Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.

Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart.

Voltage-Induced Ca²⁺ Release in Postganglionic Sympathetic Neurons in Adult Mice.

Recent studies have provided evidence that depolarization in the absence of extracellular Ca2+ can trigger Ca2+ release from internal stores in a variety of neuron subtypes. Here we examine whether postganglionic sympathetic neurons are able to mobilize Ca2+ from intracellular stores in response to depolarization, independent of Ca2+ influx. We measured changes in cytosolic ΔF/F0 in individual fluo-4 -loaded sympathetic ganglion neurons in response to maintained K+ depolarization in the presence (2 mM) and absence of extracellular Ca2+ ([Ca2+]e).

Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs.

Background: The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear.

Objective: The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF.

Methods: We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity.

Age-dependent alterations of voltage-gated Na(+) channel isoforms in rat sinoatrial node.

Multiple isoforms of voltage-gated Na(+) channels (NaChs) have been identified in sinoatrial node (SAN) and contribute to a rapid intrinsic heart rate. However, their roles in aging remain unclear. Here, we sought to clarify whether the age-related expression of NaChs contributes to the impaired SAN function during aging.

Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing.

Background: Hypokalemia increases the vulnerability to ventricular fibrillation. We hypothesize that the apamin-sensitive small-conductance calcium-activated potassium current (IKAS) is activated during hypokalemia and that IKAS blockade is proarrhythmic.

Methods And Results: Optical mapping was performed in 23 Langendorff-perfused rabbit ventricles with atrioventricular block and either right or left ventricular pacing during normokalemia or hypokalemia.

Long non-coding RNA and chromatin remodeling.

Long noncoding RNAs (lncRNAs) are pivotal regulators of genome structure and gene expression. LncRNAs can directly interact with chromatin-modifying enzymes and nucleosome-remodeling factors to control chromatin structure and accessibility of genetic information. Moreover, lncRNA expression can be controlled by chromatin-remodeling factors, suggesting a feedback circuit of regulation.

Cervical vagal nerve stimulation activates the stellate ganglion in ambulatory dogs.

Background And Objectives: Recent studies showed that, in addition to parasympathetic nerves, cervical vagal nerves contained significant sympathetic nerves. We hypothesized that cervical vagal nerve stimulation (VNS) may capture the sympathetic nerves within the vagal nerve and activate the stellate ganglion.

Materials And Methods: We recorded left stellate ganglion nerve activity (SGNA), left thoracic vagal nerve activity (VNA), and subcutaneous electrocardiogram in seven dogs during left cervical VNS with 30 seconds on-time and 30 seconds off time.

Subcutaneous nerve activity is more accurate than heart rate variability in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction.

Background: We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone.

Objective: The purpose of this study was to test the hypothesis that left thoracic SCNA is more accurate than heart rate variability (HRV) in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction (MI).

Methods: We used an implanted radiotransmitter to study left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and thoracic SCNA in 9 dogs at baseline and up to 8 weeks after MI.

SK channels and ventricular arrhythmias in heart failure.

Small-conductance Ca(2+)-activated K(+) (SK) currents are important in the repolarization of normal atrial (but not ventricular) cardiomyocytes. However, recent studies showed that the SK currents are upregulated in failing ventricular cardiomyocytes, along with increased SK channel protein expression and enhanced sensitivity to intracellular Ca(2+). The SK channel activation may be either anti-arrhythmic or pro-arrhythmic, depending on the underlying clinical situations.

Using skin sympathetic nerve activity to estimate stellate ganglion nerve activity in dogs.

Background: Stellate ganglion nerve activity (SGNA) is important in cardiac arrhythmogenesis. However, direct recording of SGNA requires access to the thoracic cavity. Skin of upper thorax is innervated by sympathetic nerve fibers originating from the stellate ganglia and is easily accessible.

Acute reversal of phospholamban inhibition facilitates the rhythmic whole-cell propagating calcium waves in isolated ventricular myocytes.

Phospholamban (PLB) inhibits the activity of cardiac sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a). Phosphorylation of PLB during sympathetic activation reverses SERCA2a inhibition, increasing SR Ca(2+) uptake. However, sympathetic activation also modulates multiple other intracellular targets in ventricular myocytes (VMs), making it impossible to determine the specific effects of the reversal of PLB inhibition on the spontaneous SR Ca(2+) release.

Subcutaneous nerve activity and spontaneous ventricular arrhythmias in ambulatory dogs.

Background: Stellate ganglion nerve activity (SGNA) is important in ventricular arrhythmogenesis. However, because thoracotomy is needed to access the stellate ganglion, it is difficult to use SGNA for risk stratification.

Objective: The purpose of this study was to test the hypothesis that subcutaneous nerve activity (SCNA) in canines can be used to estimate SGNA and predict ventricular arrhythmia.

Intracellular Na+ overload causes oxidation of CaMKII and leads to Ca2+ mishandling in isolated ventricular myocytes.

An increase of late Na(+) current (INaL) in cardiac myocytes can raise the cytosolic Na(+) concentration and is associated with activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and alterations of mitochondrial metabolism and Ca(2+) handling by sarcoplasmic reticulum (SR). We tested the hypothesis that augmentation of INaL can increase mitochondrial reactive oxygen species (ROS) production and oxidation of CaMKII, resulting in spontaneous SR Ca(2+) release and increased diastolic Ca(2+) in myocytes. Increases of INaL and/or of the cytosolic Na(+) concentration led to mitochondrial ROS production and oxidation of CaMKII to cause dysregulation of Ca(2+) handling in rabbit cardiac myocytes.

A long noncoding RNA protects the heart from pathological hypertrophy.

The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure.

Pathogenesis of arrhythmias in a model of CKD.

Patients with CKD have an increased risk of cardiovascular mortality from arrhythmias and sudden cardiac death. We used a rat model of CKD (Cy/+) to study potential mechanisms of increased ventricular arrhythmias. Rats with CKD showed normal ejection fraction but hypertrophic myocardium.

Apamin does not inhibit human cardiac Na+ current, L-type Ca2+ current or other major K+ currents.

Background: Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear.

Objective: To test the hypothesis that apamin does not inhibit any major cardiac ion currents.

Utilization rates of implantable cardioverter-defibrillators for primary prevention of sudden cardiac death: a 2012 calculation for a midwestern health referral region.

Background: Utilization rates (URs) for implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (PPSCD) are lacking in the community.

Objective: The purpose of this study was to establish the ICD UR in central Indiana.

Methods: A query run on 2 hospitals in a health information exchange database in Indianapolis identified patients between 2011 and 2012 with left ventricular ejection fraction (EF) ≤0.

Utilizing multiple in silico analyses to identify putative causal SCN5A variants in Brugada syndrome.

Brugada syndrome (BrS) is an inheritable sudden cardiac death disease mainly caused by SCN5A mutations. Traditional approaches can be costly and time-consuming if all candidate variants need to be validated through in vitro studies. Therefore, we developed a new approach by combining multiple in silico analyses to predict functional and structural changes of candidate SCN5A variants in BrS before conducting in vitro studies.

Amiodarone inhibits apamin-sensitive potassium currents.

Background: Apamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles.

Objective: To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells.

Methods: We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration.

Curve-Fitting the Intracellular Calcium Dynamics.

"No one believes modeling results except the one who performed the calculation; ...

Apamin-sensitive calcium-activated potassium currents in rabbit ventricles with chronic myocardial infarction.

Introduction: The apamin-sensitive small-conductance calcium-activated potassium current (IKAS ) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS .

Methods And Results: We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI.

Proarrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium.

Background: Small conductance calcium activated potassium (SKCa) channels are voltage insensitive and are activated by intracellular calcium. Genome-wide association studies revealed that a variant of SKCa is associated with lone atrial fibrillation in humans. Roles of SKCa in atrial arrhythmias remain unclear.

Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion.

Background: Small conductance calcium-activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges.

Objectives: To test the hypothesis that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the left stellate ganglion.

Methods: Six dogs (group 1) underwent 1-week LL-VNS of the left cervical vagus nerve.