Multiple techniques have been developed in addition to pulmonary vein isolation (PVI) to improve the outcomes of catheter ablation in patients with persistent atrial fibrillation (AF). We sought to evaluate the long-term efficacy of alternative techniques used in our laboratory for the treatment of persistent AF, including spatiotemporal dispersion (SD) and low-voltage isolation (LVI). Consecutive patients with persistent AF who underwent catheter ablation with the studied techniques between July 2016 and December 2019 were included in the study. PVI alone was compared with PVI plus SD and PVI plus LVI in terms of long-term freedom from atrial tachycardia (AT) and AF recurrence. Follow-up data were obtained from clinical records and hospital visits, which included a 7-day Holter monitor and electrocardiograms. The study was approved by the institutional review board of Rhode Island Hospital. A total of 382 patients underwent catheter ablation at our institution during the study period. One hundred seventy-two patients had paroxysmal AF and were excluded from the study. The remaining 210 patients had persistent AF and were included in the study. One hundred and three patients underwent PVI alone, while 48 had the addition of LVI and 59 had SD. Additionally, freedom from AT/AF recurrence at 18 months was 68% in the group that underwent LVI, 49% in the SD group, and 40% in the group that underwent PVI alone (log-rank P = .014). Freedom from AF recurrence was 74% in the LVI group, 71% in the SD group, and 43% in the PVI-alone group (log-rank P = .002). On multivariate Cox regression, LVI and left atrial size were found to be independent predictors of recurrence (hazard ratio, 0.39; 95% confidence interval, 0.206-0.760; P = .005 and hazard ratio, 1.4; 95% confidence interval, 1.105-1.923; P = .008, respectively). LVI and SD in addition to PVI were associated with greater freedom from AT/AF recurrence at 18 months compared to PVI alone.

Introduction Atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) are frequently associated with atrial fibrillation (AF). Targeting the slow or accessory pathways has been advocated as therapy for coexisting AF. But in practice, AF has frequently recurred after ablation, possibly because of various risk factors. The objective of this study is to investigate these risk factors and check for their significance in AF recurrence. Materials and methods A systematic review of Medline, Cochrane, and ClinicalTrials.gov databases was conducted. Articles that studied AF recurrence after either AVNRT or AVRT ablation were reviewed. Publication bias was adequately assessed, and the random method was applied for all dichotomous values. Finally, the odds ratio (OR) and confidence intervals (CI) were calculated for each risk factor. Results Four studies were included, with a total of 1,308 participants. Only 218 participants had dual tachycardia (AF with either AVNRT or AVRT). The mean follow-up time was 29 +/- 3.3 months. The mean age was 56 +/- 15 years. Age constituted the only significant risk factor for AF recurrence (OR: 3.4, CI: 2.1-5.3, p<0.001). Atrial vulnerability did not significantly correlate with a higher risk of AF recurrence (OR: 4.8, CI: 0.7-29, p<0.008). Again, neither male gender (OR: 1.5, CI: 0.8-2.8, p<0.16) nor left atrial diameter (OR: 1.5, CI: 0.2-10, p<0.67) were significant risk factors for recurrence of AF. Conclusion Older age was the only significant predictor of AF recurrence after ablation of AVNRT or AVRT. Further studies are needed to determine the age cut-off at which concomitant pulmonary vein isolation would be beneficial in patients undergoing ablation of AVNRT/AVRT.

Introduction: Cardiac resynchronization therapy (CRT) improves systolic function and decreases arrhythmic events in heart failure (HF). HF is known to be associated with a reduction in Sarco/Endopl...

In inherited long QT syndrome (LQTS), female sex is associated with a longer QT interval duration and a higher risk for potentially lethal polymorphic ventricular tachycardia (pVT) and sudden cardiac death than in males.1,2 The arrhythmogenic risk is particularly pronounced during the postpartum period—especially in patients with LQTS type 2—but relatively low during pregnancy,3 indicating a potential role for sex hormones in modulating cardiac repolarization and arrhythmogenesis in LQTS. In patients with the acquired, drug-induced LQTS variant, hormone-induced changes in QT interval duration during different phases of the menstrual cycle have been described, with a less pronounced drug-induced QT interval prolongation and hence shorter QT intervals during the luteal phase, when progesterone levels are high, than during the follicular phase with its high estradiol levels.

Introduction: Heart failure (HF) downregulates full-length cardiac sodium channel (SCN5A) mRNA and upregulates the splicing variant D (VD), which encodes a prematurely truncated, nonfunctional channel. Recently, we have shown that the ratio of circulating VD to full-length mRNA can predict the risk of sudden death. Cardiac resynchronization therapy (CRT) improves heart function and decreases arrhythmic events. Nevertheless, the mechanisms are unclear. Hypothesis: We tested whether CRT altered circulating full-length SCN5A mRNA and VD and further investigated its correlation with clinical parameters in HF. Methods: HF patients with new implantable cardioverter-defibrillators (ICDs) for primary prevention were enrolled. Circulating SCN5A and VD levels at baseline and at a follow-up visit were measured and compared using the ratio of VD to total SCN5A transcripts. The change of VD was expressed as the difference between the proportion of VD levels at baseline and at a follow-up visit. Results: A total of 81 HF patients were enrolled. At enrollment, patients with lower ejection fraction (EF) (≤30%) had higher circulating VD levels (0.80±0.11 vs. 0.73±0.07, P<0.05). After a median follow-up of 235 days, the VD ratio significantly improved (0.84±0.08 vs. 0.74±0.10, P<0.01) in patients receiving CRT. In patients without CRT, the VD ratio had significantly increased (0.77±0.07 vs 0.84±0.05, P<0.05). In patients with CRT, the change of the VD ratio significantly correlated with left ventricular end systolic diameter (r=0.853, p<0.01), EF (r=-0.643, p<0.05) and ischemic cardiomyopathy (r=0.645, p<0.05). Conclusions: CRT decreased the proportion of nonfunctional sodium channels, which may explain the lower arrhythmic risk with CRT therapy. Furthermore, the improvement was more prominent in patients with left ventricular dilation, lower EF and ischemic cardiomyopathy.

We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K(+) current [I(Ks); long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K(+) current [I(Kr); long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking I(Kr) and I(Ks).

31 Background and Objective: We have generated transgenic rabbits lacking cardiac 32 IKs (LQT1) or IKr (LQT2). Rabbits with either genotype have prolonged APD and QT intervals; 33 however, only LQT2 rabbits develop AV blocks and polymorphic ventricular tachycardia. We 34 therefore sought to characterize the genotype-specific differences in AV conduction and 35 ventricular refractoriness in LQT1 and LQT2 rabbits. 36 Methods: We carried out in vivo electrophysiological studies (EPS) in LQT1, LQT2, 37 and littermate control (LMC) rabbits at baseline, during isoproterenol-infusion, and after a 38 bolus of dofetilide, and ex vivo optical mapping studies of the AV-node/His-region at baseline 39 and during dofetilide perfusion. 40 Results: Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, 41 decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 42 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra43 His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV 44 block. The ventricular effective refractory period (VERP) in RV apex and base were 45 significantly longer in LQT2 than LQT1 (p<0.05) or LMC (p<0.01), with a greater VERP 46 dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 47 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP 48 in LQT1. 49 Conclusions: EPS and optical mapping experiments demonstrated genotype-specific 50 differences in AV conduction and ventricular refractoriness. The occurrence of infra-His 51 blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide 52 suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking 53 IKr and IKs. 54 55 Words: 250 56 57 58 59

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of I-Ks, and I-Kr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (> 50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary I-Kr and I-Ks without affecting the steady state levels of the native polypeptides. Thus, the elimination of I repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type a subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents (IKs) or rapidly activating K+ currents (IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs) prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current (IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

Journal of Cardiovascular ElectrophysiologyVolume 18, Issue 6 p. E18-E18 Response to the Editor: Peter Ott M.D., Peter Ott M.D. Sarver Heart CenterUniversity of Arizona, Tucson, ArizonaSearch for more papers by this authorMalcolm M. Kirk M.D., Malcolm M. Kirk M.D. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this authorCharles Koo M.D., Charles Koo M.D. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this authorDing Sheng He M.D., Ph.D., Ding Sheng He M.D., Ph.D. CR BardSearch for more papers by this authorBaishali Bhattacharya M.D., M.P.H., Baishali Bhattacharya M.D., M.P.H. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this authorAlfred Buxton M.D., Alfred Buxton M.D. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this author Peter Ott M.D., Peter Ott M.D. Sarver Heart CenterUniversity of Arizona, Tucson, ArizonaSearch for more papers by this authorMalcolm M. Kirk M.D., Malcolm M. Kirk M.D. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this authorCharles Koo M.D., Charles Koo M.D. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this authorDing Sheng He M.D., Ph.D., Ding Sheng He M.D., Ph.D. CR BardSearch for more papers by this authorBaishali Bhattacharya M.D., M.P.H., Baishali Bhattacharya M.D., M.P.H. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this authorAlfred Buxton M.D., Alfred Buxton M.D. Brown Medical Schooland Lifespan Academic Medical CenterProvidence, Rhode IslandSearch for more papers by this author First published: 14 May 2007 https://doi.org/10.1111/j.1540-8167.2007.00851.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume18, Issue6June 2007Pages E18-E18 RelatedInformation

Introduction: Adult women with LQT2 are at higher risk for clinical events and sudden cardiac death (SCD) than men. We have created transgenic LQT2 rabbits selectively over-expressing a pore mutant of the human HERG in the heart. All episodes of SCD in these LQT2 females occurred after sexual maturation. We hypothesize that sex hormones modulate cardiac repolarization and incidence of polymorphic VT in female LQT2 rabbits. Methods: In this ongoing study, prepubertally ovariectomized females were implanted with 90 day-release-pellets of estradiol (EST, 150mg), or dihydrotestosterone (DHT, 200mg), or placebo (OVX). A fourth group consisted of sham-operated females (SHAM). All groups underwent telemetric ECG monitoring, surface ECG after 30 days of hormone treatment, and in vivo electrophysiological studies (EPS) under isoflurane (2–5%) after 60 days. Results: EST steepened the QT/RR slope of prepubertal rabbits mimicking the adult LQT2 female phenotype (baseline: 0.608 ± 0.09, after 4 weeks: 0.69 ± 0.1, n=5, p<0.05; SHAM females: 0.699 ± 0.07, n=4). In contrast, DHT decreased the QT/RR slope (baseline: 0.739 ± 0.11, after 4 weeks: 0.521 ± 0.08, n=3, p=0.02). A smaller decrease was seen in OVX: 0.677 ± 0.01 vs. 0.599 ± 0.08, n=2. EST prolonged QT- and QTpeak-index compared to DHT rabbits. (EST, n=2: QT: 112.6% ± 1.5; QTp: 95.8% ± 1.6 vs. DHT, n=2: QT: 105.4% ± 4.1, p=0.07; QTp: 87.6% ± 0.9, p<0.05 vs. SHAM females, n=2: QT: 123.4% ± 9.5; QTp: 102.3% ± 2.5) EPS revealed a longer AERP and VERP in EST than in DHT rabbits - and a trend towards longer refractoriness than in OVX - reaching similarly prolonged refractoriness as in SHAM females (EST, n=2: AERP: 165.0 ± 35.4ms; VERP: 225.0 ± 25.0ms vs. DHT, n=3: AERP: 90.00 ± 5.8ms, p=0.03; VERP: 193.3 ± 8.8ms, p=0.07 vs. OVX, n=2: AERP: 125.0 ± 25.0ms, VERP: 205.0 ± 5.0ms, vs. SHAM females, n=2: AERP: 145.0 ± 5.0ms, VERP: 220.0 ± 20.0ms). One out of four EST-treated prepubertal rabbits died at the age of 96 days of spontaneous polymorphic VT. Conclusion: EST increases the QT/RR slope and prolongs QT and cardiac refractoriness mimicking the adult LQT2 female phenotype, whereas DHT decreases the QT/RR slope and shortens QT and refractoriness mimicking a male phenotype. EST predisposes prepubertal LQT2 rabbits to spontaneous polymorphic VT.

BACKGROUND:Cardiac resynchronization therapy (CRT) has been shown to improve cardiac function and reduce Cheyne-Stokes respiration but has not been evaluated in patients with obstructive sleep apnea (OSA). In this pilot study, we investigated the impact of both CRT and CRT plus increased rate pacing in heart failure (ie, congestive heart failure [CHF]) patients with OSA. We hypothesized that through increased cardiac output CRT/pacing would reduce obstructive events and daytime symptoms of sleepiness.METHODS:Full polysomnograms were performed on CHF patients who were scheduled for CRT, and those patients with an apnea-hypopnea index (AHI) of > 5 events per hour were approached about study enrollment. Patients had a pre-CRT implant baseline echocardiogram and an echocardiogram a mean (+/- SEM) duration of 6.6 +/- 1.4 months post-CRT implant; polysomnography; and responded to the Minnesota Living with Heart Failure questionnaire, the Epworth sleepiness scale, and the Functional Outcomes of Sleep Questionnaire. An additional third polysomnography was performed combining CRT with a pacing rate of 15 beats/min above the baseline sleeping heart rate within 1 week of the second polysomnography. Assessments for the change in cardiac output during the polysomnography were performed using circulation time to pulse oximeter as a surrogate.RESULTS:Twenty-four patients were screened, and 13 patients (mean age, 68.6 years; body mass index, 28.7 kg/m(2)) had evidence of OSA. The mean AHI decreased from 40.9 +/- 6.4 to 29.5 +/- 5.9 events per hour with CRT (p = 0.04). The mean baseline ejection fraction was 22 +/- 1.7% and increased post-CRT to 33.6 +/- 2.0% (p < 0.05). The reduction in AHI with CRT closely correlated with a decrease in circulation time (r = 0.89; p < 0.001) with CRT. Increased rate pacing made no additional impact on the AHI or circulation time. CRT had a limited impact on sleep architecture or daytime symptom scores.CONCLUSIONS:CRT improved cardiac function and reduced the AHI. Reduced circulatory delay likely stabilized ventilatory control systems and may represent a new therapeutic target in OSA.

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<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<0.05; QTp: 93.5% ± 5.6, p<0.05; Tp-e: 29.5ms ± 2.9, p<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<0.01; VERP: 178.1 ± 7.8 ms, p<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<0.01, VERP: 156.9 ± 6.2, p<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<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.

LQT1 and LQT2, the two most common inherited long QT syndromes are associated with sudden cardiac death due to due torsades the pointes (TdP). We have created two lines of transgenic rabbits overexpressing pore mutants of the human KvLQT1 (KCNQ1) and HERG (KCNH2) in the heart. Both animal models have prolonged QT interval, however, only LQT2 rabbits suffer from TdP and sudden cardiac death. To investigate the differences in the cellular phenotypes we investigated the whole cell current of acute isolated apical ventricular myocytes from LQT1 and LQT2 rabbit models using patch-clamp techniques by depolarizing to potentials between −30 to +30 mV from a holding potential of −40 mV (room temperature). I Kr and I Ks were defined as currents sensitive to E-4031 (5 μM) and chromanol 293B (30μM) respectively. Our preliminary data revealed that I Ks was selectively abolished in 8 out of 8 LQT1 cardiomyocytes, while I Kr was spared (Figure 1 ). By contrast, I Kr was selectively abolished in 13 out of 14 LQT2 cardiomyocytes while I Ks was spared. The selective elimination of I Kr resulted in a significant increase in the duration of action potential (APD 90 ) from 357±48.68ms (n=13) in control to 533.14±54.22ms (n=14) in LQT2 cardiomyoctes (P<0.05), while the elimination of I ks slightly prolonged the APD 90 to 423.37± 52.31 (n=8) (P=NS). In conclusion, expression of the pore mutants resulted in specific inhibition of I Ks in LQT1 and I Kr in LQT2 rabbits, and established these models as unique genetic counterparts of the human LQT1 and LQT2 syndrome. These models will enable detailed analyses of the electrical remodeling in LQTS.

Anticoagulation with warfarin is the most effective means of reducing stroke in AF. The generally recommended INR goal is 2-3. Aspirin provides a modest degree of stroke protection in AF but is inferior to warfarin. Assessment of stroke risk is critical in determining whether to prescribe warfarin therapy to a patient with AF. The most important risk factors for stroke in AF are age over 65 years, hypertension, prior stroke, and left ventricular dysfunction or heart failure. The risk of warfarin may be less than commonly believed, but increases when warfarin is combined with aspirin. Patients with paroxysmal AF are not at lower risk of stroke than those with persistent AF and should be treated with warfarin. Apparently successful therapy with antiarrhythmic agents does not eliminate the need for anticoagulation. New antithrombotic therapies are being studied and may soon provide an alternative to warfarin.