Accelerated QT adaptation following atropine-induced heart rate increase in LQT1 patients versus healthy controls: A sign of disturbed hysteresis.

Hysteresis, a ubiquitous regulatory phenomenon, is a salient feature of the adaptation of ventricular repolarization duration to heart rate (HR) change. We therefore compared the QT interval adaptation to rapid HR increase in patients with the long QT syndrome type 1 (LQT1) versus healthy controls because LQT1 is caused by loss-of-function mutations affecting the repolarizing potassium channel current IKs , presumably an important player in QT hysteresis. The study was performed in an outpatient hospital setting. HR was increased in LQT1 patients and controls by administering an intravenous bolus of atropine (0.04 mg/kg body weight) for 30 s. RR and QT intervals were recorded by continuous Frank vectorcardiography. Atropine induced transient expected side effects but no adverse arrhythmias. There was no difference in HR response (RR intervals) to atropine between the groups. Although atropine-induced ΔQT was 48% greater in 18 LQT1 patients than in 28 controls (p < 0.001), QT adaptation was on average 25% faster in LQT1 patients (measured as the time constant τ for the mono-exponential function and the time for 90% of ΔQT; p < 0.01); however, there was some overlap between the groups, possibly a beta-blocker effect. The shorter QT adaptation time to atropine-induced HR increase in LQT1 patients on the group level corroborates the importance of IKs in QT adaptation hysteresis in humans and shows that LQT1 patients have a disturbed ultra-rapid cardiac memory. On the individual level, the QT adaptation time possibly reflects the effect-size of the loss-of-function mutation, but its clinical implications need to be shown.

To Modify or Not to Modify: Allele-Specific Effects of 3'UTR-KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant-Negative Mutation.

Background There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele-specific effects of 3 previously published 3'UTR-KCNQ1's SNPs in a LQT1 founder population segregating a dominant-negative mutation. Methods and Results Bidirectional sequencing of the KCNQ1's 3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 in cis with p.Y111C (89%). Allele-specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR-KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P=0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P=0.010). Conclusions Allele-specific modifying effects on symptomatic phenotype of 3'UTR-KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant-negative mutation. The high prevalence of suppressive 3'UTR-KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.

ICD harm and benefit: risk scores applied to the Swedish ICD-treated LQTS population.

Objectives. The use of implantable cardioverter defibrillators (ICDs) in long QT syndrome (LQTS) patients is essential in high-risk patients. However, it is sometimes used in patients without high-risk profiles for whom the expected benefit may be lower than the risk of ICD harm. Here, we evaluated ICD benefit and harm by assessing risk according to risk scores and pre-ICD clinical characteristics. Design. We studied 109 Swedish LQTS patients drawn from the Swedish ICD and Pacemaker Registry with data collected from medical records. In addition to clinical characteristics, we used two risk scores to assess pre-ICD risk, and evaluated ICD benefit and harm. Results. Twenty percent of all patients received ≥1 appropriate shock with a first appropriate shock incidence rate of 4.3 per 100 person-years. A long QTc (≥550 ms) and double mutations were significantly associated with appropriate shock. Low risk scores among patients without pre-ICD aborted cardiac arrest were not significantly associated with low risk of first appropriate shock. The incidence rates of a first inappropriate shock and first complication were 3.0 and 7.6 per 100 person-years, respectively. Conclusion. Our findings on ICD harm emphasize the importance of careful individual pre-ICD consideration. When we applied two risk scores to patients without pre-ICD aborted cardiac arrest, we could not validate their ability to identify patients with low risk of appropriate shocks and patients who were assessed as having a low risk still received appropriate shocks. This further supports the complexity of risk stratification and the difficulty of using risk scores.

The results of health-related quality of life assessment depend on the prevailing rhythm at the assessment: Experience from the CAPTAF trial (Catheter Ablation Compared with Pharmacological Therapy for Atrial Fibrillation).

AIMS: To assess whether the prevailing rhythm at the time of replying to symptom and health-related quality of life (HR-QoL) questionnaires impacts the findings. METHOD: A total of 150 patients from the randomized Catheter Ablation Compared with Pharmacological Therapy for Atrial Fibrillation-trial, comparing atrial fibrillation (AF) ablation versus drugs, were included. The effect of the prevailing rhythm on the outcome results of the HR-QoL 36-Item Short-Form Health Survey, the symptom severity questionnaire (SSQ), and the European Heart Rhythm Association (EHRA) score for classification of AF-related symptoms was assessed. RESULTS: AF as the prevailing rhythm was independently associated with a significantly lower Vitality score; 18.4 points lower (95% confidence interval -32.7 to -4.1, p = .01) compared with sinus rhythm when adjusted for AF burden, median duration of episode, number of episodes, beta-blocker use, type of AF, and sex. The presence of AF did not affect the General Health score compared with sinus rhythm, nor did it influence symptoms assessed by the SSQ or EHRA score. CONCLUSION: The observation that the presence of AF versus sinus rhythm when conducting HR-QoL tests had a negative impact on its outcome, leaving symptom-related questionnaires unaffected, implies that the prevailing rhythm should be taken into account when results of HR-QoL questionnaires are interpreted.

Atrial fibrillation burden, episode duration and frequency in relation to quality of life in patients with implantable cardiac monitor.

AIMS: To assess the relation between atrial fibrillation (AF) characteristics and health-related quality of life (QoL), and which AF characteristic had the greatest impact. METHOD: The AF characteristics burden (percentage of time in AF), duration and number of AF episodes/month were obtained from implantable cardiac monitors during the 2-month run-in period in 150 patients included in the randomized CAPTAF trial comparing early ablation and antiarrhythmic drug therapy. The QoL was measured by the General Health and Vitality dimensions of the 36-Item Short-Form Health Survey. AF characteristics were analysed continuously and in quartiles (Q1-Q4). RESULTS: Greater AF burden (p = 0.003) and longer AF episodes (p = 0.013) were associated with impaired QoL (Vitality score only) in simple linear regression analyses. Greater AF burden was, however, the only AF characteristic associated with lower QoL, when adjusted for sex, type of AF, hypertension, heart rate above 110 beats per minute during AF, and beta-blocker use in multiple linear regression analyses. For every 10% increase in AF burden there was a 1.34-point decrease of Vitality score (95% confidence interval (CI) -2.67 to -0.02, p = 0.047). The Vitality score was 12 points lower (95% CI -22.73 to -1.27, p = 0.03) in patients with an AF burden > 33% (Q4) versus those with < 0.45% (Q1), but only in unadjusted analysis. CONCLUSION: AF burden had a greater impact on QoL (Vitality), than the duration and number of AF episodes, corroborating that AF burden may be the preferred outcome measure of rhythm control in trials including relatively healthy AF populations.

Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes.

AIMS: There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts. METHODS AND RESULTS: In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF. CONCLUSIONS: In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.

Increased risk of late pacemaker implantation after ablation for atrioventricular nodal reentry tachycardia: A 10-year follow-up of a nationwide cohort.

BACKGROUND: Catheter ablation of the slow pathway is the standard treatment of atrioventricular nodal reentry tachycardia (AVNRT) with a well described low risk of periprocedural atrioventricular block. Less is known about the risk of pacemaker implantation late after ablation. OBJECTIVE: We aimed to quantify the risk of late pacemaker implantation in a countrywide cohort undergoing first-time ablation for AVNRT. METHODS: All patients undergoing first-time ablation for AVNRT in Sweden from 2004 to 2014 were identified from the Swedish catheter ablation registry and matched against the Swedish Pacemaker and ICD registry. The cohort was compared to patients ablated for an accessory pathway (AP) and to matched controls. RESULTS: During follow-up of 2039 days, pacemaker was implanted later than 30 days after ablation in 96 of 6842 patients with AVNRT (1.4%), 29 of 4065 patients with AP (0.7%) (P = .001), and 124 of 33,270 controls (0.4%) (P < .00001). A periprocedural pacemaker (≤30 days postablation) was implanted in 32 of 6877 patients with AVNRT (0.5%) and 9 of 4079 patients with AP (0.2%) (P = .05). With cryoablation, 5 patients needed periprocedural pacemaker implantation. Pacemakers were implanted before ablation in 88 of 6977 patients with AVNRT (1.3%) and 11 of 4100 patients with AP (0.3%); the prevalence of pacemaker implants in controls was 124 of 33,270 (0.4%) (P < .00001 for both comparisons). CONCLUSION: The risk of late pacemaker implantation after AVNRT ablation was low but 3 times higher than that in the control population and 3 times higher than the risk of periprocedural pacemaker implantation. Similar results were observed with cryoablation and radiofrequency ablation. Ablation may not be the cause of increased late pacemaker implantation risk.

Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial.

Importance: Quality of life is not a standard primary outcome in ablation trials, even though symptoms drive the indication. Objective: To assess quality of life with catheter ablation vs antiarrhythmic medication at 12 months in patients with atrial fibrillation. Design, Setting, and Participants: Randomized clinical trial at 4 university hospitals in Sweden and 1 in Finland of 155 patients aged 30-70 years with more than 6 months of atrial fibrillation and treatment failure with 1 antiarrhythmic drug or ß-blocker, with 4-year follow-up. Study dates were July 2008-September 2017. Major exclusions were ejection fraction <35%, left atrial diameter >60 mm, ventricular pacing dependency, and previous ablation. Interventions: Pulmonary vein isolation ablation (n = 79) or previously untested antiarrhythmic drugs (n = 76). Main Outcomes and Measures: Primary outcome was the General Health subscale score (Medical Outcomes Study 36-Item Short-Form Health Survey) at baseline and 12 months, assessed unblinded (range, 0 [worst] to 100 [best]). There were 26 secondary outcomes, including atrial fibrillation burden (% of time) from baseline to 12 months, measured by implantable cardiac monitors. The first 3 months were excluded from rhythm analysis. Results: Among 155 randomized patients (mean age, 56.1 years; 22.6% women), 97% completed the trial. Of 79 patients randomized to receive ablation, 75 underwent ablation, including 2 who crossed over to medication and 14 who underwent repeated ablation procedures. Of 76 patients randomized to receive antiarrhythmic medication, 74 received it, including 8 who crossed over to ablation and 43 for whom the first drug used failed. General Health score increased from 61.8 to 73.9 points in the ablation group vs 62.7 to 65.4 points in the medication group (between-group difference, 8.9 points; 95% CI, 3.1-14.7; P = .003). Of 26 secondary end points, 5 were analyzed; 2 were null and 2 were statistically significant, including decrease in atrial fibrillation burden (from 24.9% to 5.5% in the ablation group vs 23.3% to 11.5% in the medication group; difference -6.8% [95% CI, -12.9% to -0.7%]; P = .03). Of the Health Survey subscales, 5 of 7 improved significantly. Most common adverse events were urosepsis (5.1%) in the ablation group and atrial tachycardia (3.9%) in the medication group. Conclusions and Relevance: Among patients with symptomatic atrial fibrillation despite use of antiarrhythmic medication, the improvement in quality of life at 12 months was greater for those treated with catheter ablation compared with antiarrhythmic medication. Although the study was limited by absence of blinding, catheter ablation may offer an advantage for quality of life. Trial Registration: clinicaltrialsregister.eu Identifier: 2008-001384-11.

Quality of life is not improved after mitral valve surgery combined with epicardial left atrial cryoablation as compared with mitral valve surgery alone: a substudy of the double blind randomized SWEDish Multicentre Atrial Fibrillation study (SWEDMAF).

Aims: Concomitant surgical ablation of atrial fibrillation (AF) in patients undergoing mitral valve surgery (MVS) has almost become routine despite lack of convincing information about improved quality-of-life (QOL) and clinical benefit. Quality-of-life was therefore assessed after MVS with or without epicardial left atrial cryoablation. Methods and results: Sixty-five patients with permanent AF randomized to MVS with or without left atrial cryoablation, in the double-blinded multicentre SWEDMAF trial, replied to the Short Form 36 QOL survey at 6 and 12 months follow-up. The QOL scores at 12 month follow-up did not differ significantly between patients undergoing MVS combined with cryoablation vs. those undergoing MVS alone regarding Physical Component Summary mean 42.8 (95% confidence interval 38.3-47.3) vs. mean 44.0 (40.1-47.7), P = 0.700 or Mental Component Summary mean 53.1 (49.7-56.4) vs. mean 48.4 (44.6-52.2), P = 0.075. All patients, irrespective of allocated procedure, reached the same QOL after surgery as an age-matched Swedish general population. The Physical Component Summary in patients with sinus rhythm did also not differ from those in AF at 12 months; mean 45.4 (42.0-48.7) vs. mean 40.5 (35.5-45.6), P = 0.096) nor was there a difference in Mental Component Summary; mean 51.0 (48.0-54.1) vs. mean 49.6 (44.6-54.5), P = 0.581). Conclusion: Left atrial cryoablation added to MVS does not improve health-related QOL in patients with permanent AF, a finding that raises concerns regarding recommendations made for this combined procedure.

Long-term outcomes of the current remote magnetic catheter navigation technique for ablation of atrial fibrillation.

OBJECTIVES: Comparisons between remote magnetic (RMN) and manual catheter navigation for atrial fibrillation (AF) ablation have earlier been reported with controversial results. However, these reports were based on earlier generations of the RMN system. DESIGN: To evaluate the outcomes of the most current RMN system for AF ablation in a larger patient population with longer follow-up time, 112 patients with AF (78 paroxysmal, 34 persistent) who underwent AF ablation utilizing RMN (RMN group) were compared to 102 AF ablation patients (72 paroxysmal, 30 persistent) utilizing manual technique (Manual group). RESULTS: The RMN group was associated with significantly shorter fluoroscopy time (10.4 ± 6.4 vs. 16.3 ± 10.9 min, p < .001) but used more RF energy (64.1 ± 19.4KJ vs. 54.3 ± 24.1 KJ, p < .05), while total procedure time showed no significant difference (201 ± 35 vs. 196 ± 44 min, NS). After 39 ± 9/44 ± 10 months of follow-up, AF-free rates at 1year, 2 years and 3.5 years post ablation were 63%, 46% and 42% in the RMN group vs. 60%, 32% and 30% (survival analysis p < .05) in the Manual group, whereas clinically effective rates were 82%, 73% and 70% for the former vs. 70%, 56% and 49% for the latter (survival analysis p < .005). CONCLUSION: Differing from previous reports, our data from a larger patient population and longer follow-up time demonstrates that compared to manual technique, the most current RMN technique is associated with better procedural and clinical outcomes for AF ablation.

Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis.

BACKGROUND: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1AP sequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations. METHODS: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs. RESULTS: A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males. CONCLUSIONS: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.

Cardioversion of atrial fibrillation does not affect obstructive sleep apnea.

BACKGROUND: Sleep apnea is common in patients with atrial fibrillation, but the effect of the cardioversion of atrial fibrillation to sinus rhythm on central and obstructive apneas is mainly unknown. The primary aim of the study was to analyze the association between cardioversion of atrial fibrillation and sleep apneas, to investigate whether obstructive or central sleep apneas are reduced following cardioversion. A secondary objective was to study the effect on sleep quality. METHODS: Twenty-three patients with atrial fibrillation were investigated using overnight polysomnography, including esophagus pressure monitoring and ECG, before and after the cardioversion of persistent atrial fibrillation. RESULTS: Obstructive sleep apnea occurred in 17/23 patients (74%), and central sleep apnea in 6/23 patients (26%). Five patients had both obstructive and central sleep apnea. Sinus rhythm at follow-up was achieved in 16 patients. The obstructive apnea-hypopnea index, central apnea-hypopnea index, and the number of patients with obstructive or central sleep apnea did not differ before and after restoration of sinus rhythm. Sleep time, sleep efficiency, time in different sleep stages, and subjective daytime sleepiness were normal and unaffected by cardioversion. CONCLUSIONS: Both obstructive and central sleep apneas are highly prevalent in patients with persistent atrial fibrillation. Obstructive sleep apneas are unaffected by the cardioversion of atrial fibrillation to sinus rhythm. The sleep pattern is normal and unaffected by cardioversion in patients with atrial fibrillation. CLINICAL TRIAL REGISTRATION: Trial number NCT00429884.

Implantable cardioverter defibrillator treatment in long QT syndrome patients: a national study on adherence to international guidelines.

OBJECTIVES: Implantable cardioverter defibrillator (ICD) treatment is effective among long QT syndrome (LQTS) patients at a high risk of sudden cardiac death. Previous studies show that the international guidelines are not always followed, and that risk stratification may be based on genotype rather than individual risk profile. We analysed data from the Swedish ICD & Pacemaker Registry and medical records to examine how international guidelines were followed with regards to phenotype and genotype. METHODS AND RESULTS: ICD treatment was used in 150 Swedish LQTS patients from 1989-2013. The annual number of implantations increased over the study period. A total of 109 patients were included in the analysis. Most patients (91%) were symptomatic before the implantation. Seventy percent of patients who received ICD treatment met the 2006 Class I or Class IIa recommendations for LQTS treatment. Thirty-one percent of the LQT3 patients received ICD treatment despite being asymptomatic. Among LQT1 patients, 45% received ICD treatment after syncope despite beta-blockers. CONCLUSIONS: Thirty percent of Swedish LQTS patients with ICD received the treatment without a strong indication based on international guidelines. LQT3 patients were over-represented among asymptomatic patients. Many LQT1 patients received ICD despite the known effect of beta-blockers in this group.

Two Cases of LQT Syndrome with Malignant Syncope after Switch from Propranolol to Bisoprolol.

Propranolol in slow-release form has been the first-line treatment in long QT (LQT) until it was withdrawn from the market. We describe two cases where a switch to bisoprolol resulted in worsening of arrhythmia control: A man with LQT2, asymptomatic on propranolol, experienced syncope after switching to bisoprolol 5 mg daily. He switched back to propranolol and has remained asymptomatic during subsequent 12 months. A man with classical Jervell Lange-Nielsen syndrome, previous gangliectomy, and ICD implantation, switched to bisoprolol 5 mg daily. Four months later he experienced a tachycardia storm. He switched back to propranolol and has remained free from arrhythmias during subsequent 12 months.

Combined electrical and global markers of dyssynchrony predict clinical response to cardiac resynchronization therapy.

AIM: To assess potential additional value of global left ventricular (LV) dyssynchrony markers in predicting cardiac resynchronization therapy (CRT) response in heart failure (HF) patients. METHODS: We included 103 HF patients (mean age 67 ± 12 years, 83% male) who fulfilled the guidelines criteria for CRT treatment. All patients had undergone full clinical assessment, NT-proBNP and echocardiographic examination. Global LV dyssynchrony was assessed using total isovolumic time (t-IVT) and Tei index. On the basis of reduction in the NYHA class after CRT, patients were divided into responders and non-responders. RESULTS: Prolonged t-IVT [0.878 (range, 0.802-0.962), p = 0.005], long QRS duration [0.978 (range, 0.960-0.996), p = 0.02] and high tricuspid regurgitation pressure drop [1.047 (range, 1.001-1.096), p = 0.046] independently predicted response to CRT. A t-IVT ≥ 11.6 s/min was 67% sensitive and 62% specific (AUC 0.69, p = 0.001) in predicting CRT response. Respective values for a QRS ≥ 151 ms were 66% and 62% (AUC 0.65, p = 0.01). Combining the two variables had higher specificity (88%) in predicting CRT response. In atrial fibrillation (AF) patients, only prolonged t-IVT [0.690 (range, 0.509-0.937), p = 0.03] independently predicted CRT response. CONCLUSION: Combining prolonged t-IVT and the conventionally used broad QRS duration has a significantly higher specificity in identifying patients likely to respond to CRT. Moreover, in AF patients, only prolonged t-IVT independently predicted CRT response.

Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families.

BACKGROUND: The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p.R518X mutation. METHODS: The study included 19 Swedish p.R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software). RESULTS: Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000). CONCLUSIONS: R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.

U22 protocol as measure of symptomatic improvement after catheter ablation of atrial fibrillation.

INTRODUCTION: Left atrial catheter ablation is useful as symptomatic treatment in selected patients with atrial fibrillation (AF). Evaluation requires measurement of arrhythmia-related symptoms. Many of the published protocols have drawbacks and have been used in AF only, with no possible comparison to other ablations that compete for the same resources. U22 is a published protocol that quantifies paroxysmal tachycardia symptoms through scales with 11 answer alternatives, translated into discrete numerical scales 0-10. It has been shown to reflect the clinical improvement after ablation of supraventricular tachycardia. Here we report the use of U22 in measuring improvement after catheter ablation for AF. MATERIAL AND METHODS: A total of 105 patients underwent first-time ablation for AF and answered U22 and SF-36 forms at baseline and follow-up 304 (SD 121) days after ablation. Independently, the patients underwent a clinical follow-up. All decisions regarding medication and reablation were taken without knowledge of the symptom scores. Results. The U22 scores for well-being, arrhythmia as cause for impaired well-being, derived time-aspect score for arrhythmia, and discomfort during attack detected relevant improvements of symptoms after the ablation. U22 showed larger improvement in patients undergoing only one procedure than in patients who later underwent repeated interventions, thus reflecting the independent clinical decision for reablation. CONCLUSION: U22 quantifies the symptomatic improvement after AF ablation with adequate internal consistency and construct validity. U22 mirrors aspects of the arrhythmia symptomatology other than SF-36.

Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene.

Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.