Heart Failure Ventricular Arrhythmias Research Articles

Increased GIRK channel activity prevents arrhythmia in mice with heart failure by enhancing ventricular repolarization

Ventricular arrhythmia causing sudden cardiac death is the leading mode of death in patients with heart failure. Yet, the mechanisms that prevent ventricular arrhythmias in heart failure are not well characterized. Using a mouse model of heart failure created by transverse aorta constriction, we show that GIRK channel, an important regulator of cardiac action potentials, is constitutively active in failing ventricles in contrast to normal cells. Evidence is presented indicating that the tonic activation of M2 muscarinic acetylcholine receptors by endogenously released acetylcholine contributes to the constitutive GIRK activity. This constitutive GIRK activity prevents the action potential prolongation in heart failure ventricles. Consistently, GIRK channel blockade with tertiapin-Q induces QT interval prolongation and increases the incidence of arrhythmia in heart failure, but not in control mice. These results suggest that constitutive GIRK channels comprise a key mechanism to protect against arrhythmia by providing repolarizing currents in heart failure ventricles.

A narrative review on sacubitril/valsartan and ventricular arrhythmias.

Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor approved by the Food and Drug Administration for marketing, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in patients with chronic heart failure with a reduced ejection fraction. However, some researchers have also found that sacubitril/valsartan has an antiarrhythmic effect. The mechanism by which sacubitril/valsartan reduces the mortality associated with malignant ventricular arrhythmias is not precise. Many studies have concluded that ventricular arrhythmia is associated with a reduction in myocardial fibrosis. This article reviews the current understanding of the effects of sacubitril/valsartan on the reduction of ventricular arrhythmia and explains its possible mechanisms. The results of this study suggest that sacubitril/valsartan reduces the occurrence of appropriate implantable cardioverter-defibrillator shocks. Meanwhile, sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias by affecting 3 pathways of B-type natriuretic peptide, Angiotensin II, and Bradykinin. The conclusion of this study is that sacubitril/valsartan reduces the number of implantable cardioverter-defibrillator shocks and ventricular arrhythmias in heart failure with reduced ejection fraction patients.

Management of ventricular arrhythmias in heart failure: Current perspectives.

Congestive heart failure (HF) is a progressive affliction defined as the inability of the heart to sufficiently maintain blood flow. Ventricular arrhythmias (VAs) are common in patients with HF, and conversely, advanced HF promotes the risk of VAs. Management of VA in HF requires a systematic, multimodality approach that comprises optimization of medical therapy and use of implantable cardioverter-defibrillator and/or device combined with cardiac resynchronization therapy. Catheter ablation is one of the most important strategies with the potential to abolish or decrease the number of recurrences of VA in this population. It can be a curative strategy in arrhythmia-induced cardiomyopathy and may even save lives in cases of an electrical storm. Additionally, modulation of the autonomic nervous system and stereotactic radiotherapy have been introduced as novel methods to control refractory VAs. In patients with end-stage HF and refractory VAs, an institution of the mechanical circulatory support device and cardiac transplant may be considered. This review aims to provide an overview of current evidence regarding management strategies of VAs in HF with an emphasis on interventional treatment.

Prospects of heart failure pharmacotherapy: the latest news about omecamtiv mecarbil

Over the past decades, an active scientific research has been continuing aimed on the search for medications that can increase myocardial contractility and improve the course of heart failure (HF). omecamtiv mecarbil, a drug from the group of cardiac myosin activators, heads the list of applicants for clinical use. By today, evidences have been collected for the ability of omecamtiv mecarbil to bind exclusively to the heads of cardiac myosin molecules without significantly affecting smooth or skeletal muscle myosin. omecamtiv mecarbil stabilizes pre‑step myosin conformation, enabling the greater number of its heads to participate in the working phase of systole.The article presents the results of several randomized clinical trials that studied the efficacy and safety of omecamtiv mecarbil in heart failure: ATOMIC‑AHF, COSMIC‑HF and GALACTIC‑HF. ATOMIC‑AHF showed a tendency to reduce the risk of developing supraventricular and ventricular arrhythmias in heart failure. COSMIC‑HF has proven the ability of omecamtiv mecarbil to improve the quality of life of patients with heart failure. GALACTIC‑HF may be a turning point in the medical treatment of heart failure. For the first time, clinical evidence of the ability of the selective cardiac myosin activator omecamtiv mecarbil to improve myocardial contractile function, reduce the severity of symptoms of heart failure and reduce the risk of cardiovascular death in patients with the reduced left ventricular injection friction was obtained. It is too early to draw final conclusions about the advisability of omecamtiv mecarbil administration for heart failure. The findings of new comparative randomized clinical trials, systemic reviews and meta‑analyses may possibly alter the standards of treatment of this pathology.

B-PO05-181 HIS BUNDLE PACING PRODUCES MORE PHYSIOLOGICAL VENTRICULAR REPOLARISATION THAN BIVENTRICULAR PACING IN HEART FAILURE WITH LEFT BUNDLE BRANCH BLOCK

Biventricular pacing (BVP) shortens left ventricular activation time (LVAT) in patients with heart failure and left bundle branch block (LBBB). His bundle pacing can correct LBBB (HBP-CRT). The effects of BVP and HBP-CRT on ventricular repolarisation are not known. To measure the effects of HBP-CRT and BVP on LV repolarisation using non-invasive epicardial mapping (ECGI). Participants were recruited in 2 groups. 1) Patients scheduled for BVP for heart failure with LBBB, 2) Individuals with normal QRS and LV function. We defined HBP-CRT as LVAT shortening >10ms. We compared the effects of HBP-CRT and BVP on ECGI-derived dispersion of repolarisation and activation-recovery intervals. 21 HBP-CRT and 21 narrow intrinsic QRS were recruited. LV repolarisation dispersion was reduced by HBP-CRT (-42.0ms, 95%CI: -52.3 to -31.7, p <0.001) but not BVP (11.9ms, -6.2 to 30.1, p=0.182, 18.5ms). Change in LV repolarisation dispersion from BVP to HBP-CRT was -56.5ms (-70.5 to 42.5, p<0.001). LV repolarisation dispersion with HBP-CRT was not different from narrow intrinsic QRS (2.8ms, -16.2 to 21.7, p=0.981). Reduction in LV repolarisation dispersion with HBP-CRT from intrinsic LBBB was similar to LVAT shortening (-45.9ms, 95%CI: -59.3 to -32.4). However, LV activation-recovery interval dispersion was also reduced by HBP-CRT (-56.5 ms, -70.5 to -42.5ms, p<0.001). HBP-CRT can normalise repolarisation dispersion, producing more physiological repolarisation than BVP. This occurs through effects on both activation and action-potential duration. HBP-CRT may prevent ventricular arrhythmias in heart failure with LBBB to a greater extent than BVP.

His resynchronization therapy produces more physiological ventricular repolarisation compared with biventricular pacing

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation BACKGROUND Biventricular pacing (BVP) is known to shorten activation time in patients with heart failure and left bundle branch block (LBBB) but its effects on repolarisation are not well studied. His bundle pacing (HBP) can correct LBBB to deliver cardiac resynchronization therapy (HBP-CRT), producing more physiological ventricular activation time and pattern than BVP. It is not known whether this translates to more physiological repolarisation, and if so whether the effect is mediated through its effects on activation. PURPOSE We measured the effects of HBP-CRT and BVP on left ventricular repolarisation using non-invasive epicardial mapping (ECGI). METHODS Patients were recruited in two groups. 1) Patients scheduled for clinically indicated BVP procedures for heart failure with LBBB, 2) Individuals with narrow QRS, normal ventricular function and intact conduction systems. Using non-invasive electrocardiographic imaging, we identified patients with LBBB in whom HBP shortened ECGI-derived left ventricular (LV) activation time by &amp;gt;10ms. We compared the effects of HBP and BVP on ECGI-derived dispersion of LV repolarisation times and activation-recovery intervals (a surrogate for action potential duration). RESULTS 21 patients in whom HBP shortened LV activation time by &amp;gt;10ms and an equal number of individuals with narrow intrinsic QRS were recruited. LV repolarisation dispersion was reduced by HBP-CRT (-42.0 ms, 95% confidence interval (CI): -52.3 to -31.7 ms, p &amp;lt;0.001) but not by BVP (11.9 ms, 95% CI: -6.24 to 30.1 ms, p = 0.182). The mean within-patient change in LV repolarisation dispersion from BVP to HBP-CRT was -56.5 ms (95% CI: -70.5 to -42.5 ms, p &amp;lt; 0.001). LV repolarisation dispersion with HBP-CRT was not different from individuals with narrow intrinsic QRS (2.75 ms, 95% CI: -16.2 to 21.7 ms, p = 0.981). The magnitude of reduction in LV repolarisation dispersion with HBP-CRT from intrinsic LBBB appeared similar to the magnitude of LV activation time shortening (-54.9 ms, 95% CI: -68.2 to -41.6 ms, p &amp;lt; 0.001). However, LV activation-recovery interval dispersion was also reduced by HBP-CRT (-44.3 ms, 95% CI: -69.2 to -19.3 ms, p &amp;lt; 0.001). Repolarisation mapping demonstrated normalisation of repolarisation pattern by HBP-CRT. CONCLUSIONS HBP-CRT can normalise repolarisation dispersion, producing more physiological repolarisation compared with BVP, which does not resolve the repolarisation abnormality of LBBB. HBP-CRT improves repolarisation through both activation resynchronization and modulation of action-potential duration. If these acute results translate to longer term outcomes, HBP-CRT may reduce the risk of ventricular arrhythmias in heart failure with LBBB to a greater extent than BVP. Abstract Figure. Epicardial Repolarisation Maps

Abstract 14553: Mitochondrial Calcium Uptake via Mitochondrial Calcium Uniporter Suppress Ventricular Arrhythmia in the Ischemic Heart Failure Mice

Background: Delayed after depolarization by calcium (Ca 2+ ) leak from sarcoplasmic reticulum (SR) via Ryanodine receptor is one of the causes of ventricular arrhythmias (VAs) in heart failure (HF). Ca 2+ uptake into mitochondria via mitochondrial calcium uniporter (MCU) is participated in Ca 2+ handling, but the relationship between VAs in HF and Ca 2+ uptake into mitochondria is unclear. Purpose: We sought to investigate whether increased Ca 2+ uptake into mitochondria via MCU reduces diastolic Ca 2+ leak and suppresses VAs in ischemic HF mice. Methods: Ten-week-old male C57BL/6J mice were divided into 2 groups; sham operation mice (Sham) or HF mice (HF) in which myocardial infarction was induced by left coronary artery ligation. After 4-6 weeks, cardiomyocyte or mitochondria were isolated respectively from the myocardium of Sham and the non-infarct myocardium of HF. Ca 2+ waves (CaWs) were measured on an epifluorescence microscopy. Calcium transients and calcium sparks were measured on a confocal microscope in linescan mode. Mitochondrial Ca 2+ uptake were measured by estimating the extra-mitochondrial Ca 2+ reduction with Fluo-5N on a spectrofluoro-photometer. VAs was induced in the Langendorff perfused hearts. Left ventricular (LV) pressure was measured using a microtip transducer catheter . Results: HF mice showed left ventricular dysfunction and increased heart and lung weights compared to Sham. Kaempferol, a MCU activator, increased mitochondrial Ca 2+ uptake in the isolated mitochondria both in Sham and HF. CaWs and Ca spark frequency in the presence of isoproterenol was attenuated by 10 μM Kaempferol. Kaempferol did not show significant changes in Ca 2+ transient amplitude, however increased the time to 50% decay significantly. The incidence of induced VAs was suppressed by Kaempferol. In vivo measurements, intravenous administration of Kaempferol (5mg/kg) did not show significant changes in hemodynamic parameters in HF mice. Conclusions: Ca 2+ uptake into mitochondria via MCU suppresses VAs in HF. Despite the adverse influence of the traditional antiarrhythmic drugs for HF condition, a novel strategy that promotes Ca 2+ uptake into mitochondria might be a potential therapeutic approach for VA treatment in HF patients.

Suppression of ventricular arrhythmia by mitochondrial calcium uptake via mitochondrial calcium uniporter in the ischemic heart failure mice

Abstract Background In heart failure (HF), diastolic calcium (Ca) leak from sarcoplasmic reticulum (SR) via ryanodine receptor (RyR) causes delayed after depolarization (DAD), leading ventricular arrhythmias (VAs). Recent study reported that Ca uptake into mitochondria via mitochondrial calcium uniporter (MCU) suppress Ca waves (CaWs) and DAD in catecholaminergic polymorphic ventricular tachycardia, in which diastolic Ca leak is thought to be a major cause of VAs as in HF. However, such anti-arrhythmic effect of mitochondrial Ca uptake via MCU remains unclear in HF. Purpose We sought to investigate whether mitochondrial Ca uptake via MCU decreases CAWs and VAs incidence in ischemic HF mice. Methods Ten-week-old male C57BL/6J mice were divided into 2 groups; sham operation mice (Sham) or HF mice (HF) in which myocardial infarction was induced by left coronary artery ligation. After 4–6 weeks, cardiomyocyte or mitochondria was isolated respectively from the myocardium of Sham and the non-infarct myocardium of HF. Influence of MCU activation on Ca dynamics, VA inducibility and left ventricular hemodynamics were evaluated using Kaemenpferol, a MCU activator. Intracellular Ca dynamics and mitochondrial Ca uptake were measured in isolated cardiomyocytes loaded with Fluo-4 AM on an epifluorescence microscopy and by estimating the extra-mitochondrial Ca reduction with Fluo-5N on a spectrofluoro-photometer, respectively. VAs was induced by programmed stimulation in the Langendorff perfused hearts. Left ventricular (LV) pressure was measured using a microtip transducer catheter. Finally, the effect of intravenous administration of Kaempferol (5mg/kg) on hemodynamic parameters was examined 30 minutes after administration in Sham and HF. Results HF mice showed left ventricular dysfunction, as well as the increased heart and lung weights compared to Sham. MCU protein expression in cardiomyocytes did not differ between Sham and HF. Kaempferol increased mitochondrial Ca uptake in the isolated mitochondria both in Sham and HF. The number of the diastolic CaWs was higher in HF compared to Sham. Such increased number of CaWs in HF was attenuated by 10 μM Kaempferol, which was, however, abolished by a MCU blocker Ruthenium Red. The incidence of induced VA was significantly higher in HF than Sham, which was suppressed by Kaempferol. In vivo measurements, intravenous administration of Kaempferol did not show significant changes in hemodynamic parameters in Sham and HF mice. Conclusions Mitochondrial Ca uptake via MCU suppresses CaWs and VAs, but did not change LV hemodynamics in HF. Whereas traditional antiarrhythmic drugs have limited use in heart failure patients, a novel strategy that promotes Ca uptake into mitochondria might be a new and safer option for treating VAs in HF. Funding Acknowledgement Type of funding source: None

P480Aldosterone plasma level as risk factor of ventricular arrhythmias in heart failure with preserved ejection fraction

Abstract Background. Sudden cardiac death, one of the most common types of cardiac death, is most often triggered by ventricular arrhythmia. Plasma aldosterone level has been shown to be an independent risk factor of life-threatening ventricular arrhythmia in patients with left ventricular systolic dysfunction following acute myocardial infarction. Whether either effect also occurs in patients with heart failure and preserved ejection fraction (HFpEF) is currently unknown. Purpose. The study aims to investigate the relationship between plasma aldosterone level and ventricular arrhythmias in long-term HFpEF. Methods. The study included 158 patients (58 men and 100 women, mean age 62.3 ± 7.4 years) with HFpEF (&amp;gt; 50%). All patients had a history of hospitalization due to HFpEF during the last 12 months, left ventricular diastolic dysfunction and / or elevated NT-proBNP level. Median confirmed HFpEF duration was 5 (range 4-8) years. Patients had no history of primary aldosteronism and did not use the mineralocorticoid receptor antagonists during the last 6 weeks. Aldosterone plasma level was measured and 24-hour electrocardiographic monitoring was performed. Results. According to laboratory results 99 patients (67.1%, 95% confidence interval (CI) 59.6-74.2%) had normal (40-160 pg/ml) aldosterone plasma level (nAld) and 59 patients (37.3%, 95% CI 30.0-45.0%) had high (&amp;gt; 160 pg/ml) aldosterone level (hAld). hAld patients more often had QTc prolongation (44.1% versus 18.2%) and ventricular arrhythmias (83.1% vs 61.6%) compared to nAld patients (all Ps &amp;lt; 0.001). The number of ventricular premature complexes in 24 hours was higher in hAld group (median 214, range 64-758) compared to nAld (median 52, range 16-198, P &amp;lt; 0.003). hAld patients more often occurred bigemy, couple ventricular ectopy and nonsustained ventricular tachycardia (39.0% vs 19.0%, P = 0.01). In Cox regression models high aldosterone plasma level was the independent risk factors of QTc prolongation (odds ratio (OR) 1.6, 95% CI 1.1-5.7, P = 0.034) and prognostically unfavorable ventricular arrhythmias (OR 1.8, 95% CI 1.2-6.8, P = 0.024). Conclusion. In long-term HFpEF plasma aldosterone level is significantly related to QTc prolongation as well as ventricular arrhythmias.

Ventricular arrhythmias in heart failure with reduced ejection fraction.

To provide a framework for approaching ventricular arrhythmias in the setting of cardiomyopathy, outline the latest evidence-based recommendations for catheter ablation and device therapy, and discuss novel treatment strategies. Risk stratification of ventricular arrhythmias in systolic heart failure has evolved, with an increasing role for cardiac magnetic resonance imaging to identify underlying substrate and scar burden. Medical therapy for heart failure has greatly improved, and the role of primary prevention defibrillators in nonischemic cardiomyopathy has become more ambiguous. Catheter ablation is superior to medical therapy for arrhythmia control and should be considered early, particularly for premature ventricular complex mediated cardiomyopathy. Novel technologies to deliver energy to previously inaccessible sites include high-impedance catheter irrigants, multicatheter bipolar ablation, specialized catheters with extendable needles, transcoronary ethanol infusion, and stereotactic body radiation therapy. Assessment and management of ventricular arrhythmias in systolic heart failure requires a systematic, multimodality approach aimed at identifying the underlying cause and reversible causes, optimizing medical therapy, assessing need for an implantable cardioverter defibrillator, and considering catheter ablation. Further research will focus on prevention of disease progression, improved risk stratification, and ablation technologies that minimize procedure duration and enable delivery of durable lesions.

Resiniferatoxin reduces ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord in rats

Excessive sympathetic activity is associated with heart failure and ventricular arrhythmias, which regulated by enhanced cardiac sympathetic afferent reflex, which can be blunted by resiniferatoxin, a selective receptor agonist of transient vanilloid potential 1 (TRPV1) + primary sensory afferents. The present study is aimed to determine whether intrathecal resiniferatoxin application affect cardiac sympathetic tone and electrophysiology, furtherly create a new effective strategy to prevent lethal arrhythmias in chronic heart failure. Four weeks after coronary artery occlusion to induce heart failure in rats, RTX (2μg/10 μl) or vehicle was injected intrathecally into the T2/T3 interspace. Cardiac sympathetic nerve activities (CSNA) and cardiac electrophysiology were evaluated two weeks later. Intrathecal resiniferatoxin significantly and selectively abolished the afferent markers expression (TRPV1 and calcitonin gene-related peptide) in dorsal horn and reduced overactivated CSNA. Electrophysiological studies revealed that resiniferatoxin administration intrathecally significantly reversed the prolongation of action potential duration (APD) and APD alternan, reduced the inducibilities of ventricular arrhythmias. Moreover, the over-activated calcium handling related protein CaMKII and RyR2 in heart failure was reversed by resiniferatoxin administration. In conclusion, these results firstly demonstrate that central chemo-ablation of the TRPV1+ afferents in spinal cord prevent heart from ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord, which suggest a novel promising therapeutic method for anti-arrhythmia in heart failure.

The role of desmin alterations in mechanical electrical feedback in heart failure

AimMechanoelectric feedback (MEF) was related to malignant arrhythmias in heart failure (HF). Desmin is a cytoskeleton protein and could be involved in MEF as a mechanoelectrical transducer. In this study, we will discuss the role of desmin alterations in mechanical electrical feedback in heart failure and its mechanisms. MethodsWe used both an in vivo rat model and an in vitro cardiomyocyte model to address this issue. For the in vivo experiments, we establish a sham group, an HF group, streptomycin (SM) group, and an MDL-28170 group. The occurrence of ventricular arrhythmias (VA) was recorded in each group. For the in vitro cardiomyocyte model, we established an NC group, a si-desmin group, and a si-desmin + NBD IKK group. The expression of desmin, IKKβ, p-IKKβ, IKBα, p-NF-κB, and SERCA2 were detected in both in vivo and in vitro experiments. The content of Ca2+ in cytoplasm and sarcoplasmic were detected by confocal imaging in vitro experiments. ResultsAn increased number of VAs were found in the HF group. SM and MDL-28170 can reduce desmin breakdown and the number of VAs in heart failure. The knockdown of desmin in the cardiomyocyte can activate the NF-κB pathway, decrease the level of SERCA2, and result in abnormal distribution of Ca2+. While treatment with NF-κB inhibitor can elevate the level of SERCA2 and alleviate the abnormal distribution of Ca2+. SignificanceOverall, desmin may participate in MEF through the NF-κB pathway. This study provides a potential therapeutic target for VA in HF.

In-hospital ventricular arrhythmia in heart failure patients: 7year follow-up of the multi-centric HEARTS registry.

AimsThe aim of this study was to determine the incidence, predictors, and short‐term and long‐term outcomes associated with in‐hospital sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) collectively termed ventricular arrhythmia (VA) in the heart failure (HF) patients.Methods and resultsThe HEart function Assessment Registry Trial in Saudi Arabia (HEARTS registry) is a prospective national registry of patients with chronic HF from18 tertiary care hospitals across Saudi Arabia. Diagnosis of HF was in accordance with American Heart Association/European Society of Cardiology definition criteria. The registry had enrolled 2610 HF patients during the 14 month recruitment period between October 2009 and December 2010. Occurrence of in‐hospital cardiac events, prognosis, and outcome were monitored during the 7 year follow‐up period. The incidence of in‐hospital VA in HF was 4.2%. VA was more common among men, and mean age was lesser than non‐VA patients (58.5 ± 16: 61.5 ± 15 years; P = 0.042). Smoking and family history of cardiomyopathy were significant risk factors of VA. Previous history of arrhythmia, ST elevated myocardial infarction, infections, and hypotension remained significant predictors of in‐hospital VA associated with three to seven times more risk. Patients with VA had higher rates of in‐hospital events like recurrent HF, haemodialysis, shock, sepsis, major bleeding, intra‐aortic balloon pump, and stroke compared with those without VA, all being highly significant (P < 0.001). After adjustment for age, gender, and co‐morbidities, in‐hospital VA increased the risk of cardiogenic shock by 24 times, dialysis and major bleeding by 10 times, and recurrent congestive HF and pacing by five times. Survival analysis showed that all‐cause mortality was significantly higher in the VA patients (P < 0.001). Presence of VA increased in‐hospital and 1 month mortality to 23 and 17 times, respectively.ConclusionsLower mean age of VA complicated HF patients is a matter of concern in the Saudi population. HF associated with VA increased in‐hospital events and all‐cause mortality indicating poor prognosis and survival. These findings enable risk stratification and reflect on the importance of early recognition of the clinical markers and predictors of VA prompting immediate management.

Substrates and potential therapeutics of ventricular arrhythmias in heart failure

Heart failure (HF) is a clinical syndrome characterized by ventricular contractile dysfunction. About 50% of death in patients with HF are due to fetal ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation. Understanding ventricular arrhythmic substrates and discovering effective antiarrhythmic interventions are extremely important for improving the prognosis of patients with HF and reducing its mortality. In this review, we discussed ventricular arrhythmic substrates and current clinical therapeutics for ventricular arrhythmias in HF. Base on the fact that classic antiarrhythmic drugs have the limited efficacy, side effects, and proarrhythmic potentials, we also updated some therapeutic strategies for the development of potential new antiarrhythmic interventions for patients with HF.

Spiral wave breakup manner in the excitable system with early afterdepolarizations

Early afterdepolarization (EAD) is an important cause of lethal ventricular arrhythmias in heart failure because afterdepolarizations can promote the transition from ventricular tachycardia to fibrillation, which is related to the transition from spiral wave to spatiotemporal chaos. However, it remains unclear about how the EAD results in the breakup of spiral wave. In this paper, we explore the manner of spiral wave breakup induced by EADs under evenly distributed cells. The two-dimensional tissue is simulated with the Greenberg-Hasting cellular automaton model. The normal cells and aging cells are introduced into the model, in which the EAD only occurs in aging cells and can excite the resting cells. The numerical results show that the EAD can produce backward waves as well as forward waves. The EAD has no influence on the behavior of spiral wave in a few cases. The ratio of the number of unaffected spiral waves to the number of all tests is about 26.4%. The EAD can have various effects on spiral wave in other cases. The small influences on spiral wave are that the EAD leads to the meander, drift, and the deformation of spiral wave. The serious influences on spiral wave are that the EAD results in the disappearance and breakup of spiral wave. We find that spiral wave can disappear through the conduction block and transition from spiral wave to target wave. We observe the eight kinds of spiral wave breakups in connection with the excitation of EADs, such as symmetry breaking-induced breakup, nonsymmetry breaking-induced breakup, asymmetric excitation-induced breakup, conduction block-induced breakup, double wave-induced breakup, etc. Spiral wave generally breaks up into multiple spiral waves and spatiotemporal chaos. The ratio of the number of spiral wave breakup to the number of all tests is about 13.8%. However, the ratio of spiral wave breakup can reach about 32.4% under appropriately chosen parameters. The results are basically consistent with the survey results of arrhythmia-induced death rate. Furthermore, we also find that the excitation of EAD can prevent the spiral wave from disappearing and promote the breakup of spiral wave. The physical mechanisms underlying those phenomena are also briefly analyzed.

Kv4.3 Modulates the Distribution of hERG

This study examines the interaction between hERG and Kv4.3. The functional interaction between hERG and Kv4.3, expressed in a heterologous cell line, was studied using patch clamp techniques, western blot, immunofluorescence, and co-immunoprecipitation. Co-expression of Kv4.3 with hERG increased hERG current density (tail current after a step to +10 mV: 26 ± 3 versus 56 ± 7 pA/pF, p < 0.01). Kv4.3 co-expression also increased the protein expression and promoted the membrane localization of hERG. Western blot showed Kv4.3 increased hERG expression by Hsp70. hERG and Kv4.3 co-localized and co-immunoprecipitated in cultured 293 T cells, indicating physical interactions between hERG and Kv4.3 proteins in vitro. In addition, Hsp70 interacted with hERG and Kv4.3 respectively, and formed complexes with hERG and Kv4.3. The α subunit of Ito Kv4.3 can interact with and modify the localization of the α subunit of IKr hERG, thus providing potentially novel insights into the molecular mechanism of the malignant ventricular arrhythmia in heart failure.

Renal Denervation Decreases Susceptibility to Arrhythmogenic Cardiac Alternans and Ventricular Arrhythmia in a Rat Model of Post-Myocardial Infarction Heart Failure

Several studies have shown the beneficial effect of renal denervation (RDN) in the treatment of ventricular arrhythmia, especially in the setting of heart failure (HF). However, the underlying mechanism of antiarrhythmic effect of RDN is unknown. Arrhythmogenic cardiac alternans, particularly spatially discordant repolarization alternans, characterized by simultaneous prolongation and shortening of action potential duration (APD) in different myocardial regions, is central to the genesis of ventricular fibrillation in HF. Whether RDN decreases the susceptibility to arrhythmogenic cardiac alternans in HF has never been addressed before. The authors used a rat model of post-myocardial infarction HF and dual voltage-calcium optical mapping to investigate whether RDN could attenuate arrhythmogenic cardiac alternans that predisposes to ventricular arrhythmias, as well as the hemodynamic effect of RDN in HF. The HF rats had increased body weights, dilated hearts, and lower blood pressure. The HF rats also had longer ventricular APDs and a delay in the decay of the calcium transient, typical electrophysiological features of human HF. Susceptibility to calcium transient alternans, APD alternans, and spatially discordant APD alternans was increased in the HF hearts. RDN significantly attenuated a delay in the decay of the calcium transient, calcium transient and APD alternans, and importantly, the discordant APD alternans, and thereby decreased the incidence of induced ventricular arrhythmia in HF. RDN did not further decrease blood pressure in HF rats. In conclusion, RDN improves calcium cycling and prevents spatially discordant APD alternans and ventricular arrhythmia in HF. RDN does not aggravate hemodynamics in HF.

195 - Dynamic Changes in High Sensitivity Cardiac Troponin I are Associated with Dynamic Changes in Sum Absolute QRST Integral on Surface Electrocardiogram in Acute Decompensated Heart Failure

Background A three-dimensional electrocardiographic (ECG) metric, the sum absolute QRST integral (SAI QRST), predicts ventricular arrhythmias in heart failure (HF) patients with implantable cardioverter defibrillator and mechanical response to cardiac resynchronization therapy. We hypothesized that there is an association between patient-specific changes in SAI QRST and myocardial injury as measured by high-sensitivity troponin I (hsTnI). Methods Sum absolute integral QRST on resting 12-lead ECG and hsTnI were measured simultaneously, every 3 hours, and during 12-hour observation period in a prospective cohort of emergency department patients (n = 398; mean age 57.8 ± 13.2 years; 54% female, 64% black), diagnosed with acute coronary syndrome (ACS, n = 28), acutely decompensated HF (acute decompensated heart failure, n = 35), cardiac non-ACS (n = 19), or noncardiac condition (n = 316). Random-effects linear regression analysis assessed the association of SAI QRST and myocardial injury, with adjustment for demographics (age, sex, race), prevalent cardiovascular disease (myocardial infarction, history of revascularization, stroke, and HF), risk factors (diabetes, smoking, hypercholesterolemia, hypertension, and cocaine use), and left bundle branch block. Results Within the entire cohort, SAI QRST decreased by 3 (95%CI −5 to −1) mV*ms every 3 hours. A 10-fold increase in hsTnI was associated with a 7.7 (0.6–14.9) mV*ms increase in SAI QRST. In the subgroup of acutely decompensated HF patients (n = 35), a 10-fold increase in hsTnI was associated with a 61.0 (5.9–116.1) mV*ms increase in SAI QRST. Conclusion Patient-specific time-varying changes in the surface ECG scalar measure of global electrical heterogeneity, as measured by SAI QRST, and in myocardial injury as measured by hsTnI, are independently and directly associated with each other, likely reflecting a common underlying mechanism.

Dynamic Changes in High-Sensitivity Cardiac Troponin I Are Associated with Dynamic Changes in Sum Absolute QRST Integral on Surface Electrocardiogram in Acute Decompensated Heart Failure.

A three-dimensional electrocardiographic (ECG) metric, the sum absolute QRST integral (SAI QRST), predicts ventricular arrhythmias in heart failure (HF) patients with implantable cardioverter defibrillator and mechanical response to cardiac resynchronization therapy. We hypothesized that there is an association between patient-specific changes in SAI QRST and myocardial injury as measured by high-sensitivity troponin I (hsTnI). Sum absolute integral QRST on resting 12-lead ECG and hsTnI were measured simultaneously, every 3 hours, and during 12-hour observation period in a prospective cohort of emergency department patients (n = 398; mean age 57.8 ± 13.2 years; 54% female, 64% black), diagnosed with acute coronary syndrome (ACS, n = 28), acutely decompensated HF (acute decompensated heart failure, n = 35), cardiac non-ACS (n = 19), or noncardiac condition (n = 316). Random-effects linear regression analysis assessed the association of SAI QRST and myocardial injury, with adjustment for demographics (age, sex, race), prevalent cardiovascular disease (myocardial infarction, history of revascularization, stroke, and HF), risk factors (diabetes, smoking, hypercholesterolemia, hypertension, and cocaine use), and left bundle branch block. Within the entire cohort, SAI QRST decreased by 3 (95%CI -5 to -1) mV*ms every 3 hours. A 10-fold increase in hsTnI was associated with a 7.7 (0.6-14.9) mV*ms increase in SAI QRST. In the subgroup of acutely decompensated HF patients (n = 35), a 10-fold increase in hsTnI was associated with a 61.0 (5.9-116.1) mV*ms increase in SAI QRST. Patient-specific time-varying changes in the surface ECG scalar measure of global electrical heterogeneity, as measured by SAI QRST, and in myocardial injury as measured by hsTnI, are independently and directly associated with each other, likely reflecting a common underlying mechanism.

Abstract 13955: Small Conductance Ca2+-activated K+ Current is Upregulated via the Phospholylation of CaMKII in Cardiac Hypertrophy

Background: Left ventricular hypertrophy is associated with increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca2+-activated K+ (SK) channel is involved in the pathogenesis of ventricular arrhythmias in heart failure. We have recently reported that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased in hypertensive cardiac hypertrophy. Objective: The aim of this study is to test the hypothesis that SK channels activity is increased via the CaMKII-dependent pathway in hypertensive cardiac hypertrophy. Methods and Results: We used normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Whole cell membrane current was recorded in isolated ventricular myocyte by the patch-clamp method, and apamin-sensitive K+ current (IKAS), inhibited by apamin (100 nM), a blocker of SK channel, was evaluated. IKAS at 40 mV was present in SHR, whereas it was hardly detectable in WKY (0.579±0.046 pA/pF vs 0.022±0.062 pA/pF, both n=6, p&lt;0.05). IKAS was almost completely abolished by 1 μM KN-93, an inhibitor of CaMKII, in SHR. Optical recordings of action potential in left ventricular anterior wall revealed that apamin prolonged the late phase of repolarization only in SHR (APD90 113.07±3.62 vs 124.95±3.62 msec, both n=4, p&lt;0.05, and APD50 37.53±4.21 vs 50.48±4.21 msec, both n=4, p&lt;0.05). Western blot analysis of SK channel protein isoform demonstrated that SK2 was significantly increased in SHR compared to WKY (SK2/GAPDH 0.66±0.07 vs 0.40±0.02, both n=6, p&lt;0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHR (pCaMKII/GAPDH 0.80±0.06 vs 0.58±0.06, both n=6, p&lt;0.05) despite comparable total amount of CaMKII between groups. Conclusion: SK channels are upregulated via the enhanced activation of CaMKII in hypertensive cardiac hypertrophy.