Remodeling of Gap Junctions in Ischemic and Nonischemic Forms of Heart Disease

Saffitz, Jeffrey E.; Hames, Kiyomi Yamada; Kanno, Shigeto

doi:10.1007/s00232-007-9031-2

Cited by 43 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…71 Remodeling of the gap junction in response to an alteration or deficiency in elements of the cardiac desmosome could have a leading role in the genesis of arrhythmias. 72 Studies of the first-described dominant JUP mutation also shed light on possible mechanisms for ARVD/C pathogenesis. 11 This in-frame insertional mutation was shown in a yeast-two-hybrid screen to create a novel interaction between mutant plakoglobin and histidine-rich calcium-binding protein.…”

Section: Theories On Mechanism Of Diseasementioning

confidence: 99%

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

2008

View full text Add to dashboard Cite

SUMMARYArrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy estimated to affect approximately 1 in 5,000 individuals. Cardinal manifestations include right ventricular enlargement and dysfunction, fibrofatty replacement of myocytes in the right ventricle, characteristic electrocardiographic abnormalities, and ventricular arrhythmia most commonly arising from the right ventricle. The disease is frequently familial and typically involves autosomal dominant transmission with low penetrance and variable expressivity. Approximately 50% of symptomatic individuals harbor a mutation in one of the five major components of the cardiac desmosome. Nevertheless, other genetic modifiers and environmental factors complicate the clinical management of mutation carriers as well as counseling of their relatives. This Review summarizes the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, describes possible origins of recurrent mutations, presents theories on the pathogenesis of disease following a mutation, and discusses the current issues surrounding clinical use of genetic analysis in the assessment of individuals with this condition.

show abstract

Section: Theories On Mechanism Of Diseasementioning

confidence: 99%

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

2008

View full text Add to dashboard Cite

show abstract

“…Reduction and redistribution of Cx43 outside the intercalated disks in the diseased myocardium have been associated with increased incidence of ventricular tachyarrhythmias (33,34). Different transgenic mice models of Cx43 deficiency have shown an increased incidence of premature ventricular beats (PVBs) and spontaneous and inducible ventricular tachyarrhythmias under baseline conditions (8,9,14,15,23,37,38).…”

mentioning

confidence: 99%

Effects of a reduction in the number of gap junction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mouse hearts

Sánchez

Rodríguez‐Sinovas

Fernández-Sanz

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

A transient reduction of cell coupling during reperfusion limits myocardial necrosis, but little is known about its arrhythmogenic effects during ischemia-reperfusion. Thus, we analyzed the effect of an extreme reduction in the number of gap junction channels or in their unitary conductance on ventricular arrhythmias during myocardial ischemia-reperfusion. Available gap junction uncouplers have electrophysiological effects independent from their uncoupling actions. Thus, isolated hearts from Cx43(Cre-ER(T)/fl) mice treated with 4-hydroxytamoxifen (4-OHT), from Cx43KI32 mice [in which connexin (Cx)43 was replaced with Cx32], and from control animals were submitted to regional ischemia and reperfusion, and spontaneous and induced ventricular arrhythmias were monitored. In additional hearts, changes in activation time and electrical impedance during global ischemia-reperfusion were assessed. In contrast to treatment with 4-OHT, replacement of Cx43 with Cx32 did not modify baseline activation time or electrical impedance. However, the number of extrasistole and ventricular tachyarrhythmias was higher in isolated hearts from Cx43KI32 and 4-OHT-treated Cx43(Cre-ER(T)/fl) animals versus wild-type animals during normoxia, ischemia (12.29 ± 3.26 and 52.17 ± 22.51 vs. 3.00 ± 1.46 spontaneous tachyarrhythmias, P < 0.05), and reperfusion. The impairment in conduction during ischemia was steeper in isolated hearts from Cx43KI32 animals, whereas changes in myocardial impedance were attenuated during ischemia in both transgenic models, suggesting altered cell-to-cell coupling at baseline. In conclusion, both reduction of Cx43 with 4-OHT and replacement of Cx43 by less-conductive Cx32 were arrhythmogenic under normoxia and ischemia-reperfusion, despite no major effects on baseline electrical properties. These results suggest that modifications in gap junction communication silent under normal conditions may be arrhythmogenic during ischemia-reperfusion.

show abstract

“…During electrical stimulation, gap junction coupling is a critical determinant of conduction velocity. In cardiac diseases, such as heart failure and ischemic heart disease, gap junctional uncoupling, because of changes in Cx expression and/or phosphorylation, is well documented (Peters et al, 1993;Matsushita et al, 1999;Dupont et al, 2001b;Akar et al, 2004;Severs et al, 2004;Ai and Pogwizd, 2005;Saffitz et al, 2007). Current theories suggest that these alterations in cell-to-cell coupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL) (van der Velden and Jongsma, 2002;Ehrlich et al, 2007;Nattel et al, 2007).…”

mentioning

confidence: 99%

The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model

Rossman¹,

Liu²,

Morgan³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p Ͻ 0.01). In the canine sterile pericarditis model, conduction time (CT; n ϭ 5), atrial effective refractory period (AERP; n ϭ 3), and AF/AFL duration/inducibility (n ϭ 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 Ϯ 1.0 versus 62.0 Ϯ 1.0 ms; p Ͻ 0.001) and 200 ms (64.4 Ϯ 0.9 versus 61.0 Ϯ 1.3 ms; p Ͻ 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 Ϯ 0.6 versus 1.6 Ϯ 0.8; p Ͻ 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.

show abstract

Remodeling of Gap Junctions in Ischemic and Nonischemic Forms of Heart Disease

Cited by 43 publications

References 21 publications

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Effects of a reduction in the number of gap junction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mouse hearts

The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model

Contact Info

Product

Resources

About