Sheep can be used as animal model of regional myocardial remodeling and controllable work
Abstract
Background: Pacing the right heart has been shown to induce reversible conduction delay and subsequent asymmetric remodeling of the left ventricle (LV) in dogs and pigs. Both species have disadvantages in animal experiments. Therefore the aim of this study was to develop a more feasible and easy-to-use animal model in sheep.
Methods: Dual-chamber (DDD) pacemakers with epicardial leads on the right atrium and right ventricular free wall were implanted in 13 sheep. All animals underwent 8 weeks of chronic rapid pacing at 180 bpm. Reported observations were made at 110 bpm.
Results: DDD pacing acutely induced a left bundle branch block (LBBB) — like pattern with almost doubling in QRS width and the appearance of a septal flash, indicating mechanical dyssynchrony. Atrial pacing (AAI) resulted in normal ventricular conduction and function. During 8 weeks of rapid DDD pacing, animals developed LV remodeling (confirmed with histology) with septal wall thinning (–30%, p < 0.05), lateral wall thickening (+22%, p < 0.05), LV volume increase (+32%, p < 0.05), decrease of LV ejection fraction (–31%, p < 0.05), and functional mitral regurgitation. After 8 weeks, segmental pressure-strain-loops, representing regional myocardial work, were recorded. Switching from AAI to DDD pacing decreased immediately work in the septum and increased it in the lateral wall (–69 and +41%, respectively, p < 0.05). Global LV stroke work and dP/dtmax decreased (–27% and -25%, respectively, p < 0.05).
Conclusions: This study presents the development a new sheep model with an asymmetrically remodeled LV. Simple pacemaker programing allows direct modulation of regional myocardial function and work. This animal model provides a new and valuable alternative for canine or porcine models and has the potential to become instrumental for investigating regional function and loading conditions on regional LV remodeling.
Keywords: animal modelregional myocardial workpacingdyssynchronyremodeling
References
- Houser SR, Margulies KB, Murphy AM, et al. American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology. Animal models of heart failure: a scientific statement from the American Heart Association. Circ Res. 2012; 111(1): 131–150.
- Strik M, van Middendorp LB, Vernooy K. Animal models of dyssynchrony. J Cardiovasc Transl Res. 2012; 5(2): 135–145.
- Conn PM. Advantages and Disadvantages of Using Large Animal Models. . Anim. Model. Study Hum. Dis. 2017: 94–95.
- Cost analysis and rate setting manual for animal research facilities. Lab Anim (NY). 2001; 30(1): 15–16.
- Fallavollita JA, Riegel BJ, Suzuki G, et al. Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005; 289(6): H2688–H2696.
- Lionetti V, Guiducci L, Simioniuc A, et al. Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 2007; 293(5): H2747–H2756.
- Soliman OII, Geleijnse ML, Theuns DA, et al. Reverse of left ventricular volumetric and structural remodeling in heart failure patients treated with cardiac resynchronization therapy. Am J Cardiol. 2008; 101(5): 651–657.
- Thambo JB, Bordachar P, Garrigue S, et al. Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation. 2004; 110(25): 3766–3772.
- Vernooy K, Verbeek XA, Peschar M, et al. Left bundle branch block induces ventricular remodelling and functional septal hypoperfusion. Eur Heart J. 2005; 26(1): 91–98.
- Prinzen FW, Cheriex EC, Delhaas T, et al. Asymmetric thickness of the left ventricular wall resulting from asynchronous electric activation: a study in dogs with ventricular pacing and in patients with left bundle branch block. Am Heart J. 1995; 130(5): 1045–1053.
- van Oosterhout MF, Prinzen FW, Arts T, et al. Asynchronous electrical activation induces asymmetrical hypertrophy of the left ventricular wall. Circulation. 1998; 98(6): 588–595.
- Leclercq C. Systolic Improvement and Mechanical Resynchronization Does Not Require Electrical Synchrony in the Dilated Failing Heart With Left Bundle-Branch Block. Circulation. 2002; 106(14): 1760–1763.
- Strik M, van Deursen CJM, van Middendorp LB, et al. Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart. Circ Arrhythm Electrophysiol. 2013; 6(4): 682–689.
- Helm PA, Younes L, Beg MF, et al. Evidence of structural remodeling in the dyssynchronous failing heart. Circ Res. 2006; 98(1): 125–132.
- Byrne MJ, Raman JS, Alferness CA, et al. An ovine model of tachycardia-induced degenerative dilated cardiomyopathy and heart failure with prolonged onset. J Card Fail. 2002; 8(2): 108–115.
- Delhaas T, Arts T, Prinzen FW, et al. Regional fibre stress-fibre strain area as an estimate of regional blood flow and oxygen demand in the canine heart. J Physiol. 1994; 477 ( Pt 3): 481–496.
- Urheim S, Rabben SI, Skulstad H, et al. Regional myocardial work by strain Doppler echocardiography and LV pressure: a new method for quantifying myocardial function. Am J Physiol Heart Circ Physiol. 2005; 288(5): H2375–H2380.
- Forrester JS, Tyberg JV, Wyatt HL, et al. Pressure-length loop: a new method for simultaneous measurement of segmental and total cardiac function. J Appl Physiol. 1974; 37(5): 771–775.
- Ono N, Yamaguchi T, Ishikawa H, et al. Morphological varieties of the Purkinje fiber network in mammalian hearts, as revealed by light and electron microscopy. Arch Histol Cytol. 2009; 72(3): 139–149.
- Rigol M, Solanes N, Fernandez-Armenta J, et al. Development of a swine model of left bundle branch block for experimental studies of cardiac resynchronization therapy. J Cardiovasc Transl Res. 2013; 6(4): 616–622.
- Salameh A, Dhein S, Blanke K, et al. Right or Left Ventricular Pacing in Young Minipigs With Chronic Atrioventricular Block: Long-Term In Vivo Cardiac Performance, Morphology, Electrophysiology, and Cellular Biology. Circulation. 2012; 125(21): 2578–2587.
- Prinzen FW, Augustijn CH, Arts T, et al. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol. 1990; 259(2 Pt 2): H300–H308.
- Gjesdal O, Remme EW, Opdahl A, et al. Mechanisms of abnormal systolic motion of the interventricular septum during left bundle-branch block. Circ Cardiovasc Imaging. 2011; 4(3): 264–273.
- Breithardt OA, Stellbrink C, Herbots L, et al. Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle branch block. J Am Coll Cardiol. 2003; 42(3): 486–494.
- Vernooy K, Cornelussen RNM, Verbeek XA, et al. Cardiac resynchronization therapy cures dyssynchronopathy in canine left bundle-branch block hearts. Eur Heart J. 2007; 28(17): 2148–2155.
- Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation. 1999; 99(23): 2993–3001.
- Prinzen FW, Hunter WC, Wyman BT, et al. Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging. J Am Coll Cardiol. 1999; 33(6): 1735–1742.
- Russell K, Eriksen M, Aaberge L, et al. A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work. Eur Heart J. 2012; 33(6): 724–733.
- Moorjani N, Catarino P, El-Sayed R, et al. A pressure overload model to track the molecular biology of heart failure. Eur J Cardiothorac Surg. 2003; 24(6): 920–925.
- Timek T, Dagum P, Lai D, et al. Pathogenesis of Mitral Regurgitation in Tachycardia-Induced Cardiomyopathy. Circulation. 2001; 104(suppl 1): I-47–I-53.
