Therapy of ventricular arrhythmias in patients suffering from isolated left ventricular non-compaction cardiomyopathy.

AIMS: Non-compaction cardiomyopathy (NCCM) is associated with high rates of mortality and morbidity. Knowledge regarding risk stratification, arrhythmogenesis, therapy, and prognosis is limited. The aim of this study was to analyse the outcome of patients suffering from NCCM and ventricular arrhythmias (VAs) focusing on a treatment with implantable cardioverter-defibrillator (ICD) therapy and catheter ablation. METHODS AND RESULTS: We conducted a multicentre observational study on 18 patients with NCCM, who underwent ICD implantation for secondary (n = 12) and primary (n = 6) prevention. In patients with multiple symptomatic episodes of VAs catheter ablation was performed. During a follow-up of 62 ± 42 months, 12 patients (67%) presented with appropriate ICD therapies [ventricular tachycardia (VT): n = 8; ventricular fibrillation (VF): n = 4; VT/VF: n = 3]. Ten patients underwent catheter ablation for VT/VF. Solely endocardial ablation was conducted in eight patients, and in two patients endo- and epicardial ablation was performed within the same procedure. Acute procedural success was achieved in 9/10 patients. Ventricular tachycardia recurrence was observed in two patients and the median arrhythmia free interval was 9.5 months (interquartile range 5.3-21 months). One patient underwent reablation, four patients died due to the underlying NCCM, and one patient received a left ventricular assist device. CONCLUSION: Ventricular arrhythmias are common in patients suffering from NCCM and ICD therapy may be effective for primary and secondary prevention. In our cohort, consisting of patients with multiple VA episodes and recurrent ICD therapy, catheter ablation offered a safe and effective therapeutically option.

Prognostic Utility of Galectin-3 for Recurrent Cardiovascular Events During Long-term Follow-up in Patients with Stable Coronary Heart Disease: Results of the KAROLA Study.

BACKGROUND: Galectin-3 has emerged as a potential useful novel biomarker for heart failure and cardiovascular disease (CVD). However, it remains unclear whether galectin-3 is associated with recurrent cardiovascular events during long-term follow-up of patients with stable coronary heart disease (CHD) after adjustment for multiple established and novel risk factors. METHODS: We measured galectin-3 at baseline in a cohort consisting of 1035 CHD patients and followed them for 13 years to assess a combined CVD end point. Moreover, we adjusted for multiple traditional and novel risk factors. RESULTS: Galectin-3 concentration was positively associated with the number of affected coronary arteries, history of heart failure, and multiple traditional risk factors. Also, galectin-3 correlated significantly with emerging risk factors [e.g., cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity (hs)-troponin]. During follow-up (median 12.0 years), 260 fatal and nonfatal CVD events occurred. The top quartile of galectin-3 concentration was significantly associated with CVD events compared to the bottom quartile after adjustment for age and sex [hazard ratio (HR) 1.88 (95% CI, 1.30-2.73), P = 0.001 for trend] as well as for established CVD risk factors (HR 1.67, 95% CI, 1.14-2.46, P = 0.011 for trend). However, after adjustment for other biomarkers available [including eGFR (estimated glomerular filtration rate), sST2 protein, GDF-15 (growth differentiation factor 15), NT-proBNP, and hs-troponin], the association was no longer statistically significant [HR 1.11 (95% CI 0.72-1.70), P = 0.82 for trend]. CONCLUSIONS: Galectin-3 does not independently predict recurrent cardiovascular events in patients with established CHD after adjustment for markers of hemodynamic stress, myocardial injury, inflammation, and renal dysfunction.

Mendelian Randomization for the Identification of Causal Pathways in Atherosclerotic Vascular Disease.

Epidemiological and clinical studies have identified many physiological traits and biomarkers that are statistically associated with coronary artery disease (CAD). For some of these traits and biomarkers it is well established that they represent true causal risk factors for CAD. For other biomarkers, however, the distinct character of association is still a matter of debate. Randomized controlled trials (RCT) had a pivotal role in establishing causal associations between risk factors and biomarkers and CAD in some settings by demonstrating that therapeutic intervention targeting risk factors/biomarkers also affect the risk for clinical outcomes, such as CAD. In other scenarios, however, RCTs did not demonstrate clear benefits associated with lowering biomarker levels and therefore suggest that the association between these biomarkers (like C reactive protein) and CAD was driven by confounding or reverse causation. Even accurately conducted RCTs are not immune against incorrect causal inference. Moreover, the extensive costs and efforts required to conduct RCTs asked for alternative study designs to elucidate potential causal associations. Mendelian Randomization studies represent one such alternative by using genetic variants as proxies for specific biomarkers to investigate potential causal relations between biomarkers and clinical outcomes. In this review, we briefly describe the principles of MR studies and summarize recent MR studies in the context of CAD.

Genetic variants associated with celiac disease and the risk for coronary artery disease.

Epidemiological evidence suggests that patients with celiac disease are at increased risk for coronary artery disease (CAD). Genetic-epidemiological analyses identified many single nucleotide polymorphisms (SNPs) associated with celiac disease. If there is a causal relation between celiac disease and CAD, one might expect that risk alleles primarily associated with celiac disease also increase the risk of CAD. In this study we identified from literature 41 SNPs that have been previously described to be genome-wide associated with celiac disease (p < 5 × 10(-08)). These SNPs were evaluated for their association with CAD in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) dataset, a meta-analysis comprising genome-wide SNP association data from 22,233 CAD cases and 64,762 controls. 24 out of 41 (58.5 %) risk alleles for celiac disease displayed a positive association with CAD (CAD-OR range 1.001-1.081). The remaining risk alleles for celiac disease (n = 16) revealed CAD-ORs of ≤1.0 (range 0.951-1.0). The proportion of CAD associated alleles was greater but did not differ significantly from the proportion of 50 % expected by chance (p = 0.069). One SNP (rs653178 at the SH2B3/ATXN2 locus) displayed study-wise statistically significant association with CAD with directionality consistent effects on celiac disease and CAD. However, the effect of this locus is most likely driven by pleiotropic effects on multiple other diseases. In conclusion, this genetically based approach provided no convincing evidence that SNPs associated with celiac disease contribute to the risk of CAD. Hence, common non-genetic factors may play a more important role explaining the coincidence of these two complex disease conditions.

Mendelian randomization studies in coronary artery disease.

Epidemiological research over the last 50 years has discovered a plethora of biomarkers (including molecules, traits or other diseases) that associate with coronary artery disease (CAD) risk. Even the strongest association detected in such observational research precludes drawing conclusions about the causality underlying the relationship between biomarker and disease. Mendelian randomization (MR) studies can shed light on the causality of associations, i.e whether, on the one hand, the biomarker contributes to the development of disease or, on the other hand, the observed association is confounded by unrecognized exogenous factors or due to reverse causation, i.e. due to the fact that prevalent disease affects the level of the biomarker. However, conclusions from a MR study are based on a number of important assumptions. A prerequisite for such studies is that the genetic variant employed affects significantly the biomarker under investigation but has no effect on other phenotypes that might confound the association between the biomarker and disease. If this biomarker is a true causal risk factor for CAD, genotypes of the variant should associate with CAD risk in the direction predicted by the association of the biomarker with CAD. Given a random distribution of exogenous factors in individuals carrying respective genotypes, groups represented by the genotypes are highly similar except for the biomarker of interest. Thus, the genetic variant converts into an unconfounded surrogate of the respective biomarker. This scenario is nicely exemplified for LDL cholesterol. Almost every genotype found to increase LDL cholesterol level by a sufficient amount has also been found to increase CAD risk. Pending a number of conditions that needed to be fulfilled by the genetic variant under investigation (e.g. no pleiotropic effects) and the experimental set-up of the study, LDL cholesterol can be assumed to act as the functional component that links genotypes and CAD risk and, more importantly, it can be assumed that any modulation of LDL cholesterol-by whatever mechanism-would have similar effects on disease risk. Therefore, MR analysis has tremendous potential for identifying therapeutic targets that are likely to be causal for CAD. This review article discusses the opportunities and challenges of MR studies for CAD, highlighting several examples that involved multiple biomarkers, including various lipid and inflammation traits as well as hypertension, diabetes mellitus, and obesity.

[Lead placement in cardiac implantable electronic devices]. / Elektrodenplatzierung in der kardialen Devicetherapie.

The implantation of electrodes for cardiac implantable electronic devices (CIED) requires profound technical understanding and precise execution. The positioning of electrodes in the right ventricle and atrium has significant implications for patient safety and the effectiveness of CIED therapy. Particular focus is given to the distinction between apical and septal stimulation in ventricular positioning. Based on current data, this article provides a practice-oriented guide that leads implanters through the individual steps of electrode positioning. The implantation of electrodes for physiological stimulation (cardiac resynchronization therapy, CRT, and conduction system pacing, CSP) is not addressed in this article.

[Venous access routes for cardiac implantable electronic devices]. / Venöse Zugangswege in der kardialen Devicetherapie.

Various venous access routes in the region of the clavicle are available for cardiac device treatment. After many years of choosing access via the subclavian vein, current data explicitly show that lateral approaches such as preparation of the cephalic vein or puncture of the axillary vein are clearly superior in terms of probe durability and risk of complications. This article describes the preparation and performance of the various access techniques and is intended to provide a practical guide for the work in cardiac pacemaker operations. This work continues a series of articles designed for advanced training in specialized rhythmology.

[Lead extraction in cardiac implantable electronic devices]. / Sondenextraktionen bei implantierbaren kardialen Devices.

Lead extraction due to infection or lead dysfunction has become more important in recent years. Patients with high risk of severe and life-threatening complications should only undergo surgery in experienced centers where appropriate personnel and equipment are available. In this review, different techniques and methods to safely and successfully perform transvenous lead extraction are summarized.

Anatomy for ablation of atrioventricular nodal reentry tachycardia and accessory pathways.

The atrioventricular (AV) valve plane and the central septum are of particular importance for electrophysiological diagnosis and interventional therapy of supraventricular tachycardias because accessory electrical connections of various types may be present in addition to the specific conduction system. Although modern 3D electroanatomic reconstruction systems including high-density mapping can be of great assistance, detailed knowledge of the anatomic structures involved, their complex three-dimensional arrangement, and their electrical properties in conjunction with electrophysiological features of supraventricular arrhythmias is essential for safe and efficient electrophysiological treatment. The aim of this article is to present current anatomical, topographical, and electrophysiological findings against the background of historical, seminal, and still indispensable literature.

[Focal atrial tachycardias: diagnostics and therapy]. / Fokale atriale Tachykardien: Diagnostik und Therapie.

In this article, typical characteristics of focal atrial tachycardias are described and a systematic approach regarding diagnostics and treatment options in the field of invasive cardiac electrophysiology (EP) is presented. Subjects of this article include the definition of focal atrial tachycardias, knowledge about localizing the origin of such, and guidance on how to approach an invasive EP study (e.g., administration of medication during the EP study to provoke tachycardias). Further, descriptions will be found on how to localize the origin of focal atrial tachycardias with the help of the 12-lead ECG and invasive three-dimensional mapping to successfully treat focal atrial tachycardias with catheter ablation.

[Atypical atrial fibrillation : Diagnostics and therapy]. / Atypisches Vorhofflattern : Diagnostik und Therapie.

In contrast to typical atrial flutter, atypical atrial flutter is a heterogeneous group of right and left atrial macro- or localized reentry tachycardias whose critical component for maintaining tachycardia is not the cavotricuspid isthmus. Atypical atrial flutter occurs more frequently after previous catheter ablation and after cardiac surgery. The intraprocedural success rate during ablation is high, although the recurrence rate depends on structural changes in the atria as well as the underlying mechanism. This article provides an overview of the mechanisms as well as mapping and ablation strategies of the most common forms of right and left atrial atypical atrial flutter. This article is part of the "EP Basics" series for targeted continuing education in invasive electrophysiology. Basics, clinic and therapy of atypical atrial flutter are presented with focus on clinically relevant aspects. Procedures and findings of invasive electrophysiological diagnostics and ablation treatment are the focus of this article.

[Pulmonary vein isolation using radiofrequency ablation]. / Pulmonalvenenisolation mittels Radiofrequenzablation.

Catheter ablation represents the primary treatment for most arrhythmias. The effectiveness of catheter ablation for the treatment of atrial fibrillation is superior to drug therapy. Therefore, catheter ablation has been established as an increasingly common procedure in clinical routine. In this context, the electrical isolation of the pulmonary veins (PVI) constitutes the cornerstone of the interventional therapy of paroxysmal and persistent atrial fibrillation. This article describes the procedure of pulmonary vein isolation utilizing radiofrequency point-by-point ablation. It shall be a practical guide for the staff in the electrophysiological laboratory. This article continues a series of manuscripts focusing on interventional electrophysiology topics in the course of EP (electrophysiology) training.This article describes the procedure of pulmonary vein isolation utilizing radiofrequency point-by-point ablation. It shall be a practical guide for the staff in the electrophysiological laboratory. This article continues a series of manuscripts dealing with topics of interventional electrophysiology in the course of EP training.

[Practical guide for safe and efficient cryoballoon ablation for atrial fibrillation : Practical procedure, tips and tricks]. / Leitfaden zur sicheren und effizienten Kryoballon-Vorhofflimmerablation : Praktisches Vorgehen, Tipps und Tricks.

In the current guidelines on treatment of atrial fibrillation, cryoballoon-based catheter ablation of atrial fibrillation is recommended in addition to radiofrequency ablation and has become established as a standard procedure in the clinical routine of many centers for index pulmonary vein isolation. A safe, simplified and often durable pulmonary vein isolation can be achieved by a systematic approach. This review article provides a practical guide for all steps of cryoballoon-based pulmonary vein isolation, including preprocedural preparation and postinterventional follow-up. Both cryoballoon systems currently available on the market are considered.

Macrophage cholesterol efflux correlates with lipoprotein subclass distribution and risk of obstructive coronary artery disease in patients undergoing coronary angiography.

BACKGROUND: Studies in patients with low HDL have suggested that impaired cellular cholesterol efflux is a heritable phenotype increasing atherosclerosis risk. Less is known about the association of macrophage cholesterol efflux with lipid profiles and CAD risk in normolipidemic subjects. We have therefore measured macrophage cholesterol efflux in 142 normolipidemic subjects undergoing coronary angiography. METHODS: Monocytes isolated from blood samples of patients scheduled for cardiac catheterization were differentiated into macrophages over seven days. Isotopic cholesterol efflux to exogenously added apolipoprotein A-I and HDL2 was measured. Quantitative cholesterol efflux from macrophages was correlated with lipoprotein subclass distribution in plasma from the same individuals measured by NMR-spectroscopy of lipids and with the extent of coronary artery disease seen on coronary angiography. RESULTS: Macrophage cholesterol efflux was positively correlated with particle concentration of smaller HDL and LDL particles but not with total plasma concentrations of HDL or LDL-cholesterol. We observed an inverse relationship between macrophage cholesterol efflux and the concentration of larger and triglyceride rich particles (VLDL, chylomicrons). Subjects with significant stenosis on coronary angiography had lower cholesterol efflux from macrophages compared to individuals without significant stenosis (adjusted p = 0.02). CONCLUSION: Macrophage cholesterol efflux is inversely correlated with lipoprotein particle size and risk of CAD.

Repeat Measurements of High Sensitivity Troponins for the Prediction of Recurrent Cardiovascular Events in Patients With Established Coronary Heart Disease: An Analysis From the KAROLA Study.

Background High-sensitivity cardiac troponins T and I (hs- cTnT and hs- cTnI ) are established biomarkers for myocardial injury and used for diagnostic and prognostic purposes. However, whether repeat measurements improve prediction of recurrent cardiovascular disease ( CVD ) events in patients with stable coronary heart disease ( CHD ) after adjustment for several other novel biomarkers remains unclear. Methods and Results We measured both troponins in 873 coronary heart disease patients from the KAROLA (Langzeiterfolge der Kardiologischen Anschlussheilbehandlung) study about 9 weeks after their initial acute event (baseline) and after 12 months, followed them for 12 years, assessed a combined CVD end point, and adjusted for several risk factors. As we found evidence for effect modification, results were stratified according to presence of myocardial infarction at baseline. During follow-up, 186 fatal and non-fatal CVD events occurred. Both baseline and 12-months troponin concentrations were significantly associated with CVD events in patients without myocardial infarction at baseline; in tendency 12 months of troponin showed stronger hazard ratios (hs- cTnT : hazard ratios 1.91 (95% CI 1.17-3.11) versus baseline values 1.71 (95% CI 1.08-2.70) and for hs- cTnI : hazard ratio 1.55 (95% CI 1.05-2.30) versus baseline value 1.22 (95% CI 0.88-1.68) in the fully and simultaneously adjusted model. Conclusions Both troponins are consistently associated with recurrent cardiovascular events after adjustment for emerging risk factors during follow-up in our study especially evident in patients without myocardial infarction at baseline. Troponin values at 12 months of follow-up showed independent associations with future CVD events in addition to baseline assessments of troponins.

[Mapping and ablation of cardiac arrhythmias : Never forget where you are coming from]. / Mapping und Ablation von Herzrhythmusstörungen : "Never forget where you are coming from".

With the rapid development of new mapping and imaging technologies as well as catheter ablation technologies, it is increasingly important to understand the basic concepts of conventional mapping and ablation of cardiac arrhythmias. Prerequisite for successful ablation is the exact identification of the tachycardia mechanism and subsequent localization of the origin or tachycardic substrate. Only intracardiac electrograms provide decisive information regarding activation time and signal morphology. In some arrhythmias, it is necessary to supplement conventional mapping with so-called pace and/or entrainment mapping. This article aims to discuss and demonstrate the fundamentals of intracardiac mapping as it relates to the mapping and ablation of supraventricular and ventricular arrhythmias based on representative clinical cases. Modern three-dimensional mapping methods make it possible to individually optimize established ablation strategies with significantly better spatial resolution. The authors aimed to demonstrate that intracardiac uni- and bipolar electrograms provide essential information about timing and morphology guiding successful catheter ablation. Furthermore, our article provides useful information about conventional cardiac mapping techniques including activation mapping, pace mapping, and individual substrate mapping.

Hs-cTroponins for the prediction of recurrent cardiovascular events in patients with established CHD - A comparative analysis from the KAROLA study.

BACKGROUND: High-sensitivity Troponins (hs-cTnT and hs-cTnI) are established biomarkers to identify patients with an acute myocardial infarction. However, data comparing the capacity of these two subtypes in predicting recurrent cardiovascular disease (CVD) events in a population with stable coronary heart disease (CHD) after adjustment for several other modern biomarkers are lacking. METHODS: We measured both troponins at baseline in 1068 CHD patients, followed them for 13years, assessed a combined CVD endpoint, and adjusted for multiple traditional and novel risk factors. RESULTS: Both troponins correlated significantly with age, low and high BMI, male gender, statin therapy, and emerging biomarkers (e.g. cystatin C, NT-proBNP, GDF-15, hsCRP or galectin 3). During follow-up of 13years, 267 fatal and non-fatal CVD events occurred. Top quartiles of both troponin concentrations were significantly associated with CVD events compared to the bottom quartile after adjustment for age, gender and established CVD risk factors (hs-cTnT: hazard ratio (HR) 2.54 (95% CI, 1.60-4.03), p for trend: <0.0001; hs-cTnI: HR 2.20 (95% CI, 1.44-3.36), p for trend: <0.0002 and 0.0003). However, after adjustment for other emerging biomarkers, the associations were no longer statistically significant (hs-cTnT: HR 1.63 (95% CI, 0.97-2.73), p for trend: 0.17; hs-cTnI: HR 1.61 (95% CI, 1.00-2.60), p for trend: 0.067). CONCLUSION: Both troponins are reliable biomarkers of recurrent cardiovascular events, especially if other novel, important markers such as NT-proBNP, GDF-15 and galectin 3 are not available. Nevertheless, a further workup is still needed to explain the complex interaction of biomarkers indicating vascular and myocardial function.

Rheumatoid Arthritis and Coronary Artery Disease: Genetic Analyses Do Not Support a Causal Relation.

OBJECTIVE: Inflammatory diseases, specifically rheumatoid arthritis (RA), are assumed to increase the risk of coronary artery disease (CAD). More recently, multiple single-nucleotide polymorphisms (SNP) associated with RA risk were identified. If causal mechanisms affecting risks of RA and CAD are overlapping, risk alleles for RA might also increase the risk of CAD. METHODS: Sixty-one SNP associating with RA in genome-wide significant analyses were tested for association with CAD in CARDIoGRAM (Coronary ARtery DIsease Genome wide Replication and Meta-analysis), a metaanalysis including genome-wide association data (22,233 CAD cases, 64,762 controls). In parallel, a set of SNP being associated with low-density lipoprotein cholesterol (LDL-C) was tested as a positive control. RESULTS: Twenty-nine RA-associated SNP displayed a directionality-consistent association with CAD (OR range 1.002-1.073), whereas 32 RA-associated SNP were not associated with CAD (OR range 0.96-0.99 per RA risk-increasing allele). The proportion (48%) of directionality-consistent associated SNP equaled the proportion expected by chance (50%, p = 0.09). Of only 5 RA-associated SNP showing p values for CAD < 0.05, 4 loci (C5orf30, IL-6R, PTPN22, and RAD51B) showed directionality-consistent effects on CAD, and 1 (rs10774624, locus SH2B3) reached study-wide significance (p = 7.29E-06). By contrast, and as a proof of concept, 46 (74%) out of 62 LDL-C-associated SNP displayed a directionality-consistent association with CAD, a proportion that was significantly different from 50% (p = 5.9E-05). CONCLUSION: We found no evidence that RA-associated SNP as a group are associated with CAD. Even though we were not able to study potential effects of all genetic variants individually, shared nongenetic factors may more plausibly explain the observed coincidence of the 2 conditions.

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.