Search

Because of its antiarrhythmic potency and due to the lack of alternatives, amiodarone is often used for antiarrhythmic therapy in patients with ICD or CRT-D systems. To date, robust data on the safety and clinical benefit of amiodarone therapy in these patients are missing OBJECTIVE: This study was designed to assess the periprocedural and post-procedural outcome of combined therapy with beta-blockers plus amiodarone compared to treatment with single beta-blockers in this "real life" cohort of ICD recipients of the German DEVICE registry.4,499 patients who underwent ICD implantation, revision, or upgrade in 49 centers participating in the German DEVICE Registry were enrolled 03/2007-02/2014.Amiodarone had no significant effect on the success of defibrillation testing. Early implantation-associated complications were similar between the groups. One-year overall mortality was, however, significantly higher in the beta-blocker plus amiodarone cohort (adjusted HR 2.09; p0.001). Interestingly, amongst the surviving patients, amiodarone was not associated with a significantly reduced risk of ICD discharges, syncopal events. Further, the occurrence of VT storm or incessant VTs and the number of patients scheduled for intracardiac ablation did not differ among both groups while the rate of rehospitalization was lower in the cohort with sole beta-blockers.While amiodarone has no adverse effect on the success of defibrillation testing, our data suggest an increased all-cause mortality under amiodarone therapy, especially in the subgroups of patients with sinus rhythm or severely reduced left ventricular function. In surviving patients, rates of arrhythmic events were comparable.

Aims Catheter ablation is recommended for symptomatic WPW-syndrome. Commonly perceived low recurrence rates were challenged recently. We sought to identify patient strata at increased risk. Method Of 12,566 patients enrolled at 52 German Ablation Registry sites from 2007 to 2010, 789 were treated for WPW-syndrome. Patients were included for symptomatic palpitations and tachycardia documentation. Follow-up duration was one year. Overall complications were defined as serious, access-related, and ablation-related. We adjudicated WPW-recurrence for re-ablation during follow-up. Risk strata included: admission for repeat ablation at registry entry; accessory pathway localization; antiarrhythmic medical treatment before the ablation. Results WPW-syndrome patients were 42.8 ± 16.2 years on average; 39.9% were women. A majority of 95.9% was symptomatic; in 84.4%, a tachycardia was documented. Seventy-six (9.6%) patients presented for repeat procedures. Accessory pathways were located in the left atrium (71.4%), right atrium (21.1%), septum (4.4%), or coronary sinus diverticula (2.1%). Prior antiarrhythmic medication was used in 43.7% of patients. No serious events occurred. The overall complication rate was 2.5% (ablation related 1.2%, access-related 1.3%). Major determinants for complications were presentation for re-ablation as registry index procedure (6.9% vs 2.2%; p = 0.016) and septal pathway location (left 2.0% vs septal 9.1%, p = 0.014). The overall re-ablation rate was 9.7%. Usage of prior antiarrhythmic medication was associated with higher recurrence rates (12.2% vs. 7.6%; p = 0.035). Conclusions Patients at higher complication risk may be identified by repeat procedure and septal pathway location. Prior antiarrhythmic medication was associated with higher recurrence rates. Our findings may help improving peri-procedural patient management and information.

Aims Impaired myocardial sympathetic innervation assessed by 123Iodine-Metaiodobenzylguanidine (123I-MIBG) scintigraphy is associated with cardiac events. Since regional disparities of structural abnormalities are common in inherited arrhythmia syndromes (iAS), a chamber-specific innervation assessment of the right (RV) and left ventricle (LV) could provide important insights for a patient-individual therapy. Aim of this study was to evaluate chamber-specific patterns of autonomic innervation by Single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with iAS with respect to clinical outcome regarding cardiac events. Methods and results We assessed ventricular sympathetic innervation (LV, RV and planar heart/mediastinum-ratios, and washout-rates) by 123I-MIBG-SPECT/CT in 48 patients (arrhythmogenic right ventricular cardiomyopathy [ARVC], n = 26; laminopathy, n = 8; idiopathic ventricular fibrillation [iVF], n = 14) in relation to a composite clinical endpoint (ventricular arrhythmia; cardiac death; cardiac hospitalization). RV tracer uptake was lower in patients with ARVC than in laminopathy and iVF patients (1.7 ± 0.4 vs. 2.1 ± 0.7 and 2.1 ± 0.5, respectively). Over a median follow-up of 2.2 years, the combined endpoint was met in 18 patients (n = 12 ventricular tachyarrhythmias, n = 5 hospitalizations, n = 1 death). LV, but not RV H/M ratio was associated with the combined endpoint (hazard-ratio 2.82 [1.30–6.10], p Conclusion We demonstrated that chamber-specific 123MIBG-SPECT/CT imaging is feasible and that reduced LV sympathetic innervation was associated with worse outcome in iAS. These findings provide novel insights into the potential role of regional autonomic nervous system heterogeneity for the evolution of life-threatening cardiac events in iAS.

Background: Early detection of atrial fibrillation (AF) and subsequent initiation of anticoagulation and rhythm control therapy markedly reduce stroke, cardiovascular death, and heart failure, but unselected ECG screening for AF is time- and resource-intensive. Combining biomarkers reflecting different biological processes may identify patients at high risk of AF, enabling targeted ECG screening. Methods: We systematically reviewed literature and patent information to define candidate biomarkers for AF detection. The top 12 biomarkers identified through this process were quantified on a high-precision, high-throughput platform in 1485 consecutive patients at risk for AF presenting acutely to hospital (median age 69 years [Q1, Q3 60,78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. A model simultaneously considering 7 key clinical characteristics and all biomarkers was developed in a randomly sampled discovery cohort (n=933) and validated in the remaining patients (n=552). Neural networks were also applied. Findings: Using backward elimination, a model using age, sex, body mass index (BMI), BMP10, ANG2, and FGF23 discriminated between patients with and without AF with an AUC of 0·743 [95% confidence interval (CI) 0·712-0·775]. The biomarkers represent distinct pathways relevant for atrial cardiomyopathy and AF, namely hypertrophy and fibrosis (FGF23), endothelial dysfunction (ANG2), and atrial oxidative stress and the genomic predisposition to AF (BMP10). The SHAP procedure for neural networks identified the same variables as the regression. The validation yielded an AUC of 0·719 (95%CI 0·677, 0·762), corroborated using deep neural networks (AUC 0·784 [95%CI 0·745, 0·822]). Interpretation: The combination of three simple characteristics (age, sex, BMI) and three biomarkers (BMP10, ANG2, and FGF23) robustly identifies patients with AF. Such an approach enables targeted screening for AF and provides a platform to develop personalised prevention and treatment in patients with AF. Funding Statement: This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) to PKi, LF, BC, SH, SK, LM, MFS, US, and no. 116074 [BigData@Heart EU IMI] to PKi, British Heart Foundation (FS/13/43/30324 and (AA/18/2/34218) to PKi and LF), German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, via a grant to AFNET to PKi), and Leducq Foundation (14CVD01) to PKi. Declaration of Interests: LF has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), and DFG and Gilead. PKi has received additional support for research from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, honoraria from several such companies. PKi and LF are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PKa is an employee of Roche Diagnostics GmbH. AZ is an employee of Roche Diagnostics Intl. All other authors have reported no relationships relevant to the contents of this paper to disclose. Ethics Approval Statement: This study complied with the Declaration of Helsinki, was approved by the National Research Ethics Service Committee (IRAS ID 97753), and was sponsored by the University of Birmingham.

Summary Background Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). Methods In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. Findings Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (p non-inferiority =0·0004; hazard ratio [HR] 0·81 [95% CI 0·62–1·06], p superiority =0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; p non-inferiority =0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59–1·13]; p=0·23). Interpretation Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. Funding Klinikum der Universitat Munchen, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

Despite a positive family history of SCD being associated with increased risk for SCD in the offspring, the genetic contribution to SCD in general and in proportion to the population at risk is considered to be small. The majority of SCD is rated a common disease with multi allelic susceptibility markers of minor effect size each. A smaller proportion of obvious familial forms of early onset SCD, or SCD in the young on the other hand is clearly linked to genetics. Here frequently, rare genetic variants with strong effects carry the major risk for SCD. Considering the genetic contribution to SCD it is imperative to specifically define the sub-phenotypes of SCD. Genomic approaches and novel sequencing technologies will allow enhancing our knowledge on the pathophysiology of arrhythmogenesis resulting in SCD. While the group of SCD in the young may account only for a smaller portion of all adult SCD, public awareness, specialized multidisciplinary centers for SCD and potentially regulations are needed to fully gain the benefit of genetic testing followed by family screening and simple but effective preventive measures that are well suited to reduce the burden of SCD in the young in the future.

Background Supplementation of calcium (Ca) and vitamin D for the prevention of osteoporosis is frequently found in Western countries. Recent re-analyses of clinical trials observed a higher risk of myocardial infarction and stroke in subjects taking Ca (+vitamin D) supplements, although the underlying mechanisms are not clear. Objective Thus, we analyzed the associations between Ca and vitamin D supplementation as well as serum concentrations of Ca and 25-hydroxyvitamin D (25(OH)D) and subclinical cardiovascular disease (CVD) phenotypes, namely intima-media thickness, ankle-brachial-index (ABI), intermittent claudication, and atrial fibrillation (AF). Design Data of 1601 participants aged 50–81 years of the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Germany were analyzed. Logistic and linear regression models were used to estimate odds ratios (OR) (95% confidence intervals (CI)) and β-estimates (p-values), respectively. Results Regular Ca supplementation showed a significant positive association with the presence of AF after multivariable adjustment (OR = 3.89; 95% CI 1.28–11.81). Higher serum 25(OH)D concentrations were independently associated with a lower prevalence of asymptomatic peripheral arterial disease as assessed by ABI measurements (β = 0.007; p = 0.01). No other significant associations between supplementation or serum concentrations of Ca or vitamin D and CVD phenotypes were identified. Conclusions Although based on few cases the finding of a significant higher prevalence of AF in Ca supplement users hints at one possible mechanism that may contribute to an increased risk of myocardial infarction and stroke. The observed association between serum 25(OH)D and ABI supports results from other studies.

To examine the association between electrocardiographic (ECG) findings and disability status in older adults.KORA-Age, a population-based cross-sectional study of the MONICA/KORA project, a randomized sample from Southern Germany of people aged 65 years or older.A total of 534 (51.5%) of 1,037 participants were characterized as disabled. Disabled participants were on average 4.5 years older than those who were not disabled. Crude associations of left-axis deviation, ventricular conduction defects, atrial fibrillation, and QT prolongation with disability status were significant (P0.05). In models controlled for age and sex, these effects remained constant except for QT prolongation. In the models adjusted for the minimal sufficient adjustment set (consisting of the variables sex, physical activity, age, obesity, diabetes, education, heart diseases, income, lung diseases, and stroke) identified by a directed acyclic graph (DAG), no significant association could be shown.Associations between specific ECG findings and disability were found in unadjusted analysis and logistic models adjusted for age and sex. However, when adjusting for other possible confounders identified by the DAG, all these associations were no longer significant. It is important to adequately identify confounding in such settings.

Background The approval of an entirely subcutaneous implantable-cardioverter defibrillator (ICD) system (S-ICD) has raised attention about this promising technology. It was developed to overcome lead failure and infection problems of conventional transvenous ICD systems. Nevertheless, lead migration of the initial design and inappropriate shock rates have raised concerns regarding its reliability and safety. Objective The purpose of this study was to report the largest multicenter series to date of patients with the new device in comparison with a matched conventional transvenous ICD collective with focus on perioperative complications, conversion of induced ventricular fibrillation (VF), and short-term follow-up. Methods/Results Sixty-nine patients (50 male and 19 female; mean age 45.7±15.7 years) received an S-ICD in three German centers and were randomly assigned to 69 sex- and age-matched conventional ICD patients. The indication was primary prevention in 41 patients (59.4%) without difference between groups (34 control patients; P = .268). The predominant underlying heart disease was ischemic cardiomyopathy in 11 (15.9%), dilated cardiomyopathy in 25 (36.2%), and hypertrophic cardiomyopathy in 10 (14.5%) in the S-ICD group. Mean implantation time was 70.8±27.9 minutes ( P = .398). Conversion rates of induced VF were 89.5% for 65 J (15-J safety margin) and 95.5% including reversed shock polarity (15-J safety margin) in the study group. Termination of induced VF was successful in 90.8% (10-J safety margin, device dependent) of the control patients ( P = .815). Procedural complications were similar between the 2 groups. Mean follow-up was 217±138 days. During follow-up, 3 patients with S-ICD were appropriately treated for ventricular arrhythmias. Three inappropriate episodes (5.2%) occurred in 3 S-ICD patients due to T-wave oversensing, whereas atrial fibrillation with rapid conduction was the predominant reason for inappropriate therapy in conventional devices ( P = .745). Conclusion The novel S-ICD system can be implanted safely with similar perioperative adverse events compared with standard transvenous devices. Our case-control study demonstrates a 10.4% failure of conversion of induced VF with the S-ICD set to standard polarity and 15-J safety margin and comparable inappropriate shock rates during short-term follow-up.

Apart from clinical symptoms the diagnosis and risk stratification in long-QT syndrome (LQTS) is usually based on the surface electrocardiogram. Studies have indicated that not only prolongation of the QT interval but also an increased short-term variability of QT interval (STV(QT)) is a marker for a decreased repolarization reserve in patients with drug-induced LQTS. The aims of this study were to determine if STV(QT) (1) is higher in patients with LQTS compared with controls, (2) if this effect is more pronounced in a high-risk LQTS population, and (3) could increase the diagnostic power of the surface electrocardiogram in identifying mutation carriers. Forty mutation carriers were compared with age- and gender-matched control subjects in the absence of beta-receptor-blocking agents. Lead II or V(5) RR and QT intervals from 30 consecutive beats were manually measured. STV(QT) was determined from Poincaré plots of QT intervals (STV(QT) = Sigma|QTn + 1 - QTn|/[30 x radical2]). Compared with controls, patients with LQTS had a prolonged QTc interval (449 +/- 41 vs 411 +/- 32 ms, p = 0.00049) and increased STV(QT) (6.4 +/- 3.2 vs 4.1 +/- 1.6 ms, p = 0.005). In patients with the highest risk of clinical events, defined as a QTc interval500 ms or symptoms before beta-blocker therapy, STV(QT) was 9 +/- 4 ms. QTc interval had a sensitivity of 43% and a specificity of 97% in identifying mutation carriers (thresholds 450 ms for men and 460 ms for women). Receiver operator characteristic analysis showed that an STV(QT) of 4.9 ms was the optimal cut-off value to predict mutation carriers. When incorporating an STV(QT)4.9 ms for those whose QTc interval was within the normal limits, sensitivity to distinguish mutation carriers increased to 83% with a specificity of 68%, so that another 15 mutation carriers could be identified. In conclusion, these are the first results in humans showing that STV(QT) is increased in congenital LQTS, this effect is increased in patients with symptoms before therapy, and, hence, STV(QT) could prove to be a useful noninvasive additive marker for diagnostic screening to bridge the gap before results of genetic testing are available.

Congestive heart failure (CHF) causes arrhythmogenic, structural and contractile remodeling, with important atrial-ventricular differences: atria show faster and greater inflammation, cell-death and fibrosis. The present study assessed time-dependent left atrial (LA) and ventricular (LV) gene-expression changes in CHF. Groups of dogs were submitted to ventricular tachypacing (VTP, 240 bpm) for 24 h or 2 weeks, and compared to sham-instrumented animals. RNA from isolated LA and LV cardiomyocytes of each dog was analyzed by canine-specific microarrays (>21,700 probe-sets). LA showed dramatic gene-expression changes, with 4785 transcripts significantly-altered (Q

Background The Brugada syndrome (BrS) is considered a rare mendelian disorder with autosomal dominant transmission. BrS is associated with an increased risk of sudden cardiac death and specific ECG features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A , encoding the pore-forming subunit of the cardiac sodium channel (Na v 1.5), are identified in ~20% of patients. However, studies in families harboring mutations in SCN5A have demonstrated low disease penetrance and, in some instances, absence of the familial SCN5A mutation in some affected members. These observations suggest a more complex inheritance model. Methods To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1115 ancestry-matched controls. Results Two genomic loci displayed significant association. Replication testing on 2 independent case/control sets from Europe (598/855) and Japan (208/1016) confirmed both associations and revealed a third locus. The cumulative effect of the 3 loci on disease susceptibility was large, with an odds ratio of 21.5 in the presence of more than 4 risk alleles vs less than 2. Two of 3 loci had previously been shown to influence ECG conduction parameters in the general population. The third locus encompasses a transcription factor that has not previously been implicated in cardiac electrical function and arrhythmia. Functional studies in mice heterozygous knockout for this transcription factor identified differences in expression of Na v 1.5 in addition to differences in conduction of the cardiac electrical impulse in the right ventricular outflow tract. Conclusions Our findings (1) indicate that common genetic variation may have a strong impact on predisposition to BrS and (2) identify a new gene involved in the pathogenesis of the disease.

La repolarisation precoce est une caracteristique electro cardiographique commune (1-5 % de la population generale). Une etude recente a montre que l’incidence de la repolarisation precoce (RP) est plus elevee chez les sujets ayant presente une fibrillation ventriculaire (31 % des patients vs 5 % des controles). A ce jour, il est encore impossible de differencier les patients presentant un aspect de RP a risque parmi la population generale. L’existence de forme familiale de RP associee a des morts subites suggere un caractere hereditaire a cette pathologie. Une etude genetique a ete realisee sur une cohorte de 96 patients. Les genes majeurs des troubles du rythme cardiaque et les genes codant les canaux ioniques impliques dans la phase de repolarisation du potentiel d’action ventriculaire ont ete exclus par sequencage chez ces patients. Les canaux potassiques ATP dependant (KATP) sont fortement exprimes dans les cardiomyocytes. L’une des hypotheses emises est qu’une augmentation de 1-2 % de l’ouverture de ces canaux genererait un courant suffisant qui pourrait affecter la phase de repolarisation ventriculaire. Les canaux KATP sont composes de sous-unites canalaires Kir6.0 (KCNJ8 codant Kir6.1 ou KCNJ11 codant Kir6.2) et de recepteurs aux sulphonylurees SUR (ABCC8 codant SUR1 ou ABCC9 codant SUR2). L’approche gene-candidat a permis de mettre en evidence le variant rare p.S422L dans le gene KCNJ8 chez une jeune patiente presentant de nombreux episodes de fibrillation ventriculaire (plus de 100) et une RP dans les derivations infero-laterales. Suite a ces premiers resultats, nous avons sequences les autres sous-unites des canaux KATP. Ainsi, 5 variants ont ete identifies dans le gene ABCC9 : 4 variants faux-sens et une substitution d’un nucleotide dans un site d’epissage. L’enquete familiale et l’analyse fonctionnelle sont en cours pour ces patients. Plusieurs hypotheses physiopathologiques (augmentation du trafic membranaire, diminution de la sensibilite a l’ATP…) vont etre testees afin de comprendre l’implication de ces variants sur le potentiel d’action ventriculaire. L’identification de 6 patients sur 96 (6.25 %) porteurs de variant dans les genes codant les canaux KATP conforte l’hypothese du role de ce courant dans le syndrome de repolarisation precoce.

Background: IRIS showed no survival benefit by prophylactic ICD implantation in selected survivors of AMI. Increase of nonsudden death rate compensated reduction of sudden death cases. The authors suggested that IRIS patients protected from arrhythmic death were prone to nonsudden death. We applied the IRIS criteria to a large cohort of post-MI patients and suggest alternative interpretations. Methods: ISAR-Risk included 2597 consecutive AMI survivors (≤80 years, sinus rhythm). IRIS-positive patients (left ventricular ejection fraction ≤40% and heart rate≥90 beats/min, or nonsustained ventricular tachycardia ≥150 beats/min) were stratified by “severe autonomic failure” (SAF) defined as abnormal heart rate turbulence and abnormal deceleration capacity. One-degree end point was 5-year mortality. Results: IRIS criteria identified 102 patients (3.9%) with a 5-year mortality rate of 34.1% comparable with that observed in the IRIS trial. Sensitivity of the IRIS criteria for prediction of 5-year total mortality was 12.6%. Severe autonomic failure separated IRIS-positive patients into 2 subgroups with substantially different prognosis. Whereas 71 (69.6%) of the 102 IRISpositive patients were SAF negative and had a good prognosis (5-year mortality rate, 17.5%), 31 (30.4%) of the 102 patients were SAF positive and had a very poor prognosis (5-year mortality rate, 72.8%). Conclusion: In unselected post-MI patients, IRIS criteria identify a small but highly heterogeneous group of patients. ICD-related switch of mode of death is conceivable in the high-risk IRIS subgroup. However, ICD-related harm is more likely in the low-risk IRIS subgroup that included more than 2 of 3 of IRIS-positive patients. IRIS findings should not be extrapolated to other risk stratification strategies.