Allan, LJ

Bennett, Hayley J.

Holt, Cathy

Kitmitto, Ashraf

Kitmitto, S

Malik, Nadim

Pinali, Christian

Walker, Rachel

Background: Myocardial infarction (MI), a consequence of coronary artery occlusion, results in extensive cardiac myocyte (CM) death triggering a healing response or remodeling [1] with replacement myofibroblasts and extracellular matrix/ fibrous tissue deposition within the surviving myocardium. The fibrous tissue extends within the border zone (adjacent to the infarct area) potentially insulating against electrical conduction between CMs and contributing towards the formation of localized re-entry circuits. We used a novel type of electron microscopy (serial block face scanning electron microscopy, SBF-SEM) to investigate nano-scale structural changes to the cells forming the border zone.Methods &amp; Results: A translationally relevant porcine model of MI, presenting mild to moderate left ventricular dysfunction (n = 3/group; control and MI) was employed [2]. We examined tissue from the border and infarct zones using SBF-SEM [3, 4] at 15 nm in the X-Y plane to investigate the t-tubular (t-t) organization of the CMs and relationship between CMs and neighbouring myofibroblasts. Border zone CMs had regions devoid of t-ts with those remaining t-ts swollen and fused to form grossly extended networks. The structural organization between the border zone CMs and myofibroblasts are consistent with (i) gap junction mediated CM-myofibroblast communication (ii) partial cell fusion and (iii) a geometric organization with an inter-cellular separation of 160 ± 38 nm (12 CM-myofibroblasts, n = 3 pigs). Conclusion: Our data showing extensive t-t remodeling provide novel structural insights towards understanding the impaired electrical properties of the CMs. Further, post-MI there are multiple modes of CM myofibroblast at the border zone, offering a potential platform for arrhythmogenic inter-cellular cross-talk. Identification and characterisation of structural remodelling and realignments could offeropportunities for the development of novel anti-arrhythmic strategies.Acknowledgements: This work was funded by the British HeartFoundationReferences:[1] Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000;101:2981-8.[2] Malik N, Farrell KA, Withers SB, Wright EJ, Holt CM. A novel porcine model of early left ventricular dysfunction for translationalresaerch. Research Reports in Clinical Cardiology. 2013;4:1-7.[3] Pinali C, Bennett H, Davenport JB, Trafford AW, Kitmitto A. Threedimensional reconstruction of cardiac sarcoplasmic reticulum reveals acontinuous network linking transverse-tubules: this organization is perturbed in heart failure. Circ Res. 2013;113:1219-30.[4] Pinali C, Kitmitto A. Serial block face scanning electron microscopy for the study of cardiac muscle ultrastructure at nanoscale resolutions. J Mol Cell Cardiol. 2014;76:1-11

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Post-myocardial infarction arrhythmogenesis

Post-myocardial infarction arrhythmogenesis:a structural basis for abnormal myocyte-myofibroblast interaction the border zone: J Mol Cell cardiol

Post-myocardial infarction arrhythmogenesis:a structural basis for abnormal myocyte-myofibroblast interaction the border zone: J Mol Cell cardiol

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