Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond

The sinoatrial (SA) node is the physiological pacemaker of the heart, and resting heart rate in humans is a well-known risk factor for cardiovascular disease and mortality. Consequently, the mechanisms of initiating and regulating the normal spontaneous SA node beating rate are of vital importance. Spontaneous firing of the SA node is generated within sinoatrial nodal cells (SANC), which is regulated by the coupled-clock pacemaker system. Normal spontaneous beating of SANC is driven by a high level of cAMP-mediated PKA-dependent protein phosphorylation, which rely on the balance between high basal cAMP production by adenylyl cyclases and high basal cAMP degradation by cyclic nucleotide phosphodiesterases (PDEs). This diverse class of enzymes includes 11 families and PDE3 and PDE4 families dominate in both the SA node and cardiac myocardium, degrading cAMP and, consequently, regulating basal cardiac pacemaker function and excitation-contraction coupling. In this review, we will demonstrate similarities between expression, distribution, and colocalization of various PDE subtypes in SANC and cardiac myocytes of different species, including humans, focusing on PDE3 and PDE4. Here, we will describe specific targets of the coupled-clock pacemaker system modulated by dual PDE3 + PDE4 activation and provide evidence that concurrent activation of PDE3 + PDE4, operating in a synergistic manner, regulates the basal cardiac pacemaker function and provides control over normal spontaneous beating of SANCs through (PDE3 + PDE4)-dependent modulation of local subsarcolemmal Ca2+ releases (LCRs).

ASYMPTOMATIC TRANSIENT SA-NODE CONDUCTION BLOCK IN A PATIENT WITH ACUTE RISPERIDONE+TRIHEXYPHENYDYL TABLET POISONING

BACKGROUND: a case report of 17year old male with acute risperidone + trihexyphenidyl poisoning with transient sinoatrial block without any CNS or neuromuscular complications. CONCLUSION: Risperidone does possess cardiotoxicity as of cardiac conduction abnormalities mainly affecting SA 1 and AV nodes rather than prolongation of QT interval without causing hypotension or myocardial injury . Such a nonlethal conduction aberrancy was observed at a dose of 75mg risperidone was only transient and reversed physiologically without any additional treatment. Further protection from extrapyramidal symptoms was offered by combined drug trihexyphenidyl at cost of sedation.

Late presentation of iatrogenic dissection of right coronary cusp: A case report

Iatrogenic dissection of coronary arteries while performing catheter engagement, in general is not uncommon. However, we encountered a relatively rare case of iatrogenic right coronary cusp dissection.Here we report an iatrogenic coronary artery dissection after diagnostic angiography in a 54-year-oldwoman presented with exertional dyspnea and chest discomfort. In our case delayed progression of sub-intimal hematoma and subsequent compression of RCA ostium an SA node branch was the cause of SA node dysfunction and subsequent junctional rhythm and atrial fibrillation.To conclude it should be said that in catastrophic cases of iatrogenic coronary ostia dissection and ensuing aortic cusp involvement, stenting of entry point at coronary ostia is a logical decision with good result.

Normal spontaneous firing of cardiac pacemaker cells is regulated by basal pkc delta activation

The spontaneous beating rate of rabbit sinoatrial node cells (SANC) is regulated by local subsarcolemmal calcium releases (LCRs) from sarcoplasmic reticulum (SR). LCRs appear during diastolic depolarization (DD) and activate an inward sodium/calcium exchange current which increases DD rate and thus accelerates spontaneous SANC firing. High basal level of protein kinase A and calcium/calmodulin-dependent protein kinase II phosphorylation are required to sustain basal LCRs and normal spontaneous SANC firing. Recently we discovered that basal PKC activation is also obligatory for cardiac pacemaker function: inhibition of PKC activity by broad spectrum PKC inhibitors Bis I or calphostin C markedly suppressed SR calcium cycling and decreased or abolished spontaneous beating of freshly isolated rabbit SANC. Here we studied which PKC isoforms mediate PKC-dependent effects on cardiac pacemaker cell automaticity. The PKC superfamily consists of 3 major subgroups: conventional, novel and atypical. All PKC isoforms were detected at the RNA level (RT-qPCR) in the rabbit SA node and ventricle, and expression levels were comparable in both tissues. Expression of PKCβ, however, was markedly higher in the rabbit SA node, compared to other PKC isoenzymes in either tissue. We verified expression of conventional PKC (α, β) and novel PKC-delta at the protein level in SANC and ventricular myocytes (VM). Western blot confirmed RNA results, showing a 6-fold higher PKCβ protein abundance in SANC compared to VM. Expression of PKCα protein was similar in both cell types, while PKC-delta protein was more abundant in VM. To study whether PKCβ regulates spontaneous beating of SANC we employed selective inhibitor of conventional (α, β, gamma) PKC isoforms Go6976 (10 μmol/L), which had no effects on either LCR characteristics (confocal microscopy, calcium indicator Fluo-3AM) or spontaneous beating of freshly isolated rabbit SANC (perforated patch-clamp technique). Because selective PKC-delta inhibitors are not available, we explored effects of PKC-delta inhibition comparing effects of Go6976 (the inhibitor of conventional PKCs) and Go6983, which inhibits conventional PKCs and PKC-delta. In contrast to Go6976, Go6983 (5 μmol/L) markedly decreased the LCR size (from 7.1±0.4 to 4.5±0.3 μm) and number per each spontaneous cycle (from 1.3±0.1 to 0.8±0.1). It also markedly increased the LCR period (time from the prior AP-induced calcium transient to the subsequent LCR) which was paralleled by an increase in the spontaneous SANC cycle length. Rottlerin, another PKC-delta inhibitor, produced similar effects on LCR characteristics, and markedly and time-dependently decreased DD rate, leading to an increase in the spontaneous cycle length, and finally abrogated the spontaneous SANC firing. Thus, our data indicate that basal activity of PKC-delta, but not that of PKCβ, is essential for generation of LCRs and normal spontaneous firing of cardiac pacemaker cells. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Intramural Research Program, National Institute on Aging, National Institute of Health, USA

P322Understanding the multiple P-wave morphologies in paroxysmal atrial fibrillation, during sinus rhythm, using computer simulation

Background Atrial Fibrillation (AF) is the most common atrial arrhythmia. The initiation and perpetuation of AF are related to atrial remodeling affecting the electrical and structural atrial characteristics. The beat-to-beat analysis of the P-wave morphology (PWM), during sinus rhythm (SR), revealed the existence of a secondary PWM, while the proportion of the P-waves which follow the secondary morphology is higher in patients with a history of paroxysmal AF (pAF). This observation has led to the hypothesis that the multiple PWM may be the result of a transient shift in the stimulus origin, possibly within the broader anatomical region of the sinoatrial (SA) node, and it is the atrial electrical remodeling that contributes to more frequent P-waves following a secondary morphology in patients with pAF. Purpose To better understand the pathophysiology of AF there is a need to link different levels of analysis, in order to interpret macroscopic observations, through a surface electrocardiogram, with changes occurring at cell and tissue level. Towards this direction, computational modeling can be used as it is a non-invasive and reproducible method of analyzing the electrical activity of the heart. Methods The CRN atrial model was used, and a two-dimensional geometry of the atrial architecture was considered, including the major anatomical structures, like Crista Terminalis, Pectinate Muscles and Pulmonary Veins. Using existing knowledge, the CRN model was adapted to describe the ionic properties of the atrial structures as well as the electrical remodeling occurring under pAF conditions. Several scenarios were considered related to the extent of the electrical remodeled tissue and Heart Rate (HR) values. The stimulation protocol was designed as 5 stimuli originated at a specific point within the SA node area whereas the sixth stimulus originated either at the same location or 1 mm far from the previous one. The temporal variations of the atrial activation as a result of the transient shift of the sixth stimulus origin were computed. Results In electrically remodeled tissue, the displacement of the excitation site within the SA node resulted in a significant increase of the differences in atrial activation compared to healthy tissue, and the greater the spatial extent of the remodeling the greater the differences in the completion of the electrophysiological processes. In addition, increased HR or HR variability led to the increase of the differences especially when electrical remodeling coexists. Conclusions The observed differences in atrial substrate activation can explain the increased number of P-waves that match a secondary PWM in pAF patients during SR, while a future perspective is to use PWM as a marker to estimate the electrical remodeling extent in the atrial tissue. These results underline the need to link the macroscopic findings to the suspected microscopic electrical activity in order to better understand the pathophysiology of AF.

EFEKTIVITAS VAGAL NERVE STIMULATION (VNS) TERHADAP DISRITMIA JANTUNG

Dysrhythmia is a heart rate disorder that includes frequency or rhythm disorders or both. One of the nursing actions to overcome is doing Vagal Nerve Stimulation (VNS), includes emphasis on one side of carotid sinus, emphasis on periorbital sinus, and performing valsalava maneuver by coughing. This is believed to increase release of acetylcholine in heart, where the acetylcholine is captured by SA node in left atrium and serves as an inhibitor of electrical stimulation of heart. The release of acetylcholine production is expected to inhibit cardiac irritability so ventricular contraction can be reduced to a minimum. This will appear clearly in state of dysrhythmias, especially atrial fibrillation. In atrial fibrillation, the impulses produced in atrium will exceed normal state, which results in electrical conductance of heart to SA node, continued to AV node and to purkinje fibers to increase ventricular contractions in projecting blood out of heart. If the impulses produced by atrium are irregular, the same thing happens to ventricles, which is to make irregular heart contractions as well. The result is the heart does not have time to relax to give blood to coronary arteries. If not handled properly, this is very dangerous for heart. VNS action by providing stimulation to vagus nerve will greatly help overcome this problem because the ends of the vagus nerve lead to SA node and AV node. By providing stimulation to vagus nerve, the signal will be sent to efferent to release ACh. It is hoped that this ACh will inhibit impulses from SA node and AV node so the heart can contract according to the body's needs.

Weighing In The Evidence: Lifestyle Modification In The Treatment Of Atrial Fibrillation

Imagine if you suddenly felt your heart “jumping out of your chest” – this is the case for an estimated 1 in 4 Canadians who experience this rapid and chaotic heartbeat characteristic of atrial brillation (AF). The healthy heart works continuously to beat regularly under the control of electrical impulses originating from the sinoatrial (SA) node, the heart’s natural pacemaker. In AF, electrical impulses do not originate in the SA node, but rather, from a different part of the atrium or in nearby pulmonary veins. These abnormal electrical signals become rapid and disorganized, radiating throughout the atrial walls in an uncoordinated manner. This can cause the walls of the atrium to quiver, or brillate, which results in irregular electrical transmission from the atria to the ventricles. A normal heart rate at rest should be between 60-100 beats per minute at rest, but in AF, it can be considerably higher than 140 beats per minute1. Affecting more than 33 million individuals worldwide, AF is the most common sustained irregular heart rhythm encountered in clinical practice2. The progression and maintenance of AF results in adverse events, including an increase in hospitalizations and a ve-fold increase in the risk of stroke3. Given this evidence and anticipated increases in life expectancy within the next several decades, there are clear public health implications for the aging Canadian population.