Lethal Ventricular Arrhythmias Research Articles

The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome.

Type 3 long QT syndromes (LQT3) are associated with arrhythmogenic gain-of-function mutations in the cardiac voltage-gated Na+ channel (hNaV1.5). The citrus flavanone hesperetin (HSP) was previously suggested as a template molecule to develop new anti-arrhythmic drugs, as it blocks slowly-inactivating currents carried by the LQT3-associated hNaV1.5 channel mutant R1623Q. Here we investigated whether HSP also has potentially beneficial effects on another LQT3 hNaV1.5 channel variant, the ΔKPQ, which is associated to lethal ventricular arrhythmias. We used whole-cell patch-clamp to record Na+ currents (INa) in HEK293T cells transiently expressing hNaV1.5 wild type or ΔKPQ mutant channels. HSP blocked peak INa and the late INa carried by ΔKPQ mutant channels with an effective concentration of ≈300 μM. This inhibition was largely voltage-independent and tonic. HSP decreased the rate of inactivation of ΔKPQ channels and, consequently, was relatively weak in reducing the intracellular Na+ load in this mutation. We conclude that, although HSP has potential value for the treatment of the R1623Q LQT3 variant, this compound is inadequate to treat the LQT3 associated to the ΔKPQ genetic variant. Our results underscore the precision medicine rationale of better understanding the basic pathophysiological and pharmacological mechanisms to provide phenotype- genotype-directed individualization of treatment.

Purkinje system hyperexcitability and ventricular arrhythmia risk in type 3 long QT syndrome

Gain-of-function variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3) andmultifocal ectopic Purkinje-related premature contractions. Although the Purkinje system is uniquely sensitive to the action potential-prolonging effects of LQT3-causative variants, the existence of additional Purkinje phenotype(s) in LQT3 is unknown. The purpose of this study was to determine the prevalence and clinical implications of frequent fascicular/Purkinje-related premature ventricular contractions (PVCs) and short-coupled ventricular arrhythmias (VAs), suggestive of Purkinje system hyperexcitability (PSH), in a single-center LQT3 cohort. A retrospective analysis of 177 SCN5A-positive patients was performed to identify individuals with a LQT3 phenotype. Available electrocardiographic, electrophysiology study, device, and genetic data from 91 individuals with LQT3 were reviewed for evidence of presumed fascicular PVCs and short-coupled VAs. The relationship between PSH and ventricular fibrillation events was assessed by Kaplan-Meier and Cox regression analyses. Overall, 30 of 91 patients with LQT3 (33%) exhibited evidence of presumed PSH (fascicular PVCs 30 of 30 [100%]; short-coupled VAs 17 of 30 [56%]). Kaplan-Meier and Cox regression analyses demonstrated an increased risk of ventricular fibrillation events in individuals with LQT3 and PSH (log-rank, P < .03; hazard ratio 3.95; 95% confidence interval 1.15-15.7; P = .03). Interestingly, variants in the voltage-sensing domain regions of Nav1.5 were more frequently observed in patients with LQT3 and PSH than those without (19 of 30 [63%] vs 9 of 61 [15%]; P <.0001). This study demonstrates that a discernible Purkinje phenotype is present in one-third of LQT3 cases and increases the risk of potentially lethal VAs. Further study is needed to determine whether a distinct cellular electrophysiology phenotype underlies this phenomenon.

Use of Chloroquine and Hydroxychloroquine in COVID-19 and Cardiovascular Implications: Understanding Safety Discrepancies to Improve Interpretation and Design of Clinical Trials.

Author(s): Oren, Ohad; Yang, Eric H; Gluckman, Ty J; Michos, Erin D; Blumenthal, Roger S; Gersh, Bernard J

Transcriptional Patterning of the Ventricular Cardiac Conduction System.

The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood. To study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning. Using mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5, and T-box transcriptional repressor, Tbx3, determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS. The CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.

Detection of arrhythmogenic substrate within QRS complex in patients with cardiac sarcoidosis using wavelet-transformed ECG.

Signal-averaged electrocardiography (SAECG) has been known to be useful for prediction of lethal ventricular arrhythmias (VA). However, this technique has limitations in patients with intraventricular conduction disturbance (IVCD), which is common in cardiac sarcoidosis (CS). Meanwhile, wavelet-transformed ECG (WTECG) has been reported to be useful for detecting arrhythmogenic substrate hidden within QRS complex. The objective of this study was to assess the utility of WTECG for detecting arrhythmogenic substrate in patients with CS. Forty-four CS patients including 18 patients with VA were retrospectively investigated. The parameters on the signal-averaged electrocardiography (SAECG) and the power of frequency components on WTECG were compared between VA group and non-VA group. Eighteen patients have VA (VT: n = 17, VF: n = 1). LP were detected in 17 in VA group and 24 in non-VA group. WTECG showed that high-frequency components (HFC; 80-150Hz) were developed in VA group. Peak power value at 150Hz (P150) was significantly higher in VA group than that in non-VA group (442.9 ± 160.2 vs 316.7 ± 100.8, p = 0.006). The receiver operating characteristic (ROC) curve analysis showed an optimal cutoff point of 336 of P150 for detecting patients with VA, with 82.4% sensitivity, 61.5% specificity, and area under the curve of 0.74 (95% confidence interval [CI] 0.59-0.89). WTECG may be useful for detecting CS patients who are prone to VA.

Next-generation sequencing identified novel Desmoplakin frame-shift variant in patients with Arrhythmogenic cardiomyopathy

BackgroundArrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown.MethodsA 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation.ResultsThe proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of β-catenin, when compared with WT.ConclusionWe infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.

Biophysical mechanisms for QRS- and QTc-interval prolongation in mice with cardiac expression of expanded CUG-repeat RNA

Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, results from the expression of toxic gain-of-function transcripts containing expanded CUG-repeats. DM1 patients experience cardiac electrophysiological defects, including prolonged PR-, QRS-, and QT-intervals, that increase susceptibility to sudden cardiac death (SCD). However, the specific biophysical and molecular mechanisms that underlie the electrocardiograph (ECG) abnormalities and SCD in DM1 are unclear. Here, we addressed this issue using a novel transgenic mouse model that exhibits robust cardiac expression of expanded CUG-repeat RNA (LC15 mice). ECG measurements in conscious LC15 mice revealed significantly prolonged QRS- and corrected QT-intervals, but a normal PR-interval. Although spontaneous arrhythmias were not observed in conscious LC15 mice under nonchallenged conditions, acute administration of the sodium channel blocker flecainide prolonged the QRS-interval and unveiled an increased susceptibility to lethal ventricular arrhythmias. Current clamp measurements in ventricular myocytes from LC15 mice revealed significantly reduced action potential upstroke velocity at physiological pacing (9 Hz) and prolonged action potential duration at all stimulation rates (1-9 Hz). Voltage clamp experiments revealed significant rightward shifts in the voltage dependence of sodium channel activation and steady-state inactivation, as well as a marked reduction in outward potassium current density. Together, these findings indicate that expression of expanded CUG-repeat RNA in the murine heart results in reduced sodium and potassium channel activity that results in QRS- and QT-interval prolongation, respectively.

Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models

Cancer chemotherapies have improved prognosis in cancer patients, resulting in a large and rapidly increasing number of cancer survivors. “Onco-cardiology” or “cardio-oncology” is a new discipline for addressing the unanticipated cardiac side effects of newly developed cancer drugs. Lapatinib, a tyrosine kinase inhibitor suppressing the epidermal growth factor receptor and ErbB2, has been used in advanced or metastatic breast cancer treatment. Reportedly, lapatinib has induced cardiovascular adverse events including QT-interval prolongation and heart failure. However, they have not been predicted by preclinical studies. Hence, a new method to assess the tyrosine kinase inhibitor-induced adverse effects needs to be established. Here, we intravenously administered lapatinib to halothane-anaesthetised dogs, evaluating cardiohemodynamic, electrophysiological, and echocardiographic profiles for pharmacological safety assessments. We intravenously administered lapatinib to chronic atrioventricular block beagle dogs to assess its proarrhythmic potential. The therapeutic concentration of lapatinib significantly increased total peripheral vascular resistance, QT, QTc, monophasic action potential (MAP)90(sinus), MAP90(CL400), effective refractory period, and plasma concentration of cardiac troponin I (cTnI), suggesting that lapatinib prolonged the ventricular repolarization without inducing lethal ventricular arrhythmia. Careful monitoring of plasma cTnI concentration and an electrocardiogram could be supportive biomarkers, predicting the onset of lapatinib-induced cardiovascular adverse events.

Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of Spontaneous SR Ca 2+ Release.

Early afterdepolarization (EAD) is known to cause lethal ventricular arrhythmias in long QT syndrome (LQTS). In this study, dynamical mechanisms of EAD formation in human ventricular myocytes (HVMs) were investigated using the mathematical model developed by ten Tusscher and Panfilov (Am J Physiol Heart Circ Physiol 291, 2006). We explored how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current (ICaL), Na+/Ca2+ exchanger current (INCX), and intracellular Ca2+ handling via the sarcoplasmic reticulum (SR) contribute to initiation, termination and modulation of phase-2 EADs during pacing in relation to bifurcation phenomena in non-paced model cells. Parameter-dependent dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points to construct bifurcation diagrams. Action potentials (APs) and EADs during pacing were reproduced by numerical simulations for constructing phase diagrams of the paced model cell dynamics. Results are summarized as follows: (1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs in LQTS type 2 and β-adrenergic stimulation-induced EADs in LQTS type 1. (2) Two types of EADs with different initiation mechanisms, ICaL reactivation–dependent and spontaneous SR Ca2+ release–mediated EADs, were detected. (3) Termination of EADs (AP repolarization) during pacing depended on the slow activation of IKs. (4) Spontaneous SR Ca2+ releases occurred at higher Ca2+ uptake rates, attributable to the instability of steady-state intracellular Ca2+ concentrations. Dynamical mechanisms of EAD formation and termination in the paced model cell are closely related to stability changes (bifurcations) in dynamical behaviors of the non-paced model cell, but they are model-dependent. Nevertheless, the modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of EAD-related arrhythmias in LQTS.

Sudden cardiac death in children and young adults without structural heart disease: a comprehensive review

Sudden cardiac death (SCD) is a rare clinical encounter in pediatrics, but its social impact is immense because of its unpredicted and catastrophic nature in previously healthy individuals. Unlike in adults where the primary cause of SCD is related to ischemic heart disease, the etiology is diverse in young SCD victims. Although certain structural heart diseases may be identified during autopsy in some SCD victims, autopsy-negative SCD is more common in pediatrics, which warrants the diagnosis of sudden arrhythmic death syndrome (SADS) based upon the assumption that the usual heart rhythm is abruptly replaced by lethal ventricular arrhythmia. Despite current advances in molecular genetics, the causes of more than half of SADS cases remain unanswered even after postmortem genetic testing. Moreover, the majority of these deaths occur at rest or during sleep even in the young. Recently, sudden unexpected death in epilepsy (SUDEP) has emerged as another etiology of SCD in children and adults, suggesting critical involvement of the central nervous system (CNS) in SCD. Primary cardiac disorders may not be solely responsible for SCD; abnormal CNS function may also contribute to the unexpected lethal event. In this review article, we provide an overview of the complex pathogenesis of SADS and its diverse clinical presentation in the young and postulate that SADS is, in part, induced by unfortunate miscommunication between the heart and CNS via the autonomic nervous system.

Prognostic value of the model for end-stage liver disease excluding INR score (MELD-XI) in patients with adult congenital heart disease.

Patients with adult congenital heart disease (ACHD) are at increased risk of developing late cardiovascular complication. However, little is known about the predictive factors for long-term outcome. The Model for End-Stage Liver Disease eXcluding INR (MELD-XI) score was originally developed to assess cirrhotic patients and has the prognostic value for heart failure (HF) patients. In the present study, we examined whether the score also has the prognostic value in this population. We retrospectively examined 637 ACHD patients (mean age 31.0 years) who visited our Tohoku University hospital from 1995 to 2015. MELD-XI score was calculated as follows; 11.76 x ln(serum creatinine) + 5.11 x ln(serum total bilirubin) + 9.44. We compared the long-term outcomes between the high (≥10.4) and the low (<10.4) score groups. The cutoff value of MELD-XI score was determined based on the survival classification and regression tree (CART) analysis. The major adverse cardiac event (MACE) was defined as a composite of cardiac death, HF hospitalization, and lethal ventricular arrhythmias. During a mean follow-up period of 8.6 years (interquartile range 4.4–11.4 years), MACE was noted in 51 patients, including HF hospitalization in 37, cardiac death in 8, and lethal ventricular arrhythmias in 6. In Kaplan-Meier analysis, the high score group had significantly worse MACE-free survival compared with the low score group (log-rank, P<0.001). Multivariable Cox regression analysis showed that the MELD-XI score remained a significant predictor of MACE (hazard ratio 1.36, confidence interval 1.17–1.58, P<0.001) even after adjusting for patient characteristics, such as sex, functional status, estimated glomerular filtration rate, and cardiac function. Furthermore, CART analysis revealed that the MELD-XI score was the most important variable for predicting MACE. These results demonstrate that the MELD-XI score can effectively predict MACE in ACHD patients, indicating that ACHD patients with high MELD-XI score need to be closely followed.

Abstract 369: Implantable Cardioverter Defibrillator Therapy in Patients With Vasospastic Angina After Sudden Cardiac Arrest

Introduction: The prognosis of vasospastic angina (VSA) treated with optimal medication therapy is generally good. However, the patients resuscitated from sudden cardiac arrest (SCA) caused by lethal ventricular arrhythmias are at high risk of recurrent cardiovascular events. Moreover, little is known about the efficacy of implantable cardioverter defibrillator (ICD) therapy in this population The aim of this study is to evaluate the incidence of lethal arrhythmic events in VSA patients with secondary prophylaxis for SCA. Methods: Data from patients who received an ICD as a secondary prophylaxis in our institution between January 2012 and November 2018 were retrospectively analyzed. A total of 123 patients were enrolled in this study and divided into 16 patients with VSA (VSA group) and 107 patients without VSA (non-VSA group). VSA was diagnosed by acetylcholine provocation test or coronary angiography alone on arrival. Results: Current smoker was more prevalent and cardiac function was better in the VSA group. Diabetes mellitus was more prevalent in the non-VSA group. Although VSA patients were treated with calcium-channel blockers, with or without nitrates, 3 patients (18.8%) experienced appropriate ICD therapies due to lethal arrhythmias during a follow-up of 3.2 years. There were no significant differences in the proportion of appropriate and inappropriate therapy between 2 groups. (Table) Conclusions: Recurrent lethal arrhythmic events were common in patients with VSA after SCA. In addition to optimal medical therapy, ICD therapy should be aggressively considered in patients with VSA and a history of lethal arrhythmia.

Ventricular Arrhythmias in First Acute Myocardial Infarction: Epidemiology, Mechanisms, and Interventions in Large Animal Models.

Ventricular arrhythmia and subsequent sudden cardiac death (SCD) due to acute myocardial infarction (AMI) is one of the most frequent causes of death in humans. Lethal ventricular arrhythmias like ventricular fibrillation (VF) prior to hospitalization have been reported to occur in more than 10% of all AMI cases and survival in these patients is poor. Identification of risk factors and mechanisms for VF following AMI as well as implementing new risk stratification models and therapeutic approaches is therefore an important step to reduce mortality in people with high cardiovascular risk. Studying spontaneous VF following AMI in humans is challenging as it often occurs unexpectedly in a low risk subgroup. Large animal models of AMI can help to bridge this knowledge gap and are utilized to investigate occurrence of arrhythmias, involved mechanisms and therapeutic options. Comparable anatomy and physiology allow for this translational approach. Through experimental focus, using state-of-the-art technologies, including refined electrical mapping equipment and novel pharmacological investigations, valuable insights into arrhythmia mechanisms and possible interventions for arrhythmia-induced SCD during the early phase of AMI are now beginning to emerge. This review describes large experimental animal models of AMI with focus on first AMI-associated ventricular arrhythmias. In this context, epidemiology of first AMI, arrhythmogenic mechanisms and various potential therapeutic pharmacological targets will be discussed.

P1603Nicorandil suppresses ischemia-induced cardiac interstitial norepinephrine enhancement and ventricular arrhythmia in hypertrophic hearts

Abstract Background Myocardial infarction (MI) is a major cause of death in western countries and Japan, and hypertension is a major risk factor of MI. In hypertensive heart, acute myocardial infarction often leads to lethal ventricular arrhythmia. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute myocardial infarction. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, KATP in neuroterminals is known to regulate norepinephrine release, but the effect of nicorandil on ischemic norepinephrine release in cardiac tissue has remained unexplored. Purpose We examined whether nicorandil suppressed norepinephrine release via neuronal KATP and ventricular arrhythmia during acute ischemia in pressure overload-induced hypertrophic hearts. Methods SD Rats were divided into two groups; abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography. Then, myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method and concentration of cyclic AMP, a second messenger of norepinephrine, in cardiac tissue was measured by ELISA. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results Four weeks after constriction, remarkable left ventricular wall thickening was observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (- 40 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group. Ischemia obviously increased norepinephrine concentration in both groups time dependently and AAC further increased norepinephrine than Sham group. Concentration of cyclic AMP in cardiac tissue was raised in early ischemic period (- 40 min) and then gradually decreased. Nicorandil significantly suppressed the number of ventricular arrhythmias, and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations. Nicorandil also attenuated norepinephrine and cAMP enhancement in acute ischemic period in both groups. Conclusion Ischemia-induced ventricular arrhythmia was more frequent and severe in hypertrophic hearts and interstitial norepinephrine enhancement may play a role in this ischemic arrhythmia. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in normal and hypertrophic hearts.

P5697J-wave elevation in the inferior leads is a predictor of lethal ventricular arrhythmia initiated by premature ventricular contractions with right bundle branch block and superior axis

Abstract Background Lethal-ventricular-arrhythmia (VA) could be sometimes initiated by idiopathic Premature Ventricular Contractions (PVCs) originated form inferior wall. Furthermore, J-wave elevation in inferior leads was sometimes associated with lethal-VA. However, it was unclear the relationship between these PVCs and J-wave elevation in patients with lethal-VA. Purpose The aim of this study was to investigate the relationship between PVCs and J-wave elevation. Methods and results We studied 32 patients who underwent radiofrequency (RF) ablation of idiopathic PVCs with RBBB and superior axis. These PVCs were originating from inferior wall of left ventricular. Lethal-VA was defined as ventricular fibrillation (VF) or ventricular tachycardia (VT) with loss of consciousness (LOC). Among 32 patients, 3 had VF and 2 had VT with LOC. Other 27 had non-lethal-VA. Baseline clinical characteristics were not significantly difference between lethal and non-lethal-VA. The ratio of J-wave elevation in lethal-VA was significant higher as compared to those with non-lethal-VA (5/5 (100%) vs. 3/27 (11.1%), p&lt;0.0001). Furthermore, no patients had recurrence of lethal-VA with J wave elevation in inferior leads after RF ablation of these PVCs with RBBB and superior axis, Conclusions We speculated that J-wave elevation in inferior leads might be a predictor of lethal-VA initiated by PVCs with RBBB and superior axis. RF ablation of these PVCs were useful method of treating lethal-VA. Acknowledgement/Funding None

Activation of β1-adrenoceptors may not be involved in arrhythmogenesis in ischemic heart disease

Although ischemic heart disease is invariably associated with marked activation of sympathetic nervous system, elevated levels of circulating catecholamines and lethal ventricular arrhythmias, the mechanisms of arrhythmogenesis due to myocardial ischemia are not fully understood. Since catecholamines are known to produce stimulatory effects in the heart mainly by acting on β1-adrenoceptors, this study was undertaken to test the involvement of these receptors in the development of arrhythmias due to myocardial infarction (MI) induced upon occluding the left coronary artery in rats for a period of 2 h. The animals were treated with or without atenolol (20 mg/kg; daily), a selective β1-adrenoceptors blocker, for 14 days before inducing MI. No alterations in the number of MIinduced episodes and incidence or duration of different types of arrhythmias were observed. In fact, the incidence of trigemines and reversible ventricular fibrillation due to MI were significantly increased in the atenolol-treated animals. These observations support the view that the activation of β;1-adrenoceptors may not be exclusively involved in the development of arrhythmias during the occurrence of ischemic heart disease and other mechanisms can underlie the electric instability of such damaged heart.

Neuromuscular electrical stimulation is feasible in patients with acute heart failure.

AimsIn acute heart failure (AHF), immobilization is caused because of unstable haemodynamics and dyspnoea, leading to protein wasting. Neuromuscular electrical stimulation (NMES) has been reported to preserve muscle mass and improve functional outcomes in chronic disease. NMES may be effective against protein wasting frequently manifested in patients with AHF; however, whether NMES can be implemented safely without any adverse effect on haemodynamics has remained unknown. This study aimed to examine the feasibility of NMES in patients with AHF.Methods and resultsPatients with AHF were randomly assigned to the NMES or control group. The intensity of the NMES group was set at 10–20% maximal voluntary contraction level, whereas the control group was limited at a visible or palpable level of muscle contraction. The sessions were performed 5 days per week since the day after admission. Before the study implementation, we set the feasibility criteria with following items: (i) change in systolic blood pressure (BP) > ±20 mmHg during the first session; (ii) increase in heart rate (HR) > +20 b.p.m. during the first session; (iii) development of sustained ventricular arrhythmia, atrial fibrillation (AF), and paroxysmal supraventricular tachycardia during all sessions; (iv) incidence of new‐onset AF during the hospitalization period < 40%; and (v) completion of the planned sessions by >70% of patients. The criteria of feasibility were set as follows; the percentage to fill one of (i)–(iii) was <20% of the total subjects, and both (iv) and (v) were satisfied. A total of 73 patients (median age 72 years, 51 men) who completed the first session were analysed (NMES group, n = 34; control group, n = 39). Systolic BP and HR variations were not significantly different between two groups (systolic BP, P = 0.958; HR, P = 0.665). Changes in BP > ±20 mmHg or HR > +20 b.p.m. were observed in three cases in the NMES group (8.8%) and five in the control group (12.8%). New‐onset arrhythmia was not observed during all sessions in both groups. During hospitalization, one patient newly developed AF in the NMES group (2.9%), and one developed AF (2.6%) and two lethal ventricular arrhythmia in the control group. Thirty‐one patients in the NMES group (91%) and 33 patients in the control group (84%) completed the planned sessions during hospitalization. This study fulfilled the preset feasibility criteria.ConclusionsNMES is feasible in patients with AHF from immediately after admission.

J-Wave Elevation in the Inferior Leads Predicts Lethal Ventricular Arrhythmia Initiated by Premature Ventricular Contractions With Right Bundle Branch Block and Superior Axis.

Lethal ventricular arrhythmia (VA) can be initiated by idiopathic premature ventricular contractions (PVCs) originating from the left ventricular (LV) inferior wall. Furthermore, J-wave elevation in the inferior leads on ECG is sometimes associated with lethal VA. However, the relationship between these PVCs and J-wave elevation in patients with lethal VA is unclear, so we investigated it in the present study. We studied 32 consecutive patients who underwent radiofrequency (RF) ablation of idiopathic PVCs with right bundle branch block (RBBB) and superior axis. Thee PVCs were originating from the inferior wall of the LV. Lethal VA was defined as ventricular fibrillation (VF) or ventricular tachycardia (VT) with loss of consciousness (LOC). Among 32 patients, 3 had VF and 2 had VT with LOC. Other 27 had non-lethal VA. Baseline clinical characteristics were not significantly difference between lethal and non-lethal VA. The ratio of J-wave elevation in lethal VA was significantly higher as compared with non-lethal VA (100% vs. 11.1%, P<0.0001). Furthermore, no patients with J-wave elevation in the inferior leads had recurrence of lethal VA after RF ablation of the PVCs. We speculate that J-wave elevation in the inferior leads might be a predictor of lethal VA initiated by PVCs with RBBB and superior axis. RF ablation of these PVCs was a useful method of treating lethal VA.

Abstract 576: Phosphodiesterase 2 in Cardiac Arrhythmias and Heart Failure

Heart failure (HF) patients often suffer from lethal ventricular arrhythmias leading to sudden cardiac arrests. Phosphodiesterase 2 (PDE2), a cGMP activated enzyme hydrolyzing cAMP, is upregulated in HF. Cardiac-specific PDE2 overexpression revealed strong anti-arrhythmic and heart rate lowering effects of PDE2. Here, we validated the cardioprotective role of PDE2 upon modulating cardiac PDE2 activity, first, via assessing cardiac function of cardiac-specific PDE2-KO mice and second, via potentiating PDE2 mediated cGMP/cAMP crosstalk using natriuretic peptide type C (CNP), which are upstream of the cGMP/PDE2 axis. Cardiac function and arrhythmia susceptibility of PDE2-KO were assessed via echocardiography and ECG telemetry under basal conditions and after myocardial infarction (MI). Patch clamp technique was used to investigate CNP effects on action potentials and ion currents in WT isolated cardiomyocytes and in-vivo via ECG-telemetry. Already under basal conditions, PDE2-KO displayed severe irregularities in RR-intervals. 14 days post MI, PDE2-KO showed lower cardiac function and delayed increase in heart rate after arrhythmia provocation (double isoprenaline (ISO) injection (2 mg/kg i.p.) compared to WT controls, indicating diminished cardiac responsiveness. On the other hand, CNP treatment in WT displayed a PDE2-dependent antiarrhythmogenic effect. CNP (1 μM) significantly reduced the total number of delayed afterdepolarizations and spontaneous action potentials upon acute ISO (10 nM) stimulation. Furthermore, CNP significantly reduced the ISO-mediated increase of the L-type Ca 2+ and late Na + currents as well as SR Ca 2+ waves. These effects were reversed upon specific PDE2 inhibition with BAY 60-7550. Finally, in vivo, CNP (33 μg/g i.p.) significantly reduced the number of ventricular extrasystoles after arrhythmia provocation. This effect was significantly attenuated after PDE2 inhibition with BAY 60-7550. Here we provide evidence for acute antiarrhythmic effects of CNP upon downstream stimulation of cGMP-stimulated PDE2 and a critical role of PDE2 on heart rate regulation. Therefore, pharmacologically enhancing myocardial PDE2 activity may represent a novel cardioprotective strategy in cardiac arrhythmia and HF.

Generation of a cohort of whole-torso cardiac models for assessing the utility of a novel computed shock vector efficiency metric for ICD optimisation

Implanted cardiac defibrillators (ICDs) seek to automatically detect and terminate potentially lethal ventricular arrhythmias by applying strong internal electric shocks across the heart. However, the optimisation of the specific electrode design and configurations represents an intensive area of research in the pursuit of reduced shock strengths and fewer device complications and risks. Computational whole-torso simulations play an important role in this endeavour, although knowing which specific metric should be used to assess configuration efficacy and assessing the impact of different patient anatomies and pathologies, and the corresponding effect this may have on different metrics has not been investigated. We constructed a cohort of CT-derived high-resolution whole torso-cardiac computational models, including variants of cardiomyopathies and patients with differing torso dimensions. Simulations of electric shock application between electrode configurations corresponding to transveneous (TV-ICD) and subcutaneous (S-ICD) ICDs were modelled and conventional metrics such as defibrillation threshold (DFT) and impedance computed. In addition, we computed a novel metric termed the shock vector efficiency (η), which quantifies the fraction of electrical energy dissipated in the heart relative to the rest of the torso. Across the cohort, S-ICD configurations showed higher DFTs and impedances than TV-ICDs, as expected, although little consistent difference was seen between healthy and cardiomyopathy variants. η was consistently <2% for S-ICD configurations, becoming as high as 13% for TV-ICD setups. Simulations also suggested that a total torso height of approximately 20 cm is required for convergence in η. Overall, η was seen to be approximately negatively correlated with both DFT and impedance. However, important scenarios were identified in which certain values of DFT (or impedance) were associated with a range of η values, and vice-versa, highlighting the heterogeneity introduced by the different torsos and pathologies modelled. In conclusion, the shock vector efficiency represents a useful additional metric to be considered alongside DFT and impedance in the optimisation of ICD electrode configurations, particularly in the context of differing torso anatomies and cardiac pathologies, which can induce significant heterogeneity in conventional metrics of ICD efficacy.