Connexin and Infarction Connexin 43 as a Determinant of Myocardial Infarct Size Following Coronary Occlusion in Mice

OBJECTIVES The purpose of this study was to define the role of cell–cell coupling as an independent determinant of infarct size following coronary occlusion. BACKGROUND Electrical uncoupling induced by acute ischemia enhances arrhythmogenesis, but it may also protect the heart by limiting intercellular spread of chemical mediators of injury. METHODS The left anterior descending coronary artery was ligated in wild-type (Cx43 / ) mice and Cx43-deficient (Cx43 / ) mice that are heterozygous for a null allele in the gene encoding the major gap junction channel protein, connexin43 (Cx43). Ventricular remodeling and infarct size were compared in both groups. RESULTS Echocardiography at 1 and 10 weeks after infarction showed that left ventricular end-diastolic volume and mass increased and ejection fraction decreased in proportion to infarct size in both Cx43 / and Cx43 / hearts. However, infarct size measured histologically in healing infarcts (eight days after infarction) was 29% smaller in Cx43 / hearts (17 14% of total left ventricular area, n 30) than in Cx43 / hearts (24 15%, n 23; p 0.037). Fully healed infarcts were smaller than healing infarcts, owing to resorption of necrotic tissue and maturation of scar, but infarct size at 10 weeks after coronary occlusion was still smaller (by 50%) in Cx43 / hearts (6 5%, n 9) compared with Cx43 / hearts (12 7%, n 17; p 0.037). CONCLUSIONS Cx43-deficient mice develop smaller infarcts than wild-type mice following coronary ligation. New therapies designed to decrease the risk of arrhythmias by enhancing intercellular communication could lead to larger infarcts caused by persistent coronary occlusion. (J Am Coll Cardiol 2003;41:681–6) © 2003 by the American College of Cardiology Foundation

[1]  V. Hachinski,et al.  Connexin43 null mutation increases infarct size after stroke , 2001, The Journal of comparative neurology.

[2]  J E Saffitz,et al.  High resolution optical mapping reveals conduction slowing in connexin43 deficient mice. , 2001, Cardiovascular research.

[3]  M. Mirabet,et al.  Persistence of gap junction communication during myocardial ischemia. , 2001, American journal of physiology. Heart and circulatory physiology.

[4]  T. Opthof,et al.  Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes. , 2000, Cardiovascular research.

[5]  R Wilders,et al.  Gap junctions in cardiovascular disease. , 2000, Circulation research.

[6]  K. A. Yamada,et al.  Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. , 2000, Circulation.

[7]  Steven Goldman,et al.  Gap-junction-mediated propagation and amplification of cell injury , 1998, Nature Neuroscience.

[8]  J E Saffitz,et al.  Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction. , 1998, Circulation.

[9]  J. Soler‐Soler,et al.  Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion. , 1997, Circulation.

[10]  J E Saffitz,et al.  Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. , 1997, The Journal of clinical investigation.

[11]  N S Peters,et al.  Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. , 1997, Circulation.

[12]  P. Poole‐Wilson,et al.  Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. , 1993, Circulation.

[13]  J E Saffitz,et al.  Remodeling of ventricular conduction pathways in healed canine infarct border zones. , 1991, The Journal of clinical investigation.