Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study From 1996 to 2016.

BACKGROUND: Population-based epidemiologic studies of aortic dissections (ADs) are needed. This study aimed to report clinical characteristics, incidences, and mortality rates for adult patients admitted to Danish hospitals with type A AD (TAAD) or type B AD (TBAD) from 1996 through 2016. METHODS: We conducted a nationwide, population-based register study. All cases of AD registered with International Classification of Diseases, Tenth Revision codes in the Danish National Patient Registry at time of admission to a hospital with available medical records underwent validation. Data were merged between nationwide health registries including the cause of death registry. Patients with validated AD were matched 1:10 on sex and age with patients with hypertension from the general Danish population. RESULTS: Of 5018 registered cases of AD, 4183 cases underwent review and 3023 (60.2%) were validated as AD. After exclusions, the distribution of validated TAAD and TBAD was 1620 (60.5%) and 1059 (39.5%; P<0.001), 67.5% and 67.0% of patients were men, and mean ages at dissection were 63.5±12.9 and 67.5±12.2 years (P<0.001), respectively. The most prevalent comorbidities for TAAD were hypertension (55.2%), thoracic aortic aneurysms (14.6%), and chronic obstructive pulmonary disease (13.1%); for TBAD, the most prevalent comorbidities were hypertension (64.1%), aortic aneurysms at any location (7.5% to 12.0%), and chronic obstructive pulmonary disease (15.7%). The overall mean annual incidence rate was 4.2/100 000 patient-years. Incidence was significantly higher for TAAD (2.2/100 000) compared with TBAD (1.5/100 000; P<0.001). The 30-day mortality rates for validated TAAD and TBAD were 22.0% and 13.9% (P<0.001), respectively, with no significant changes over time or between sexes. Adjusted 5-year overall mortality rates for TAAD and TBAD were hazard ratio 3.2 (2.9 to 3.5; P<0.001; aortic-related cause of death, 57.0%) and hazard ratio 2.1 (1.9 to 2.4; P<0.001; aortic-related cause of death, 42.8%), respectively, compared with the general hypertensive population. Among patients who survived 30 days from dissection, the adjusted 5-year overall mortality rates were hazard ratio 1.1 (1.0 to 1.3; P=0.12; aortic-related cause of death, 23.2%) and hazard ratio 1.4 (1.2 to 1.6; P<0.001; aortic-related cause of death, 25.6%) for TAAD and TBAD, respectively. CONCLUSIONS: Hypertension, aortic aneurysms, and chronic obstructive pulmonary disease were the most prevalent comorbidities. The 30-day mortality frequencies were consistent over time with no significant differences between sexes. The 5-year mortality rate was higher for TAAD than TBAD. If the patient survived 30 days from dissection, the mortality rate for patients with TAAD was comparable with that of the general hypertensive population, but the mortality rate was significantly higher in patients with TBAD.

The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.

AIMS: Variants in SCN5A encoding Nav1.5 are associated with cardiac arrhythmias. We aimed to determine the mechanism by which c.638G>A in SCNA5 resulting in p.Gly213Asp (G213D) in Nav1.5 altered Na+ channel function and how flecainide corrected the defect in a family with multifocal ectopic Purkinje-related premature contractions (MEPPC)-like syndrome. METHODS AND RESULTS: Five patients carrying the G213D variant were treated with flecainide. Gating pore currents were evaluated in Xenopus laevis oocytes. The 638G>A SCN5A variant was introduced to human-induced pluripotent stem cell (hiPSC) by CRISPR-Cas9 gene editing and subsequently differentiated to cardiomyocytes (hiPSC-CM). Action potentials and sodium currents were measured in the absence and presence of flecainide. Ca2+ transients were measured by confocal microscopy. The five patients exhibited premature atrial and ventricular contractions which were suppressed by flecainide treatment. G213D induced gating pore current at potentials negative to -50 mV. Voltage-clamp analysis in hiPSC-CM revealed the activation threshold of INa was shifted in the hyperpolarizing direction resulting in a larger INa window current. The G213D hiPSC-CMs had faster beating rates compared with wild-type and frequently showed Ca2+ waves and alternans. Flecainide applied to G213D hiPSC-CMs decreased window current by shifting the steady-state inactivation curve and slowed the beating rate. CONCLUSION: The G213D variant in Nav1.5 induced gating pore currents and increased window current. The changes in INa resulted in a faster beating rate and Ca2+ transient dysfunction. Flecainide decreased window current and inhibited INa, which is likely responsible for the therapeutic effectiveness of flecainide in MEPPC patients carrying the G213D variant.

Complications of implantable cardioverter-defibrillator treatment in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up. METHODS AND RESULTS: The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P < 0.05), whereas sex, age at implant, and device type were not (all P > 0.05). CONCLUSION: Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.

Severity of congenital long QT syndrome disease manifestation and risk of depression, anxiety, and mortality: a nationwide study.

AIMS: We examined if a congenital long QT syndrome (cLQTS) diagnosis and severity of cLQTS disease manifestation was associated with increased risk of depression, anxiety, and all-cause mortality. METHODS AND RESULTS: All patients with known cLQTS in Denmark were identified using nationwide registries and specialized inherited cardiac disease clinics (1994-2016) and followed for up to 3 years after their cLQTS diagnosis. Risk factors for depression, anxiety, and all-cause mortality were determined using multivariable Cox proportional-hazards regression. An age- and sex-matched control population was identified (matching 1:4). Overall, 589 patients with cLQTS were identified of which 119/589 (20.2%) developed depression or anxiety during follow-up compared with 302/2356 (12.8%) from the control population (P < 0.001). Severity of cLQTS disease manifestation was identified for 324/589 (55%) of patients with cLQTS; 162 were asymptomatic, 119 had ventricular tachycardia (VT)/syncope, and 43 had aborted sudden cardiac death (aSCD). In multivariable models, patients with aSCD, VT/syncope, or unspecified cLQTS disease manifestation had a higher risk of developing depression or anxiety compared with the control population (hazard ratio [HR]=2.4, 95% confidence interval [CI]: 1.1-5.1; HR = 1.9, 95% CI: 1.2-3.0; HR = 1.6, 95% CI: 1.1-2.3, respectively). Asymptomatic patients had similar risk of developing depression or anxiety as the control population (HR = 1.2, 95% CI: 0.8-1.9). During follow-up, 10/589 (1.7%) patients with cLQTS died compared with 27/2356 (1.1%) from the control population (P = 0.5). Furthermore, 4/10 who died had developed depression or anxiety. CONCLUSION: A severe cLQTS disease manifestation was associated with a greater risk of depression or anxiety. All-cause mortality for patients with cLQTS was low.

Long-term outcomes in young patients with atrioventricular block of unknown aetiology.

AIMS: Atrioventricular block (AVB) of unknown aetiology is rare in the young, and outcome in these patients is unknown. We aimed to assess long-term morbidity and mortality in young patients with AVB of unknown aetiology. METHODS AND RESULTS: We identified all Danish patients younger than 50 years receiving a first pacemaker due to AVB between January 1996 and December 2015. By reviewing medical records, we included patients with AVB of unknown aetiology. A matched control cohort was established. Follow-up was performed using national registries. The primary outcome was a composite endpoint consisting of death, heart failure hospitalization, ventricular tachyarrhythmia, and cardiac arrest with successful resuscitation. We included 517 patients, and 5170 controls. Median age at first pacemaker implantation was 41.3 years [interquartile range (IQR) 32.7-46.2 years]. After a median follow-up of 9.8 years (IQR 5.7-14.5 years), the primary endpoint had occurred in 14.9% of patients and 3.2% of controls [hazard ratio (HR) 3.8; 95% confidence interval (CI) 2.9-5.1; P < 0.001]. Patients with persistent AVB at time of diagnosis had a higher risk of the primary endpoint (HR 10.6; 95% CI 5.7-20.0; P < 0.001), and risk was highest early in the follow-up period (HR 6.8; 95% CI 4.6-10.0; P < 0.001, during 0-5 years of follow-up). CONCLUSION: Atrioventricular block of unknown aetiology presenting before the age of 50 years and treated with pacemaker implantation was associated with a three- to four-fold higher rate of the composite endpoint of death or hospitalization for heart failure, ventricular tachyarrhythmia, or cardiac arrest with successful resuscitation. Patients with persistent AVB were at higher risk. These findings warrant improved follow-up strategies for young patients with AVB of unknown aetiology.

Repeat pulmonary vein isolation in patients with atrial fibrillation: low ablation index is associated with increased risk of recurrent arrhythmia.

OBJECTIVES: We aimed to investigate the predictors of recurrent arrhythmia after repeated pulmonary vein isolation (PVI) performed in the era of contact force without additional substrate ablation. One of the predictors studied, ablation index (AI), incorporates power, contact force, and time in a weighted formula and is reported to predict lesion size in animals. Design. Consecutive patients (n = 108) undergoing repeat PVI without additional substrate modification using a contact force sensing catheter were included retrospectively at a tertiary center. All ablation points were analyzed offline. A new variable, normalized AI (AI corrected for the location of the lesion-anterior vs. posterior) was calculated. The patients were systematically followed with clinical visit and 12-lead ECG as well as review of the regional electronic patient files at 3 and 12 months after the procedure with 5-day Holter at 12 months. Results. Electrical reconnection to at least one pulmonary vein (PV) was seen in 97% of the patients. The recurrence rate was 35%. There was no recurrence in patients with nAI above 1.15 (n = 26). Patients with electrical reconnection of up to two PVs had a higher risk of recurrence compared with patients having electrical reconnection of three or four PVs (p = .003), and this risk was especially high in patients with persistent atrial fibrillation (69 [39-91]%). Conclusions. The risk of recurrence is higher in patients with ablations performed with low levels of AI and in patients with reconnection to up to two PVs. Our data may indicate the need for higher target levels of AI during repeat PVI than normally used during de-novo PVI.

Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Pregnancies, ventricular arrhythmias, and substrate progression in women with arrhythmogenic right ventricular cardiomyopathy in the Nordic ARVC Registry.

AIMS: Women with arrhythmogenic right ventricular cardiomyopathy (ARVC) are at relatively lower risk of ventricular arrhythmias (VAs) than men, but the physical burden associated with pregnancy on VA risk remains insufficiently studied. We aimed to assess the risk of VA in relation to pregnancies in women with ARVC. METHODS AND RESULTS: We included 199 females with definite ARVC (n = 121) and mutation-positive family members without ascertained ARVC diagnosis (n = 78), of whom 120 had at least one childbirth. Ventricular arrhythmia-free survival after the latest childbirth was compared between women with one (n = 20), two (n = 67), and three or more (n = 37) childbirths. Cumulative probability of VA for each pregnancy (n = 261) was assessed from conception through 2 years after childbirth and compared between those pregnancies that occurred before (n = 191) or after (n = 19) ARVC diagnosis and in mutation-positive family members (n = 51). The nulliparous women had lower median age at ARVC diagnosis (38 vs. 42 years, P < 0.001) and first VA (22 vs. 41 years, P < 0.001). Ventricular arrhythmia-free survival after the latest childbirth was not related to the number of pregnancies. No pregnancy-related VA was reported among the family members. Women who gave birth after ARVC diagnosis had elevated risk of VA postpartum (hazard ratio 13.74, 95% confidence interval 2.9-63, P = 0.001), though only two events occurred during pregnancies. CONCLUSION: In women with ARVC, pregnancy was uneventful for the overwhelming majority and the number of prior completed pregnancies was not associated with VA risk. Pregnancy-related VA was primarily related to the phenotypical severity rather than pregnancy itself.

Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality.

AIMS: It is Class I recommendation that congenital long QT syndrome (cLQTS) patients should avoid drugs that can cause torsades de pointes (TdP). We determined use of TdP risk drugs after cLQTS diagnosis and associated risk of ventricular arrhythmia and all-cause mortality. METHODS AND RESULTS: Congenital long QT syndrome patients (1995-2015) were identified from four inherited cardiac disease clinics in Denmark. Individual-level linkage of nation-wide registries was performed to determine TdP risk drugs usage (www.crediblemeds.org) and associated risk of ventricular arrhythmias and all-cause mortality. Risk analyses were performed using Cox-hazards analyses. During follow-up, 167/279 (60%) cLQTS patients were treated with a TdP risk drug after diagnosis. Most common TdP risk drugs were antibiotics (34.1%), proton-pump inhibitors (15.0%), antidepressants (12.0%), and antifungals (10.2%). Treatment with a TdP risk drug decreased 1 year after diagnosis compared with 1 year before (28.4% and 23.2%, respectively, P < 0.001). Five years after diagnosis, 33.5% were in treatment (P < 0.001). Risk factors for TdP risk drug treatment were age at diagnosis (5-year increment) [hazard ratio (HR) = 1.07, confidence interval (CI) 1.03-1.11] and previous TdP risk drug treatment (HR = 2.57, CI 1.83-3.61). During follow-up, nine patients were admitted with ventricular arrhythmia (three were in treatment with a TdP risk drug). Eight patients died (four were in treatment with a TdP risk drug). No significant association between TdP risk drug use and ventricular arrhythmias or all-cause mortality was found (P = 0.53 and P = 0.93, respectively), but events were few. CONCLUSION: Torsades de pointes risk drug usage was common among cLQTS patients after time of diagnosis and increased over time. A critical need for more awareness in prescribing patterns for this high-risk patient group is needed.

Aetiologies and temporal trends of atrioventricular block in young patients: a 20-year nationwide study.

AIMS: To describe aetiologies and temporal trends in young patients with atrioventricular block (AVB). METHODS AND RESULTS: We identified all patients in Denmark, receiving their first pacemaker because of AVB before the age of 50 years between 1996 and 2015. Medical records were reviewed and clinical information and diagnostic work-up results were obtained to evaluate the aetiology. We used Poisson regression testing for temporal trends. One thousand and twenty-seven patients were identified, median age at time of implantation was 38 (interquartile range 25-45) years, 584 (56.9%) were male. The aetiologies were complications to cardiac surgery [n = 157 (15.3%)], congenital AVB [n = 93 (9.0%)], cardioinhibitory reflex [n = 52 (5.0%)], congenital heart disease [n = 43 (4.2%)], complication to radiofrequency ablation [n = 35 (3.4%)], cardiomyopathy [n = 31 (3.0%)], endocarditis [n = 18 (1.7%)], muscular dystrophy [n = 14 (1.4%)], ischaemic heart disease [n = 14 (1.4%)], sarcoidosis [n = 11 (1.1%)], borreliosis [n = 9 (0.9%)], hereditary [n = 6 (0.6%)], side-effect to antiarrhythmics [n = 6 (0.6%)], planned His-ablation [n = 5 (0.5%)], complication to alcohol septal ablation [n = 5 (0.5%)], and other known aetiologies [n = 11 (1.1%)]. The aetiology remained unknown in 517 (50.3%) cases. While the number of patients with unknown aetiology increased during the study period (P < 0.001), we observed no significant change in the number of patients with identified aetiology (P = 0.35). CONCLUSION: In a nationwide cohort, the aetiology of AVB was identified in only half the patients younger than 50 years referred for first-time pacemaker implantation. The number of patients with unknown aetiology increased during the study period. These findings indicate need for better insight into aetiologies of AVB and improved diagnostic work-up guidelines.

Radiofrequency ablation lesions in low-, intermediate-, and normal-voltage myocardium: an in vivo study in a porcine heart model.

AIMS: Contact force (CF) between radiofrequency (RF) ablation catheter and myocardium and ablation index (AI) correlates with RF lesion depth and width in normal-voltage (>1.5 mV) myocardium (NVM). We investigate the impact of CF on RF lesion depth and width in low (<0.5 mV) (LVM) and intermediate-voltage (0.5-1.5 mV) myocardium (IVM) following myocardial infarction. Correlation between RF lesion depth and width evaluated by native contrast magnetic resonance imaging (ncMRI) and gross anatomical evaluation was investigated. METHODS AND RESULTS: Twelve weeks after myocardial infarction, 10 pigs underwent electroanatomical mapping and endocardial RF ablations were deployed in NVM, IVM, and LVM myocardium. In vivo ncMRI was performed before the heart was excised and subjected to gross anatomical evaluation. Ninety (82%) RF lesions were evaluated. Radiofrequency lesion depth and width were smaller in IVM and LVM compared with NVM (P < 0.001). Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM (CF and AI P < 0.001) and IVM (CF and AI depths P < 0.001; CF and AI widths P < 0.05). Native contrast magnetic resonance imaging evaluated RF lesion depth and width correlated with gross anatomical depth and width (NVM and IVM P < 0.001; LVM P < 0.05). CONCLUSIONS: Radiofrequency lesions deployed by similar duration, power and CF are smaller in IVM and LVM than in NVM. Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM and IVM but not in LVM. Native contrast magnetic resonance imaging may be useful to assess RF lesion depth and width in NVM, IVM, and LVM.

Implantable cardioverter-defibrillator therapy and device-related complications in young patients with inherited cardiomyopathies or channelopathies: a 17-year cohort study.

Aims: To quantify appropriate and inappropriate therapy and complications related to implantable cardioverter-defibrillator (ICD) treatment in young patients receiving an ICD for a hereditary cardiomyopathy or channelopathy. Methods and results: This was a retrospective study including 117 consecutive patients who had received an ICD at Aarhus University Hospital, Denmark from 1 January 1999 to 31 December 2015. Patients were followed from the date of ICD implantation until migration, death, heart transplantation, or end of follow-up on 1 February 2017. Mean age at implantation was 30.5 ± 12.8 years, and the patients were followed for a mean period of 7.1 ± 4.4 years. The cumulative incidence at 1, 5, and 10 years was 17%, 29%, and 48% for appropriate ICD therapy, 6%, 13%, and 20% for inappropriate ICD therapy, and 7%, 18%, and 33% for device-related complications, respectively. Patients with an ICD implanted for secondary prevention had a higher risk of appropriate therapy compared with patients implanted for primary prevention [adjusted hazard ratio (HR) 5.18, 95% confidence interval (CI) 2.22-12.09; P < 0.01]. There was no difference in the risk of inappropriate therapy (adjusted HR 1.58, 95% CI 0.55-4.56; P = 0.40) or device-related complications (adjusted HR 1.22, 95% CI 0.56-2.68; P = 0.62) between patients with primary and secondary preventive indication. Conclusion: We observed high absolute risk estimates for appropriate ICD therapy in young patients with an ICD indicated by a hereditary cardiomyopathy or channelopathy. Also risks for inappropriate ICD therapy and device-related complications were significant.

Voltage and pace-capture mapping of linear ablation lesions overestimates chronic ablation gap size.

Aims: Conducting gaps in lesion sets are a major reason for failure of ablation procedures. Voltage mapping and pace-capture have been proposed for intra-procedural identification of gaps. We aimed to compare gap size measured acutely and chronically post-ablation to macroscopic gap size in a porcine model. Methods and results: Intercaval linear ablation was performed in eight Göttingen minipigs with a deliberate gap of ∼5 mm left in the ablation line. Gap size was measured by interpolating ablation contact force values between ablation tags and thresholding at a low force cut-off of 5 g. Bipolar voltage mapping and pace-capture mapping along the length of the line were performed immediately, and at 2 months, post-ablation. Animals were euthanized and gap sizes were measured macroscopically. Voltage thresholds to define scar were determined by receiver operating characteristic analysis as <0.56 mV (acutely) and <0.62 mV (chronically). Taking the macroscopic gap size as gold standard, error in gap measurements were determined for voltage, pace-capture, and ablation contact force maps. All modalities overestimated chronic gap size, by 1.4 ± 2.0 mm (ablation contact force map), 5.1 ± 3.4 mm (pace-capture), and 9.5 ± 3.8 mm (voltage mapping). Error on ablation contact force map gap measurements were significantly less than for voltage mapping (P = 0.003, Tukey's multiple comparisons test). Chronically, voltage mapping and pace-capture mapping overestimated macroscopic gap size by 11.9 ± 3.7 and 9.8 ± 3.5 mm, respectively. Conclusion: Bipolar voltage and pace-capture mapping overestimate the size of chronic gap formation in linear ablation lesions. The most accurate estimation of chronic gap size was achieved by analysis of catheter-myocardium contact force during ablation.

The QTc interval and risk of cardiac events in bulimia nervosa: A long-term follow-up study.

OBJECTIVE: An association between bulimia nervosa (BN) and prolonged corrected QT interval (QTc) in the electrocardiogram has been suggested, but results of previous studies are conflicting, and the risk of cardiac events in patients with BN has yet to be investigated. METHOD: We estimated mean QTc interval and relative risk of borderline (QTc >440 ms) and prolonged QTc (QTc >460 ms) between adult women with BN (N = 531) and healthy controls (N = 123). In follow-up analyses, we investigated the risk of a primary endpoint (syncope, ventricular tachycardia, and cardiac arrest) and all-cause mortality in patients with BN (N = 702) compared with a population-based cohort derived from the Danish Civil Register (N = 7,020). RESULTS: Mean QTc did not differ between patients with BN and controls. Relative risk of borderline prolonged QTc was 2.3 (p = 0.28). The number of patients and controls with prolonged QTc was small, and the risk did not differ between patients with BN and controls. Median follow-up was 10.6 years. Although there appeared to be increased risks after 5 years of follow-up, long-term risks of the primary endpoint (Hazard ratio [HR] = 1.4, p = 0.37) and all-cause mortality (HR = 1.7, p = .28), respectively, were not increased in patients with BN compared to a population-based cohort. DISCUSSION: Mean QTc did not differ between patients with BN and healthy controls, and the risk of prolonged QTc was not increased in patients with BN. There was no difference in the long-term risk of cardiac events, and long-term all-cause mortality did not differ significantly between patients with BN and a population-based cohort.

Cardiac magnetic resonance and electroanatomical mapping of acute and chronic atrial ablation injury: a histological validation study.

AIMS: To provide a comprehensive histopathological validation of cardiac magnetic resonance (CMR) and endocardial voltage mapping of acute and chronic atrial ablation injury. METHODS AND RESULTS: 16 pigs underwent pre-ablation T2-weighted (T2W) and late gadolinium enhancement (LGE) CMR and high-density voltage mapping of the right atrium (RA) and both were repeated after intercaval linear radiofrequency ablation. Eight pigs were sacrificed following the procedure for pathological examination. A further eight pigs were recovered for 8 weeks, before chronic CMR, repeat RA voltage mapping and pathological examination. Signal intensity (SI) thresholds from 0 to 15 SD above a reference SI were used to segment the RA in CMR images and segmentations compared with real lesion volumes. The SI thresholds that best approximated histological volumes were 2.3 SD for LGE post-ablation, 14.5 SD for T2W post-ablation and 3.3 SD for LGE chronically. T2-weighted chronically always underestimated lesion volume. Acute histology showed transmural injury with coagulative necrosis. Chronic histology showed transmural fibrous scar. The mean voltage at the centre of the ablation line was 3.3 mV pre-ablation, 0.6 mV immediately post-ablation, and 0.3 mV chronically. CONCLUSION: This study presents the first histopathological validation of CMR and endocardial voltage mapping to define acute and chronic atrial ablation injury, including SI thresholds that best match histological lesion volumes. An understanding of these thresholds may allow a more informed assessment of the underlying atrial substrate immediately after ablation and before repeat catheter ablation for atrial arrhythmias.

Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2.

BACKGROUND: Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A. METHODS: We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. RESULTS: Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 "unrelated" families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000. CONCLUSION: The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.

His or para-His pacing preserves left ventricular function in atrioventricular block: a double-blind, randomized, crossover study.

AIMS: To compare left ventricular function after a long-term His or para-His pacing (HP) and right ventricular septal pacing (RVSP) in patients with atrioventricular block (AVB). METHODS AND RESULTS: We included consecutive patients with AVB, a narrow QRS < 120 ms, and a preserved left ventricular ejection fraction (LVEF) >0.40, in a prospective, randomized, double-blinded, crossover design. All patients were treated with 12 months HP and 12 months RVSP. A total of 38 patients [mean age, 67 ± 10 years; 30 (79%) men] were included. The primary endpoint was LVEF, which was significantly lower after a 12 months RVSP (0.50 ± 0.11) than after 12 months of HP (0.55 ± 0.10), P = 0.005. We measured the difference in time-to-peak systolic velocity between opposite basal segments in the apical views by using tissue Doppler imaging. In the four-chamber view, the difference was 58 (±7) ms after RVSP and 49 (±7) ms after HP, P = 0.27; in the two-chamber view, the difference was 45 (±5) ms after RVSP and 31 ±(4) ms after HP, P = 0.02, and in the apical long-axis view, the difference was 63 (±6) after RVSP and 44 (±7) after HP, P = 0.03. There was no difference in New York Heart Association class, 6-min hall walk test, quality-of-life assessments, or device-related complications. The mean threshold was significantly higher in HP leads than in RVSP leads. CONCLUSION: His or para-His pacing preserves LVEF and mechanical synchrony as compared with RVSP after 12 months pacing in patients with AVB, narrow QRS, and LVEF > 0.40.