Ventricular Refractory Period Research Articles

Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 +/- 45 vs post: 235 +/- 47; P = 0.003) but not during 400-ms (pre: 275 +/- 28 vs post: 248 +/- 32; P = 0.490) or 600-ms (pre: 252 +/- 42 vs post: 179 +/- 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 +/- 7 vs post: 245 +/- 9; P = 0.028) but not during the 500-ms (pre: 248 +/- 7 vs post: 253 +/- 9; P = 0.150) or 600-ms (pre: 254 +/- 8 vs post: 259 +/- 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.

Short QT Syndrome

The past 2 decades have witnessed the emergence of many disease states related to ion-channel disorders, the so-called "channelopathies," usually associated with structurally normal hearts. The initial emphasis was directed toward the congenital long QT syndrome and the Brugada syndrome. Recently, the hereditary short QT syndrome has emerged as yet another rare channelopathy. This autosomal dominant syndrome can afflict infants, children, or young adults; often a remarkable family background of sudden cardiac death is elucidated. The electrocardiogram is characterized by a strikingly short QT interval (typically <320 milliseconds); virtual absence of the ST segment; and tall, peaked, narrow-based T waves. There is a marked propensity for paroxysmal atrial fibrillation, and increased risk for sudden cardiac death from ventricular tachyarrhythmias. At electrophysiology study, short atrial and ventricular refractory periods are found, with easily inducible atrial fibrillation and polymorphic ventricular tachycardia with programmed electrical stimulation. Gain-of-function mutations in 3 genes encoding potassium channels have been identified, which explain the abbreviated repolarization seen in this condition. The suggested treatment is an implantable cardioverter-defibrillator, though the possibilities of inappropriate shocks have caused some concern, especially in younger patients. The ability of quinidine and disopyramide to prolong the QT interval has the potential to be effective pharmacological therapy for patients with short QT syndrome, but awaits additional confirmatory clinical data.

Recurrent syncope associated with a distinct ECG pattern consisting of short QT interval, early repolarization and atrioventricular block

A 17-year-old apparently healthy individual with recurrent syncopal episodes during walking was referred to our institution for further evaluation. Baseline ECG showed sinus rhythm with prominent J-waves and ST-segment elevation and a short QT interval of 320 ms (Fig. 1). The corrected QT (QTc) interval was 283, 295 and 288 m using the Bazett’s, the Fredericia’s and the Framingham’s formula, respectively. There was no family history of sudden cardiac death. Transthoracic echocardiography revealed a structurally normal heart. Exercise treadmill test failed to induce any arrhythmic or ischemic events, while the early repolarization features (J-waves and ST-segment elevation) were normalized. A drug-free tilt table test was negative for neurocardiogenic syncope. Holter monitoring revealed several asymptomatic episodes of abrupt advanced AV block during day and night, with a maximum pause of 4.2 s (Fig. 2). No episodes of atrial or ventricular arrhythmic events were recorded. Late potentials (RMS-40, LAS-40) as detected and calculated by signal-averaged ECG were positive. Sodium channel blocking test with procainamide (10 mg/kg) failed to induce the diagnostic type 1 ECG pattern of Brugada syndrome (BS) in the right precordial leads. Quinidine administration (900 mg) normalized the absolute QT and QTc values to 380 and 425 m, respectively. Electrophysiological study (EPS) demonstrated normal AH (110 ms) and HV (49 ms) intervals. Right ventricular programmed stimulation at three basic cycle lengths (600, 500 and 430 m) with up to three extra stimuli failed to induce any ventricular arrhythmias. The atrial and ventricular refractory periods were 190 and 200 ms, respectively. No atrial arrhythmias were induced and no episodes of AV block were documented during EPS. A dual-chamber cardioverter defibrillator (ICD) was implanted. The patient was asymptomatic after a 12-month follow-up period. Genomic DNA was prepared from peripheral blood lymphocytes using standard methods. The entire open reading frame of the KCNQ1, KCNH2 and SCN5A genes was analyzed. The following non-coding genetic variants were identified: KCNQ1 (1638 G [ A S546S), KCNH2 (G3152 ? 22 G [ A) and SCN5A (5457 C [ T D1819D, 3183 G [ A E1061E). The KCNJ2, CACNA1C and CACNB2 genes were not screened for mutations.

Human Model Simulating Right Ventricular Outflow Tract Tachycardia by High‐Frequency Stimulation in the Left Pulmonary Artery: Autonomics and Idiopathic Ventricular Arrhythmias

Frequent monomorphic premature ventricular contractions (PVC) and/or ventricular tachycardia (VT) in patients with structurally normal heart usually arise from the right ventricular outflow tract (RVOT). An animal model simulating RVOT tachycardia by high-frequency stimulation (HFS) of the sympathetic input to the proximal pulmonary artery (PA) has been previously described. The aim of this study was to similarly induce RVOT tachycardia in humans. In 9 patients with no history of ventricular arrhythmias, a circumferential catheter was placed in the left, main, and proximal PA to contact the endovascular circumference of the PA. A 50-ms train of HFS (200 Hz/0.3 ms pulse duration), coupled to atrial pacing, was applied at each bipolar pair of the circumferential catheter. The coupling interval was adjusted so that the 50-ms train occurred during the ventricular refractory period. In 6 out of 9 patients, HFS in the left PA during dobutamine infusion induced monomorphic PVCs and/or VT with left bundle branch block (LBBB) morphology and inferior axis at an average stimulation level of 12.5 +/- 2.7 V. HFS in the main PA and in the proximal PA did not induce any ventricular arrhythmias with the highest energy of 15 V in baseline state and during dobutamine infusion. HFS in the left PA was associated with hiccough in all patients. Stimulation of the sympathetic input to the left PA during dobutamine infusion induces PVCs and/or VT exhibiting LBBB-morphology and inferior axis, closely simulating clinical RVOT tachycardia in humans.

Estradiol and Progesterone Exert Opposite Effects on Cardiac Repolarization and Arrhythmogenesis in Transgenic Long QT Syndrome 2 Rabbits

Introduction: Adult women with LQT2 are at higher risk for sudden cardiac death (SCD) than men with an increased risk during the postpartum. We have created transgenic rabbits over-expressing a pore mutant of the human ERG channel in the heart (LQT2) and showing the human long QT phenotype (Brunner et al. JCI, 2008). 4/4 LQT2 females used for breeding died of SCD during the postpartum. We hypothesize that sex hormones modulate cardiac repolarization and arrhythmogenesis in LQT2 females.Methods: Prepubertal ovariectomized LQT2 females were implanted with 90day release-pellets of estradiol (EST), progesterone (Prog), dihydrotestosterone (DHT), or placebo (OVX) (n=6 each). All groups underwent telemetric ECG monitoring and in vivo electrophysiological studies (EPS) after 8 weeks and first optical mapping experiments were performed in OVX, EST- and DHT-treated rabbits.Results: EST treatment steepened the QT/RR slope of prepubertal rabbits (p<0.05), whereas DHT or OVX decreased the QT/RR slope steepness (p<0.05). Prog did not alter the QT/RR slope. In vivo EPS revealed a longer ventricular refractory period (VERP) in EST- than in DHT- or Prog-treated rabbits (DHT: p<0.05, Prog: p<0.01). Within 8 weeks of hormone-treatment, 4 of 6 EST-treated rabbits died of polymorphic VT, while no SCD occurred in 6 DHT- and 6 Prog-treated LQT2 females (p<0.05). Preliminary optical mapping experiments revealed heterogeneous APD dispersion with islands of prolonged refractoriness in EST- rabbits contrasting with smoother APD dispersion in OVX and DHT-treated rabbits.Conclusions: EST increases the QT/RR steepness and prolongs cardiac refractoriness, whereas DHT and Prog shorten cardiac refractoriness. EST predisposes prepubertal LQT2 rabbits to polymorphic VT. Heterogeneous ADP dispersion might underlie this proarrhythmic effect of EST. We are currently using high-throughput molecular approaches to elucidate the underlying mechanisms.

Is there a significant transmural gradient in repolarization time in the intact heart?

Is there a significant transmural gradient in repolarization time in the intact heart?

High-throughput analysis of drug binding interactions for the human cardiac channel, Kv1.5

The voltage-gated potassium channel Kv1.5 is one of the key regulators of membrane potential repolarization in human atrial myocytes and is considered a potential drug target to treat atrial fibrillation. In this study we sought to determine molecular mechanism of action of DPO-1, a diphenylphosphine oxide derivative recently shown to terminate experimental atrial arrhythmia without affecting ventricular refractory period. In addition, we provided similar analysis for additional two small molecule blockers, representing different structural classes: cyclohexanones (PAC) and nor-triterpenoids (correolide). To rapidly identify the residues within the Kv1.5 channel critical for blocking activity of these molecules, two functional high-throughput ion channel assays were employed together with site-directed mutagenesis. Our study revealed that the residues critical for blocking activity of for DPO-1 include T480, localized at the outer mouth of the pore, and two residues along S6 helix: V505 and I508. The overlapping site was identified for PAC and included residues T480 and V505. In contrast to DPO-1, the I508A mutation resulted in only a modest reduction in the block of Kv1.5 by PAC (9-fold). Correolide, the largest molecule examined, made widespread interactions along the entire length of the pore (from T480 to V516). In summary, we have identified multiple residues involved in forming high affinity binding site for Kv1.5 blockers. Similar approaches of high-throughput ion channel technologies, combined with site-directed mutagenesis, may allow for parallel, rapid and accurate analysis of ion channel interactions with multiple compounds and could facilitate the design of more potent and selective ion channel blockers.

Ibutilide Therapy for Atrial Fibrillation - Five-Year Experience in a Community Hospital

Background: Ibutilide fumarate is a class III antiarrhythmic agent whose sole indication is the acute conversion of atrial fibrillation or atrial flutter to sinus rhythm. Ibutilide blocks potassium channels and activates slow inward sodium channels, which delays repolarization. These actions prolong the action potential in atrial and ventricular refractory periods, leading to arrhythmia termination. Many institutions restrict the use of ibutilide because of the potential risk of polymorphic ventricular tachycardia (PMVT).

Coupled Pacing Does Not Impair Heart Rate Response to Exercise

Background: Inserting an early pacing stimulus just beyond the ventricular refractory period causes contractility to increase on the next beat. When the early pace is applied after each intrinsically conducted beat, it is called coupled pacing (CP). CP also slows the ventricular mechanical rate, the number of ejecting contractions per minute, and may be useful in heart failure (HF) patients due to the increase in contractility. However, it is unknown if CP affects the normal increase in mechanical heart rate (HR) in response to exercise.

Clinical and molecular genetics of the short QT syndrome

Sudden cardiac death in patients without structural heart disease remains a challenge in diagnostics and risk stratification. Genetically determined arrhythmias are a potential cause for a primary electrical disease. A recently discovered primary electrical disease is discussed. The inherited short QT syndrome is a recently recognized genetic condition, which is associated with atrial fibrillation, syncope and/or sudden cardiac death. Attention has been focused on diagnostic ECG features, the identification of underlying mutations and mechanisms of arrhythmogenesis. The short QT syndrome is clinically associated with atrial fibrillation, syncope and sudden cardiac death. A shortened QT interval (QTc <360 ms) and reduced ventricular refractory period together with an increased dispersion of repolarization constitute the potential substrate for reentry and life-threatening ventricular tachyarrhythmia. To date, gain-of-function mutations in KCNH2, KCNQ1, KCNJ2, encoding potassium channels and loss-of-function mutations in CACNA1C and CACNB2b, encoding L-type calcium channel subunits have been identified. The therapy of choice is the implantable cardioverter defibrillator in symptomatic patients. Quinidine has been shown to prolong the QT interval and to normalize the effective refractory periods of the atrium and ventricle in patients with short QT-1 syndrome.

Atrial Antifibrillatory Effects of Structurally Distinct IKurBlockers 3-[(Dimethylamino)methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one and 2-Phenyl-1,1-dipyridin-3-yl-2-pyrrolidin-1-yl-ethanol in Dogs with Underlying Heart Failure

Drug discovery efforts have focused recently on atrial-selective targets, including the Kv1.5 channel, which underlies the ultrarapid delayed rectifier current, I(Kur), to develop novel treatments for atrial fibrillation (AF). Two structurally distinct compounds, a triarylethanolamine TAEA and an isoquinolinone 3-[(dimethylamino)-methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (ISQ-1), blocked I(Kur) in Chinese hamster ovary cells expressing human Kv1.5 with IC(50) values of 238 and 324 nM, respectively. In anesthetized dogs, i.v. infusions of TAEA and ISQ-1 elicited comparable 16% increases in atrial refractory period, with no effect on ventricular refractory period or QTc interval. Plasma concentrations at end infusion for TAEA and ISQ-1 were 58.5 +/- 23.6 and 330.3 +/- 43.5 nM, respectively. The abilities of TAEA and ISQ-1 to terminate AF, with comparison to the rapidly activating component of delayed rectifier potassium current blocker (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride (MK-499) and the class IC 1-[2-[2-hydroxy-3-(propylamino)-propoxy]phenyl]-3-phenyl-1-propanone (propafenone), were assessed in conscious dogs with heart failure and inducible AF (entry criterion). All test agents administered in i.v. bolus regimens terminated AF in at least half of animals tested; conversely no agent was universally effective. MK-499, ISQ-1, TAEA, and propafenone terminated AF in five of six, four of seven, four of six, and five of six animals at plasma concentrations of 32.6 +/- 18.7, 817 +/- 274, 714 +/- 622, and 816 +/- 240 nM, respectively. Directed cardiac electrophysiologic studies in anesthetized dogs using i.v. bolus (consistent with AF studies) plus infusion regimens with TAEA and ISQ-1 demonstrated significant increases in atrial refractory period (12-15%), A-H and P-A intervals, but no effects on ventricular refractory period, H-V, and HEG intervals. The demonstration of AF termination with TAEA and ISQ-1 in the dog heart failure model extends the profile of antiarrhythmic efficacy of Kv1.5 blockade.

Abstract 1352: Gender Differences In Cardiac Repolarization In Transgenic Long QT Syndrome 2 (LQT2) Rabbits

Introduction: Adult women with LQT2 are at higher risk for clinical events and sudden cardiac death (SCD) than men. We have created transgenic rabbits over-expressing pore mutants of the human KvLQT1 (LQT1) and HERG (LQT2) selectively in the heart. We report the gender differences in cardiac repolarization, incidence of polymorphic VT and SCD in these cohorts. Methods: Adult female and male LQT1, LQT2, and littermate controls (ages 5 to 33 mo were similar in f/m, LQT2 were younger due to higher mortality) underwent telemetric ECG monitoring, surface ECG and in vivo electrophysiological studies under general anaesthesia with isoflurane (2–5%). Results: Monitoring data showed a steeper QT/RR slope in female (0.745 ± 0.05, n=4) than in male (0.513 ± 0.06, n=9; p&lt;0.05) LQT2 rabbits. No significant gender differences were observed in QT/RR slopes in either LQT1 or WT rabbits. QT-, QTpeak-index and Tp-e were significantly longer in female than in male LQT2 rabbits (females, n=6: QT: 129.2% ± 3.9; QTp: 105.9% ± 2.1; Tp-e: 42.9ms ± 4.1 vs. males, n=8: QT: 117.5% ± 4.3; p&lt;0.05; QTp: 93.5% ± 5.6, p&lt;0.05; Tp-e: 29.5ms ± 2.9, p&lt;0.02). EP studies revealed significantly longer atrial (AERP) and ventricular (VERP) refractory periods in LQT2 females compared to males (females, n=4: AERP: 143.3 ± 5.8 ms; VERP: 212.5 ± 22.2 ms vs. males, n=8: AERP: 102.5 ± 7.7 ms, p&lt;0.01; VERP: 178.1 ± 7.8 ms, p&lt;0.05). AERP and VERP were significantly longer in LQT2 females than in LQT1 females (LQT1 females, n=7: AERP: 101.4 ± 7.7 ms, p&lt;0.01, VERP: 156.9 ± 6.2, p&lt;0.001), whereas in male LQT rabbits this genotype difference was only found in VERP but not in AERP. Survival was significantly shorter in female LQT2 rabbits compared to LQT1 or WT controls, with 4 sudden deaths among 10 LQT2, 1 among 19 WT and no SCD in 13 LQT1 females (p&lt;0.02). No gender difference was observed in mortality. All cases of SCD occurred after sexual maturation and two LQT2 females died during lactation. Monitoring revealed the cause of SCD was polymorphic VT. Conclusions: Monitoring of LQT rabbits reveal gender differences in LQT2 rabbits. QT/RR slope is steeper in female than in male adult LQT2 rabbits. AERP and VERP are longer in LQT2 females than in males. Finally, in LQT2 females, SCD was associated with lactation, but not pregnancy.

Abstract 744: Arrhythmogenesis in Heart Failure: Role of Interstitial Fibrosis

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p&lt;0.05), other electrocardiographic and electrophysiologic variables were similar among the 3 groups (p=NS), including heart rate, QT duration, and mean VT threshold. As expected, VT (≥3beats) was readily inducible by programmed stimulation in sTAB mice (7/10). By contrast, VT was less inducible in caPKD mice (4/12; p=0.1 vs TAB and &lt;0.05 vs WT), and uninducible in unoperated controls (0/12). VT was polymorphic in both models, but episodes of VT were both slower (VT cycle length caPKD 58±4.0 msec vs 48±1 sTAB, p=0.016) and longer in caPKD mice (caPKD 1.8±0.7 sec vs 0.47±0.3 sTAB, p=0.038). Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

The Effect of Vernakalant (RSD1235), an Investigational Antiarrhythmic Agent, on Atrial Electrophysiology in Humans

To determine the acute effects of vernakalant (RSD1235) on electrophysiologic (EP) properties in humans. Vernakalant is an investigational mixed ion channel blocker that can terminate acute atrial fibrillation (AF) in humans at 2 to 5 mg/kg and may be more "atrial-selective" than available agents. Patients (N=19; 53% male; age, 48+/-11 years) underwent EP study before and after 25 minutes of intravenous vernakalant administration: 2 mg/kg over 10 min+0.5 mg/kg/hr for 35 min or 4 mg/kg over 10 min+1 mg/kg/hr for 35 min. EP measurements, including atrial refractory period (AERP) and ventricular refractory period (VERP), were obtained. The lower dose prolonged AERP at 600, but not at 400 or 300 msec paced cycle length. The higher dose significantly prolonged AERP from 203+/-31 msec to 228+/-24 msec at 600 msec, 182+/-30 msec to 207+/-27 msec at 400 msec, and 172 msec+/-24 to 193+/-21 msec at 300 msec. There was no significant prolongation of VERP at either dose or at any cycle length. There was a small but significant prolongation of AV nodal refractoriness; Wenckebach cycle length prolonged by 18+/-12 msec (from baseline 343+/-54 msec) at the higher dose (P<0.05). Sinus node recovery time also increased by 123+/-158 msec (from baseline 928+/-237 msec) at the higher dose (P<0.05). There was a slight prolongation of QRS duration at the higher dose, during ventricular pacing at CL=400 msec (15+/-15 msec, P=0.0547). QT and HV intervals were unchanged. At doses similar to those tested clinically, vernakalant dose-dependently prolonged atrial refractoriness, prolonged AV nodal conduction and refractoriness, and slightly prolonged QRS duration, but it had no effect on ventricular refractoriness.

In Vivo Cardiac Electrophysiologic and Antiarrhythmic Effects of an Isoquinoline IKur Blocker, ISQ-1, in Rat, Dog, and Nonhuman Primate

The cardiac electrophysiologic effects of ISQ-1, an isoquinolinone I(Kur) blocker, were characterized in vivo. In rat, ISQ-1 elicited maximal 33% to 36% increases in atrial and ventricular refractoriness at a plasma concentration of 11.5 microM. In African green monkey, ISQ-1 increased atrial refractory period (maximal 17% at plasma concentration up to 20 microM) with no effect on ventricular refractory period or ECG QTc. Likewise in dog, ISQ-1 increased atrial refractory period (maximal 16% at plasma concentration up to 2 microM) with no effect on ventricular refractory period or QTc. In contrast, studies with ibutilide in nonhuman primate and dog demonstrated concomitant increases in atrial and ventricular refractoriness and QTc. Additionally, in a dog model of atrial flutter, ISQ-1 terminated ongoing flutter at doses (2.5 +/- 0.5 mg/kg IV) that selectively prolonged atrial refractoriness (13% increase), whereas flutter termination with ibutilide occurred at doses that increased both atrial and ventricular refractoriness as well as QTc. Of note, the cardiac electrophysiologic profiles displayed by ISQ-1 in these species were similar to those reported previously by our lab with a structurally distinct I(Kur) blocker. Taken together, these results further support the inhibition of I(Kur) as an approach to terminate atrial arrhythmia.

In Vitro and In Vivo Effects of the Atrial Selective Antiarrhythmic Compound AVE1231

The novel compound AVE1231 was investigated in order to elucidate its potential against atrial fibrillation. In CHO cells, the current generated by hKv1.5 or hKv4.3 + KChIP2.2b channels was blocked with IC50 values of 3.6 microM and 5.9 microM, respectively. In pig left atrial myocytes, a voltage-dependent outward current was blocked with an IC50 of 1.1 microM, mainly by accelerating the time constant of decay. Carbachol-activated IKACh was blocked by AVE1231 with an IC50 of 8.4 microM. Other ionic currents, like the IKr, IKs, IKATP, ICa, and INa were only mildly affected by 10 microM AVE1231. In guinea pig papillary muscle the APD90 and the upstroke velocity were not significantly altered by 30 microM AVE1231. In anesthetized pigs, oral doses of 0.3, 1, and 3 mg/kg AVE1231 caused a dose-dependent increase in left atrial refractoriness (LAERP), associated by inhibition of left atrial vulnerability to arrhythmia. There were no effects on the ECG intervals, ventricular monophasic action potentials, or ventricular refractory periods at 3 mg/kg AVE1231 applied intravenously. In conscious goats, both AVE1231 (3 mg/kg/h iv) and dofetilide (10 microg/kg/h iv) significantly prolonged LAERP. After 72 hours of tachypacing, when LAERP was shortened significantly (electrical remodelling), the prolongation of LAERP induced by AVE1231 was even more pronounced than in sinus rhythm. In contrast, the effect of dofetilide was strongly decreased. The present data demonstrate that AVE1231 blocks early atrial K channels and prolongs atrial refractoriness with no effects on ECG intervals and ventricular repolarisation, suggesting that it is suited for the prevention of atrial fibrillation in patients.

Editorial

Increasingly, general cardiologists and heart failure specialists are faced with a growing clinical dilemma. Simply put, can anything beyond pharmacologic therapy be proffered to patients with symptomatic severe left ventricular dysfunction and a normal QRS duration to improve quality of life? 1 Sandhu R. Bahler R.C. Prevalence of QRS prolongation in a community hospital cohort of patients with heart failure and its relation to left ventricular systolic dysfunction. Am J Cardiol. 2004; 93: 244-246 Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar , 2 Shenkman H.J. Pampati V. Khandelwal A.K. McKinnon J. Nori D. Kaatz S. Sandberg K.R. McCullough P.A. Congestive heart failure and QRS duration: establishing prognosis study. Chest. 2002; 122: 528-534 Crossref PubMed Scopus (204) Google Scholar To date, cardiac electrophysiologists and implantologists have had little to offer from their device armamentaria in this regard. In this issue of Heart Rhythm, Neelagaru et al 3 Neelagaru S.B. Sanchez J.E. Lau S.K. Greeberg S.M. Raval N.Y. Worley S. Kalman J. Merliss A.D. Krueger S. Wood M. Wish M. Burkhoff D. Nadamanee K. Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm. 2006; 3: 1140-1147 Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar present a pilot study addressing this large clinical problem with a fascinating new technology—the implantable OPTIMIZER system (IMPULSE Dynamics, Orangeburg, NY, USA). The physiologic rationale for this proposed therapy is intriguing. Prior experimental animal studies have suggested that extracellular electrical signals can enhance transsarcolemmal calcium influx and thus increase peak intracellular calcium levels, with a resulting enhancement of myocardial contractility, 4 Mohri S. Shimizu J. Mika Y. Shemer I. Wang J. Ben-Haim S. Burkhoff D. Electric currents applied during the refractory period enhance contractility and systolic calcium in the ferret heart. Am J Physiol Heart Circ Physiol. 2003; 284: H1119-H11123 PubMed Google Scholar , 5 Morita H. Suzuki G. Haddad W. Mika Y. Tanhehco E.J. Sharov V.G. Goldstein S. Ben-Haim S. Sabbah H.N. Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure. J Card Fail. 2003; 9: 69-75 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Hence, the OPTIMIZER system with its prepectoral canister and transvenous leads is designed to deliver high-energy but nonexcitatory electrical signals during the ventricular absolute refractory period to improve global left ventricular performance. Earlier publications of the initial use of this novel technology in small, unblinded, nonrandomized uncontrolled human studies have appeared promising. 6 Pappone C. Augello G. Rosanio S. Vicedomini G. Santinelli V. Romano M. Agricola E. Maggi F. Buchmayr G. Morreti G. Mika Y. Ben-Haim S.A. Wolzt M. Stix G. Schmidinger H. First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study. J Cardiovasc Electrophysiol. 2004; 15: 418-427 Crossref PubMed Scopus (72) Google Scholar , 7 Stix G. Borggrefe M. Wolpert C. Hindricks G. Kottkamp H. Bocker D. Wichter T. Mika Y. Ben-Haim S. Burkhoff D. Wolzt M. Schmidinger H. Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J. 2004; 25: 626-628 Crossref PubMed Scopus (66) Google Scholar

Is acquired short QT due to digitalis intoxication responsible for malignant venticular arrhythmias?

It is well-known that the presence of an inherited or acquired long QT interval can be the cause of lifethreatening ventricular arrhythmias, in particular torsade de pointes (TdP), which often spontaneously interrupts causing presyncope or syncope. However, sometimes it can degenerate in ventricular fibrillation (VF) causing sudden death. Recently, a new genetic syndrome associated to a high risk of sudden death has been described. These subjects have a short QT interval at electrocardiogram (ECG) (b300 ms) with only slight modifications of the QT interval with heart rate changes, the T waves are often tall, peaked, and narrow-based. The patients have structurally normal hearts. These patients generally suffer from palpitations and syncope and may die suddenly even during childhood. More recently, Maury et al reported a family with short QT syndrome (SQTS) and a not so short corrected QT (QTc) interval (up to 340 F 20 ms). These data suggest that the definition of SQTS should be less restrictive. The substrate of ventricular arrhythmias responsible for sudden death has been suggested to be the presence of very short ventricular refractory periods and the heterogeneous shortening of the action potential (AP) duration among the different layers of the ventricular wall. Until now, mutations in 3 different genes have been identified in this syndrome: 2 different missense mutations, which provoke an amino acid change (N588K) in the S5-P loop region of the cardiac Ikr channel HERG (KCNH2); 2 different mutations in the KCNQ1 gene, which encodes the slow component of the cardiac delayed rectifier K+ current; and a mutation in the KCNJ2 gene. In all cases, there is an increase in the repolarizing currents leading to a

Vermeidung von intermittierendem T-Wellen-Oversensing durch Programmierung

We report the case of a 35-year-old man who was suffering from severe heart failure due to cardiomyopathy. He underwent heart transplantation years ago and developed complex ventricular arrhythmias in the following months in combination with recurrent episodes of syncope due to hypertrophic non-obstructive cardiomyopathy in the transplanted heart, so a dual chamber ICD was implanted. Months later repetitive episodes of intermittent T-wave oversensing with consecutive activation of the ICD could be observed. Surgical revision of the electrode was performed and the patient was closely followed up. One year later, further episodes of T-wave oversensing led to multiple inappropriate IDC-shocks. A very short AV-conduction time was programmed to allow ventricular capture whenever possible, because T-wave oversense after ventricular capture would be annotated as single ventricular ectopy not resulting in antitachycardia pacing. As a consequence, the patient was free from inappropriate ICD-shocks, but showed several shorter episodes of T-wave oversensing. They were all initiated by atrial activity that was seen in the refractory period, thus leading to a loss of AV synchrony. Programming a very short post ventricular atrial refractory period (PVARP) in addition to a short AV-delay led to the complete disappearance of T-wave oversensing in this patient. During a 9-month follow-up, no further tachycardia episodes were detected by the device.

Experimental Model Simulating Right Ventricular Outflow Tract Tachycardia: A Novel Technique to Initiate RVOT‐VT

The mechanism(s) whereby a discrete area of myocardium in the RVOT becomes arrhythmogenic remains unknown. In 13 dogs, a circular catheter was placed in the proximal pulmonary artery (PA) to contact the endovascular circumference of the PA. A 50-msec train of high-frequency stimulation (HFS, 200 Hz), coupled to atrial pacing, was applied at each bipolar pair of the circular catheter. The coupling interval was adjusted so that the 50-msec train occurred during the ventricular refractory period, that is, the QRS complex, in order to prevent stimulation of the myocardial sleeve within the proximal PA. In all dogs, HFS induced ventricular premature depolarizations and VTs with a left bundle branch block (LBBB) morphology and inferior axis (average 6.8 +/- 1.6 V). Earliest activation was consistently recorded from the proximal PA. Esmolol, a short-acting beta-blocker (1 mg/kg), was administered intravenously in 11 dogs. The inducible ventricular ectopy was abolished in 10 dogs (>12 V, P < 0.05) and the response to HFS was blunted in one dog (10-11 V). After 30 minutes, the response to HFS returned to pre-esmolol levels. Stimulation of the sympathetic input to the proximal PA induces ventricular ectopy and VTs exhibiting a left bundle branch block morphology and inferior axis, closely simulating clinical RVOT-VT. Beta-blockade either abolishes or blunts this response, corroborating the sympathetic etiology in this model and in some clinical cases of RVOT tachycardias.