CLINICAL STUDY: CONNEXIN AND INFARCTION
Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice
Shigeto Kanno, MD, PhD*,
Attila Kovacs, MD*,
Kathryn A. Yamada, PhD* and
Jeffrey E. Saffitz, MD, PhD, FACC*,*
* Departments of Surgery, Medicine, and Pathology, and the Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri, USA
Manuscript received July 12, 2002;
revised manuscript received September 30, 2002,
accepted November 19, 2002.
* Reprint requests and correspondence: Dr. Jeffrey E. Saffitz, Washington University, Department of Pathology, Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110USA.
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.
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Abbreviations and Acronyms
| | Cx43 | | connexin43 | | Cx43+/+ | | mice with two wild-type alleles for the Cx43 gene | | Cx43+/– | | mice with one null allele for the Cx43 gene | | LAD | | left anterior descending coronary artery | | LV | | left ventricle or ventricular | | MI | | myocardial infarct or infarction |
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