Ventricular Refractory Period Research Articles

P6591Arrhythmogenic effects of non-steroidal anti-inflammatory drugs (NSAID)

Abstract Background Clinical and experimental data suggest potential deleterious effects of non-steroidal anti-inflammatory drugs (NSAID) in cardiac disease. The aim of the present study was to characterize potential direct arrhythmogenic effects of ibuprofen or indometacin on cardiac electrophysiology. Methods and results In 13 isolated rabbit hearts, indometacin was administered in increasing concentrations (10, 30 and 50μM) after obtaining baseline data. In further 13 hearts, ibuprofen was infused (10, 30 and 50μM). Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant decrease of QT-interval in indometacin- (50μM: −60ms, p<0.05) and ibuprofen-treated hearts (50μM: −81ms, p<0.01). This was accompanied by a similar decrease of action potential duration (APD). Effective refractory period (ERP) was also reduced by indometacin (−24ms, p<0.05) and ibuprofen (−22ms, p<0.05) while spatial dispersion of repolarisation remained stable with both drugs. Programmed ventricular stimulation and burst stimulation were employed for provocation of ventricular arrhythmias. In the indomethacin group 7 episodes of ventricular arrhythmias were inducible at baseline. The incidence was increased to 22 (10μM), 37 (30μM) and 51 (50μM) with higher concentrations of indometacin. In the ibuprofen group 15 episodes were inducible at baseline. After infusion of 10μM ibuprofen, also 15 episodes of ventricular arrhythmias occurred while 34 episodes were inducible with 30μM ibuprofen. Conclusion Infusion of the NSAID ibuprofen and indometacin resulted in a significant abbreviation of myocardial repolarization and a shortening of ventricular refractory periods. This resulted in an enhanced inducibility of ventricular arrhythmias and may contribute to the proposed deleterious effects of NSAID in the presence of cardiac disease.

Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart.

A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1μM), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78±10 vs. 68±10 ms) and after atropine (76±8 vs. 67±10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53±8 vs. 42±7 ms and 50±6 vs. 40±6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5±1.5% vs. 15.1±3.8%) and, decreased after atropine (15.1±3.8% vs. 12.2±2.4%) in the control group. The trained group showed higher NE values before (0.40±0.04 vs. 0.36±0.05) and after atropine (0.37±0.04 vs. 0.34±0.06; p = 0.08). Training decreased the CV of NE both before (23.3±2% vs. 25.2±4%; p = 0.08) and after parasympathetic blockade (22.6±1% vs. 26.1±5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34±8 vs. 41±5), and increased after atropine in the control group (41±5 vs. 48±9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.

Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( IKslow,1) (conducted by KV1.5) and Ito,f (conducted by KV4) and an increase in IKslow,2 (conducted by KV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where KV2.1 was also detected in both Kcne5-/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducing KV2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of KV2.1 in mouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length.

Aim: The cardiac electrophysiology of mice and rats has been analyzed extensively, often in the context of pathological manipulations. However, the effects of beating rate on the basic electrical properties of the rodent heart remain unclear. Due to technical challenges, reported electrophysiological studies in rodents are mainly from ex vivo preparations or under deep anesthesia, conditions that might be quite far from the normal physiological state. The aim of the current study was to characterize the ventricular rate-adaptation properties of unanesthetized rats and mice.Methods: An implanted device was chronically implanted in rodents for atrial or ventricular pacing studies. Following recovery from surgery, QT interval was evaluated in rodents exposed to atrial pacing at various frequencies. In addition, the frequency dependence of ventricular refractoriness was tested by conventional ventricular programmed stimulation protocols.Results: Our findings indicate total absence of conventional rate-adaptation properties for both QT interval and ventricular refractoriness. Using monophasic action potential recordings in isolated mice hearts we could confirm the previously reported shortening of the action potential duration at fast pacing rates. However, we found that this mild shortening did not result in similar decrease of ventricular refractory period.Conclusion: Our findings indicate that unanesthetized rodents exhibit flat QT interval and ventricular refractory period rate-dependence. This data argue against empirical use of QT interval correction methods in rodent studies. Our new methodology allowing atrial and ventricular pacing of unanesthetized freely moving rodents may facilitate more appropriate utility of these important animal models in the context of cardiac electrophysiology studies.

Measurement variability of right atrial and ventricular monophasic action potential and refractory period measurements in the standing non-sedated horse

BackgroundIn human and veterinary medicine, monophasic action potential (MAP) analysis and determination of local refractory periods by contact electrode technique gives valuable information about local cardiac electrophysiological properties. It is used to investigate dysrhythmias and the impact of drugs on the myocardium. Precise measurement of total MAP duration is difficult, therefore the MAP duration is usually determined at a repolarization level of 90% (APD90). Until now, no studies are published about the feasibility of this technique in the standing non-sedated horse. In 6 healthy Warmblood horses, on two different days, an 8F quadripolar contact catheter was passed through a jugular introducer sheath and placed under ultrasound guidance at the level of the intervenous tubercle or right atrial free wall (RA), and in the right ventricular apex (RV) to record the MAP. The MAP amplitude and APD90 were measured at a resting sinus rhythm (heart rate of 30-42 bpm) and at pacing cycle lengths (PCL) of 1000 and 600 ms. The effective refractory period (ERP) was determined at PCL of 1000 and 600 ms.ResultsThe overall mean (±SD) APD90 (rest), APD90 (1000) and APD90 (600) were 263 ± 39 ms, 262 ± 41 ms, 236 ± 47 ms for the RA and 467 ± 23 ms, 412 ± 38 ms, 322 ± 29 ms for the RV. The mean ERP1000 and ERP600 were 273 ± 24 ms and 256 ± 22 ms for the RA and 386 ± 40 ms and 293 ± 30 ms for the RV. The measurement variability for the amplitude, APD90 and ERP measurements in the RA ranged between 36 and 44, 9–22 and 7–8%, respectively. The measurement variability for the amplitude, APD90 and ERP measurements in the RV ranged between 49 and 66, 6–7 and 10–12%, respectively.ConclusionsRA and RV MAP duration and ERP can be obtained by a contact electrode in standing non-sedated horses. The measurement variability varies with catheter location.

Fast nonclinical ventricular tachycardia inducible after ablation in patients with structural heart disease: Definition and clinical implications

Noninducibility of ventricular tachycardia (VT) with an equal or longer cycle length (CL) than that of the clinical VT is considered the minimum ablation endpoint in patients with structural heart disease. Because their clinical relevance remains unclear, fast nonclinical VTs are often not targeted. However, an accepted definition for fast VT is lacking. The shortest possible CL of a monomorphic reentrant VT is determined by the ventricular refractory period (VRP). The purpose of this study was to propose a patient-specific definition for fast VT based on the individual VRP (fVTVRP) and assess the prognostic significance of persistent inducibility after ablation of fVTVRP for VT recurrence. Of 191 patients with previous myocardial infarction or with nonischemic cardiomyopathy undergoing VT ablation, 70 (age 63 ± 13 years; 64% ischemic) remained inducible for a nonclinical VT and composed the study population. FVTVRP was defined as any VT with CL ≤VRP400 + 30 ms. Patients were followed for VT recurrence. After ablation, 30 patients (43%) remained inducible exclusively for fVTVRP and 40 (57%) for any slower VT. Patients with only fVTVRP had 3-year VT-free survival of 64% (95% confidence interval [CI] 46%-82%) compared to 27% (95% CI 14%-48%) for patients with any slower remaining VT (P = .013). Inducibility of only fVTVRP was independently associated with lower VT recurrence (hazard ratio 0.38; 95% CI 0.19-0.86; P = .019). Among 36 patients inducible for any fVTVRP, only 1 had recurrence with fVTVRP. In patients with structural heart disease, inducibility of exclusively fVTVRP after ablation is associated with low VT recurrence.

Cohort of Patients Referred for Brugada Syndrome Investigation in an Electrophysiology Service - 19-Year Registry.

BackgroundBrugada syndrome (SBr) is an arrhythmic condition characterized by ST-T segment abnormalities in the right precordial leads associated with a high risk of ventricular arrhythmias and sudden death. Local data regarding the clinical characteristics of patients with a typical electrocardiographic (ECG) pattern undergoing electrophysiological study are scarce.ObjectiveTo evaluate patients with an ECG pattern suggestive of SBr referred for electrophysiological evaluation in a specialized center.MethodsCohort study of patients referred for electrophysiological study because of an ECG pattern compatible with SBr between January 1998 and March 2017.ResultsOf the 5506 procedures, 35 (0.64%) were for SBr investigation, 25 of which (71.42%) were performed in men. The mean age was 43.89 ± 13.1 years. The ECG patterns were as follows: type I, 22 (62.85%); type II, 12 (34.30%); and type III, 1 (2.85%). Twenty-three patients (65.7%) were asymptomatic, 6 (17.14%) had palpitations, 5 (14.3%) had syncope, and 3 (8.6%) had a family history of sudden death. Electrophysiological study induced ventricular tachyarrhythmias in 16 cases (45.7%), the mean ventricular refractory period being 228 ± 36 ms. Ajmaline / procainamide was used in 11 cases (31.4%), changing the ECG pattern to type I in 7 (63.6%). Sixteen cases (45.7%) received an implantable cardioverter defibrillator (ICD). In a mean 5-year follow-up, 1 of the 16 patients (6.25%) with ICD had appropriate therapy for ventricular fibrillation. There was no death. Other arrhythmias occurred in 4 (11.4%) cases.ConclusionsMost patients are men, and a type I ECG pattern is the main indication for electrophysiological study. Class IA drugs have a high ECG conversion rate. The ICD event rate was 6%.

Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.

Normal Values for Heart Electrophysiology Parameters of Healthy Swine Determined on Electrophysiology Study.

Swine are a well-recognized animal model for human cardiovascular diseases. Despite the widespread use of porcine model in experimental electrophysiology, still no reference values for intracardiac electrical activity and conduction parameters determined during an invasive electrophysiology study (EPS) have been developed in this species thus far. The aim of the study was to develop a set of normal values for intracardiac electrical activity and conduction parameters determined during an invasive EPS of swine. The study included 36 healthy domestic swine (24-40 kg body weight). EPS was performed under a general anesthesia with midazolam, propofol and isoflurane. The reference values for intracardiac electrical activity and conduction parameters were calculated as arithmetic means ± 2 standard deviations. The reference values were determined for AH, HV and PA intervals, interatrial conduction time at its own and imposed rhythm, sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), anterograde and retrograde Wenckebach points, atrial, atrioventricular node and ventricular refractory periods. No significant correlations were found between body weight and heart rate of the examined pigs and their electrophysiological parameters. The hereby presented reference values can be helpful in comparing the results of various studies, as well as in more accurately estimating the values of electrophysiological parameters that can be expected in a given experiment.

Restitution analysis of alternans using dynamic pacing and its comparison with S1S2 restitution in heptanol-treated, hypokalaemic Langendorff-perfused mouse hearts.

Action potential duration (APD) and conduction velocity restitution explain the dependence of these parameters on the previous diastolic interval (DI). It is considered to be an adaptive mechanism for preserving diastole at fast heart rates. Hypokalaemia is known to induce ventricular arrhythmias that could be prevented by heptanol, the gap junction uncoupler, mediated through increases in ventricular refractory period (VERP) without alterations in APDs. The present study investigated alternans and restitution properties during normokalaemia, hypokalaemia alone or hypokalaemia with heptanol (0.1 mM) in Langendorff-perfused mouse hearts using a dynamic pacing protocol. APD90 alternans were elicited in the epicardium and endocardium during normokalaemia. Hypokalaemia increased the amplitudes of epicardial APD90 alternans when basic cycle lengths (BCLs) were ≤65 msec, which was associated with increases in maximum APD90 restitution gradients, critical DIs and APD90 heterogeneity. Heptanol (0.1 mM) did not exacerbate or reduce the APD90 alternans or alter these restitution parameters further. By contrast, endocardial APD90 alternans did not show increases in amplitudes during hypokalaemia at short BCLs studied, and restitution parameters were also unchanged. This was true whether in the presence or absence of 0.1 mM heptanol. The study demonstrates that anti-arrhythmic effects of heptanol exerted during hypokalaemia occurred despite exacerbation of APD90 alternans. This would suggest that even in the presence of arrhythmogenic APD90 alternans, arrhythmias could still be prevented by influencing VERP alone. Restitution data obtained here by dynamic pacing were compared to previous data from S1S2 pacing.

Performance of a specific algorithm to minimize right ventricular pacing: A multicenter study

In Boston Scientific dual-chamber devices, the RYTHMIQ algorithm aims to minimize right ventricular pacing. We evaluated the performance of this algorithm determining (1) the appropriateness of the switch from the AAI(R) mode with backup VVI pacing to the DDD(R) mode in case of suspected loss of atrioventricular (AV) conduction and (2) the rate of recorded pacemaker-mediated tachycardia (PMT) when AV hysteresis searches for restored AV conduction. In this multicenter study, we included 157 patients with a Boston Scientific dual-chamber device (40 pacemakers and 117 implantable cardioverter-defibrillators) without permanent AV conduction disorder and with the RYTHMIQ algorithm activated. We reviewed the last 10 remote monitoring-transmitted RYTHMIQ and PMT episodes. We analyzed 1266 episodes of switch in 142 patients (90%): 207 (16%) were appropriate and corresponded to loss of AV conduction, and 1059 (84%) were inappropriate, of which 701 (66%) were related to compensatory pause (premature atrial contraction, 7%; premature ventricular contraction, 597 (56%); or both, 27 (3%)) or to a premature ventricular contraction falling in the post-atrial pacing ventricular refractory period interval (219, 21%) and 94 (10%) were related to pacemaker dysfunction. One hundred fifty-four PMT episodes were diagnosed in 27 patients (17%). In 85 (69%) of correctly diagnosed episodes, the onset of PMT was directly related to the algorithm-related prolongation of the AV delay, promoting AV dissociation and retrograde conduction. This study highlights some of the limitations of the RYTHMIQ algorithm: high rate of inappropriate switch and high rate of induction of PMT. This may have clinical implications in terms of selection of patients and may suggest required changes in the algorithm architecture.

First clinical trial of specific IKACh blocker shows no reduction in atrial fibrillation burden in patients with paroxysmal atrial fibrillation: pacemaker assessment of BMS 914392 in patients with paroxysmal atrial fibrillation.

To assess the efficacy of BMS 914392 on atrial fibrillation (AF) burden reduction in 20 patients with pacemakers and paroxysmal atrial fibrillation (PAF). BMS 914392 is a potent, selective, oral inhibitor of the IKACh current and has been shown to suppress AF, whilst having no effect on the ventricular refractory period. This is the first efficacy study of BMS 914392 in patients with PAF. The study was a four-way, crossover, double-blind design. A total of 20 patients with PAF and dual-chamber pacemakers were recruited. The pacemakers allowed beat-to-beat monitoring. Anti-arrhythmic drugs were withdrawn. Patients received low-dose (10 mg OD), medium-dose (10 mg TDS), and high-dose (20 mg TDS) BMS 914392 or placebo for 3 weeks before being crossed to the next phase. Patients underwent a washout period, four treatment phases and a final washout phase. Atrial fibrillation burden was downloaded from their pacemakers at the end of each study phase. BMS 914392 did not reduce AF burden when compared with placebo (10 mg OD P = 0.56, 10 mg TDS P = 0.22, 20 mg TDS P = 0.23). Heart rate and corrected QT (QTc) were not affected by BMS 914392. Adverse event (AE) rates did not differ from placebo in any of the treatment groups, with no serious AEs recorded. BMS 914932 has not been shown to reduce AF burden in patients with PAF and pacemakers using beat-to-beat pacemaker monitoring throughout the study. BMS 914392 was well tolerated and did not affect QTc or reduce heart rate. Clinicaltrials.gov: NCT01356914.

Failure of a cardiac resynchronization therapy-defibrillator sensing lead to correctly detect a fatal arrhythmia because of a newly emerged intraventricular conduction abnormality induced by cardiac sarcoidosis

Here, we report the case of a 59-year-old man with cardiac sarcoidosis (CS) who experienced the failure of a cardiac resynchronization therapy-defibrillator (CRT-D) because the sensing lead failed to operate correctly. The sensing lead, which was inserted into the right ventricular outflow tract (RVOT), failed because of a newly emerged intraventricular conduction abnormality (IVCA) resulting from the progression of the CS). For determining the cause of the failure, an electrophysiological study was conducted with catheters placed to the right ventricle apex (RVA) and RVOT. The IVCA was not seen during rapid pacing at 180 bpm but was observed during rapid pacing at over 190 bpm; however, this phenomenon may also develop as a result of the restitution property of conduction velocity due to the relative ventricular refractory period, even in the absence of CS. A voltage map recorded by the CARTO mapping system revealed a markedly low voltage area between the RVA and RVOT. Therefore, we assumed the heart rate for the ventricular tachyarrhythmia was underestimated by the CRT-D sensing lead and had thereby led to its operation failure. An appropriate intervention was accomplished by inserting an additional sensing lead to the RVA, and the same phenomenon has not occurred to date. To our knowledge, no similar report has previously been published, and thus makes this case an extremely rare and didactic case. Key words: cardiac sarcoidosis, CRT-D, under-count, ventricular tachyarrhythmia.

The kidney-heart connection during electrical storm: from bedside back to bench.

One of the most challenging clinical pre-sentations for cardiologists is the ‘electrical storm’ of incessant ventricular tachycardia (VT). This often occurs in patients with previous myocardial infarctions or non-ischaemic cardiomyopathies, who are already on the maximally tolerated doses of cardiac medications (including β-blockers). Such patients may have already been implanted with a cardiac defibrillator (ICD) and are therefore likely to receive multiple therapies from their device. The cardiologist corrects plasma electrolytes, administers additional antiarrhythmic drugs (such as amiodarone and lidocaine) and reprograms the ICD in an attempt to suppress the storm, but ultimately many patients will require general anaesthesia and emergency ablation of their VT. This is a perilous ‘last-ditch’ procedure with limited long-term success. It may, however, stabilize the patient long enough for consideration of heart transplantation. Case reports and small case series have highlighted novel procedures aimed at reducing cardiac sympathetic drive as possible adjunct therapies in such patients. This builds on over 50 years of intense research linking cardiac sympathetic drive to arrhythmogenicity (Shen & Zipes, 2014). Even sedation or general anaesthesia in itself can be antiarrhythmic, because sympathetic hyperactivity during the electrical storm can be reinforced by chest pain from VT and ICD shocks received whilst still conscious. Recent publications have advocated stellatectomy (Schwartz, 2014), thoracic epidural anaesthesia and renal sympathetic nerve denervation (Bradfield et al. 2014) as potential approaches. In this context, the paper by Huang et al. (2014) in this issue of Experimental Physiology is of particular interest. In anaesthetized dogs following renal sympathetic denervation or a sham procedure, Huang et al. (2014) performed catheter-based measurements of ventricular refractory period and action potential duration (APD) restitution at multiple epicardial sites. This is the first publication to my knowledge to characterize ventricular electrophysiological changes in response to renal denervation. Interestingly, the flattening in the slope of the APD restitution curve, prolongation of the refractory period and reduced ability to induce APD alternans mirrors previous reports of the action of selective cardiac sympathetic stimulation on these parameters. Moreover, renal denervation reduced the incidence of ventricular arrhythmias in the hour following ligation of the left anterior descending coronary artery. The paper by Huang et al. (2014) also follows the recently published failure of renal sympathetic nerve denervation to produce a significant reduction in blood pressure in patients with resistant hypertension when compared with a sham procedure in the Symplicity HTN-3 trial (Bhatt et al. 2014). There are a number of interesting methodological differences in the approach to renal denervation taken by Huang et al. (2014) compared with that used in Symplicity HTN-3. In human subjects, renal denervation is usually undertaken via an endovascular approach using a radiofrequency ablation catheter introduced via the femoral artery. Discrete lesions are made circumferentially in a spiral pattern along both renal arteries, but unfortunately there is no way of determining that successful denervation has been achieved during the procedure. Huang et al. (2014) performed epivascular ablation via small bilateral retroperitoneal flank incisions. Furthermore, they demonstrated as evidence of successful denervation that high-frequency electrical stimulation of the adventitia no longer caused hypertension following ablation. This is a useful and novel approach, and a similar clinical end-point of success in patients is clearly needed. The fact that afferent and efferent nerves innervate the kidney through a plexus surrounding the renal arteries has long been appreciated. Renal afferent nerves are able to stimulate the hypothalamus in response to renal hypoxia and ischaemia and thereby increase global sympathetic activity. Likewise, sympathetic efferent nerves cause renin release, sodium and water retention, and through angiotensin II, reinforce sympathetic drive both centrally and by increasing catecholamine release peripherally (Singh et al. 2014). Renal denervation as a method to reduce cardiac sympathetic drive therefore appears logical, although many questions regarding this approach remain unanswered. Can a reduction in cardiac sympathetic activity following renal denervation be measured directly? Do the electrophysiological changes in APD and refractory period observed in the normal canine heart also occur in ischaemic and non-ischaemic cardiomyopathy? How long do these electrophysiological changes persist for and what are the underlying mechanisms by which they occur? In the clinical case reports of renal denervation for electrical storm, patients were already maximally β-blocked. Is the antiarrhythmic action of this procedure therefore independent of β-receptors, and if so, which other receptors or sympathetic cotransmitters play a role? This promises to be an active area of research, which may help us to identify new antiarrhythmic targets as well as refine our approach to renal denervation in patients. Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/expphysiol;99/11/1451 None declared. N.H. is a British Heart Foundation CRE Intermediate Fellow at the University of Oxford.

The consequences of contracting early and often

Frequent premature ventricular contractions (PVCs) are associated with structural heart disease and an increase in sudden and overall mortality. PVCs themselves, if in sufficient numbers, may be associated with the development of a reversible form of cardiomyopathy (CM). A number of small series have suggested that PVC density and features, such as QRS duration, location of origin, and coupling, may increase the predilection to cause CM in structurally normal and diseased hearts. Moreover, elimination of PVCs by catheter ablation has improved ventricular function. Thus, frequent PVCs are a previously underappreciated target for therapeutic intervention in CM. However, the fundamental triggers for the development of myopathy and the details of structural and electrical remodeling have been impeded by the development of a suitable model system. Pacing has been exploited to generate reversible forms of tachycardia-induced CM. Huizar et al have used a premature pacing algorithm to create a model of PVC-induced CM in structurally normal hearts. The algorithm generates a high PVC burden, in this case in a bigeminal pattern pacing from the right ventricular apex. PVC pacing increased the heart rate, on average, from 80 bpm to approximately 130 bpm over 4 months of pacing. Previous characterization of this model demonstrated reversible cardiac dilation and reduced ejection fraction with a compromise in repolarizing reserve evidenced by an increase in ventricular refractory periods. This occurred in the absence of inflammation, fibrosis, increased programmed cell death, or compromised oxidative phosphorylation. In a study reported in this issue of HeartRhythm, Wang et al describe heterogeneously prolonged action potential durations (APD) in myocytes isolated from the left ventricular free wall, associated with reductions in the transient outward (Ito) and inward rectifier (IK1) potassium currents without significant changes in the delayed rectifier (IKr, IKs) currents. The decrease in repolarizing reserve is associated

Cardiac Resynchronization Therapy Plus Coupled Pacing Improves Acutely Myocardial Function in Heart Failure Patients

Coupled pacing (CP), which consists of an additional beat delivered after ventricular refractory period, has been proposed to reduce ventricular rate and increase ventricular contractility. We hypothesized that CP may be added to cardiac resynchronization therapy (CRT) to improve CRT effect in heart failure (HF) patients. The study included 20 consecutive HF patients in sinus rhythm referred for CRT-defibrillator (CRT-D) implantation (baseline left ventricular ejection fraction [LVEF] 27 ± 6%, baseline QRS duration 149 ± 33 ms, age = 63 ± 11 years). CP associated with CRT (CRT + CP) was delivered during CRT-D implantation from the right and left ventricular leads simultaneously. Echocardiography data were collected at baseline, during CRT and CRT + CP to assess changes in LVEF, cardiac output (CO), longitudinal global strain assessed by speckle tracking, and LV dyssynchrony (opposing wall delay using tissue Doppler imaging). Compared to the conventional CRT, heart rate (HR) markedly decreased during CRT + CP (79 ± 20 beats/min vs 51 ± 8 beats/min, P < 0.0001) and was associated with a significant increase in LVEF (30 ± 8% vs 35 ± 8%, P = 0.0002) and peak of longitudinal global strain (-6 ± 2% vs -8 ± 2%, P < 0.0001). Importantly, during CRT + CP, CO increased (3.8 ± 1.0 L/min vs 4.4 ± 1.4 L/min, P = 0.004) and cardiac synchronicity remained unchanged (38 ± 24 ms for CRT alone vs 27 ± 18 ms for CRT + CP, P = 0.1). In sinus rhythm HF patients, acute CP application in addition to CRT decreases HR and contributes to myocardial contractility and CO improvement without deleterious impact on ventricular synchronicity.

Abstract 18485: Transgenic Expression of a Kir6.1 Gain-of-Function Mutation in the Mouse Heart Results in Av Nodal Conduction Abnormalities

While consensus exists that Kir6.2 gives rise to the pore forming subunit of KATP channels in mouse heart, there is growing evidence that Kir6.1 is also present in mouse cardiomyocytes. Furthermore, Kir6.1 gain-of-function mutation (GOF) is associated with Early Repolarization (ERS) and Brugada Syndromes. It is unclear, however, whether the consequences of the Kir6.1 GOF result from abnormalities in cardiomyocytes, or other cell types in the heart. To assess the consequence of Kir6.1 GOF in cardiomyocytes, we generated Kir6.1[G343D] (GOF) mice under α-myosin heavy chain promoter. Patch-clamp data shows decreased sensitivity to ATP inhibition in GOF myocytes (EC50 = 43.5 ± 6.1 μM in GOF, 8.3 ± 3.1 μM in WT; p = 0.0007), with no significant change in peak current density (WT: 128 ± 23 pA/pF; GOF: 103 ± 24 pA/pF, p = NS). In vivo electrophysiology testing using programmed electrical stimulation (PES) shows slowed sinus cycle length (SCL, ms) (WT:120 ± 8.7; GOF: 134.0 ± 19.7, p = 0.04), and prolonged atrioventricular interval (AVI, ms) for GOF (WT: 38.0 ± 4.3; GOF: 46.7 ± 4.3, p = 0.02). Kir6.1 GOF mice show prolonged atrioventricular effective refractory period (AVERP, ms) (WT: 49.2 ± 6.6; GOF: 65.7 ± 8.4, p = 0.0001) and diminished anterograde AV node conduction, as seen by right atrial (RA) pacing resulting in 1:1 capture (pacing cycle length, ms) (WT: 73.0 ± 8.4, GOF: 85.0 ± 5.0, p = 0.02), Wenckebach (WT: 68.0 ± 8.4; GOF: 79.3 ± 6.1, p = 0.049) and 2:1 capture (WT: 54 ± 4.2; GOF: 63.6 ± 6.3, p = 0.049). However, the Kir6.1 GOF mice did not show any differences in either atrial refractory period (AERP, ms) (WT: 37.5 ± 2.7, GOF: 37.1 ± 10.75, p = NS) or ventricular refractory period (VERP, ms) (WT: 45 ± 9.4, GOF: 44.2 ± 7.36, p = NS). In summary, Kir6.1 GOF mice display significant AV nodal conduction abnormalities, providing a potential model of Kir6.1-dependent ERS.

Congenital short QT syndrome: Landmarks of the newest arrhythmogenic cardiac channelopathy

Congenital or familial short QT syndrome is a genetically heterogeneous cardiac channelopathy without structural heart disease that has a dominant autosomal or sporadic pattern of transmission affecting the electric system of the heart. Patients present clinically with a spectrum of signs and symptoms including irregular palpitations due to episodes of paroxysmal atrialfibrillation, dizziness and fainting (syncope) and/or sudden cardiac death due to polymorphic ventricular tachycardia and ventricular fibrillation. Electrocardiographic (ECG) findings include extremely short QTc intervals (QTc interval ≤330 ms) not significantly modified with heart rate changes and T waves of great voltage witha narrow base. Electrophysiologic studies are characterized by significant shortening of atrial and ventricular refractory periods and arrhythmias induced by programmed stimulation. A few families have been identified with specific genotypes: 3 with mutations in potassium channels called SQT1 (Iks), SQT2 (Ikr) and SQT3 (Ik1). These 3 potassium channel variants are the "genetic mirror image" of long QT syndrome type 2, type 1 and Andersen-Tawil syndrome respectively because they exert opposite gain-of-function effects on the potassium channels in contrast to the loss-of-function of the potassium channels in the long QT syndromes. Three new variants with overlapping phenotypes affecting the slow inward calcium channels havealso been described. Finally, another variant with mixed phenotype affecting the sodium channel was reported. This review focuses the landmarks of this newest arrhythmogenic cardiac channelopathy on the main clinical, genetic, and proposed ECG mechanisms. In addition therapeutic options and the molecular autopsy of this fascinating primary electrical heart disease are discussed.

The funny and not-so-funny effects of dronedarone

The funny and not-so-funny effects of dronedarone

Myths and realities of the cardiac vagus.

There is continuing belief that cardiac parasympathetic postganglionic fibres are sparse or absent from the ventricles. This review of the literature shows that the supposition is a myth. Early studies considered that fine silver-stained fibres coursing amongst ventricle myocardial cells were most likely cardiac parasympathetic postganglionic fibres. The conclusions were later supported by acetyl cholinesterase staining using a method that appeared not to be associated with noradrenaline nerve fibres. The conclusion is critically examined in the light of several recent histological studies using the acetyl cholinesterase method and also a more definitive technique (CHAT), that suggest a widespread location of parasympathetic ganglia and a relatively dense parasympathetic innervation of ventricular muscle in a range of mammals including man. The many studies demonstrating acetylcholine release in the ventricle on vagal nerve stimulation and a high density of acetylcholine M2 receptors is in accord with this as are tests of ventricular performance from many physiological studies. Selective control of cardiac functions by anatomically segregated parasympathetic ganglia is discussed. It is argued that the influence of vagal stimulation on ventricular myocardial action potential refractory period, duration, force and rhythm is evidence that vagal fibres have close apposition to myocardial fibres. This is supported by clear evidence of accentuated antagonism between sympathetic activity and vagal activity in the ventricle and also by direct effects of vagal activity independent of sympathetic activity. The idea of differential control of atrial and ventricular physiology by vagal C and vagal B preganglionic fibres is examined as well as differences in chemical phenotypes and their function. The latter is reflected in medullary and supramedullary control. Reference is made to the importance of this knowledge to understanding the normal physiology of cardiac autonomic control and significance to pathology.