Monophasic Action Potential Duration Research Articles

Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury

The search for new approaches to treatment and prevention of heart failure is a major challenge in medicine. The adenosine triphosphate-sensitive potassium (KATP) channel has been long associated with the ability to preserve myocardial function and viability under stress. High surface expression of membrane KATP channels ensures a rapid energy-sparing reduction in action potential duration (APD) in response to metabolic challenges, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, thus sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force. In healthy hearts, calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates the Kir6.2 KATP channel subunit initiating a cascade responsible for KATP channel endocytosis. Here, activation of CaMKII in a transaortic banding (TAB) model of heart failure is coupled with a 35–40% reduction in surface expression of KATP channels compared to hearts from sham-operated mice. Linkage between KATP channel expression and CaMKII is verified in isolated cardiomyocytes in which activation of CaMKII results in downregulation of KATP channel current. Accordingly, shortening of monophasic APD is slowed in response to hypoxia or heart rate acceleration in failing compared to non-failing hearts, a phenomenon previously shown to result in significant increases in oxygen consumption. Even in the absence of coronary artery disease, failing myocardium can be further injured by ischemia due to a mismatch between metabolic supply and demand. Ischemia-reperfusion injury, following ischemic preconditioning, is diminished in hearts with CaMKII inhibition compared to wild-type hearts and this advantage is largely eliminated when myocardial KATP channel expression is absent, supporting that the myocardial protective benefit of CaMKII inhibition in heart failure may be substantially mediated by KATP channels. Recognition of CaMKII-dependent downregulation of KATP channel expression as a mechanism for vulnerability to injury in failing hearts points to strategies targeting this interaction for potential preventives or treatments.

Role of potassium channel in remifentanil-induced prolongation of monophasic action potential duration in myocardium of rabbits

Objective To investigate the role of potassium channel in remifentanil-induced prolongation of monophasic action potential duration (MAPD) in the myocardium of rabbits. Methods Eighteen adult rabbit hearts successfully perfused in a Langendorff apparatus were randomly divided into 3 groups (n=6 each) using a random number table: control group (group C), remifentanil group (group R), and K+ channel blocker tetraethylammonium group (group T). After 15 min stabilization with K-H solution, group C was continuously perfused with K-H solution for 60 min, and R and T groups were perfused with K-H solution containing 12 ng/ml remifentanil and 10 ng/ml tetraethylammonium, respectively, for 60 min.At 15 min of stabilization, and 15, 30 and 60 min of perfusion, heart rate, MAPD of all the three layers of the myocardium in the anterior wall of the left ventricular was recorded.MAPD at 50% and 90% repolarization (MAPD50, MAPD90) were calculated. Results Compared with group C, heart rate was significantly decreased, MAPD50 and MAPD90 were prolonged in R and T groups (P <0.05). Conclusion The mechanism by which remifentanil prolongs MAPD in the myocardium of rabbits is associated with blockade of the potassium channels. Key words: Piperidines; Potassium channels; Action potentials; Bradycardia

Beat-to-Beat Variability in Preload Unmasks Latent Risk of Torsade de Pointes in Anesthetized Chronic Atrioventricular Block Dogs.

Beat-to-beat variability in ventricular repolarization (BVR) associates with increased arrhythmic risk. Proarrhythmic remodeling in the dog with chronic AV-block (CAVB) compromises repolarization reserve and associates with increased BVR, which further increases upon dofetilide infusion and correlates with Torsade de Pointes (TdP) arrhythmias. It was hypothesized that these pro-arrhythmia-associated increases in BVR are induced by beat-to-beat variability in preload. Left ventricular monophasic action potential duration (LVMAPD) was recorded in acute (AAVB) and CAVB dogs, before and after dofetilide infusion. BVR was quantified as short-term variability of LVMAPD. The PQ-interval was controlled by pacing: either a constant or an alternating preload pattern was established, verified by PV-loop. The effect of the stretch-activated channel blocker, streptomycin, on BVR was evaluated in a second CAVB group. At alternating preload only, BVR was increased after proarrhythmic remodeling (0.45±0.14 ms AAVB vs. 2.2±1.1 ms CAVB, P<0.01). At CAVB, but not at AAVB, dofetilide induced significant proarrhythmia. Preload variability augmented the dofetilide-induced BVR increase at CAVB (+1.5±0.8 ms vs. +0.9±0.9 ms, P=0.058). In the second group, the increase in baseline BVR by alternating preload (0.3±0.03 ms to 1.0±0.8 ms, P<0.01) was abolished by streptomycin (0.5±0.2 ms, P<0.05). In CAVB dogs, the inverse relation between BVR and repolarization reserve originates from an augmented sensitivity of ventricular repolarization to beat-to-beat preload changes. Stretch-activated channels appear to be involved in the mechanism of BVR. (Circ J 2016; 80: 1336-1345).

Effects of Ang Ⅱ perfusion on transmural heterogeneous of Cx43 in acute myocardial ischemia reperfusion.

To observe the effects of angiotensin Ⅱ(Ang Ⅱ) perfusion on transmural heterogeneity of Cx43 expression in the rabbit model with acute myocardial ischemia reperfusion (MIR), and investigate the role of rennin-angiotensin system in malignant ventricular arrhythmia induced by MIR. Twenty rabbits were randomly divided into MIR group (n=10) and Ang Ⅱ group (n=10). MIR model was produced with traditional ligation and opening of the anterior descending coronary artery in all animal. The hearts invitro in the MIR group and the Ang Ⅱ group were perfused with simply improved Tyrode's solution and containing Ang Ⅱ Tyrode's solution respectively. 90% monophasic action potential repolarization duration, transmural dispersion of repolarization, Cx43 protein (Cx43-pro) and mRNA (Cx43-Cq) expression in subepicardial, midmyocardial and subendocardial myocardium were measured in both groups. The greatest differences of Cx43-pro and Cx43-Cq among three myocardial layers were calculated and shown with ΔCx43-pro and ΔCx43-Cq respectively. After Ang Ⅱ perfusion, 90% monophasic action potential repolarization duration among three myocardial layer were significantly prolonged (P<0.05 and P<0.01), and transmural dispersion of repolarization also significantly increased compared with the MIR group (P<0.05). Compare with the MIR group, three myocardial Cx43-pro and Cx43-Cq expression in the Ang Ⅱ group were significantly decreased (P<0.05 and P<0.01), but ΔCx43-pro and ΔCx43-Cq were significant increased. Renin-angiotensin system increases transmural heterogeneity of Cx43 expression in the rabbit model with MIR by Ang Ⅱ, and enlarge transmural dispersion of repolarization among three myocardial layers of left ventricular which induces malignant ventricular arrhythmia.

Abstract 14577: Kvβ1.1 Binds Pyridine Nucleotides and Alters Cardiac Action Potential

Introduction: Kvβ1 subunits demonstrate a unique ability to bind pyridine nucleotides and alter Kv channel function. Pyridine nucleotide levels are altered in cardiovascular diseases resulting in higher NADH levels. Therefore coupling of the Kvβ1 subunit with Kv channels may be important in how the repolarization is modulated in presence of NADH. Hypothesis: The Kvβ1 subunits are highly expressed in the heart and bind to multiple Kv channels (Kv4.x and Kv1.x) and regulate Kv channel activity. Therefore, we evaluated pyridine nucleotide changes in cardiovascular disease in the presence and absence of Kvβ1 and how they modulate Kv channel activity. Methods: Wild type (WT) and Kvβ1 knockout (KO) mice hearts (n=7 each group) using the ex-vivo Langendorff system were exposed to both acute and chronic alterations of lactate to induce an increase in NADH levels. Cardiac monophasic action potentials (MAPs) were measured before and 10 min after perfusion of the lactate, for chronic alterations mice were injected with isoprenaline to induce cardiac hypertrophy and demonstrated significant NADH increase. In addition we performed pull-down assays to identify binding partners of Kvβ1.1 in the heart. Results: We observed that, lactate exposure (10mmole/L) ( p &lt;0.05) prolonged left ventricular MAP duration in WT (9.4±0.7 vs. 15.6±1.2* at APD50) however KO mice demonstrated no significant difference (10.9±0.5 vs. 11.7±1.1). NADH levels in lactate exposed hearts demonstrated a 3 fold increase compared with control Krebs buffer. Lactate prolonged MAP durations in WT hearts, which was reversal by adding pyruvate (20mmole/L) to its control (pre-lactate; 8±0.5 vs. 13.6±0.6* vs. 8.4±0.6). The chronic model, MAP duration significantly ( p &lt;0.01) prolonged in the WT (9.7±0.7 vs. 15.3±1.1*) mouse hearts after isoprenaline infusion but not KO mouse (12.4±1.8 vs. 14.4±1). Immunoprecipitation experiments indicate that Kvβ1.1 interacts with Kv4.2 and Kv1.5 from mouse heart. Conclusions: Results obtained from this study suggested that the Kvβ1.1 subunit has the ability to sense redox changes including NAD/NADH alterations and modulate MAP through Kv activity. This study highlights the physiological role Kvβ1.1 plays in cardiac repolarization physiology and cardiac disease.

Flecainide attenuates rate adaptation of ventricular repolarization in guinea-pig heart

Objectives: Flecainide is class Ic antiarrhythmic agent that was found to increase the risk of sudden cardiac death. Arrhythmic responses to flecainide could be precipitated by exercise, suggesting a role played by inappropriate rate adaptation of ventricular repolarization. This study therefore examined flecainide effect on adaptation of the QT interval and ventricular action potential duration (APD) to abrupt reductions of the cardiac cycle length. Design: ECG and ventricular epicardial and endocardial monophasic APD were recorded in isolated, perfused guinea-pig heart preparations upon a sustained cardiac acceleration (rapid pacing for 30 s), and following a single perturbation of the cycle length evoked by extrasystolic stimulation. Results: Sustained increase in heart rate was associated with progressive bi-exponential shortening of the QT interval and APD. Flecainide prolonged ventricular repolarization, delayed its rate adaptation, and decreased the amplitude of QT interval and APD shortening upon rapid cardiac pacing. During extrasystolic stimulation, flecainide attenuated APD shortening in premature ventricular beats, with effect being greater upon using a longer basic drive cycle length (S1-S1=550 ms versus S1-S1=300 ms). Conclusions: Flecainide-induced arrhythmia may be partly accounted for by attenuated adaptation of ventricular repolarization to sudden changes in cardiac cycle length provoked by transient tachycardia or ectopic beats.

Effects of low-level carotid baroreflex stimulation on atrial electrophysiology.

This study aimed to investigate the effects of low-level carotid baroreflex stimulation (LL-CBS) on atrial electrophysiology. In protocol 1 (LL-CBS on physiological state), anesthetized rabbits were subjected to LL-CBS (n = 10) or surgical exposure (n = 6) for 1 h. In protocol 2 (LL-CBS on acute rapid atrial pacing), anesthetized rabbits underwent 3 h of rapid atrial pacing (RAP) with concomitant LL-CBS in the third hour (n = 7) or 3h-RAP without LL-CBS (n = 6). Carotid baroreceptor surrounded by electrodes allowed LL-CBS at 20 % below the voltage required to reduce systolic blood pressure or heart rate. Effective refractory period (ERP) and monophasic action potential duration (MAPD) were determined, and power spectral of heart rate variability (HRV) was analyzed at baseline as well as after interventions in all groups, respectively. In protocol 1, LL-CBS significantly prolonged the ERPs, MAPD90, and MAPD50 and increased high-frequency (HF) HRV component but it decreased low-frequency (LF) HRV component and LF/HF ratio. In protocol 2, 3h-RAP significantly shortened ERPs, MAPD90, and MAPD50 and decreased HF but it increased LF and LF/HF ratio. However, LL-CBS reversed the variations caused by RAP. LL-CBS prolongs ERPs and MAPD of the left atrium and attenuates RAP-induced atrial electrical remodeling including the shortening of ERPs and MAPD, probably by modulating the autonomic nervous system.

0298 : Action potential shortening in the pig right ventricular outflow tract epicardium

The right ventricular outflow tract (RVOT) has a distinct embryological origin from the rest of the right ventricle (RV) and is a frequent origin for idiopathic and disease-related arrhythmias. We hypothesised that heterogeneous action potential duration (APD) across the right ventricle (RV) may contribute to RVOT arrhythmia generation. Pigs were anesthetized and monophasic action potentials (MAPs) recorded in sinus rhythm from the epicardium of the RV free wall and RVOT. The RV was isolated and perfused via both right and left anterior coronary arteries. The preparation was paced (1-5Hz) and the electrical activity optically mapped (di-4-ANEPPS, 10μM) on both epicardial (EPI) and endocardial (ENDO) surfaces. The expression of potassium channels was assessed by RT-PCR. In vivo, MAP durations measured at 20% and 80% repolarization were both significantly shorter in the RVOT than in the RV free wall EPI (P<0.05). Similar APD variations were observed ex vivo as RVOT APD20 and APD80 were decreased by 29% and 15% respectively compared to free wall (P<0.01). Interestingly, no APD difference was observed on the ENDO resulting in a larger transmural APD difference in the RVOT than in the RV free wall. The RVOT EPI APD80 shortening was preserved over a range of stimulation frequencies leading to a downward shift of the restitution curve and a significant decrease of its slope (P<0.05). In accordance with these results, expression level of mRNA coding for Kv4.3 (Ito) and Kv11.1 (IKr) were upregulated in the RVOT compared to the RV free wall epicardium (P<0.01) while no difference was found for Kv7.1 (IKs) or Kv4.2 (Ito). Moreover, no variation in K+ channel expression was observed across the RV endocardium. Action potentials are shorter in the RVOT than elsewhere in the RV EPI. This electrophysiological signature was mirrored by regional variations in specific K+ channels. The resulting APD dispersion may facilitate RV re-entrant arrhythmias in the context of a RVOT ectopy.

Late gadolinium enhancement on cardiac magnetic resonance represents the depolarizing and repolarizing electrically damaged foci causing malignant ventricular arrhythmia in hypertrophic cardiomyopathy.

The presence of a myocardial scar detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) has been described as a predictor of all-cause mortality in hypertrophic cardiomyopathy (HCM). However, the detailed spatial relationship between LGE site and electrical abnormality is unclear in high-risk HCM with malignant arrhythmia. The purpose of this study was to elucidate the detailed relationship between the site on CMR imaging and the electrically damaged site, a potential origin of ventricular arrhythmias in patients with HCM. Fifty consecutive HCM patients underwent contrast-enhanced CMR. Of those patients, 18 patients with ventricular tachycardia underwent electrophysiology study including endocardial mapping of the left ventricle (LV). The LGE area was calculated at 12 different LV sites: anterior, lateral, posterior, and septal segments of the basal, middle, and apical portions. At each LV site, the bipolar electrogram, effective refractory period (ERP), and monophasic action potential were recorded. LGE-positive segments demonstrated a significantly lower amplitude (4.0 ± 2.8 mV vs 7.3 ± 3.6 mV; P < .001), longer duration (54.7 ± 17.8 vs 40.6 ± 7.8 ms; P < .001), longer ERP (320 ± 42 ms vs 284 ± 37 ms; P = .001), and longer monophasic action potential duration measured at 90% repolarization (321 ± 19 ms vs 283 ± 25 ms; P < .001) than did LGE-negative segments. The LGE area negatively correlated with the amplitude (r = -0.59; P < .001) and positively correlated with the duration (r = 0.64; P < .001), ERP (r = 0.44; P < .001), and action potential duration measured at 90% repolarization (r = 0.63; P < .001). All the observed VTs originated from LGE-positive segments. The spatial distribution of LGE significantly correlates with depolarizing and repolarizing electrical damage in high-risk HCM with malignant ventricular arrhythmia.

ASSA14-03-47 Ivabradine prolongs action potential duration and causes atrial arrhythmia in the heart

Objective Ivabradine (IVA) selectively inhibits I f current in the sinus node and is used to treat inappropriate sinus tachycardia. Previous studies indicated that IVA also inhibited I Kr at concentrations higher than therapeutic range. However, the proarrhythmic risk of IVA has not been fully determined. Sea anemone toxin (ATX) –II treated hearts have an increased risk of proarrhythmia and therefore was used to detect low-risk QT prolonging drugs. The objective of this study was to determine the effect of IVA on the atrial and ventricular monophasic action potential duration (MAPD) and the arrhythmic activities in the absence and presence of ATX-II. Methods Female rabbit isolated hearts were perfused by Langendorff mode. Hearts were paced at right atria appendage, and left atrial and ventricular MAPD 90 were recorded and analysed. Results When hearts were paced at 2.8 Hz, the atrial, and endocardial and epicardial ventricular MAPD 90 were 49.6 ± 3, 136.3 ± 7 and 127.4 ± 4 ms. IVA (3–10 μm) significantly prolonged them by 15.9 ± 2 (n = 6, p 90 by 41.2 ± 3 and 31.6 ± 4 ms (n = 5, p 90 by 36.5 ± 5 ms, and LV endocardial and epicardial MAPD 90 by 19.9 ± 3 and 19.5 ± 4 ms. In the continued presence of ATX-II (3 nM), IVA (6–10 μm) reduced the atrial MAPD 90 by 14.4 ± 4 ms (n = 6, p 90 by 36.2 ± 7 and 27.5 ± 5 ms (n = 6, p 90 and transmural dispersion of MAPD 90 , and caused no ventriculararrhythmia both in the absence and presence of ATX-II, (n = 6, p > 0.05; n = 6, p > 0.05) . Conclusion IVA prolongs both atrial and ventricular MAPD and causes atrial arrhythmias in hearts when late sodium current is increased, without proarrhythmic activities in the ventricles. This result may explain the results in clinical research.

ASSA14-03-46 Inhibition of late sodium current reduces the reverse rate dependence of action potential duration prolongation induced by L-type calcium channel activator

Objective Late sodium current (late I Na ) has been confirmed to contribute to the reverse rate dependence (RRD) of action potential duration (APD) prolongation induced by potassium inhibitor. This study is to determine the role of endogenous late sodium current in the induced RRD of APD prolongation in hearts treated with L-type calcium channel activator Bay K 8644. Methods New Zealand White rabbit isolated heart preparations were perfused with modified Krebs-Henseleit solution. Hearts were paced at increasing cycle lengths (CLs) of 400, 500, 667, 1000, 1333 and 2000 ms after atrioventricle (AV) block was introduced by themo-ablation of the AV nodal area. Epicardial monophasic action potential duration at 90% completion of an action potential (epi-MAPD 90 ) from the left ventricular free wall were recorded and measured. Tetrodotoxin (TTX) at the concentration of 1 µmol/L was used to inhibit late I Na selectively. Results At CL of 400 ms, epi-MAPD 90 was 150.5 ± 2.2 ms (n = 12). When the pacing CL was increased to 500, 667, 1000, 1333 and 2000 ms, the epi-MAPD 90 was significantly increased by 10.6 ± 2.9, 27.2 ± 3.0, 39.2 ± 3.8, 48.8 ± 3.5 and 56.6 ± 5.2 ms (n = 12, p 90 at all pacing rates (n = 12, P .01 vs control), and the increase was greater at longer CLs (72.8 ± 6.1 at CL of 2000 ms) than at shorter CLs (16.1 ± 2.4 at CL of 400 ms, p 90 and abolished the ventricular tachycardia. Conclusion Endogenous late sodium current contributes to the enhanced RRD of APD prolongation induced by L-type calcium channel activator.

Abstract 17272: Ionic Current Remodeling Delays the Electrical Recovery of the Senescent Heart

Cardiac aging is associated with lengthening of the QT interval, a condition that enhances malignant ventricular arrhythmias and sudden death. The aim of this study was to establish whether ionic currents are altered in old myocytes contributing to the protracted electrical recovery of the senescent heart. Thus, mice at 3-30 months of age were studied by ECG and patch-clamp; these physiological determinations were complemented with molecular assays for the analysis of ion channel proteins. By surface ECG and telemetry system, PR, QRS and QT intervals were prolonged in mice at 25 months or older. These delays were maintained in ex-vivo Langendorff preparations. In comparison to young, epicardial monophasic action potential (AP) duration at 50% and 90% repolarization were 1.6- and 1.2-fold larger in old LV, respectively. Moreover, senescent hearts presented a 60% higher incidence of arrhythmias. In isolated myocytes, prolongation of the early (+47%), intermediate (+117%) and late (+75%) repolarization phases of the AP were identified in cells from old animals, whereas resting membrane potential, upstroke amplitude and +dV/dt were preserved. Voltage-clamp experiments were then performed to measure ionic current properties. The rapidly activating K+ current, which consists of the transient outward and ultrarapid delayed rectifier (Ito+Kur), is responsible for the early repolarization of the AP, and was significantly reduced in old myocytes. Molecular studies revealed low levels of transcripts and proteins for K+ channel subunits Kv1.4, Kv1.5 and KChiP2 in senescent cells. Also, the late Na+ current INaL, which presents slow inactivation kinetics and is operative during AP repolarization, was 1.5-fold larger in old cells. These changes were associated with alterations in gene and protein expression of Na+ channel subunits. Inhibition of INaL with mexiletine significantly shortened the intermediate and late repolarization phases of the AP in both myocytes and perfused myocardium from old mice. Importantly, INaL inhibition in vivo shortened the QT interval of senescent mice by 12%. Thus, defects in ionic current occur with aging resulting in prolongation of the AP and delays in electrical recovery which may lead to malignant ventricular arrhythmias.

MICE THAT OVEREXPRESS A FRAMESHIFT MUTATION IN HUMAN NATRIURETIC PEPTIDE PRECURSOR A GENE EXHIBIT INCREASED ATRIAL FIBRILLATION BURDEN BUT NO ATRIAL STRUCTURAL REMODELING.

A frameshift mutation in natriuretic peptide precursor A gene (NPPA) encoding a mutant atrial natriuretic peptide (ANP) has been linked with familial atrial fibrillation (AF). Mutant ANP shortened monophasic action potential duration and effective refractory period in retrogradely perfused rat hearts suggesting a potential mechanism for AF. We engineered 2 transgenic mouse lines that overexpress either mutant human NPPA (h-M) or human wild-type NPPA (h-WT) to test the hypothesis that h-M mice are more prone to develop AF.

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.

Low-level carotid baroreceptor stimulation suppresses ventricular arrhythmias during acute ischemia.

BackgroundThe autonomic imbalance during acute ischemia is involved in the occurrence of life-threatening arrhythmias.ObjectiveTo investigate the effect of autonomic nervous system (ANS) modulation by low-level carotid baroreceptor stimulation (LL-CBS) on ventricular ischemia arrhythmias.MethodsAnesthetized dogs were received either sham treatment (SHAM group, n = 10) or LL-CBS treatment (LL-CBS group, n = 10). The voltage lowering the blood pressure was used as the threshold for setting LL-CBS at 80% below the threshold. Treatment started 1 hour before left anterior descending coronary (LAD) occlusion, and continued until the end of experience. Ventricular effective refractory periods (ERP), monophasic action potential duration at 90% (APD90), ventricular arrhythmias, indices of heart rate variability, left stellate ganglion nerve activity (LSGNA) and infarct sizes were measured and analyzed.ResultsVentricular ischemia resulted in an acute reduction of blood pressure, which was not significantly affected by LL-CBS. After 1 hour of LL-CBS, there was a progressive and significant increase in ERP, increase in APD90, and decrease in LSGNA vs the SHAM group (all P<0.05). LL-CBS apparently reduced premature ventricular contractions (PVC, 264±165 in the SHAM group vs 60±37 in the LL-CBS group; P<0.01) during LAD occlusion. Number of episodes of ventricular fibrillation (VF) was 8 in the Control group versus 3 in the LL-CBS group (80% versus 30%, P<0.05). LL-CBS obviously increased high frequency (HF) component (P<0.05) and decreased low frequency/high frequency ratio (P<0.05) compared with the SHAM group. Ischemic size was not affected by LL-CBS between the two groups.ConclusionsLL-CBS reduced the occurrences of ventricular arrhythmias during acute ischemia without affecting blood pressure. The procedure was associated with changes of electrophysiological characteristics, nerve activity and heart rate variability. Therefore, LL-CBS may protect from ventricular arrhythmias during acute ischemic events by modulating ANS.

Cardiac overexpression of constitutively active Galpha q causes angiotensin II type1 receptor activation, leading to progressive heart failure and ventricular arrhythmias in transgenic mice.

BackgroundTransgenic mice with transient cardiac expression of constitutively active Galpha q (Gαq-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gαq becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gαq-TG mice.Methodology/Principal FindingsOlmesartan (1 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gαq-TG but in none of 10 olmesartan-treated Gαq-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gαq-TG than in vehicle-treated Gαq-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gαq-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT1) receptor was increased in Gαq-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gαq-TG. Moreover, it increased AT1 receptor in Gαq-TG.Conclusions/SignificanceThese findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Gαq-TG mouse model of heart failure.

Streptomycin inhibits electrophysiological changes induced by stretching of chronically infarcted rat hearts.

To investigate stretch-induced electrophysiological changes in chronically infarcted hearts and the effect of streptomycin (SM) on these changes in vivo. Sixty Wistar rats were divided randomly into four groups: a control group (n=15), an SM group (n=15), a myocardial infarction (MI) group (n=15), and an MI+SM group (n=15). Chronic MI was obtained by ligating the left anterior descending branch (LAD) of rat hearts for eight weeks. The in vivo blockade of stretch-activated ion channels (SACs) was achieved by intramuscular injection of SM (180 mg/(kg∙d)) for seven days after operation. The hearts were stretched for 5 s by occlusion of the aortic arch. Suction electrodes were placed on the anterior wall of left ventricle to record the monophasic action potential (MAP). The effect of stretching was examined by assessing the 90% monophasic action potential duration (MAPD90), premature ventricular beats (PVBs), and ventricular tachycardia (VT). The MAPD90 decreased during stretching in both the control (from (50.27±5.61) ms to (46.27±4.51) ms, P<0.05) and MI groups (from (65.47±6.38) ms to (57.47±5.76 ms), P<0.01). SM inhibited the decrease in MAPD90 during inflation ((46.27±4.51) ms vs. (49.53±3.52) ms, P<0.05 in normal hearts; (57.47±5.76) ms vs. (61.87±5.33) ms, P<0.05 in MI hearts). The occurrence of PVBs and VT in the MI group increased compared with that in the control group (PVB: 7.93±1.66 vs. 1.80±0.86, P<0.01; VT: 7 vs. 1, P<0.05). SM decreased the occurrence of PVBs in both normal and MI hearts (0.93±0.59 vs. 1.80±0.86 in normal hearts, P<0.05; 5.40±1.18 vs. 7.93±1.66 in MI hearts, P<0.01). Stretch-induced MAPD90 changes and arrhythmias were observed in chronically infarcted myocardium. The use of SM in vivo decreased the incidence of PVBs but not of VT. This suggests that SACs may be involved in mechanoelectric feedback (MEF), but that there might be other mechanisms involved in causing VT in chronic MI.

Effects of amlodipine and perindoprilate on the structure and function of mitochondria in ventricular cardiomyocytes during ischemia‐reperfusion in the pig

The aim of this study was to determine whether amlodipine and/or perindoprilate injected intravenously (iv) prior to ischemia exerted protective effects on mitochondria structural and functional alterations induced by ischemia and aggravated by reperfusion. Heart rate, the duration of monophasic action potentials (dMAP), peak of the time derivative of left ventricular pressure (LV dP/dt max), mitochondria structural and functional parameters in the left ventricle ischemic area were measured after 45-min ischemia and 1-min reperfusion in domestic pigs either untreated or pretreated with amlodipine, perindoprilate or amlodipine + perindoprilate. Ischemia-reperfusion (I/R) induced tachycardia, reduced dMAP and LV dP/dt max, and causes alterations of mitochondria structural and functional parameters with decreased oxygen consumption, increased reactive oxygen species production and reduced calcium retention capacity (CRC) with opening of mitochondrial permeability transition pores. This opening is mainly due to oxidative stress and calcium overload and seems to be the pivotal event in cell death after I/R. No drug treatment changed haemodynamic and electrophysiological parameters, but amlodipine and perindoprilate, either alone or combined, prevented mitochondrial alterations but only partially. The preservation of mitochondrial structure and functions reported in our study probably plays an important role in preventing calcium overload and mPTP opening during myocardial I/R by a specially increased CRC, which can explain their cardioprotective effects.

Heptanol decreases the incidence of ischemia-induced ventricular arrhythmias through altering electrophysiological properties and connexin 43 in rat hearts.

Heptanol is a type of gap junction inhibitor that decreases electrical conduction velocity. However, little is known regarding the effects of heptanol on the arrhythmias induced by regional myocardial ischemia. This study aimed to investigate the effects of heptanol on ventricular arrhythmias and the underlying mechanisms. On the Langendorff apparatus, isolated hearts of Sprague-Dawley rats underwent 30 min of ischemia, with or without pretreatment with heptanol (0.1, 0.3 or 0.5 mM), 15 min prior to the induction of regional ischemia through ligation of the left anterior descending coronary artery. The incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were recorded after ligation. Heptanol decreased the incidence of ventricular arrhythmias (45% in the control group vs. 10% in the 0.1 mM group, 0% in the 0.3 mM group and 0% in the 0.5 mM group, P<0.05), whereas it prolonged the PR interval, QT interval and monophasic action potential duration at 90% repolarization (MAPD90). As evaluated with immunofluorescence microscopy, heptanol was able to partly reverse the downregulation of connexin 43 (Cx43) induced by ischemia. The results of the reverse transcription-polymerase chain reaction were consistent with those of immunofluorescence. In conclusion, heptanol significantly decreased the incidence of VT and VF induced by regional ischemia and prolonged the PR interval, QT interval and MAPD90. Heptanol also partly reversed the downregulation of Cx43 induced by ischemia.

Effects of Na+ Channel Blockers on Extrasystolic Stimulation-evoked Changes in Ventricular Conduction and Repolarization

Antiarrhythmic agents which belong to class Ia (quinidine) and Ic (flecainide) reportedly increase propensity to ventricular tachyarrhythmia, whereas class Ib agents (lidocaine and mexiletine) are recognized as safe antiarrhythmics. Clinically, tachyarrhythmia is often initiated by a premature ectopic beat, which increases spatial nonuniformities in ventricular conduction and repolarization thus facilitating reentry. This study examined if electrical derangements evoked by premature excitation may be accentuated by flecainide and quinidine, but unchanged by lidocaine and mexiletine, which would explain the difference in their safety profile. In perfused guinea pig hearts, a premature excitation evoked over late repolarization phase was associated with prolonged epicardial activation time, reduced monophasic action potential duration (APD), and increased transepicardial dispersion of the activation time and APD. Flecainide and quinidine increased conduction slowing evoked by extrasystolic stimulation, prolonged APD, and accentuated spatial heterogeneities in ventricular conduction and repolarization associated with premature excitation. Spontaneous episodes of nonsustained monomorphic ventricular tachycardia were observed in 50% of heart preparations exposed to drug infusion. In contrast, lidocaine and mexiletine had no effect on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization or arrhythmic susceptibility. These findings suggest that flecainide and quinidine may promote arrhythmia by exaggerating electrophysiological abnormalities evoked by ectopic beats.