). All studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health Publication No. 85-23, revised 1985). In the rabbit and rat MI models, echocardiography demonstrated severe impairment of left ventricle systolic function. In the rat PHT and MI models, there was a decrease in the intrinsic heart rate (evidence of SAN dysfunction; measured in Langendorff heart experiments). Tissue was sampled from the right atrium and SAN, and expression of mRNAs for ion channels and related proteins was measured using quantitative PCR. Expression of between 33 and 80 mRNAs was measured. During HF, a relatively small number of significant changes in expression were observed in atrial muscle (6, 27 and 7% in rabbit, rat PHT and rat MI models), but a larger number was observed in the SAN (48, 58 and 40% in rabbit, rat PHT and rat MI models). In the rabbit and rat PHT models, the HF-related bradycardia can perhaps be explained by a downregulation of expression of HCN4 (of -87 and -41%), Cav1.2 (of 51 and -38%) and NCX1 (of -46 and -38%), all of which carry inward current. However, in the rat MI model, there was an upregulation of expression of HCN4 (of +63%), Cav1.2 (of +55%) and NCX1 (of +37%), and instead the HF-related bradycardia can perhaps be explained by an upregulation of expression of channels carrying outward current, including ERG (of +100%), KvLQT1 (of +50%), Kir2.4 (of +267%) and TWIK2 (of 73%). Interestingly, there was a downregulation of expression of ERG (of -50 and -70%) and KvLQT1 (of -57 and -33%) in the rabbit and rat PHT models. These results show the dynamic nature of ion channel expression in the SAN. Also, these results suggest that there are perhaps two pathways to SAN dysfunction in HF, one involving a downregulation of inward current-carrying channels and one involving an upregulation of outward current-carrying channels.

Where applicable, experiments conform with Society ethical requirements