Complete atrioventricular block under epidural ropivacaine infusion in a patient with first-degree atrioventricular block and myasthenia gravis: a case report.

BACKGROUND: First-degree atrioventricular block (AVB) may lead to complete AVB. Herein, we present a case of a complete AVB under thoracic epidural catheter infusion of ropivacaine with fentanyl in a patient with first-degree AVB and myasthenia gravis. CASE PRESENTATION: A 74-year-old woman with first-degree AVB underwent thymectomy for myasthenia gravis. Continuous thoracic epidural catheter infusion of 0.2% ropivacaine with fentanyl was initiated at 15 min before the end of the surgery. At 9 h postoperatively, the electrocardiogram showed a 10-s-long pause due to complete AVB. Thus, a temporary pacemaker was implanted, and at 19 h postoperatively on postoperative day 1, cardiac pacing was initiated and lasted approximately 30 s. After catheter removal, she had no further episodes of complete AVB. CONCLUSION: First-degree AVB may lead to complete AVB under the influence of thoracic epidural infusion of ropivacaine in patients with myasthenia gravis.

The cardiac pacemaker-specific channel Hcn4 is a direct transcriptional target of MEF2.

AIMS: Hcn4, which encodes the hyperpolarization-activated, cyclic nucleotide-sensitive channel (I(h)), is a well-established marker of the cardiac sino-atrial node. We aimed to identify cis-elements in the genomic locus of the Hcn4 gene that regulate the transcription of Hcn4. METHODS AND RESULTS: We screened evolutionarily conserved non-coding sequences (CNSs) that are often involved in the regulation of gene expression. The VISTA Enhancer Browser identified 16 regions, termed CNS 1-16, within the Hcn4 locus. Using the luciferase reporter assay in primary neonatal rat cardiomyocytes, we found that CNS13 conferred a prominent enhancer activity (more than 30-fold) on the Hcn4 promoter. Subsequent mutation analysis revealed that the Hcn4 enhancer function was dependent on myocyte enhancer factor-2 (MEF2) and activator protein-1 (AP1) binding sequences located in CNS13. Electrophoretic mobility shift assay and chromatin immunoprecipitation confirmed that MEF2 and AP1 proteins bound CNS13. Furthermore, overexpression of a dominant negative MEF2 mutant inhibited the enhancer activity of CNS13, decreased Hcn4 mRNA expression and also decreased the amplitude of I(h) current in myocytes isolated from the inflow tract of embryonic heart. CONCLUSION: These results suggest that the novel enhancer CNS13 and MEF2 may play a critical role in the transcription of Hcn4 in the heart.

NRSF regulates the developmental and hypertrophic changes of HCN4 transcription in rat cardiac myocytes.

The HCN4 channel shows differential expression patterns during the embryonic development and hypertrophy of hearts. Briefly, HCN4 expression is maximally activated in embryonic hearts and quickly diminishes after birth. However, it is reactivated during cardiac hypertrophy. The sequence analysis of HCN4 gene revealed the presence of a conserved NRSE motif, which is known to bind the transcriptional factor neuron-restrictive silencing factor (NRSF). A promoter analysis of HCN4 with rat cardiac myocytes identified the region inducing a basal transcriptional activity. This region drove a high activity in embryonic myocytes, but not in neonatal myocytes treated with hypertrophic agents. After confirming that NRSF protein binds to the NRSE, HCN4 promoter activities modified by NRSE were evaluated. With wild-type NRSE, the promoter activity correlated well with the developmental and hypertrophic changes of HCN4 expression, whereas mutant NRSE constructs failed. We conclude that the NRSE-NRSF system was implicated in HCN4 expression in cardiac myocytes.

Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice.

The matrix metalloproteinase (MMP) family (approximately 25 members in mammals) has been implicated in extracellular matrix remodeling associated with embryonic development, cancer formation and progression, and various other physiological and pathological events. Inactivating mutations in individual matrix metalloproteinase genes in mice described so far, however, are nonlethal at least up to the first few weeks after birth, suggesting functional redundancy among MMP family members. Here, we report that mice lacking two MMPs, MMP-2 (nonmembrane type) and MT1-MMP (membrane type), die immediately after birth with respiratory failure, abnormal blood vessels, and immature muscle fibers reminiscent of central core disease. In the absence of MMP-2 and MT1-MMP, myoblast fusion in vitro is also significantly retarded. These findings suggest functional overlap in mice between the two MMPs with distinct molecular natures.

NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.

Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuron-restrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and alpha-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I(f) and I(Ca,T), which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.

Role of individual ionic current systems in the SA node hypothesized by a model study.

This paper discusses the development of a cardiac sinoatrial (SA) node pacemaker model. The model successfully reconstructs the experimental action potentials at various concentrations of external Ca2+ and K+. Increasing the amplitude of L-type Ca2+ current (I(CaL)) prolongs the duration of the action potential and thereby slightly decreases the spontaneous rate. On the other hand, a negative voltage shift of I(CaL) gating by a few mV markedly increases the spontaneous rate. When the amplitude of sustained inward current (I(st)) is increased, the spontaneous rate is increased irrespective of the I(CaL) amplitude. Increasing [Ca2+](o) shortens the action potential and increases the spontaneous rate. When the spontaneous activity is stopped by decreasing I(CaL) amplitude, the resting potential is nearly constant (-35 mV) over 1-15 mM [K+](o) as observed in the experiment. This is because the conductance of the inward background non-selective cation current balances with the outward [K+](o)-dependent K+ conductance. The unique role of individual voltage- and time-dependent ion channels is clearly demonstrated and distinguished from that of the background current by calculating an instantaneous zero current potential ("lead potential") during the course of the spontaneous activity.

Role of individual ionic current systems in ventricular cells hypothesized by a model study.

Individual ion channels or exchangers are described with a common set of equations for both the sinoatrial node pacemaker and ventricular cells. New experimental data are included, such as the new kinetics of the inward rectifier K+ channel, delayed rectifier K+ channel, and sustained inward current. The gating model of Shirokov et al. (J Gen Physiol 102: 1005-1030, 1993) is used for both the fast Na+ and L-type Ca2+ channels. When combined with a contraction model (Negroni and Lascano: J Mol Cell Cardiol 28: 915-929, 1996), the experimental staircase phenomenon of contraction is reconstructed. The modulation of the action potential by varying the external Ca2+ and K+ concentrations is well simulated. The conductance of I(CaL) dominates membrane conductance during the action potential so that an artificial increase of I(to), I(Kr), I(Ks), or I(KATP) magnifies I(CaL) amplitude. Repolarizing current is provided sequentially by I(Ks), I(Kr), and I(K1). Depression of ATP production results in the shortening of action potential through the activation of I(KATP). The ratio of Ca2+ released from SR over Ca2+ entering via I(CaL) (Ca2+ gain = approximately 15) in excitation-contraction coupling well agrees with the experimental data. The model serves as a predictive tool in generating testable hypotheses.

Regulation of cardiac inwardly rectifying potassium channels by membrane lipid metabolism.

Types and distributions of inwardly rectifying potassium (Kir) channels are one of the major determinants of the electrophysiological properties of cardiac myocytes. Kir2.1 (classical inward rectifier K(+) channel), Kir6.2/SUR2A (ATP-sensitive K(+) channel) and Kir3.1/3.4 (muscarinic K(+) channels) in cardiac myocytes are commonly upregulated by a membrane lipid, phosphatidylinositol 4,5-bisphosphates (PIP(2)). PIP(2) interaction sites appear to be conserved by positively charged amino acid residues and the putative alpha-helix in the C-terminals of Kir channels. PIP(2) level in the plasma membrane is regulated by the agonist stimulation. Kir channels in the cardiac myocytes seem to be actively regulated by means of the change in PIP(2) level rather than by downstream signal transduction pathways.