Several studies have disagreed on measurements of cardiac conduction velocity (CV) in mice with a heterozygous knockout of the connexin gene Gja1 – a mutation that reduces the gap junction (GJ) protein, Connexin43 (Cx43) by 50%. We noted that perfusate ionic composition varied between studies and hypothesized that extracellular ionic concentration modulates CV dependence on GJs. CV was measured by optically mapping wild type (WT) and heterozygous null (HZ) hearts serially perfused with solutions previously associated with no change (Solution 1) or CV slowing (Solution 2). In WT hearts, CV was similar for Solutions 1 and 2. However, consistent with the hypothesis, Solution 2 in HZ hearts slowed transverse CV (CVT) relative to Solution 1. Previously, we showed CV slowing in a manner consistent with ephaptic conduction correlated with increased perinexal inter-membrane width (WP) at GJ edges. Thus, WP was measured following perfusion with systematically adjusted [Na+]o and [K+]o in Solutions 1 and 2. A wider WP was associated with reduced CVT in WT and HZ hearts, with the greatest effect in HZ hearts. Increasing [Na+]o increased CVT only in HZ hearts. Increasing [K+]o slowed CVT in both WT and HZ hearts with large WP but only in HZ hearts with narrow WP. Conclusion: When perinexi are wide, decreasing excitability by modulating [Na+]o and [K+]o increases CV sensitivity to reduced Cx43. By contrast, CV is less sensitive to Cx43 and ion composition when perinexi are narrow. These results are consistent with cardiac conduction dependence on both GJ and non-GJ (ephaptic) mechanisms.

Breast cancer has been increasing at an alarming rate and is considered to be of epidemic proportions in the United States, with current estimates indicating that 1 in 8 women will develop breast cancer during their lifetimes, according to Breast Cancer Facts and Figures, 1997, by the American Cancer Society [ACS]. In spite of the advances in technology to improve early diagnosis and an increased emphasis on education to promote awareness of early detection, 46,000 women die annually. A significant number of these losses could be prevented through risk reduction measures, yet many women do not practice breast self-exam (BSE) or receive adequate clinical screening. The purpose of this integrative review is to provide an analysis of the barriers to breast cancer screening with recommendations for future research. The studies will be categorized using the three modalities for breast cancer screening, mammography, clinical breast exam (CBE) and BSE. Demographic variables that impede breast cancer screening will be integrated into each section. The evidence is clear that in spite of breast cancer screening guidelines, increased awareness and access to mammography screening, women in the United States are not being screened adequately. Recommendations for future research will be included.

Background Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction due to reduced sodium current driving force, termed “self-attenuation.” We tested the novel hypothesis that self-attenuation can “mask” the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs). Methods and Results Acute interstitial edema (AIE) was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, AIE exacerbated action potential duration prolongation and produced EADs, in particular at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, while for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs. Conclusions We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.

We previously demonstrated that altering extracellular sodium (Nao) and calcium (Cao) can modulate a form of electrical communication between cardiomyocytes termed “ephaptic coupling” (EpC), especially during loss of gap junction coupling. We hypothesized that altering Nao and Cao modulates conduction velocity (CV) and arrhythmic burden during ischemia. Electrophysiology was quantified by optically mapping Langendorff-perfused guinea pig ventricles with modified Nao (147 or 155 mM) and Cao (1.25 or 2.0 mM) during 30 min of simulated metabolic ischemia (pH 6.5, anoxia, aglycemia). Gap junction-adjacent perinexal width ( WP), a candidate cardiac ephapse, and connexin (Cx)43 protein expression and Cx43 phosphorylation at S368 were quantified by transmission electron microscopy and Western immunoblot analysis, respectively. Metabolic ischemia slowed CV in hearts perfused with 147 mM Nao and 2.0 mM Cao; however, theoretically increasing EpC with 155 mM Nao was arrhythmogenic, and CV could not be measured. Reducing Cao to 1.25 mM expanded WP, as expected during ischemia, consistent with reduced EpC, but attenuated CV slowing while delaying arrhythmia onset. These results were further supported by osmotically reducing WP with albumin, which exacerbated CV slowing and increased early arrhythmias during ischemia, whereas mannitol expanded WP, permitted conduction, and delayed the onset of arrhythmias. Cx43 expression patterns during the various interventions insufficiently correlated with observed CV changes and arrhythmic burden. In conclusion, decreasing perfusate calcium during metabolic ischemia enhances perinexal expansion, attenuates conduction slowing, and delays arrhythmias. Thus, perinexal expansion may be cardioprotective during metabolic ischemia. NEW & NOTEWORTHY This study demonstrates, for the first time, that modulating perfusate ion composition can alter cardiac electrophysiology during simulated metabolic ischemia.