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Altered Patterns of Gap Junction Distribution in Ischemic Heart Disease an Immunohistochemical Study of Human Myocardium Using Laser Scanning Confocal Microscopy

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Altered Patterns of Gap Junction Distribution in Ischemic Heart Disease an Immunohistochemical Study of Human Myocardium Using Laser Scanning Confocal Microscopy American Journal ofPathology, Vol. 139, No. 4, October 1991 Copright X American Association ofPathologit Altered Patterns of Gap Junction Distribution in Ischemic Heart Disease An Immunohistochemical Study of Human Myocardium Using Laser Scanning Confocal Microscopy Jonathan H. Smith,* Colin R. Green,* ble for reentry arrhythmias has been localized-the Nicholas S. Peters,t Stephen Rothery,t and organization of gap Junctions was markedly disor- Nicholas J. Severst dered; instead ofbeing aggregated into discrete inter- From the Department ofAnatomy and Developmental calated disks, gap-junctional immunostaining was Biology, * University College London, and the Department of spread extensively over myocyte surfaces. Some inf- Cardiac Medicine,t National Heart and Lung Institute, arctzones were bridged by continuous strands ofmy- London, United Kingdom ocytes, coupled to one another by gap junctions, thereby linking healthy myocardium on either side. At their thinnest, these bridges were in some instances no wider than a single attenuated myocyte. The con- Arrhythmias are a common and potentially life- clusions are 1) a widesprea4 generalized derange- threatening complication of myocardial ischemia ment ofgap junction organization does not appear and infarction in humans The structural pathways to underlie functional impairment in the ischemic for the rapid intercellular conduction of the electri- heart, 2) a disorderly arrangement typifies gapjunc- cal impulse that stimulates coordinated contraction tions in myocytes ofthe infarct border zone, and this in the myocardium are formed by the gapjunctions may contribute to alterations in conduction that are situated at intercalated disks. By raising antibodies capable ofprecipitating reentry arrythmias, and 3) to cardiac gap-junctional protein; and using these delicate chains of myocytes traverse some healed in- antibodies in an immunohistochemicalprocedure in farcts, apparently forming electrically coupled combination with the technique of laser scanning bridges across what would otherwise constitute confocal microscopy, we have succeeded in localiz- blocked zones The weakest link in this chain can be ing gapjunctions with a clarity notpreviously pos- a single, degenerating myocyte; avoidance of ar- sible, through thick volumes of human myocardial rhythmia may therefore depend on the continued tissue To explore the structural basis for ischemia survival of this single cell.(Am J Pathol 1991, and infarction-related arrhythmogenesis, antibody 139:801-821) labeling and laser scanning confocal microscopy were applied to study the organization, distribution, and other characteristics ofgap junctions in the ex- Cardiovascular disorders are the leading cause of pre- planted hearts ofpatients undergoing cardiac trans- mature death and disability in most western countries, plantation for advanced ischemic heart disease. In and of this group of diseases, ischemic heart disease is areas ofmyocardiumfreefrom histologically detect- the most prevalent. Abnormalities in the conduction and able structural damage, there was no significant dif- ference in the size ofdistribution oflabeledgapjunc- tions, or in their number per intercalated disk, be- Supported by grants from the Medical Research Council, Brtish Heart tween left ventricular tissue (in which functional Foundation, Wellcome Trust, and Royal Society. Dr. Colin Green is a impairment was severe) and right ventricular tissue Royal Society University Research Fellow. Accepted for publication June 3, 1991. (in which functional impairment was minimal). Address repnnt requests to Dr. Nicholas J. Severs, Departnent of However, in myocytes at the border of healed inf- Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, arcts-zones to which the slow conduction responsi- London SW3 6LY, UK. 801 802 Smith et al AJP October 1991, Vol. 139, No. 4 propagation of the electrical impulse that stimulates car- umes of tissue, than has previously been possible.19 This diac contraction are frequently associated with myocar- has provided new opportunities for investigating the role dial ischemia and infarction, and resulting arrhythmias of gap-junction distribution in relation to myocardial func- are believed to be directly responsible for more than half tion in the normal and diseased heart. the deaths due to this disease.1 Electrophysiologic stud- The precise nature of the structural basis for the ab- ies have shown that a major cause of such arrhythmias normalities in impulse-transmission pathways that lead to involves circulating excitation and re-entry in the vicinity arrhythmogenesis in ischemia and infarction is unclear. of the ischemic or infarcted zone.2'3 The low resistance The present study therefore set out to investigate, with the pathways that allow the electrical impulse to flow rapidly aid of antibody labeling and laser-scanning confocal mi- and repeatedly between cardiac muscle cells, ensuring croscopy, the organization, distribution, and other char- that their mechanical responses are orderly and synchro- acteristics of gap junctions in the hearts of patients who nous in the healthy heart, are formed by gap junctions.' have advanced ischemic heart disease. In "working" myocardium, gap junctions are characteris- tically organized, together with fasciae adherentes and desmosomes, in discrete zones of interaction between Materials and Methods adjacent plasma membranes called intercalated disks.4'6 Gap junctions consist of aggregates of channels that Human Myocardial Tissue span the plasma membranes of neighboring cells, linking their cytoplasmic compartments together. Apart from The principal series of specimens comprised myocardial their role in transmission of the action potential between samples of left and right ventricle free wall (midregion), myocytes, gap junctions between cells in general permit obtained from the explanted hearts of patients who were the direct intercellular exchange of ions and small mole- undergoing heart transplantation because of advanced cules (up to - 1 kDa), including those that regulate dif- ischemic heart disease. Five hearts, from male patients, ferentiation, tissue patterning, and development.7'8 The aged 40-60 years, were studied. In addition, for compar- component channels of gap junctions are formed from ison, samples of one heart from a female transplant pa- pairs of connexons aligned with one another so as to tient (aged 47 years) who had primary pulmonary hyper- bridge the narrow gap between the adjacent mem- tension were obtained for study. Blocks of tissue, approx- branes. Each connexon consists of six subunits, each imately 1 cm3, were excised from the freshly removed subunit being formed from a separate protein mole- hearts of these transplant patients for fixation as de- cule.9'10 The gap-junctional proteins, termed connexins, scribed later. A second series of specimens was ob- are similar though not always identical in different tissues tained after acquiring informed consent from three pa- and species; so far, four distinct members of the "con- tients (males, aged 51, 54, and 60 years, all with three- nexin family" have been identified in mammals, and fur- vessel disease and previous infarction), who were ther members have been reported in nonmammalian undergoing coronary artery bypass grafting for arterio- species. sclerotic coronary artery disease. Using isofluorane an- The principal gap-junctional protein reported in the esthesia and after establishment of right atrial/aortic car- mammalian heart, as identified by molecular techniques, diopulmonary bypass at 310C, the ventricles were de- is a 43kDa species, connexin43.17'18 From the predicted compressed and the heart was stopped using ischemic amino acid sequence of this molecule, we have recently arrest and fibrillation. Within 60 seconds of arrest, trans- raised a set of three polyclonal antibodies to the cardiac mural biopsies were taken using a 14-gauge (1.5 mm gap junction.19-' These antibodies were raised to syn- specimen diameter) biopsy needle from the left ventric- thetic peptides that had been constructed to match dif- ular apex and right ventricular free wall. ferent portions of the connexin43 molecule that were de- All specimens were immediately placed in Zamboni's duced to be situated on the cytoplasmic side of the mem- fixation21 (2% paraformaldehyde, 0.2% picric acid, 0.1 M brane. 17'19 By immunocytochemistry and Western phosphate-buffered saline, pH 7.4) for 2 to 6 hours. For blotting, we have confirmed that these antibodies bind the transplant material, fixation was carried out as soon specifically to cardiac myocyte gap-junctional proteins.20 as possible after removal of the heart. Because this could We have further showed that one of the antibodies in not be done in the operating theater, hearts were pre- particular, when used for immunohistochemistry of fixed served using cold cardioplegia during transport to the tissue in combination with laser scanning confocal mi- laboratory. After fixation, all samples were washed in tap croscopy, enables localization of individual gap junctions water, dehydrated in alcohol, placed in chloroform, and with greatly improved clarity, over more extensive vol- embedded in wax after standard histologic procedures. Gap Junctions in Ischemic Heart Disease 803 AJP October 1991, Vol. 139, No. 4 Sections of all material were routinely examined by light MRC-500. Gain and contrast levels were set according to microscopy after staining with hematoxylin and eosin. procedures standardized
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