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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population.

Measurements of the Q-T interval are less reliable in children than in adults. Identification of superior diagnostic tools is warranted. This study aimed to investigate whether a vectorcardiogram (VCG) recorded from three orthogonal leads (X, Y, Z) according to Frank is superior to a 12-lead electrocardiogram (ECG) in providing a correct long Q-T syndrome (LQTS) diagnosis in children. This LQTS group consisted of 35 genetically confirmed carriers of mutations in the KCNQ1 (n = 29) and KCNH2 (n = 6) genes. The control group consisted of 35 age- and gender-matched healthy children. The mean age was 7 years in the LQTS group and 6.7 years in the control group (range, 0.5-16 years). The corrected Q-T interval (QT(c)) was measured manually (QT(man)) by one author (A.W.). The 12-lead ECG automatic measurements (QT(ECG)) and interpretation (QT(Interpret)) of QT(c) were performed with the Mac5000 (GE Medical System), and the VCG automatic measurements (QT(VCG)) were performed with the Mida1000, CoroNet (Ortivus AB, Sweden). By either method, a QT(c) longer than 440 ms was considered prolonged and indicative of LQTS. Of the 35 children with genetically confirmed LQTS, 30 (86 %) received a correct diagnosis using QT(VCG), 29 (82 %) using QT(man), 24 (69 %) using QT(ECG), and 17 (49 %) using QT(Interpret). Specificity was 0.80 for QT(VCG), 0.83 for QT(man), 0.77 for QT(ECG), and 0.83 for QT(Interpret). The VCG automatic measurement of QT(c) seems to be a better predictor of LQTS than automatic measurement and interpretation of 12-lead ECG.

Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden.

AIMS: To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death. METHODS AND RESULTS: A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on ß-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 ± 62 vs. 518 ± 50 ms, P = 0.016). ß-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. ß-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death. CONCLUSION: Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent ß-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed.

Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing.

BACKGROUND: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort. METHODS: Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT). RESULTS: In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death. CONCLUSION: In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique.

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.

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.

Right ventricular lead positioning does not influence the benefits of cardiac resynchronization therapy in patients with heart failure and atrial fibrillation.

AIMS: Little is known about the optimal right ventricular (RV) pacing site in cardiac resynchronization therapy (CRT). This study compares bi-ventricular pacing at the left ventricular (LV) free wall combined with two different RV stimulation sites: RV outflow tract (RVOT+LV) vs. RV-apex (RVA+LV). METHODS AND RESULTS: Thirty-three patients (32 males) with chronic heart failure, NYHA class III-IV, optimal drug therapy, QRS-duration ≥150 ms, and chronic atrial fibrillation (AF) received CRT with two different RV leads, in the apex (RVA) or outflow tract (RVOT), together with an LV lead, all connected to a bi-ventricular pacemaker. Randomization to pacing in RVOT+LV or RVA+LV was made 1 month after implantation and cross-over to the alternate pacing configuration occurred after 3 months. The median age of patients was 69 ± 10 years, the mean QRS was 179 ± 23 ms, and 58% of patients had ischaemic heart disease. Seven patients had pacemaker rhythm at inclusion and 60% were treated with atrioventricular-junctional ablation before randomization. In the RVA+LV and RVOT+LV pacing modes, 67 and 63% (nonsignificant) responded symptomatically with a decrease of at least 10 points in the Minnesota Living with Heart Failure score. The secondary end-points (6-min walk test, peak oxygen uptake, N-Terminal fragment of B-type Natriuretic Peptide, and left ventricular ejection fraction) showed significant improvement between baseline and CRT, but not between RVOT+LV and RVA+LV. CONCLUSION: In this randomized controlled study, the exact RV pacing site, either apex or outflow tract, did not influence the benefits of CRT in a group of patients with chronic heart failure and AF. ClinicalTrials.gov ID: NCT00457834.

Effect of heart rate on ventricular repolarization in healthy individuals applying vectorcardiographic T vector and T vector loop analysis.

BACKGROUND: Ventricular repolarization (VR) is strongly influenced by heart rate (HR) and autonomic nervous activity, both of which also are important for arrhythmogenesis. Their relative influence on VR is difficult to separate, but might be crucial for understanding while some but not other individuals are at risk for life-threatening arrhythmias at a certain HR. This study was therefore designed to assess the "pure" effect of HR increase by atrial pacing on the ventricular gradient (VG) and other vectorcardiographically (VCG) derived VR parameters during an otherwise unchanged condition. METHODS: In 19 patients with structurally normal hearts, a protocol with stepwise increased atrial pacing was performed after successful arrhythmia ablation. Conduction intervals were measured on averaged three-dimensional (3D) QRST complexes. In addition, various VCG parameters were measured from the QRS and T vectors as well as from the T loop. All measurements were performed after at least 3 minutes of rate adaptation of VR. RESULTS: VR changes at HR from 80 to 120 bpm were assessed. The QRS and QT intervals, VG, QRSarea, Tarea, and Tamplitude were markedly rate dependent. In contrast, the Tp-e/QT ratio was rate independent as well as the T-loop morphology parameters Tavplan and Teigenvalue describing the bulginess and circularity of the loop. CONCLUSIONS: In healthy individuals, the response to increased HR within the specified range suggests a decreased heterogeneity of depolarization instants, action potential morphology, and consequently of the global VR.

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.

Ischemic ST-segment episodes during the initial 24 hours of ST elevation myocardial infarction predict prognosis at 1 and 5 years.

OBJECTIVES: The aims of the study were to assess the prognostic value of recurrent ischemic episodes during the first 24 hours in ST elevation myocardial infarction (STEMI) treated with thrombolysis and to explore those episodes as a part of a low-risk prognostic feature. DESIGN: Two hundred twenty patients with STEMI treated with thrombolysis were monitored for 24 hours with continuous online vectorcardiography assessing ST vector changes to record recurrent ischemic events. RESULTS: Ischemic events measured as an increase in ST-change vector magnitude (STC-VM) more than 50 muV for at least 2 minutes during 4- to 24-hour predicted mortality in a 5-year follow-up based on a multivariable analysis (hazard ratio, 1.18/episode; confidence interval, 1.01-1.37). The more episodes there were, the worse the prognosis. A low-risk group with a 1-year mortality of 1.9% could be identified. CONCLUSION: Continuous ST-segment monitoring during the first 24 hours of a myocardial infarction is a valuable tool for identifying high- and low-risk patients. The STC-VM events during 4 to 24 hours of the first day of a myocardial infarction predict mortality within 5 years.