Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs.

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Prolongation of the cardiac QRS complex is linked to increased mortality and may result from drug-induced inhibition of cardiac sodium channels (hNaV 1.5). There has been no systematic evaluation of preclinical and marketed drugs for their additional potential to cause QRS prolongation via gap junction uncoupling.

Related collections

Most cited references 46

Record: found
Abstract: not found
Article: not found

A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays

J-H Zhang (1999)

0 comments Cited 359 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia.

Jeffrey Innis, Catherine E. Keegan, Helen C. Christian … (2003)

Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and signaling molecules. These channels consist of connexin family proteins that allow for diversity of channel composition and conductance properties. The human connexin 43 gene, or GJA1, is located at human chromosome 6q22-q23 within the candidate region for the oculodentodigital dysplasia locus. This autosomal dominant syndrome presents with craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Syndactyly type III and conductive deafness can occur in some cases, and cardiac abnormalities are observed in rare instances. We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. Sixteen different missense mutations and one codon duplication were detected. These mutations may cause misassembly of channels or alter channel conduction properties. Expression patterns and phenotypic features of gja1 animal mutants, reported elsewhere, are compatible with the pleiotropic clinical presentation of oculodentodigital dysplasia.

0 comments Cited 133 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block.

Susan Cheng, R Vasan, Christopher Newton-Cheh … (2009)

Prolongation of the electrocardiographic PR interval, known as first-degree atrioventricular block when the PR interval exceeds 200 milliseconds, is frequently encountered in clinical practice. To determine the clinical significance of PR prolongation in ambulatory individuals. Prospective, community-based cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 54% women) who underwent routine 12-lead electrocardiography. The study cohort underwent prospective follow-up through 2007 from baseline examinations in 1968-1974. Multivariable-adjusted Cox proportional hazards models were used to examine the associations of PR interval with the incidence of arrhythmic events and death. Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. During follow-up, 481 participants developed AF, 124 required pacemaker implantation, and 1739 died. At the baseline examination, 124 individuals had PR intervals longer than 200 milliseconds. For those with PR intervals longer than 200 milliseconds compared with those with PR intervals of 200 milliseconds or shorter, incidence rates per 10 000 person-years were 140 (95% confidence interval [CI], 95-208) vs 36 (95% CI, 32-39) for AF, 59 (95% CI, 40-87) vs 6 (95% CI, 5-7) for pacemaker implantation, and 334 (95% CI, 260-428) vs 129 (95% CI, 123-135) for all-cause mortality. Corresponding absolute risk increases were 1.04% (AF), 0.53% (pacemaker implantation), and 2.05% (all-cause mortality) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazard ratio (HR) of 1.11 (95% CI, 1.02-1.22; P = .02) for AF, 1.22 (95% CI, 1.14-1.30; P < .001) for pacemaker implantation, and 1.08 (95% CI, 1.02-1.13; P = .005) for all-cause mortality. Individuals with first-degree atrioventricular block had a 2-fold adjusted risk of AF (HR, 2.06; 95% CI, 1.36-3.12; P < .001), 3-fold adjusted risk of pacemaker implantation (HR, 2.89; 95% CI, 1.83-4.57; P < .001), and 1.4-fold adjusted risk of all-cause mortality (HR, 1.44, 95% CI, 1.09-1.91; P = .01). Prolongation of the PR interval is associated with increased risks of AF, pacemaker implantation, and all-cause mortality.