Ventricular Effective Refractory Period Research Articles

Median nerve stimulation elevates ventricular fibrillation threshold via the cholinergic anti-inflammatory pathway in myocardial infarction canine model.

Median nerve stimulation (MNS) diminishes regional myocardial ischemia and ventricular arrhythmia; however, the underlying mechanism has not been elucidated. In this study, we randomly categorized 22 adult mongrel dogs into a control group, MNS group 1, and MNS group 2. After a 4-week experimental myocardial infarction (MI), ventricular electrophysiology was measured in the MNS group 1 before and after 30 min of MNS. The same measurements were performed in the MNS group 2 dogs via bilateral vagotomy. Venous blood and ventricular tissue were collected to detect molecular indicators related to inflammation and cholinergic pathways by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and Western blot (WB). No significant changes were reported in the ventricular effective refractory period (ERP) in the MNS group 1 and MNS group 2 dogs before and after MNS. The ventricular fibrillation threshold (VFT) in the MNS group 1 was significantly higher than that in the MNS group 2 (20.3 ± 3.7 V vs. 8.7 ± 2.9 V, P < 0.01). The levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear transcription factor-κB (NF-κB) were lower (P < 0.01), whereas the levels of Ach were higher in the peri-infarct zone tissues in the MNS group 1 dogs than those in the MNS group 2 dogs (P < 0.01). This study demonstrated that MNS increases VFT in a canine model with MI. The effects of MNS on VFT are potentially associated with the cholinergic anti-inflammatory pathway.

Evaluation of the direct protective effects of Canagliflozin on the Isoproterenol-induced cell injury in rat cardiomyocytes

Abstract Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors are agents that act by inhibiting glucose and sodium reabsorption in the proximal renal tubule which promotes urinary glucose excretion. More recently, significant benefit data of SGLT2 inhibitors in patients with heart failure, independent of the presence of type 2 diabetes has been reported. We have previously demonstrated that Canagliflozin (Cana), a SGLT2 inhibitor, reduced the ventricular effective refractory period in isoproterenol (ISP)-induced myocardial injury rat model accompanied with the suppression of reactive oxygen species and the elevation of ketone bodies, suggesting the effect of Cana on electrical cardiac remodeling. The direct effect of Cana to the cardiomyocytes and its underlying molecular mechanism was remained to be clarified. We therefore established an ISP-induced neonatal rat ventricular cardiomyocyte (NRVCM) in vitro model, pretreated with Cana and/or ketone bodies. Methods Primary NRVCM were isolated from Wistar rats, were pretreated by Cana with or without βOHB (the most abundant ketone body in circulation), followed by a stimulation of ISP (10μM). Cells without drug or ketone body pretreatment were used as control. We then analyzed its effect on cell viability, apoptosis, and mitochondrial membrane potential using MTT assay, TUNEL assay, and mitochondrial membrane potential assay, respectively. MTT assay was also performed with or without PI3k inhibitor, LY294002. The end-labeling of DNA fragmentation were labelled with FITC, followed by the nuclei counterstain with DAPI and were observed with confocal microscope. The apoptotic index was defined as the percentage of TUNEL positive cells / total nuclei. Results Cana rescued the reduction of NRVCM cell viability induced by ISP stimulation for 24 hours which was inhibited by LY294002 compared to cells without pretreatment. Interestingly, pretreatment of βOHB with or without Cana improved also the NRCVM cell viability whereas there was no significant difference between these two conditions or with cells treated with Cana only, suggesting the direct protective effect of Cana. In 48 hours of ISP stimulation, the apoptotic index intends to decrease in Cana and/or βOHB compared to cells without pretreatment (Figure 1). Although the mitochondrial function was maintained in Cana-pretreated cells compared to cells without pretreatment, there was no significant difference in βOHB-pretreated cells. Conclusions Cana has a direct protective effect on cardiomyocytes cell viability, apoptosis as well as the mitochondrial function impaired by ISP through the cell survival signaling PI3K/Akt pathway. This brings a new insight to the therapeutic target of cardiovascular disease. Funding Acknowledgement Type of funding sources: None.

Bmal1 knockdown in the left stellate ganglion inhibits neural activity and prevents ventricular arrhythmias after myocardial ischemia.

ObjectivesThe neural activity of the left stellate ganglion (LSG) is closely related to the occurrence of ventricular arrhythmias (VAs). Bmal1 modulates genes associated with neural activity in the central nervous system. However, few studies indicated the role of Bmal1 in the LSG and the subsequent effect on the heart. Therefore, we aimed to investigate the influence of Bmal1 knockdown in the LSG on its neural activity and cardiac electrophysiology and to explore the mechanisms.Materials and methodsWe used adeno-associated virus (AAV) to knock down Bmal1 in the LSG. Male beagles were randomized into the Bmal1 knockdown group and the control group. After 4 weeks of injection, the LSG function, neural activity, left ventricular effective refractory period (ERP), and action potential duration (APD) were measured. Electrocardiography for 1 h was recorded for VAs analysis after myocardial ischemia. Nerve growth factor (NGF) and c-fos in the LSG were quantified by immunofluorescence. Transcriptomic analysis was performed to assess the gene expression in the LSG.ResultsBmal1 was sufficiently knocked down by AAV. Compared with the control group, heart rate variability (HRV) in the knockdown group was altered. Bmal1 knockdown inhibited neural activity and function of LSG. It also prolonged ERP as well as APD90. Ischemia-induced VAs were significantly reduced. Nerve growth factor (NGF) and c-fos in the LSG were reduced. Bmal1 knockdown led to the expression changes of genes associated with neural activity in the LSG.ConclusionBmal1 knockdown in the LSG suppresses neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Colchicine prevents ventricular arrhythmias vulnerability in diet-induced obesity rats

AimsThis study aimed to assess the role of colchicine in ventricular arrhythmias (VAs) induced by high fat diet (HFD)-fed rats. Methods and resultsMale rats were divided into four groups: CTL, normal diet plus saline; CTC, normal diet plus colchicine; HFD, HFD plus saline; HFC: HFD plus colchicine. Metabolic parameters, ECG parameters, ventricular electrophysiological parameters, ventricular histology, Western blot and RT-qPCR were measured. Compared with the HFD group, colchicine treatment significantly improved metabolic parameters, reduced ventricular fibrosis, increased the expression of Cav1.2, Kv4.2, Nav1.5, and Cx43, reduced CaMKII, p-CaMKII, p-RyR2 (S2808), and p-RyR2 (S2814) expression in LV. Furthermore, colchicine inhibited the inflammatory responses, prolonged ventricular effective refractory period (ERP), reduced corrected QT interval (QTc) and Tpeak–Tend interval, so as to reduce the susceptibility to VAs in obesity rats. ConclusionsColchicine could mitigate ventricular fibrosis, ventricular electrical remodeling, as well as the expression of ion channels, and inhibit obesity-induced inflammatory responses, which provides a new idea for colchicine to prevent VAs in obese individuals.

Pinocembrin mediates antiarrhythmic effects in rats with isoproterenol-induced cardiac remodeling

BackgroundHigh levels of circulating catecholamines are related to raise risk of cardiac arrhythmias. In addition, our recent studies have suggested that pinocembrin could decrease the susceptibility to arrhythmias in several rat models, including chronic ischemic heart failure, myocardial infarction and depression. In this research, the effects of pinocembrin on ventricular fibrillation (VF) susceptibility were investigated in rats treated with isoproterenol (ISO) and further explored the possible mechanism. MethodsCardiac remodeling was induced by intraperitoneally injection ISO (5 mg/kg) 7 days. Simultaneously, Rats were received pinocembrin (5 mg/kg) or saline by tail vein injection. The effects of pinocembrin were evaluated by electrocardiogram parameters, ventricular electrophysiological parameters, echocardiographic, western blot, ventricular histology, biochemical examinations. In vitro, we cultured H9C2 cardiomyocytes to further define the mechanisms. ResultsCompared with ISO group, pinocembrin remarkably decreased VF inducibility rate, attenuated the shortening of QT and corrected QT (QTc) interval, action potential duration (APD), ventricular effective refractory period (ERP), and increased the protein levels of Kv4.2 and Kv4.3 and Cav1.2 and decreased phosphorylated Ca2+ calmodulin-dependent kinase Ⅱ (p-CaMK Ⅱ). Pinocembrin also alleviated ventricular fibrosis, hypertrophy and increased expression of connexin protein 43 (Cx43). In addition, pinocembrin markedly downregulated levels of malondialdehyde (MDA), hydrogen peroxide (H2O2), oxidized glutathione (GSSG) and increased the activity of superoxide dismutase (SOD) and glutathione (GSH) levels in circulation and cardiac tissue. Pinocembrin reduced the reactive oxygen species (ROS) levels. Furthermore, after treatment of pinocembrin the content of NADPH Oxidase-4 (NOX4) and NADPH Oxidase-2 (NOX2) was significantly lower and the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly higher. In vitro, we found that Nrf2 inhibitor remarkably reduced the antioxidant effects of pinocembrin, which further demonstrated that the effect of pinocembrin was related to activation of Nrf2. ConclusionOur data demonstrate that pinocembrin decreases ventricular electrical remodeling, ion remodeling, ventricular fibrosis, hypertrophy and suppresses isoproterenol-induced oxidative stress. The findings shown that pinocembrin mediates antiarrhythmic effects in rats with isoproterenol-induced cardiac remodeling related to Nrf2/HO-1 pathway.

Abstract 11402: Targeting RyR2 to Suppress Ventricular Arrhythmias and Improve Left Ventricular Function in Chronic Ischemic Heart Disease

Introduction: Sarcoplasmic reticulum Ca +2 leak from RyR2 is a common finding in chronic ischemic heart disease (CIHD) and may be a key driver for ventricular arrhythmias and reduced excitation-contraction coupling in failingm myocytes. Here, we test the hypothesis that targeting Ca +2 leak using the non-selective RyR inhibitor, Dantrolene, suppresses ventricular arrhythmias and improves left ventricular contractile function in CIDH. Methods: CHID was induced in 24 C57BL/6J mice by left coronary artery ligation. Four weeks after myocardial infarction (MI), subcutaneous osmotic pumps were placed to deliver continuous dantrolene (20 mg/kg/day) or vehicle (0.9% Saline). Left ventricular (LV) function was assessed by echocardiogram at 4-, 7- and 10-weeks post-MI. Peripheral muscle strength was assessed by provoked electromyogram at 6 weeks. Inducibility of ventricular tachycardia (VT) was assessed by rapid transesophageal pacing with isoproterenol at 10 weeks. Results: Dantrolene reduced the peripheral muscle strength in mice (0.014±0.001 vs 0.010±0.001 N, P&lt;0.05), but had no adverse effects on weight loss or mortality. Dantrolene increased fractional shortening (18.7±1.3% vs 22.1±1.6%, P&lt;0.001) and mean velocity fiber shortening (mVcfc 1.37±0.09 vs 1.74±0.1 circ/sec, P&lt;0.002) in non-infarcted regions at 10 weeks. This prevented the progression in LV ejection fraction reduction from 4 to 10 weeks (Saline: 35.6±3.4% to 30.6%±3.4%; Dantrolene 34.6±2.4% to 38.1±1.9% vs, P&lt;0.01). Dantrolene reduced VT frequency per animal (0.083±0.04 vs 0.028±0.02 VT/pacing train, P&lt;0.02) and the total duration of inducible VT per animal (59.2±24 secs vs 1.2±0.6 sec, P&lt;0.04). Dantrolene significantly prolonged the ventricular effective refractory period (VERP) (35.1±1.6 msec vs 42.0±0.9 msec, P&lt;0.005). Conclusion: Dantrolene suppression of RyR2 diastolic Ca +2 leak in chronic ischemic heart failure improves the systolic function of surviving myocardium and reduces VT burden by prolonging the VERP, preventing the re-entry circuit for VT in this model. RyR2 inhibition may represent a new therapeutic target for the treatment of CIDH with ventricular arrhythmias.

Simultaneous analyses of hemodynamic and electrophysiological effects of oseltamivir along with its pharmacokinetic profile using the canine paroxysmal atrial fibrillation model

Since information of antiviral drug oseltamivir on the anti-atrial fibrillation (AF) property is still limited, we assessed it using the canine paroxysmal AF model. Oseltamivir in doses of 3 and 30 mg/kg/10 min was intravenously infused to the isoflurane-anesthetized, chronic atrioventricular block dogs (n = 6) with monitoring hemodynamic and electrophysiological variables, in which AF was induced by 10 s of burst pacing on atrial septum. Oseltamivir decreased AF incidence and AF duration, and prolonged AF cycle length in a dose-dependent manner. The low and high doses attained the peak plasma drug concentrations of 9.7 and 96.5 μg/mL, which were approximately 100 and 1000 times greater than those observed in human clinical cases, respectively. The low dose of oseltamivir decreased mean blood pressure without altering sinoatrial or idioventricular rate, whereas its high dose reduced each of them. Oseltamivir delayed inter-atrial conduction in dose- and frequency-dependent manners, whereas it prolonged atrial effective refractory period in dose-dependent but frequency-independent manners. The high dose prolonged ventricular effective refractory period, which was not detected with the low dose. These findings can be used for repurposing oseltamivir as an anti-AF drug candidate.

Anti-arrhythmic and anti-heart failure effects of low-level electrical stimulation on aortic root ventricular ganglionated plexi.

It remains uncertain whether low-level electrical stimulation (LL-ES) of the ventricular ganglionated plexi (GP) improves heart function. This study investigated the anti-arrhythmic and anti-heart failure effects of LL-ES of the aortic root ventricular GP (ARVGP). Thirty dogs were divided randomly into control, drug, and LL-ES groups after performing rapid right ventricular pacing to establish a heart failure (HF) model. The inducing rate of arrhythmia; levels of bioactive factors influencing HF, including angiotensin II type I receptor (AT-1R), transforming growth factor-beta (TGF-β), matrix metalloproteinase (MMP), and phosphorylated extracellular signal-regulated kinase (p-ERK1/2); left ventricular stroke volume (LVSV), and left ventricular ejection fraction (LVEF)were measured after treatment with placebo, drugs, and LL-ES. The inducing rate of atrial arrhythmia decreased from 60% in the control group to 50% in the drug group and 10% in the LL-ES group (p=.033vs. drug group) after 1week of treatment. The ventricular effective refractory period was prolonged from 139 ± 8ms in the drug group to 166 ± 13ms in the LL-ES group (p=.001). Compared to the drug group, the expressions of AT-1R, TGF-β, and MMP proteins were down-regulated in the LL-ES group, whereas that of p-ERK1/2 was significantly increased (all p=.001). Moreover, in the LL-ES group, LVSV increased markedly from 13.16 ± 0.22 to 16.86 ± 0.27mL, relative to that in the drug group (p=.001), and LVEF increased significantly from 38.48% ± 0.53% to 48.94% ± 0.57% during the same time frame (p=.001). Short-term LL-ES of ARVGP had both anti-arrhythmic and anti-inflammatory effects and contributed to the treatment of tachycardia-induced HF and its associated arrhythmia.

Effects of post-treatment electroacupuncture on ventricular monophasic action potential and cardiac function in a rat model of ischemia/reperfusion injury.

To determine the effects of post-treatment electroacupuncture (EA) on the electrophysiological properties of ventricular muscle in rats with ischemia/reperfusion (IR) injury. Male Sprague-Dawley (SD) rats were randomly assigned into sham-operated (SH), IR and IR + EA groups (n = 8 each). The IR model was generated by ligation of the left anterior descending (LAD) coronary artery for 30 min. After establishing the IR model, EA was administered at PC6 for 30 min while opening the coronary artery and allowing reperfusion for 30 min. Heart rate (HR), mean arterial pressure and monophasic action potential (MAP) of cardiac muscle in the outer membrane of the antetheca of the left ventricle before coronary artery ligation (T0), after coronary artery ligation for 30 min (T1) and after reperfusion for 30 min (T2) were recorded. At the same time, ventricular electrophysiological parameters including ventricular effective refractory period (ERP), conduction velocity (CV) and ventricular fibrillation threshold (VFT) were measured. Then, the cardiac function and the levels of creatine kinase-muscle/brain (CK-MB) and cardiac troponin I (cTnI) were monitored. Based on these data, monophasic action potential amplitude (MAPA), the maximum depolarization velocity (Vmax) and the MAP durations at 50% and 90% repolarization (MAPD50 and MAPD90) were calculated to determine the incidence of arrhythmia during reperfusion. Compared with the SH group, the IR group showed an obviously decreased HR as well as reduced mean arterial pressure, Vmax, CV, ERP and MAPA. All indices of cardiac function except left ventricular end-diastolic pressure (LVEDP) decreased (i.e. ventricular systolic pressure (LVSP), left ventricular ejection fraction (LVEF), fractional shortening (FS) and rate of the ventricular pressure rise/drop (±dp/dt)). Furthermore, the MAPD50 and MAPD90 were prolonged, and the levels of CK-MB and cTnI increased (p < 0.05). In comparison to the IR group, HR and the mean arterial pressure were increased. All indices of cardiac function except LVEDP increased (LVSP, LVEF, FS and ±dp/dt). Vmax, CV, ERP and MAPA were also increased in the IR + EA group. However, MAPD50 and MAPD90 were distinctly shortened, and the levels of CK-MB and cTnI decreased (p < 0.05). There were no statistically significant differences in VFT between the three groups (p > 0.05). EA post-treatment can relieve prolongation of repolarization and slowed depolarization of ventricular muscle during IR, thus decreasing the rate of incidence of reperfusion arrhythmia.

Blockade of NaV1.8 Increases the Susceptibility to Ventricular Arrhythmias During Acute Myocardial Infarction.

SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 μmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.

Histone deacetylase 2-dependent ventricular electrical remodeling in a porcine model of early heart failure

AimsHeart failure (HF) is linked to electrical remodeling that promotes ventricular arrhythmias. Underlying molecular signaling is insufficiently understood, in particular concerning patients with early disease stages. Previous observations suggest a key role for epigenetic mechanisms in cardiac remodeling processes. We hypothesized that histone deacetylases (HDACs) 1 and 2 contribute to cellular electrophysiological dysregulation in ventricular cardiomyocytes during HF development. Materials and methodsHDAC and ion channel expression was quantified in a porcine model of early HF induced by short-term atrial tachypacing, resulting in atrial fibrillation with rapid ventricular rate response. Anti-Hdac1 and anti-Hdac2 siRNA treatment was employed in neonatal murine cardiomyocytes (NMCM) to study effects of HDACs on ion channel mRNA expression and action potential duration (APD). Key findingsEarly HF was characterized by mild reduction of left ventricular ejection fraction, prolonged QTc intervals, and increased ventricular effective refractory periods. Delayed repolarization was linked to significant downregulation of HDAC2 in left ventricular (LV) tissue. In addition, there was a tendency towards reduced transcript expression of KCNJ2/Kir2.1 K+ channels. In NMCM, knock-down of Hdac2 recapitulated AP prolongation. Finally, siRNA-mediated suppression of Hdac2 reduced Kcnh2/Kv11.1 K+ channel expression. SignificanceSuppression of HDAC2 is linked to ventricular electrical remodeling of APD and ion channel expression in early stages of heart failure. This previously unrecognized mechanism may serve as basis for future approaches to prevention and treatment of ventricular arrhythmias.

Glucagon-like peptide-1 directly increases heart rate and shortens atrial refractoriness: an in vivo and ex vivo study in pigs

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Synergy program Novo Nordisk Foundation Center for Basic Metabolic Research Background Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes not only reduces hyperglycaemia, but also improves cardiovascular outcomes. However, GLP-1 RA treatment also increases heart rate: an apparent paradox. Purpose Whether the heart rate increase is a direct effect, and whether GLP-1 affects other aspects of cardiac electrophysiology, remain unclear. To answer these questions we investigated the effect of GLP-1 infusion on cardiac electrophysiology in vivo and ex vivo in pigs and pig hearts, respectively, during sinus rhythm and pacing. Methods Anaesthetised pigs (n = 8) received infusions of GLP-1 (10 pmol/kg/min). Electrocardiogram, atrial monophasic action potentials and atrial conduction velocity data were collected and atrial and ventricular effective refractory periods (ERP) were measured. For the ex vivo studies, pig hearts (n = 7) were excised, retrogradely perfused and exposed to consecutive bolus perfusions of 2 and 4 nmol GLP-1, 100 nmol of the GLP-1 receptor antagonist exendin-9-39 and a final 4 nmol bolus of GLP-1. The same electrophysiological parameters were measured. Results In anaesthetised pigs, GLP-1 increased heart rate, cardiac output and diastolic pressure, while systemic vascular resistance was decreased. Infusion of GLP-1 decreased PQ interval in sinus rhythm (P = 0.019, n = 8) and during atrial pacing (P = 0.027, n = 6) with 8 ± 3 % and 12 ± 3 %, respectively. Additionally, GLP-1 decreased atrial ERP at all pacing cycle lengths (P = 0.04, n = 7), while ventricular ERP was unaffected (P = 0.29, n = 7). In the isolated perfused heart, GLP-1 increased heart rate with 13 ± 2 bpm (P = 0.001, n = 7). This increase in heart rate was completely abolished by pre-administration of exendin-9-39. Atrial ERP shortened after GLP-1 perfusion (P = 0.01, n = 7) comparable to the in vivo studies, with an average decrease of 11 ± 2 %. This effect was also abolished by exendin-9-39. Conclusion GLP-1 increases heart rate through activation of the GLP-1 receptor in the isolated perfused heart, suggesting a direct effect of GLP-1 rather than activation through the central nervous system. Additionally, GLP-1 affects atrial electrophysiology, but not ventricular electrophysiology, in vivo and ex vivo independent of the increase in heart rate.

Dynamic spatial dispersion of repolarization is present in regions critical for ischemic ventricular tachycardia ablation.

BackgroundThe presence of dynamic substrate changes may facilitate functional block and reentry in ventricular tachycardia (VT).ObjectiveWe aimed to study dynamic ventricular repolarization changes in critical regions of the VT circuit during sensed single extrastimulus pacing known as the Sense Protocol (SP).MethodsTwenty patients (aged 67 ± 9 years, 17 male) underwent VT ablation. A bipolar voltage map was obtained during sinus rhythm (SR) and right ventricular SP pacing at 20 ms above ventricular effective refractory period. Ventricular repolarization maps were constructed. Ventricular repolarization time (RT) was calculated from unipolar electrogram T waves, using the Wyatt method, as the dV/dtmax of the unipolar T wave. Entrainment or pace mapping confirmed critical sites for ablation.ResultsThe median global repolarization range (max-min RT per patient) was 166 ms (interquartile range [IQR] 143–181 ms) during SR mapping vs 208 ms (IQR 182–234) during SP mapping (P = .0003 vs intrinsic rhythm). Regions of late potentials (LP) had a longer RT during SP mapping compared to regions without LP (mean 394 ± 40 ms vs 342 ± 25 ms, P < .001). In paired regions of normal myocardium there was no significant spatial dispersion of repolarization (SDR)/10 mm2 during SP mapping vs SR mapping (SDR 11 ± 6 ms vs 10 ± 6 ms, P = .54). SDR/10 mm2 was greater in critical areas of the VT circuit during SP mapping 63 ± 29 ms vs SR mapping 16 ± 9 ms (P < .001).ConclusionVentricular repolarization is prolonged in regions of LP and increases dynamically, resulting in dynamic SDR in critical areas of the VT circuit. These dynamic substrate changes may be an important factor that facilitates VT circuits.

Effects of Angiotensin Receptor-Neprilysin Inhibitor in Arrhythmogenicity Following Left Atrial Appendage Closure in an Animal Model.

Left atrial appendage (LAA) closure decreases atrial natriuretic peptide (ANP) levels, which indirectly increases the risk of arrhythmogenicity. We aimed to determine the effect of a combined angiotensin receptor-neprilysin inhibitor (ARNi) on arrhythmogenicity following LAA closure in an animal model. Twenty-four rabbits were randomized into four groups: (1) control, (2) LAA closure (LAAC), (3) heart failure (HF)-LAAC, and (4) HF-LAAC with sacubitril/valsartan (+ARNi). HF models were developed in the HF-LAAC and HF-LAAC+ARNi groups. Epicardial LAA exclusion was performed in the LAAC, HF-LAAC, and HF-LAAC+ARNi groups. ANP levels were measured. An electrophysiological study was performed. The myocardium was harvested for histopathological analysis. The ANP level decreased in the LAAC group (785 ± 103pg/mL, p = 0.03), failed to increase in the HF-LAAC group (917 ± 172pg/mL, p = 0.3), and increased in the HF-LAAC+ARNi group (1524 ± 126pg/mL, p < 0.01) compared to that in the control group (1014 ± 56pg/mL). The atrial effective refractory period (ERP) was prolonged in the HF-LAAC group and restored to baseline in the HF-LAAC+ARNi group. Ventricular ERP was the longest in the HF-LAAC group. The atrial fibrillation window of vulnerability (AF WOV) was elevated in the LAAC, HF-LAAC, and HF-LAAC+ARNi groups, with the latter group having lower AF WOV than the two former groups. Ventricular fibrillation (VF) inducibility was the highest in the HF-LAAC group (51 ± 5%, p < 0.001), followed by the LAAC group (30 ± 4%, p = 0.006) and the HF-LAAC+ARNi group (25 ± 5%, p = 0.11) when compared to the control group (18 ± 4%). Atrial and ventricular fibrosis were noted in all groups except the control group. LAA closure decreased ANP, which in turn increased AF and VF inducibility. Atrial and ventricular arrhythmogenicity was suppressed by ARNi.

The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model.

BackgroundUpregulation of the two-pore-domain potassium channel TASK-1 (hK2P3.1) was recently described in patients suffering from atrial fibrillation (AF) and resulted in shortening of the atrial action potential. In the human heart, TASK-1 channels facilitate repolarization and are specifically expressed in the atria. In the present study, we tested the antiarrhythmic effects of the experimental ion channel inhibitor A293 that is highly affine for TASK-1 in a porcine large animal model of persistent AF.MethodsPersistent AF was induced in German landrace pigs by right atrial burst stimulation via implanted pacemakers using a biofeedback algorithm over 14 days. Electrophysiological and echocardiographic investigations were performed before and after the pharmacological treatment period. A293 was intravenously administered once per day. After a treatment period of 14 days, atrial cardiomyocytes were isolated for patch clamp measurements of currents and atrial action potentials. Hemodynamic consequences of TASK-1 inhibition were measured upon acute A293 treatment.ResultsIn animals with persistent AF, the A293 treatment significantly reduced the AF burden (6.5% vs. 95%; P < 0.001). Intracardiac electrophysiological investigations showed that the atrial effective refractory period was prolonged in A293 treated study animals, whereas, the QRS width, QT interval, and ventricular effective refractory periods remained unchanged. A293 treatment reduced the upregulation of the TASK-1 current as well as the shortening of the action potential duration caused by AF. No central nervous side effects were observed. A mild but significant increase in pulmonary artery pressure was observed upon acute TASK-1 inhibition.ConclusionPharmacological inhibition of atrial TASK-1 currents exerts in vivo antiarrhythmic effects that can be employed for rhythm control in a porcine model of persistent AF. Care has to be taken as TASK-1 inhibition may increase pulmonary artery pressure levels.

Close-coupled pacing to identify the “functional” substrate of ventricular tachycardia: Long-term outcomes of the paced electrogram feature analysis technique

The conduction delay and block that compose the critical isthmus of macroreentrant ventricular tachycardia (VT) is partly "functional" in that they only occur at faster cycle lengths. Close-coupled pacing stresses the myocardium's conduction capacity and may reveal late potentials (LPs) and fractionation. Interest has emerged in targeting this functional substrate. The purpose of this study was to assess the feasibility and efficacy of a functional substrate VT ablation strategy. Patients with scar-related VT undergoing their first ablation were recruited. A closely coupled extrastimulus (ventricular effective refractory period + 30 ms) was delivered at the right ventricular apex while mapping with a high-density catheter. Sites of functional impaired conduction exhibited increased electrogram duration due to LPs/fractionation. The time to last deflection was annotated on an electroanatomic map, readily identifying ablation targets. A total of 40 patients were recruited (34 [85%] ischemic). Median procedure duration was 330 minutes (interquartile range [IQR] 300-369), and ablation time was 49.4 minutes (IQR 33.8-48.3). Median functional substrate area was 41.9 cm2 (IQR 22.1-73.9). It was similarly distributed across bipolar voltage zones. Noninducibility was achieved in 34 of 40 patients (85%). Median follow-up was 711 days (IQR 255.5-972.8), during which 35 of 39 patients (89.7%) did not have VT recurrence, and 3 of 39 (7.5%) died. Antiarrhythmic drugs were continued in 53.8% (21/39). Functional substrate ablation resulted in high rates of noninducibility and freedom from VT. Mapping times were increased considerably. Our findings add to the encouraging trend reported by related techniques. Randomized multicenter trials are warranted to assess this next phase of VT ablation.

Reverse translational analysis of clinically reported, lamotrigine-induced cardiovascular adverse events using the halothane-anesthetized dogs.

Lamotrigine has been used for patients with epilepsy and/or bipolar disorder, overdose of which induced the hypotension, elevation of the atrial pacing threshold, cardiac conduction delay, wide complex tachycardia, cardiac arrest and Brugada-like electrocardiographic pattern. To clarify how lamotrigine induces those cardiovascular adverse events, we simultaneously assessed its cardiohemodynamic and electrophysiological effects using the halothane-anesthetized dogs (n = 4). Lamotrigine was intravenously administered in doses of 0.1, 1 and 10mg/kg/10min under the monitoring of cardiovascular variables, possibly providing subtherapeutic to supratherapeutic plasma concentrations. The low or middle dose of lamotrigine did not alter any of the variables. The high dose significantly delayed the intra-atrial and intra-ventricular conductions in addition to the prolongation of ventricular effective refractory period, whereas no significant change was detected in the other variables. Lamotrigine by itself has relatively wide safety margin for cardiohemodynamics, indicating that clinically reported hypotension may not be induced through its direct action on the resistance arterioles or capacitance venules. The electrophysiological effects suggested that lamotrigine can inhibit Na+ channel in the in situ hearts. This finding may partly explain the onset mechanism of lamotrigine-associated cardiac adverse events in the clinical cases. In addition, elevation of J wave was induced in half of the animals, suggesting that lamotrigine may have some potential to unmask Brugada electrocardiographic genotype in susceptible patients.

Modulating the Infarcted Ventricle’s Refractoriness with an Epicardial Biomaterial

Patients diagnosed with heart failure with reduced ejection fraction (HFrEF) are at increased risk of monomorphic ventricular tachycardia (VT) and ventricular fibrillation. The presence of myocardial fibrosis provides both anatomical...

Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model.

BackgroundCardiac contractility modulation (CCM) is non-excitatory electrical stimulation for improving cardiac function. This study aimed to evaluate the effects of CCM on structural and electrical remodeling in a rabbit model of chronic heart failure (CHF).MethodsThirty rabbits were randomly divided into the sham, CHF, and CCM groups. The CHF model was induced 12 weeks after trans-aortic constriction by pressure unloading and CCM was delivered to the myocardium for 4 weeks. Corrected QT intervals, the ventricular effective refractory period, and inducibility of ventricular tachycardia were measured by an electrophysiological examination. Connective tissue growth factor, galectin-3, Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were measured by western blotting.ResultsThe CHF group had a significantly prolonged corrected QT interval and ventricular effective refractory period, and increased inducibility of ventricular tachycardia. Prominent myocardial fibrosis and increased hydroxyproline content were observed in the CHF group, but these were suppressed in the CCM group. Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were significantly lower in the CHF group, but treatment with CCM partially restored their levels.ConclusionsCCM attenuates myocardial structural and electrical remodeling during CHF. These findings provide evidence for clinical use of CCM in treating CHF.

Preparation of Silver Nanoparticle Composite Material and Its Role in Electrocardiogram Treatment of Acute Myocardial Infarction

The surface resonance scattering of silver nanoparticles, commonly used to enhance the matrix of the Raman, is the most active of all metal nano particles which can greatly improve the sensitivity of the detected molecules. At the same time, the sterilization ability of silver is also highly recommended in the field of biology. In this study, cytosine nucleoside was used as a template to quickly synthesize silver-based composite nanomaterials (Ag–C/Au) with enhanced fluorescence and good water solubility. Then, the fluorescence spectrum, lifetime, the ultraviolet-visible absorption spectrum of the material, and the size and shape of the grain size were studied through characterization. After that, the interaction between the silver-based composite nanomaterial Ag–C/Au and the recombinant protein ephrin-b2 was studied by spectroscopy, and the mixed metalloprotein was used for electrocardiogram treatment of myocardial infarction in SD rats to establish a rat modeling, then the rats were grouped according to the different injections, and the heart rhythm variability (HRV) of different groups of rats with myocardial infarction (MI) was recorded. Finally, the program electrical stimulation (PES) was used to analyze the ventricular effective refractory period (VERP) and ventricular arrhythmia (VAs) in rats. In the experiment, Ag–C/Au nanomaterials produced strong yellow fluorescence under 370 nm ultraviolet excitation, with an approximate particle size of 1.6 nm; through spectral data fitting, it was found that the recombinant protein ephrin-b2 could be adsorbed on the surface of the composite nanomaterials, making the intensity of the characteristic peak decreased; the myocardial indicators of myocardial infarction rats based on ephrin- b2 + Ag–C/Au group were significantly improved, while the grouping of rats using Ag–C/Au alone didn't affect the electrophysiological characteristics after myocardial infarction, that is, ephrin-b2 could improve arrhythmia after myocardial infarction, and the improvement effect would be further strengthened when Ag–C/Au was added.