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Circulation: Arrhythmia and Electrophysiology
There are limited data on mapping and ablation to control ventricular arrhythmias in patients with Brugada syndrome. This study analyzed 135 consecutive symptomatic patients with Brugada syndrome who underwent a combined epicardial-endocardial mapping procedure with ajmaline to better characterize the epicardial substrate followed by radiofrequency ablation. The authors found that ajmaline increased the arrhythmogenic electrophysiological substrate regions that were commonly found in the right ventricular epicardium and that ablation was successful in eliminating inducible ventricular tachycardia and ventricular fibrillation in nearly all patients. The results suggest that substrate ablation can be considered a potential therapy for preventing recurrent ventricular tachycardia and ventricular fibrillation.
Electric Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome
Carlo Pappone, MD, PhD
Josep Brugada, MD, PhD
Gabriele Vicedomini, MD
Giuseppe Ciconte, MD
Francesco Manguso, MD, PhD
Massimo Saviano, MD
Raffaele Vitale, MD
Amarild Cuko, MD
Luigi Giannelli, MD
Zarko Calovic, MD
Manuel Conti, MD
Paolo Pozzi, Eng
Andrea Natalizia, PhD, Eng
Simonetta Crisà, Eng
Valeria Borrelli, PhD
Ramon Brugada, MD, PhD
Georgia Sarquella-Brugada, MD, PhD
Marco Guazzi, MD
Alessandro Frigiola, MD
Lorenzo Menicanti, MD
Vincenzo Santinelli, MD
Correspondence to: Carlo Pappone, MD, PhD, Department of Arrhythmology, IRCCS Policlinico San Donato, Piazza E Malan, 20097-San Donato Milanese, Italy. E-mail
BACKGROUND: There is emerging evidence that localization and elimination of abnormal electric activity in the epicardial right ventricular outflow tract may be beneficial in patients with Brugada syndrome.
METHODS AND RESULTS: A total of 135 symptomatic Brugada syndrome patients having implantable cardiac defibrillator were enrolled: 63 (group 1) having documented ventricular tachycardia (VT)/ventricular fibrillation (VF) and Brugada syndrome–related symptoms, and 72 (group 2) having inducible VT/VF without ECG documentation at the time of symptoms. About 27 patients of group 1 experienced multiple implantable cardiac defibrillator shocks for recurrent VT/VF episodes. Three-dimensional maps before and after ajmaline determined the arrhythmogenic electrophysiological substrate (AES) as characterized by prolonged fragmented ventricular potentials. Primary end point was identification and elimination of AES leading to ECG pattern normalization and VT/VF noninducibility. Extensive areas of AES were found in the right ventricle epicardium, which were wider in group 1 (P=0.007). AES increased after ajmaline in both groups (P<0.001) and was larger in men (P=0.008). The increase of type-1 ST-segment elevation correlated with AES expansion (r=0.682, P<0.001). Radiofrequency ablation eliminated AES leading to ECG normalization and VT/VF noninducibility in all patients. During a median follow-up of 10 months, the ECG remained normal even after ajmaline in all except 2 patients who underwent a repeated effective procedure for recurrent VF.
CONCLUSIONS: In Brugada syndrome, AES is commonly located in the right ventricle epicardium and ajmaline exposes its extent and distribution, which is correlated with the degree of coved ST-elevation. AES elimination by radiofrequency ablation results in ECG normalization and VT/VF noninducibility. Substrate-based ablation is effective in potentially eliminating the arrhythmic consequences of this genetic disease.
Circ Arrhythm Electrophysiol. 2017;10:e005053. DOI: 10.1161/CIRCEP.117.005053.
Circulation: Cardiovascular Genetics
Mapping for admixture among blacks can help detect genetic variants from excess local ancestry associated with cardiovascular disease. This study examines the association of local European ancestry with carotid artery intima-media thickness in blacks from the MESA (Multi-Ethnic Study of Atherosclerosis) cohort and confirmed in the Atherosclerosis Risk in Communities cohort. The authors confirmed an association of several carotid artery intima-media thickness–associated local European ancestry genes with clinical events in MESA. These findings may contribute to the development of race-specific interventional strategies.
Admixture Mapping of Subclinical Atherosclerosis and Subsequent Clinical Events Among African Americans in 2 Large Cohort Studies
Aditi Shendre, PhD
Howard Wiener, PhD
Marguerite R. Irvin, PhD
Degui Zhi, PhD
Nita A. Limdi, PhD
Edgar T. Overton, MD
Christina L. Wassel, PhD
Jasmin Divers, PhD
Jerome I. Rotter, MD
Wendy S. Post, MD
Sadeep Shrestha, PhD
Correspondence to: Sadeep Shrestha, PhD, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Ryals Room 217L, 1720 2nd Avenue S, Birmingham, AL 35294. E-mail
BACKGROUND: Local ancestry may contribute to the disproportionate burden of subclinical and clinical cardiovascular disease among admixed African Americans compared with other populations, suggesting a rationale for admixture mapping.
METHODS AND RESULTS: We estimated local European ancestry (LEA) using Local Ancestry inference in adMixed Populations using Linkage Disequilibrium method (LAMP-LD) and evaluated the association with common carotid artery intima–media thickness (cCIMT) using multivariable linear regression analysis among 1554 African Americans from MESA (Multi-Ethnic Study of Atherosclerosis). We conducted secondary analysis to examine the significant cCIMT–LEA associations with clinical cardiovascular disease events. We observed genome-wide significance in relation to cCIMT association with the SERGEF gene (secretion-regulating guanine nucleotide exchange factor; β=0.0137; P=2.98×10−4), also associated with higher odds of stroke (odds ratio=1.71; P=0.02). Several regions, in particular CADPS gene (Ca2+-dependent secretion activator 1) region identified in MESA, were also replicated in the ARIC cohort (Atherosclerosis Risk in Communities). We observed other cCIMT–LEA regions associated with other clinical events, most notably the regions harboring CKMT2 gene (creatine kinase, mitochondrial 2) and RASGRF2 gene (Ras protein–specific guanine nucleotide–releasing factor 2) with all clinical events except stroke, the LRRC3B gene (leucine-rich repeat containing 3B) with myocardial infarction, the PRMT3 gene (protein arginine methyltransferase 3) with stroke, and the LHFPL2 gene (lipoma high mobility group protein I-C fusion partner-like 2) with hard and all coronary heart disease.
CONCLUSIONS: We identified several novel LEA regions, in addition to previously identified genetic variations, associated with cCIMT and cardiovascular disease events among African Americans.
Circ Cardiovasc Genet. 2017;10:e001569. DOI: 10.1161/CIRCGENETICS.116.001569.
Circulation: Cardiovascular Imaging
Appropriate sizing in aortic valve replacement is crucial to avoid complications such as paravalvular leakage and annular rupture. This retrospective study of 78 patients between 2012 and 2014 undergoing surgical aortic valve replacement for severe aortic stenosis used preoperative multidetector computerized tomographic imaging measurements to analyze sizing typically performed intraoperatively in clinical practice. The results show that preoperative multidetector computerized tomographic assessment would have predicted larger sizes for valves in 40% of cases and may be a useful tool for patients at risk for patient-prosthesis mismatch.
Aortic Valve Annular Sizing
Intraoperative Assessment Versus Preoperative Multidetector Computed Tomography
Isaac George, MD
Laura C. Guglielmetti, MD
Nicolas Bettinger, MD
Catherine Wang, MD
Rebecca Hahn, MD
Susheel Kodali, MD
Martin Leon, MD
Vinayak Bapat, MD
Michael A. Borger, MD
Mathew Williams, MD
Craig Smith, MD
Omar K. Khalique, MD
Correspondence to: Isaac George, MD, Division of Cardiothoracic Surgery, New York Presbyterian Hospital–College of Physicians and Surgeons of Columbia University, MHB 7GN-435, 177 Ft Washington Avenue, New York, NY 10032. E-mail
BACKGROUND: Appropriate valve sizing is critical in aortic valve replacement. We hypothesized that direct intraoperative valve sizing results in smaller aortic annular diameters compared with sizing based on systolic-phase multidetector computerized tomographic (MDCT) imaging.
METHODS AND RESULTS: We retrospectively analyzed 78 patients undergoing surgical aortic valve replacement for severe aortic stenosis between 2012 and 2014 at our institution. Preoperative MDCT measurements of the aortic annulus served as basis for assignment to a theoretical surgical valve size, which was then (1) compared to the implanted valve size and (2) to a theoretical transcatheter aortic valve replacement valve size. To quantify the resulting differences, geometric orifice areas (GOA) were calculated. MDCT-based sizing produced the same valve size for n=34 patients (group CT-same), a larger valve with a 25% increased GOA in n=32 patients (group CT-Lg) and a smaller GOA by 22% in n=12 patients (group CT-Sm). On the basis of MDCT measurements, 41% of valves implanted were undersized. The comparison of intraoperative implanted to a theoretical transcatheter aortic valve replacement valve size resulted in GOAs 25% larger for patients in group CT-same, 40.6% larger in group CT-Lg and 14.6% larger in group CT-Sm.
CONCLUSIONS: Preoperative MDCT measurements differ substantially from direct intraoperative assessment of the aortic annulus. Implanted surgical aortic valve replacement valves were smaller relative to MDCT-based sizing in 41% of patients, and the potential GOA was between 25% and 40.6% larger if patients had undergone transcatheter aortic valve replacement.
Circ Cardiovasc Imaging. 2017;10:e005968. DOI: 10.1161/CIRCIMAGING.116.005968.
Circulation: Cardiovascular Interventions
This meta-analysis compared everolimus-eluting bioresorbable vascular scaffolds with everolimus-eluting stents in randomized trials with regard to long-term efficacy and safety in which data are limited. The results suggest that at 1 year bioresorbable vascular scaffolds are associated with an increased risk of target lesion revascularization and stent/scaffold thrombosis compared with everolimus-eluting stents.
Long-Term Efficacy and Safety of Everolimus-Eluting Bioresorbable Vascular Scaffolds Versus Everolimus-Eluting Metallic Stents
A Meta-Analysis of Randomized Trials
Ahmed N. Mahmoud, MD
Amr F. Barakat, MD
Akram Y. Elgendy, MD
Erik Schneibel, MD
Amgad Mentias, MD
Ahmed Abuzaid, MD
Islam Y. Elgendy, MD
Correspondence to: Islam Y. Elgendy, MD, Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100277, Gainesville, FL 32610. E-mail
BACKGROUND: Data regarding the long-term efficacy and safety of everolimus-eluting bioresorbable vascular scaffolds (BVS) compared with everolimus-eluting stents are limited. This meta-analysis aimed to compare the long-term outcomes with both devices.
METHODS AND RESULTS: Randomized trials reporting clinical outcomes beyond 1 year and comparing BVS with everolimus-eluting stents were included. Summary estimates risk ratios (RRs) were constructed. The primary efficacy outcome was target lesion failure, defined as cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization, and the primary safety outcome was definite or probable stent/scaffold thrombosis. Six trials with 5392 patients were included (mean follow-up, 25 months). BVS had a higher rate of target lesion failure (RR, 1.33; 95% confidence interval [CI], 1.11–1.58) driven by the higher rates of target vessel myocardial infarction (RR, 1.65; 95% CI, 1.26–2.17) and target lesion revascularization (RR, 1.39; 95% CI, 1.08–1.78). The risk of definite or probable stent/scaffold thrombosis (RR, 3.22; 95% CI, 1.89–5.49) and very late stent/scaffold thrombosis (>1 year; RR, 4.78; 95% CI, 1.66–13.8) was higher with BVS. The risk of cardiac and all-cause mortality was similar in both groups.
CONCLUSIONS: Compared with everolimus-eluting stents, BVS is associated with increased risk of target lesion failure driven by the increased rates of target vessel myocardial infarction and ischemia-driven target lesion revascularization in these studies (mean follow-up, 25 months). The risk of definite or probable stent/scaffold thrombosis and very late stent/scaffold thrombosis seems to be higher with BVS. Further information from randomized trials is critical to evaluate clinical outcomes with BVS on complete resolution of the scaffold.
Circ Cardiovasc Interv. 2017;10:e005286. DOI: 10.1161/CIRCINTERVENTIONS.117.005286.
Circulation: Cardiovascular Quality and Outcomes
This study analyzes the adoption of 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines and the recommendation of the use of the CHA2DS2-VASc score among patients with a low CHADS2 score for thromboembolic risk stratification. It recategorizes 64.5% of patients with atrial fibrillation as at higher stroke risk by using the CHA2DS2-VASc instead of the CHADS2 score, suggesting that many patients previously in lower risk categories meet the new guideline criteria for oral anticoagulation initiation on the basis of the contemporary CHA2DS2-VASc score. Accordingly, prescriptions of oral anticoagulants increased during the study period between 2008 and 2014.
Contemporary Trends in Oral Anticoagulant Prescription in Atrial Fibrillation Patients at Low to Moderate Risk of Stroke After Guideline-Recommended Change in Use of the CHADS2 to the CHA2DS2-VASc Score for Thromboembolic Risk Assessment
Analysis From the National Cardiovascular Data Registry’s Outpatient Practice Innovation and Clinical Excellence Atrial Fibrillation Registry
David F. Katz, MD
Thomas M. Maddox, MD, MSc
Mintu Turakhia, MD
Anil Gehi, MD
Emily C. O’Brien, PhD
Steven A. Lubitz, MD, MPH
Alexander Turchin, MD, MS
Gheorghe Doros, PhD
Lanyu Lei, MS
Paul Varosy, MD
Lucas Marzec, MD
Jonathan C. Hsu, MD, MAS
Correspondence to: Jonathan C. Hsu, MD, MAS, Section of Cardiac Electrophysiology, Division of Cardiology, University of California San Diego, 9454 Medical Center Drive, 3rd Floor, Room 3E-417, La Jolla, CA 92037. E-mail
BACKGROUND: Use of the CHA2DS2-VASc score instead of the CHADS2 score for thromboembolic risk stratification and initiation of oral anticoagulation (OAC) was recommended in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation (AF) guidelines. We sought to define the proportion of patients with AF qualifying for and receiving OAC in contemporary practice by applying the CHA2DS2-VASc score to patients with a low CHADS2 score.
METHODS AND RESULTS: Among patients with AF enrolled in the American College of Cardiology National Cardiovascular Data Registry’s outpatient Practice Innovation and Clinical Excellence registry (2008–2014) CHADS2 score of 0 or 1, we calculated the impact of adoption of the CHA2DS2-VASc score on the proportion of patients with an indication for OAC. We examined trends in prescription of OAC overall, direct OAC (dabigatran/rivaroxaban/apixaban), and multivariable associations between clinical characteristics and OAC use. Of 346 068 patients with AF aged 65±12 years, 61% were men and 65% were white. In total, 24% of those with CHADS2=0 and 81% of those with a CHADS2=1 were reclassified as having a definite indication for OAC (CHA2DS2-VASc score ≥2). OAC use increased from 37% to 48% during the study period, and direct OAC use increased from 5% to 30%. Increasing CHA2DS2-VASc score (odds ratio, 2.07; 95% confidence interval, 1.97–2.19 for score of 4 versus 0) and rhythm control strategy (odds ratio, 1.34; 95% confidence interval, 1.30–1.39) were associated with increased OAC use.
CONCLUSIONS: Adoption of the CHA2DS2-VASc score reclassifies 64.5% of patients with AF with low CHADS2 scores into a class I indication for OAC prescription. Overall OAC prescription increased between 2011 and 2014.
Circ Cardiovasc Qual Outcomes. 2017;10:e003476. DOI: 10.1161/CIRCOUTCOMES.116.003476.
Circulation: Heart Failure
The fundamental mechanisms of the clinical benefit of β-adrenoceptor blockers and downstream molecular consequences are somewhat uncertain. Substantial evidence shows that calcium/calmodulin-dependent protein kinase II (CaMKII) is a mediator of catecholamine-induced cardiotoxicity and that inhibition of CaMKII is a potential treatment strategy. This study analyzes the link between β-adrenoceptor blockers and myocardial CaMKII activity. The results showed that CaMKII is not effectively targeted by β-blockers in failing hearts and that directly targeting CaMKII may be an additional treatment option to enhance the therapeutic effects of β-blockers in patients with heart failure.
Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure
Matthias Dewenter, MD
Stefan Neef, MD
Christiane Vettel, PhD
Simon Lämmle, PhD
Christina Beushausen, MD
Laura C. Zelarayan, PhD
Sylvia Katz, PhD
Albert von der Lieth, MS
Stefanie Meyer-Roxlau, MS
Silvio Weber, PhD
Thomas Wieland, PhD
Samuel Sossalla, MD
Johannes Backs, MD
Joan H. Brown, PhD
Lars S. Maier, MD
Ali El-Armouche, MD
Correspondence to: Ali El-Armouche, MD, Institute of Pharmacology and Toxicology, University of Technology Dresden, Fetscherstraße 74, 01307 Dresden, Germany. E-mail
BACKGROUND: Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF.
METHODS AND RESULTS: Immunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with β-AR blockers revealed no difference in CaMKII activity when compared with non–β-AR blocker–treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKIIδC transgenic mice were treated with the β1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n≥29; P<0.001), attenuated the development of cardiac hypertrophy (−14±6% heart weight/tibia length; P<0.05), and strongly reduced ventricular arrhythmias (−70±22% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A–dependent phospholamban and ryanodine receptor 2 phosphorylation (−42±9% for P-phospholamban-S16 and −22±7% for P-ryanodine receptor 2-S2808; P<0.05). However, this was paralleled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n≥11). The lack of CaMKII modulation by β-AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol.
CONCLUSIONS: Chronic β-AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of β-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to β-AR blockade.
Circ Heart Fail. 2017;10:e003840. DOI: 10.1161/CIRCHEARTFAILURE.117.003840.
Circulation is available at http://circ.ahajournals.org.
- © 2017 American Heart Association, Inc.