Oligodendrocytes of adult rodents express three different connexins: connexin29 (Cx29), Cx32, and Cx47. In this study, we show that Cx29 is localized to the inner membrane of small myelin sheaths, whereas Cx32 is localized on the outer membrane of large myelin sheaths; Cx29 does not colocalize with Cx32 in gap junction plaques. All oligodendrocytes appear to express Cx47, which is largely restricted to their perikarya. Cx32 and Cx47 are colocalized in many gap junction plaques on oligodendrocyte somata, particularly in gray matter. Cx45 is detected in the cerebral vasculature, but not in oligodendrocytes or myelin sheaths. This diversity of connexins in oligodendrocytes (in different populations of cells and in different subcellular compartments) likely reflects functional differences between these connexins and perhaps the oligodendrocytes themselves.
Background—
The prognosis for patients experiencing ventricular arrhythmias (VAs) while on continuous flow left ventricular assist device (LVAD) support has not been well elucidated. Accordingly, the role of implantable cardioverter-defibrillators (ICDs) in this patient population remains undefined.
Methods and Results—
Records of 106 consecutive patients undergoing implantation of the HeartMate II LVAD at a single center were reviewed. For patients surviving >30 days postimplant (98 patients), the impact of VAs and ICDs on survival was analyzed. Mean age was 56.6±11.4 years, 82.1% were male, 42.5% had an ischemic cardiomyopathy, 87.7% were bridge to transplantation, and median length of support was 217 days. Twenty-one (19.8%) patients died, 60 (56.6%) survived to transplantation, and 25 patients (23.6%) reached the end of study, had the LVAD explanted, or were lost to follow-up. Post-LVAD VAs occurred in 37 patients (34.9%) but were not associated with increased mortality (hazard ratio, 0.58 [0.18–1.90]). Sixty-two (63.3%) patients had an active ICD, and 36 (36.7%) patients had no ICD or an inactivated ICD post-LVAD. Patients with an ICD were more likely to be INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) level 3 or 4 at the time of implant (54.8% versus 33.3%;
P
=0.04). An appropriate shock was delivered in 27.3% of patients, but the presence of an active ICD was not associated with improved survival (hazard ratio, 1.12 [0.37–3.35]).
Conclusions—
VAs are common in patients with continuous flow LVADs. Although some episodes may be clinically significant, VAs are not associated with a worse prognosis, and concomitant ICDs in these patients may not reduce mortality.
In rodents, oligodendrocytes and myelinating Schwann cells express connexin32 (Cx32) and Cx29, which have different localizations in the two cell types. We show here that, in contrast to Cx32, Cx29 does not form gap junction plaques or functional gap junctions in transfected cells. Furthermore, when expressed together, Cx29 and Cx32 are not colocalized and do not coimmunoprecipitate. To determine the structural basis of their divergent behavior, we generated a series of chimeric Cx32-Cx29 proteins by exchanging their intracellular loops and/or their C-terminal cytoplasmic tails. Although some chimerae reach the cell membrane, others appear to be largely localized intracellularly; none form gap junction plaques or functional gap junctions. Substituting the C-terminus or the intracellular loop and the C-terminus of Cx32 with those of Cx29 does not disrupt their colocalization or coimmunoprecipitation with Cx32. Substituting the C-terminus of Cx29 with that of Cx32 does not disrupt the coimmunoprecipitation or the colocalization with Cx29, whereas substituting both the intracellular loop and the C-terminus of Cx32 with those of Cx29 diminishes the coimmunoprecipitation with Cx29. Conversely, the Cx32 chimera that contains the intracellular loop of Cx29 coimmunoprecipitates with Cx29, indicating that the intracellular loop participates in Cx29-Cx29 interactions. These data indicate that homomeric interactions of Cx29 and especially Cx32 largely require other domains: the N-terminus, transmembrane domains, and extracellular loops. Substituting the intracellular loop and/or tail of Cx32 with those of Cx29 appears to prevent Cx32 from forming functional gap junctions.
Although PAF is not associated with worse outcomes in patients with the HMII LVAD, PeAF may be associated with increased mortality and HF hospitalization. Patients with AF also may have thromboembolic events at higher INR levels.
Murine oligodendrocytes express the gap junction (GJ) proteins connexin32 (Cx32), Cx47, and Cx29. CNS phenotypes in patients with X-linked Charcot-Marie-Tooth disease may be caused by dominant effects of Cx32 mutations on other connexins. Here we examined the expression of Cx31.3 (the human ortholog of murine Cx29) in human brain and its relation to the other oligodendrocyte GJ proteins Cx32 and Cx47. Furthermore, we investigated in vitro whether Cx32 mutants with CNS manifestations affect the expression and function of Cx31.3. Cx31.3 was localized mostly in the gray matter along small myelinated fibers similar to Cx29 in rodent brain and was coexpressed with Cx32 in a subset of human oligodendrocytes. In HeLa cells Cx31.3 was localized at the cell membrane and appeared to form hemichannels but no GJs. Cx32 mutants with CNS manifestations were retained intracellularly, but did not alter the cellular localization or function of co-expressed Cx31.3. Thus, Cx31.3 shares many characteristics with its ortholog Cx29. Cx32 mutants with CNS phenotypes do not affect the trafficking or function of Cx31.3, and may have other toxic effects in oligodendrocytes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.