Abnormal Automaticity Research Articles

Targeting NLRP3 signaling reduces myocarditis-induced arrhythmogenesis and cardiac remodeling

BackgroundMyocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear.MethodsRats with myosin peptide–induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat’s RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs.ResultsThe LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+–Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups.ConclusionMyocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.

Ivabradine restores tonic cardiovascular autonomic control and reduces tachycardia, hypertension and left ventricular inflammation in post-weaning protein malnourished rats

Malnutrition results in autonomic imbalance and heart hypertrophy. Overexpression of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the left ventricles (LV) is linked to hypertrophied hearts and abnormal myocardium automaticity. Given that ivabradine (IVA) has emerging pleiotropic effects, in addition to the widely known bradycardic response, this study evaluated if IVA treatment could repair the autonomic control and cardiac damages in malnourished rats. Aim: Assess the impact of IVA on tonic cardiovascular autonomic control and its relationship with hemodynamics regulation, LV inflammation, and HCN gene expression in post-weaning protein malnutrition condition. Main methods: After weaning, male rats were divided into control (CG; 22 % protein) and malnourished (MG; 6 % protein) groups. At 35 days, groups were subdivided into CG-PBS, CG-IVA, MG-PBS and MG-IVA (PBS 1 ml/kg or IVA 1 mg/kg) received during 8 days. We performed jugular vein cannulation and electrode implant for drug delivery and ECG registration to assess tonic cardiovascular autonomic control; femoral cannulation for blood pressure (BP) and heart rate (HR) assessment; and LV collection to evaluate ventricular remodeling and HCN gene expression investigation. Key findings: Malnutrition induced BP and HR increases, sympathetic system dominance, and LV remodeling without affecting HCN gene expression. IVA reversed the cardiovascular autonomic imbalance; prevented hypertension and tachycardia; and inhibited the LV inflammatory process and fiber thickening caused by malnutrition. Significance: Our findings suggest that ivabradine protects against malnutrition-mediated cardiovascular damage. Moreover, our results propose these effects were not attributed to HCN expression changes, but rather to IVA pleiotropic effects on autonomic control and inflammation.

Lysosomal Ca2+ flux modulates automaticity in ventricular cardiomyocytes and correlates with arrhythmic risk.

Automaticity involves Ca2+ handling at the cell membrane and sarcoplasmic reticulum (SR). Abnormal or acquired automaticity is thought to initiate ventricular arrhythmias associated with myocardial ischemia. Ca2+ flux from mitochondria can influence automaticity, and lysosomes also release Ca2+. Therefore, we tested whether lysosomal Ca2+ flux could influence automaticity. We studied ventricular human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), hiPSC 3D engineered heart tissues (EHTs), and ventricular cardiomyocytes isolated from infarcted mice. Preventing lysosomal Ca2+ cycling reduced automaticity in hiPSC-CMs. Consistent with a lysosomal role in automaticity, activating the transient receptor potential mucolipin channel (TRPML1) enhanced automaticity, and two channel antagonists reduced spontaneous activity. Activation or inhibition of lysosomal transcription factor EB (TFEB) increased or decreased total lysosomes and automaticity, respectively. In adult ischemic cardiomyocytes and hiPSC 3D EHTs, reducing lysosomal Ca2+ release also inhibited automaticity. Finally, TRPML1 was up-regulated in cardiomyopathic patients with ventricular tachycardia (VT) compared with those without VT. In summary, lysosomal Ca2+ handling modulates abnormal automaticity, and reducing lysosomal Ca2+ release may be a clinical strategy for preventing ventricular arrhythmias.

A rapid wide complex tachycardia

A rapid wide complex tachycardia

Lysosomal Ca2+-flux contributes to abnormal automaticity-related arrhythmia in ventricular cardiomyopathy.

Abnormal automaticity contributes to ventricular arrhythmias during cardiac ischemia. This mechanism involves Ca2+ handling at the membrane and the sarcoplasmic reticulum (SR). We have described a contribution of mitochondrial Ca2+ flux to automaticity. Recent publications showed that lysosomal Ca2+ release influences SR Ca2+ release. Therefore, we determined if lysosomal Ca2+ flux could modify abnormal automaticity in ventricular cardiomyocytes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiomyocytes (CMs) derived from infarcted mice were studied. The spontaneous beating rate of CMs was determined from action potentials or cytoplasmic Ca2+ transients. The hiPSC-CMs transfected with lysosomal transient receptor potential mucolipin Ca2+ release channel (TRPML1) siRNA had significantly reduced automaticity and a significantly increased SR Ca2+ release time constant. Moreover, the TRPML1 specific agonist, ML-SA1, accelerated the spontaneous beating while a TRPML1 specific antagonist, ML-SI1 substantially decreased this frequency. Proteasome inhibition by MG132 activated lysosomal transcription factor EB (TFEB). TFEB activation increased lysosomes and resulted in increased automaticity. Proteasome inhibition had the opposite effect. Blocking the lysosomal two-pore Ca2+ channel (TPC2) or inhibiting the V-type ATPase responsible for lysosomal Ca2+ loading had similar effects on automaticity. Furthermore, inhibition lysosomal Ca2+ release reduced the abnormal automaticity in adult cardiomyocytes isolated after myocardial infarction. As expected based upon hiPSC-CMs and mouse cardiomyocytes data, the protein level of TRPML1 in heart failure (HF) patients with tachycardia (VT) was significantly enhanced when compared with that in HF patients without VT. Lysosomes Ca2+-cycling modulated automaticity in ventricular hiPSC-CMs or cardiomyocytes from infarcted mouse hearts and contributed to HF patient VT events, implying that changes in lysosomal Ca2+ handling may play an important role in abnormal automaticity related arrhythmia.

Atrial tachycardia in a patient with severe pectus excavatum

A 68-year-old woman underwent catheter ablation of drug-refractory atrial tachycardia (AT; cycle length 490 ms). A computed tomography scan of her chest showed severe pectus excavatum (PEX) (Figure 1A ). A voltage map using a multipolar high-density mapping catheter with the EnSite X mapping system (Abbott Technologies, Minneapolis, MN) revealed severe distortion of the right atrium (RA) and an extensive low-voltage area (LVA; <0.5 mV), which occupied 32% of the RA surface (Figure 1B). The AT demonstrated a centrifugal activation pattern arising at the inferior portion of the cavotricuspid isthmus (Online Supplemental Video 1), and the AT was eliminated by ablation at the earliest activation site on the LVA. In PEX, distortion of the right heart cavities can cause traction on the myocardial wall resulting in wall thinning. 1 Oezcan S. Attenhofer Jost C.H. Pfyffer M. et al. Pectus excavatum: echocardiography and cardiac MRI reveal frequent pericardial effusion and right-sided heart anomalies. Eur Heart J Cardiovasc Imaging. 2012; 13: 673-679 Crossref PubMed Scopus (44) Google Scholar In the present case, an extensive LVA was found in the area apart from the RA free wall and thus in the lower part of the RA and in the entire peri-tricuspid annulus, where more tractions can exert than normal and may result in wall thinning (Figure 1B). This makes it likely that the mechanism of the AT was either abnormal automaticity or microreentry caused by damage to the RA by severe PEX. This report adhered to CARE case report guidelines (https://www.care-statement.org/).

Progress of Pathogenesis in Pediatric Multifocal Atrial Tachycardia.

Multifocal atrial tachycardia (MAT) is defined as irregular P-P, R-R, and P-R intervals, isoelectric baseline between P waves, and ventricular rate over 100 beats/min. Although the prognosis of pediatric MAT in most patients is favorable, adverse outcomes of MAT have been reported, such as cardiogenic death (3%), respiratory failure (6%), or persistent arrhythmia (7%), due to delayed diagnosis and poorly controlled MAT. Previous studies demonstrated that pediatric MAT is associated with multiple enhanced automatic lesions located in the atrium or abnormal automaticity of a single lesion located in the pulmonary veins via multiple pathways to trigger electrical activity. Recent studies indicated that pediatric MAT is associated with the formation of a re-entry loop, abnormal automaticity, and triggering activity. The occurrence of pediatric MAT is affected by gestational disease, congenital heart disease, post-cardiac surgery, pulmonary hypertension, and infectious diseases, which promote MAT via inflammation, redistribution of the autonomic nervous system, and abnormal ion channels. However, the pathogenesis of MAT needs to be explored. This review is aimed to summarize and analyze the pathogenesis in pediatric MAT.

Bidirectional Ventricular Tachycardia: Challenges and Solutions.

Bidirectional ventricular tachycardia (BiVT) is a rare form of ventricular tachycardia that manifests on surface electrocardiogram by dual QRS morphologies alternating on a beat-to-beat basis. It was first reported in the 1920s as a complication of digoxin, and since then, it has been reported in other conditions including fulminant myocarditis, sarcoidosis, catecholaminergic polymorphic ventricular tachycardia, and Andersen-Tawil syndrome. The mechanism for BiVT is not as well known as other forms of ventricular tachycardia but appears to include typical mechanisms including triggered activity from afterdepolarizations, abnormal automaticity, or reentry. This review will go beyond the definition, surface electrocardiogram, mechanisms, causes, and treatment of BiVT as per our current understanding.

Interest of ivabradine in pediatric arrhythmia. About a case and review of the literature

By inhibiting the pacemaker current if of the sinoatrial node (SN), ivabradine was first use as an alternative to betablockers in the treatment of heart failure [1] . For a few years, it has been proposed as an adjuvant therapy for postoperative [2] or congenital junctional ectopic tachycardia [3] . But ivabradine can also be effective on atrial and ventricular abnormal automaticity [4] . We report the case of a 9 years old girl who was diagnosed of polymorphic atrial tachycardia at birth. The child was first treated by amiodarone. When amiodarone had to be withdraw because of thyroid dysfunction, multiple antiarrhythmic drugs were tested alone or in association: betablockers, flecainide, digoxine. Despite medication, the child experimented multiple high rate non-sustained tachycardia per day. After an antiarrhythmic washout, ivabradine was started. Fig. 1 is the patient Holter without any treatment showing a very anarchic rhythm, mostly rapid arrhythmia. Fig. 2 is the patient Holter after only 2 takes of ivabradine that shows a marked efficacy of the drug. Ivabradine inhibits selectively the If current that is responsible of the pacemaker activity of the SN and the AV node. If current can also be responsible of abnormal automaticity of the atrial and ventricular myocardium. In such case, ivabradine is highly effective to control the arrhythmia. Still, ivabradine efficacy is difficult to predict, but regarding its overall safety, it can be tested. In a randomized, double-blind trial of pediatric patient with dilated cardiomyopathy, Bonnet et al. did not report more adverse event with ivabradine than with placebo [5] . The outcome of atrial ectopic arrhythmia in the pediatric population is good: 78% will resolve spontaneously when diagnosed under 3 years old [6] . Ivabradine could be an alternative to catheter ablation in the very young or in pediatric patient with multifocal arrhythmia or organized arrhythmia close to the AV conduction system.

Premature ventricular complexes : Systematic review, evaluation and management

Premature ventricular complexes (PVCs) are a common finding in general population and can be even considered physiologic in most cases. Nevertheless, very frequent isolated PVCs may lead to the development of a usually reversible left ventricular dysfunction or be a manifestation of an underlying cardiac condition that could be associated with more severe ventricular arrhythmias, heart failure or cardiac death. Three causative mechanisms of the PVCs have been proposed: abnormal automaticity, triggered activity and reentry supposing different diagnostic and therapeutic implications. Although many patients with PVCs remain completely asymptomatic, others may suffer from a wide range of symptoms like palpitations, fatigue, dyspnoea or dizziness of a variable degree. Proper characterisation of the PVCs, their burden and features, as well as the identification of their sites of origin and mechanisms should be pursued to establish the convenience of a conservative or therapeutic approach. Specific treatment with medical therapy or catheter ablation must be contemplated in symptomatic patients or in those who develop related systolic dysfunction or other kind of complications.

Exercise-Induced Sustained Ventricular Tachycardia without Structural Heart Disease: A Case Report

Patient: Female, 51-year-oldFinal Diagnosis: Ventricular tachycardiaSymptoms: Chest pain • shortness of breathMedication: —Clinical Procedure: Treadmill stress echocardiogramSpecialty: CardiologyObjective:Unusual clinical courseBackground:Exercise-induced ventricular tachycardia (VT) has been widely reported in patients with preexisting structural heart disease or underlying ischemia and is attributed to reentry tachycardia and abnormal automaticity. However, studies regarding exercise-induced VT in individuals without evident structural heart disease are still limited.Case Report:A 51-year-old woman came to our practice for a treadmill stress echocardiogram. The patient experienced only mild chest discomfort and was otherwise asymptomatic. Cardiovascular risk factors were significant only for obesity and positive family history of coronary artery disease in the mother. During the exercise stress test, the patient developed wide complex VT with multiple capture beats accompanied by nausea and dizziness, which lasted approximately 2 minutes before resolving spontaneously. Subsequent evaluation with magnetic resonance imaging, transthoracic echocardiography, and coronary angiography revealed an absence of apparent structural heart disease.Conclusions:Exercise-induced VT in the absence of structural heart disease, although rare, can pose a life-threatening event and requires different considerations for management. The benefits of currently available therapeutic options have yet to be elucidated for this subset of patients. Thus, we assert that there is a need for further investigation on the approach of exercise-induced VT in patients without structural heart disease.

Sodium-Calcium Exchanger (NCX1) is Essential for Atrioventricular Node Automaticity and Conduction, as Revealed through Atrial-Specific Knockout of NCX1

The atrioventricular node (AVN), unlike the sinoatrial node (SAN), can act as an oscillator and conductor of the proximal cardiac conduction system. Using a sarcolipin cre-induced atrial-specific sodium-calcium exchanger 1 (NCX1) KO mouse, we previously demonstrated that NCX1 (and the calcium clock) is an essential component of SAN automaticity (Groenke et al., 2013; Torrente et al., 2015). Here, we used the same mouse to test the hypothesis that NCX1 and the calcium clock are necessary components of AVN automaticity and conduction. qPCR analysis confirmed a 79% reduction of NCX mRNA in AVN tissue, and ECGs demonstrated a slow junctional escape rhythm driving the heart rate. Voltage mapping and confocal imaging of isolated NCX1 KO AVN tissue showed slowed or absent AVN automaticity compared to WT, as action potential and calcium transient rates decreased by 94% (p <0.05) and 78% (p <0.01), respectively. To characterize the conduction properties of the AVN in NCX1 KO mice, we used in vivo catheter pacing of the atrium and simultaneous recording of surface ECG. Resting heart rates in control mice were 542 +/- 16.65 BPM (cycle length of 111 +/- 3.32 ms) and could be paced up to 954 +/- 18.86 BPM (63 +/- 1.23 ms) before developing atrioventricular block (43% increase). In line with their slow junctional rhythm at rest, NCX KO mice had a reduced resting heart rate of 356.8 +/- 12.24 BPM (169 +/- 5.83 ms) and could only tolerate a 17% increase in pacing rate (436 +/-27.48 BPM or 140 +/- 10.44 ms) before exhibiting AV Block. Thus, lack of NCX1 in atrial tissue results in abnormal AVN automaticity and conduction. These data indicate an essential role for NCX1 in AVN function.

Hyperuricemia as a Risk Factor for Atrial Fibrillation Due to Soluble and Crystalized Uric Acid.

Among the several independent risk factors for atrial fibrillation (AF), hyperuricemia has been widely accepted as associated with the incidence of paroxysmal or persistent AF, as well as with the risk of AF in patients undergoing cardiovascular surgery. The electrophysiological mechanism of AF involves electrical remodeling of the arrhythmogenic substrate and abnormal automaticity as trigger. Both electrical and structural remodeling mediated by oxidative stress derived from either xanthine oxidoreductase (XOR), soluble uric acid (UA) or monosodium urate (MSU) crystals might be plausible explanations for the association of AF with hyperuricemia. XOR generates reactive oxygen species (ROS) that lead to atrial structural remodeling via inflammation. Soluble UA accumulates intracellularly through UA transporters (UAT), shortening the atrial action potential via enhanced expression and activity of Kv1.5 channel proteins. Intracellular accumulation of soluble UA generates ROS in atrial myocytes via nicotinamide adenine dinucleotide phosphate oxidase, which phosphorylates ERK/Akt and heat shock factor 1 (HSF1), thereby increasing transcription and translation of Hsp70, which stabilizes Kv1.5. In macrophages, MSU activates the NLRP3 inflammasome and proteolytic processing mediated by caspase-1 with enhanced interleukin (IL)-1β and IL-18 secretion. Use of an XOR inhibitor, antioxidants, a UAT inhibitor such as a uricosuric agent, and an NLRP3 inflammasome inhibitor, might become a potential strategy to reduce the risk of hyperuricemia-induced AF, and control serum UA level.

Hypokalaemia: Clinical Signifi cance and Role in the Mechanisms Underlying Cardiac Arrhythmogenesis

Hypokalaemia is the most common electrolyte abnormality seen in cardiac patients, which represents a side effect of diuretic therapy or results from the overactivation of the renin-angiotensinaldosterone system and the sympathetic nervous system in heart failure. Hypokalaemia is known to contribute to an increased risk of ventricular arrhythmias whose mechanism is based on the dynamic interplay of the provocative trigger and the vulnerable substrate. A premature ectopic impulse acts as a provocative trigger, whereas the vulnerable substrate is created by the structural and functional myocardial changes that favour the impulse circulation within a closed conducting pathway, thus perpetuating the re-entrant activation. The premature ectopic impulse that serves as the initiating event for arrhythmia can be generated due to abnormal automaticity or triggered activity. Hypokalaemia facilitates abnormal automaticity by increasing the rate of spontaneous diastolic depolarisation in Purkinje fi bres, which then start to exhibit pacemaker activity that interferes with the regular activations set by the sinoatrial node. The triggered activity is attributable to the early and delayed afterdepolarisations in cardiac myocytes. The early afterdepolarisations are typically precipitated by an excessive lengthening of the cardiac action potential duration that results from the inhibition of the repolarising K+ currents in the setting of hypokalaemia. The delayed afterdepolarisations are related to calcium overload in cardiac cells, which is provoked by hypokalaemia via inhibition of the Na+-K+ ATPase on myocyte sarcolemma. This translates to the increased intracellular Na+ levels, which in turn activate the reverse mode of the Na+-Ca2+ exchange, leading to increased cytosolic Ca2+ concentration. With regard to creating a vulnerable substrate for re-entry, hypokalaemia is known to induce a non-uniform increase in the action potential duration in different myocardial regions, which amplifi es spatial heterogeneities in the recovery of ventricular excitability during the fi nal repolarisation phase. This sets favourable conditions for a unidirectional conduction block upon premature ectopic activation, which initiates the impulse propagation around a small area of refractory cardiac tissue. In addition, hypokalaemia slows cardiac conduction by inducing hyperpolarisation of the myocyte sarcolemma that results in markedly increased excitation threshold. The induced conduction delay in the re-entrant circuit then allows suffi cient time for recovery from refractoriness in the cardiac cells ahead of the excitation wavefront, which sustains re-entrant activation. The risk of ventricular tachyarrhythmia becomes particularly high when hypokalaemia is combined with the administration of cardiac glycosides or class III antiarrhythmic agents.

Cardiac Electrical Modeling for Closed-Loop Validation of Implantable Devices.

Evaluating and testing cardiac electrical devices in a closed-physiologic-loop can help design safety, but this is rarely practical or comprehensive. Furthermore, in silico closed-loop testing with biophysical computer models cannot meet the requirements of time-critical cardiac device systems, while simplified models meeting time-critical requirements may not have the necessary dynamic features. We propose a new high-level (abstracted) physiologically-based computational heart model that is time-critical and dynamic. The model comprises cardiac regional cellular-electrophysiology types connected by a path model along a conduction network. The regional electrophysiology and paths are modeled with hybrid automata that capture non-linear dynamics, such as action potential and conduction velocity restitution and overdrive suppression. The hierarchy of pacemaker functions is incorporated to generate sinus rhythms, while abnormal automaticity can be introduced to form a variety of arrhythmias such as escape ectopic rhythms. Model parameters are calibrated using experimental data and prior model simulations. Regional electrophysiology and paths in the model match human action potentials, dynamic behavior, and cardiac activation sequences. Connected in closed loop with a pacing device in DDD mode, the model generates complex arrhythmia such as atrioventricular nodal reentry tachycardia. Such device-induced outcomes have been observed clinically and we can establish the key physiological features of the heart model that influence the device operation. These findings demonstrate how an abstract heart model can be used for device validation and to design personalized treatment.

Pinacidil, a KATP channel opener, stimulates cardiac Na+/Ca2+ exchanger function through the NO/cGMP/PKG signaling pathway in guinea pig cardiac ventricular myocytes.

Pinacidil, a nonselective ATP-sensitive K+ (KATP) channel opener, has cardioprotective effects for hypertension, ischemia/reperfusion injury, and arrhythmia. This agent abolishes early afterdepolarizations, delayed afterdepolarizations (DADs), and abnormal automaticity in canine cardiac ventricular myocytes. DADs are well known to be caused by the Na+/Ca2+ exchange current (INCX). In this study, we used the whole-cell patch-clamp technique and Fura-2/AM (Ca2+-indicator) method to investigate the effect of pinacidil on INCX in isolated guinea pig cardiac ventricular myocytes. In the patch-clamp study, pinacidil enhanced INCX in a concentration-dependent manner. The half-maximal effective concentration values were 23.5 and 23.0μM for the Ca2+ entry (outward) and Ca2+ exit (inward) components of INCX, respectively. The pinacidil-induced INCX increase was blocked by L-NAME, a nitric oxide (NO) synthase inhibitor, by ODQ, a soluble guanylate cyclase inhibitor, and by KT5823, a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) inhibitor, but not by N-2-mercaptopropyonyl glycine (MPG), a reactive oxygen species (ROS) scavenger. Glibenclamide, a nonselective KATP channel inhibitor, blocked the pinacidil-induced INCX increase, while 5-HD, a selective mitochondria KATP channel inhibitor, did not. In the Fura-2/AM study pinacidil also enhanced intracellular Ca2+ concentration, which was inhibited by L-NAME, ODQ, KT5823, and glibenclamide, but not by MPG and 5-HD. Sildenafil, a phosphodiesterase 5 inhibitor, increased further the pinacidil-induced INCX increase. Sodium nitroprusside, a NO donor, also increased INCX. In conclusion, pinacidil may stimulate cardiac Na+/Ca2+ exchanger (NCX1) by opening plasma membrane KATP channels and activating the NO/cGMP/PKG signaling pathway.

RECURRENT VT IN CARDIAC SARCOIDOSIS

Cardiac sarcoidosis (CS) is characterized by granulomatous scarring that creates foci of abnormal automaticity and macro reentrant arrhythmias promoting monomorphic VT. 60 year old male with biopsy proven pulmonary sarcoidosis presented with worsening exertional dyspnea. TTE showed a newly reduced

The role of the Purkinje network in premature ventricular complex-triggered ventricular fibrillation.

The Purkinje network (PN) is the distal part of the ventricular conduction system, which has shown to play a central role in the pathophysiology of ventricular fibrillation (VF). Abnormal automaticity and triggered activity are commonly seen in the PN, and the resulting premature ventricular complexes (PVCs) are frequently recognized as triggers of this life-threatening arrhythmia. Catheter ablation targeting PN-related PVCs can be successfully performed in patients with medically refractory VF in a variety of arrhythmic substrates.

Coupling interval variability of premature ventricular contractions in patients with different underlying pathology: an insight into the arrhythmia mechanism

PurposeCoupling interval (CI) variability of premature ventricular contractions (PVCs) is influenced by the underlying arrhythmia mechanism. The aim of this study was to compare CI variability of PVCs in different myocardial disease entities, in order to gain insight into their arrhythmia mechanism.MethodsSixty-four patients with four underlying pathologies were included: idiopathic (n = 16), non-ischemic dilated cardiomyopathy (NIDCM) (n = 16), familial cardiomyopathy (PLN/LMNA) (n = 16), and post-MI (n = 16)-associated PVCs. The post-MI group was included as a reference, on account of its known re-entry mechanism. On Holter registrations, the first 20 CIs of the dominant PVC morphology were measured manually after which median ΔCI and mean SD of CI/√R-R (= CI of PVC corrected for underlying heart rate) were obtained. Two observers independently measured PVC CIs on pre-selected Holter registrations in order to determine inter- and intra-observer reliability.ResultsThe largest ΔCI was seen in the PLN/LMNA group (220 ms (120–295)), the lowest in the idiopathic group (120 ms (100–190)). The ΔCI in the PLN/LMNA group was significantly larger than the post-MI group (220 ms (120–295) vs 130 ms (105–155), p = 0.023). Mean SD of CI/√R-R in the PLN/LMNA group was also significantly higher than in the post-MI group (p = 0.044). Inter- and intra-observer reliability was good (ICC = 0.91 vs 0.86 and 0.96 vs 0.77, respectively).ConclusionsLow ΔCI and SD of CI/√R-R of idiopathic and NIDCM PVCs suggest that the underlying arrhythmia mechanisms might be re-entry or triggered activity. Abnormal automaticity or modulated parasystole are unlikely mechanisms. High CI variability in PLN/LMNA patients suggests that the re-entry and triggered activity are less likely mechanisms in this group.

Contribution of small conductance K+ channels to sinoatrial node pacemaker activity: insights from atrial-specific Na+ /Ca2+ exchange knockout mice.

Repolarizing currents through K+ channels are essential for proper sinoatrial node (SAN) pacemaking, but the influence of intracellular Ca2+ on repolarization in the SAN is uncertain. We identified all three isoforms of Ca2+ -activated small conductance K+ (SK) channels in the murine SAN. SK channel blockade slows repolarization and subsequent depolarization of SAN cells. In the atrial-specific Na+ /Ca2+ exchanger (NCX) knockout mouse, cellular Ca2+ accumulation during spontaneous SAN pacemaker activity produces intermittent hyperactivation of SK channels, leading to arrhythmic pauses alternating with bursts of pacing. These findings suggest that Ca2+ -sensitive SK channels can translate changes in cellular Ca2+ into a repolarizing current capable of modulating pacemaking. SK channels are a potential pharmacological target for modulating SAN rate or treating SAN dysfunction, particularly under conditions characterized by abnormal increases in diastolic Ca2+ . Small conductance K+ (SK) channels have been implicated as modulators of spontaneous depolarization and electrical conduction that may be involved in cardiac arrhythmia. However, neither their presence nor their contribution to sinoatrial node (SAN) pacemaker activity has been investigated. Using quantitative PCR (q-PCR), immunostaining and patch clamp recordings of membrane current and voltage, we identified all three SK isoforms (SK1, SK2 and SK3) in mouse SAN. Inhibition of SK channels with the specific blocker apamin prolonged action potentials (APs) in isolated SAN cells. Apamin also slowed diastolic depolarization and reduced pacemaker rate in isolated SAN cells and intact tissue. We investigated whether the Ca2+ -sensitive nature of SK channels could explain arrhythmic SAN pacemaker activity in the atrial-specific Na+ /Ca2+ exchange (NCX) knockout (KO) mouse, a model of cellular Ca2+ overload. SAN cells isolated from the NCX KO exhibited higher SK current than wildtype (WT) and apamin prolonged their APs. SK blockade partially suppressed the arrhythmic burst pacing pattern of intact NCX KO SAN tissue. We conclude that SK channels have demonstrable effects on SAN pacemaking in the mouse. Their Ca2+ -dependent activation translates changes in cellular Ca2+ into a repolarizing current capable of modulating regular pacemaking. This Ca2+ dependence also promotes abnormal automaticity when these channels are hyperactivated by elevated Ca2+ . We propose SK channels as a potential target for modulating SAN rate, and for treating patients affected by SAN dysfunction, particularly in the setting of Ca2+ overload.