Caldwell, J

Kirkwood, GJ

Lawless, M

Pearman, C

Radcliffe, E

Trafford, AW

English

Chronic RV apical pacing can have adverse effects on LV function and up to 10% ofpatients develop Pacemaker-induced Cardiomyopathy. The pathophysiology of thisis incompletely understood, although previous work has shown that alteredventricular activation patterns can cause abnormal calcium handling and apoptosis.The aim of this work was to determine whether physiological-rate RV apical pacingcould cause a cellular heart failure phenotype and if this could be prevented bypacing from the RV outflow tract (RVOT).Adult sheep were paced at physiological heart rates for 3 months from the RV apexor RVOT. Another group underwent rapid ventricular pacing to cause tachycardiainducedheart failure. Cardiomyocytes from the LV free wall were studied usingpatch clamp techniques and confocal microscopy.RV apical pacing caused a cellular phenotype similar to heart failure, withattenuation of the calcium transient, reduction of ICa-L and disruption of T-tubules.These features did not occur with RVOT pacing.Changes appeared prior to clinical or echocardiographic evidence of heart failureand may therefore represent the initial stages of Pacemaker-inducedCardiomyopathy

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The University of Manchester ResearchPacemaker-induced cardiomyopathy in the sheep: RVA butnot RVOT pacing results in a heart failure cellularphenotypeLink to publication record in Manchester Research ExplorerCitation for published version (APA):Kirkwood, GJ., Lawless, M., Pearman, C., Radcliffe, E., Caldwell, J., & Trafford, AW. (2015). Pacemaker-inducedcardiomyopathy in the sheep: RVA but not RVOT pacing results in a heart failure cellular phenotype. Postersession presented at EHRA Europace/ Cardiostim (39th Meeting of the ESC Working Group on Cardiac CellularElectrophysiology), Milan.Citing this paperPlease note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscriptor Proof version this may differ from the final Published version. If citing, it is advised that you check and use thepublisher's definitive version.General rightsCopyright and moral rights for the publications made accessible in the Research Explorer are retained by theauthors and/or other copyright owners and it is a condition of accessing publications that users recognise andabide by the legal requirements associated with these rights.Takedown policyIf you believe that this document breaches copyright please refer to the University of Manchester’s TakedownProcedures [http://man.ac.uk/04Y6Bo] or contact uml.scholarlycommunications@manchester.ac.uk providingrelevant details, so we can investigate your claim.Download date:08. Jun. 2022Poster Title Researchers’/Presenters’ Names Institution/Organization/Company Methods Abstract Background Results Conclusions References 1. Yu et al. (2009), NEJM 361:2123-34 2. Jeyaraj et al. (2013), . Am J Physiol Heart Circ Physiol 305(3):H410-H419 3. Briston et al. (2011), J Physiol 589(Pt 6):1367-82 4. Caldwell et al. (2014), Circ Res 115(986-996) Right ventricular apical (RVA) pacing can be detrimental to cardiac health. Although most apparent with pre-existing heart failure, chronic pacing can also cause heart failure in patients with previously normal ventricular function. Pacemaker-Induced Cardiomyopathy (PiCM) affects up to 10% of patients with high RV pacing burdens within 1 year of implant1. This causes deterioration of left ventricular (LV) function and may be associated with symptoms of heart failure. These changes are largely reversible by cardiac resynchronisation therapy. Mechanisms for PiCM are only partially understood, but are likely to result from abnormal wall stress within the LV. Pacing from the RV apex alters the LV activation pattern, which can result in stretching and delayed contraction of the LV free wall. This reduces the mechanical efficiency of LV contraction and may identify patients at risk of developing PiCM.  Short-term alterations in ventricular activation result in cellular changes that underlie the phenomenon of cardiac memory, including an increased calcium transient magnitude in late-activated regions2. However, there is no data as to how this may relate to the long-term development of PiCM, in particular as heart failure typically causes dramatic attenuation of the calcium transient3. Furthermore, no studies have investigated the cellular effects of chronic pacing from the RV outflow tract (RVOT). This is generally considered to give a more ‘physiological’ electrical activation pattern, although this does not result in consistent clinical benefits. To address these aspects, we developed a novel sheep model of chronic physiological rate RVA pacing. We studied cellular calcium handling to determine whether changes previously described in tachycardia-induced cardiomyopathy may also underlie PiCM, and whether these could be prevented by pacing from the RVOT.           Chronic RV apical pacing can have adverse effects on LV function and up to 10% of patients develop Pacemaker-induced Cardiomyopathy. The pathophysiology of this is incompletely understood, although previous work has shown that altered ventricular activation patterns can cause abnormal calcium handling and apoptosis. The aim of this work was to determine whether physiological-rate RV apical pacing could cause a cellular heart failure phenotype and if this could be prevented by pacing from the RV outflow tract (RVOT). Adult sheep were paced at physiological heart rates for 3 months from the RV apex or RVOT. Another group underwent rapid ventricular pacing to cause tachycardia-induced heart failure. Cardiomyocytes from the LV free wall were studied using patch clamp techniques and confocal microscopy. RV apical pacing caused a cellular phenotype similar to heart failure, with attenuation of the calcium transient, reduction of ICa-L and disruption of T-tubules. These features did not occur with RVOT pacing. Changes appeared prior to clinical or echocardiographic evidence of heart failure and may therefore represent the initial stages of Pacemaker-induced Cardiomyopathy. 3 months of physiological rate RV apical pacing resulted in a heart failure cellular phenotype, characterized by calcium transient abnormalities and T-tubule disruption. These features were not observed with RVOT pacing. These findings occurred before clinical or echocardiographic features of heart failure and may therefore represent the initial stages of Pacemaker-induced Cardiomyopathy.                                  graeme.kirkwood@manchester.ac.uk Experiments were performed in adult female Welsh Mountain sheep, in accordance with national regulations and local ethical review. Under general anaesthetic and fluoroscopic screening, transvenous pacing leads (Medtronic Novus 4076) were implanted via the right internal jugular vein and attached to a generator positioned in a cervical pocket. After 1 week to recover from surgery, pacing was commenced according to the experimental model. Department of Cardiac Physiology, University of Manchester, UK Supported by research fellowships from the British Heart Foundation Pacemaker-induced cardiomyopathy in the sheep: RVA but not RVOT pacing results in a heart failure cellular phenotype. GJ Kirkwood MBBS PhD, M Lawless PhD, C Pearman MBBS PhD, E Radcliffe, J Caldwell, AW Trafford PhD RV pacing Model Heart Failure Model Leads were positioned in the right atrial appendage and either RV apex or RVOT. These were connected to a Medtronic Sensia dual chamber pacemaker. Pacing was performed in VDD mode. The sensed AV delay was adjusted between 30-50ms to give 100% RV pacing with no fusion beats. Pacing continued for 3 months, during which time animals displayed no clinical symptoms. A single lead was positioned at the RV apex. This was connected to a Medtronic Consulta implantable defibrillator.  A high rate pacing program provided by the company allowed continuous ventricular pacing at a rate of 210 bpm, which is approximately double  the normal resting heart rate in the sheep. This resulted in tachycardia-induced cardiomyopathy developing over 4 – 6 weeks. Animals were sacrificed when they displayed clinical symptoms of end-stage heart failure (pallor, lethargy and pulmonary oedema). Fluoroscopic RAO projections demonstrating RVA (left) and RVOT (right) lead positions. Septal orientation was confirmed using LAO projections.  D: Diaphragm Sp: Spine St: Sternum Animals from both groups underwent weekly ECG and transthoracic echocardiographic examinations. Rapid ventricular pacing resulted in LV dilatation and loss of contractile function with the development of resting tachycardia. These changes did not occur with either RV pacing model. Isolated Cardiomyocyte Studies After death, cells were isolated from the mid layer of the LV free wall using enzymatic digestion and loaded with the ratiometric calcium indicator Fura-2AM. The perforated patch current clamp technique was used to study the steady-state triggered calcium transient. Whole cell voltage clamp studies were performed to measure L-Type calcium current (ICa-L). Studies were performed in Tyrode’s solution with 1.8mM [Ca2+] at 37C. In selected animals, cardiomyocytes were stained with di-4-ANEPPS and studied with confocal microscopy to examine the transverse tubule structure4. Experimental animals were compared with uninstrumented controls, matched approximately for age and weight. ** ** * * * * * Systolic peak [Ca2+] and calcium transient magnitude were reduced in heart failure and after RVA pacing (left). This appeared to result from reduction of ICa-L (right).      *p<0.05, **p<0.005 RVA but not RVOT pacing causes a heart failure cellular phenotype RVA but not RVOT pacing caused disruption of T-tubule structure, similar to that seen in heart failure. Figures are presented as mean +/- SEM where normally distributed, otherwise as median/ IQR. Statistical significance was tested using ANOVA/ ANOVA by ranks.  Group sizes 6-18 subjects, 8-24 cells * * 

Pacemaker-induced cardiomyopathy in the sheep: RVA but not RVOT pacing results in a heart failure cellular phenotype

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Pacemaker-induced cardiomyopathy in the sheep: RVA but not RVOT pacing results in a heart failure cellular phenotype

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