Circulation: Arrhythmia and Electrophysiology
Previously unsuspected inherited arrhythmia syndromes are potential causes of sudden unexpected death. In this prospective registry, systematic screening of first degree family members revealed cardiac abnormalities likely related to arrhythmia risk in 30%. These findings support a systematic approach to screening families who have experienced a sudden unexpected death of unknown cause.
Cardiac Abnormalities in First Degree Relatives of Unexplained Cardiac Arrest Victims
A Report from the CASPER Registry
Christian Steinberg, MD Gareth J. Padfield, MBChB, PhD Jean Champagne, MD Shubhayan Sanatani, MD Paul Angaran, MD Jason G. Andrade, MD Jason D. Roberts, MD, MAS Jeffrey S. Healey, MD, MSc Vijay S. Chauhan, MD David H. Birnie, MBChB, MD Mikyla Janzen, BScH Brenda Gerull, MD George J. Klein, MD Richard Leather, MD Christopher S. Simpson, MD Colette Seifer, MD Mario Talajic, MD Martin Gardner, MD Andrew D. Krahn, MD
Correspondence to: Dr Andrew Krahn, Heart Rhythm Vancouver, 211–1033 Davie Street, Vancouver, BC V6E 1M7. E-mail
BACKGROUND: Unexplained cardiac arrest (UCA) may be explained by inherited arrhythmia syndromes. The CASPER registry prospectively assessed first-degree relatives of UCA or sudden unexplained death (SUD) victims to screen for cardiac abnormalities.
METHODS AND RESULTS: 398 first-degree family members (186 UCA, 212 SUD relatives; mean age 44±17 years) underwent extensive cardiac workup including ECG, SAECG, exercise testing, cardiac imaging, Holter-monitoring and selective provocative drug testing with epinephrine or procainamide. Genetic testing was performed when a mutation was identified in the UCA survivor or when the diagnostic workup revealed a phenotype suggestive of a specific inherited arrhythmia syndrome. The diagnostic strength was classified as definite, probable or possible based on previously published definitions. Cardiac abnormalities were detected in 120/398 patients (30.2%) with 67/398 having a definite or probable diagnosis (17%) including long-QT Syndrome (13%), CPVT (4%), ARVC (4%) and Brugada syndrome (3%). The detection yield was similar for family members of UCA and SUD victims (31% versus 27%; P=0.59). Genetic testing was performed more often in family members of UCA patients (29% versus 20%;P=0.03). Disease-causing mutations were identified in 20/398 relatives (5%). The most common pathogenic mutations were RyR2 (2%), SCN5A (1%) and KNCQ1 (0.8%).
CONCLUSIONS: Cardiac screening revealed abnormalities in 30% of first-degree relatives of UCA or SUD victims, with a clear working diagnosis in 17%. Long-QT, ARVC and CPVT were the most common diagnoses. Systematic cascade screening and genetic testing in asymptomatic individuals will lead to preventive lifestyle and/or medical interventions with potential to prevent sudden cardiac death.
Circ Arrhythm Electrophysiol. 2016;9:e004274. DOI: 10.1161/CIRCEP.115.004274.
Circulation: Cardiovascular Genetics
Whole exome sequencing is an emerging genetics discovery tool that offers promise for identifying novel causative mutations for inherited diseases. This study investigates a whole exome sequencing approach for identifying causative mutations in familial congenital heart disease. The findings suggest this approach is more effective than panel-based testing, as more genes associated with CHD are identified, allowing for an updated CHD candidate gene list and reevaluation of the whole exome sequencing data.
Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease
Stephanie LaHaye, BS Don Corsmeier, DVM Madhumita Basu, PhD Jessica L. Bowman, MD Sara Fitzgerald-Butt, MS Gloria Zender, BS Kevin Bosse, PhD Kim L. McBride, MD, MS Peter White, PhD Vidu Garg, MD
Correspondence to: Peter White, PhD, or Vidu Garg, MD, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, Ohio 43205. E-mailor E-mail
BACKGROUND: Congenital heart disease (CHD) is the most common type of birth defect with family- and population-based studies supporting a strong genetic cause for CHD. The goal of this study was to determine whether a whole exome sequencing (WES) approach could identify pathogenic-segregating variants in multiplex CHD families.
METHODS AND RESULTS: WES was performed on 9 kindreds with familial CHD, 4 with atrial septal defects, 2 with patent ductus arteriosus, 2 with tetralogy of Fallot, and 1 with pulmonary valve dysplasia. Rare variants (<1% minor allele frequency) that segregated with disease were identified by WES, and variants in 69 CHD candidate genes were further analyzed. These selected variants were subjected to in silico analysis to predict pathogenicity and resulted in the discovery of likely pathogenic mutations in 3 of 9 (33%) families. A GATA4 mutation in the transactivation domain, p.G115W, was identified in familial atrial septal defects and demonstrated decreased transactivation ability in vitro. A p.I263V mutation in TLL1 was identified in an atrial septal defects kindred and is predicted to affect the enzymatic functionality of TLL1. A disease-segregating splice donor site mutation in MYH11 (c.4599+1delG) was identified in familial patent ductus arteriosus and found to disrupt normal splicing of MYH11 mRNA in the affected individual.
CONCLUSIONS: Our findings demonstrate the clinical utility of WES to identify causative mutations in familial CHD and demonstrate the successful use of a CHD candidate gene list to allow for a more streamlined approach enabling rapid prioritization and identification of likely pathogenic variants from large WES data sets.
CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique Identifier: NCT0112048.
Circ Cardiovasc Genet. 2016;9:320–329. DOI: 10.1161/CIRCGENETICS.115.001324.
Circulation: Cardiovascular Imaging
This study evaluates the relationship between smoking and echocardiographic measures in a large elderly cohort free of overt coronary artery disease and heart failure. The findings suggest that active smoking and greater cigarette exposure are associated with alterations in LV structure and function. These results may explain the higher risk of heart failure reported for smokers independent of coronary artery disease.
Smoking and Cardiac Structure and Function in the Elderly
The ARIC Study (Atherosclerosis Risk in Communities)
Wilson Nadruz Jr, MD, PhD Brian Claggett, PhD Alexandra Gonçalves, MD, PhD
Gabriela Querejeta-Roca, MD Miguel M. Fernandes-Silva, MD, PhD
Amil M. Shah, MD, MPH Susan Cheng, MD, MPH Hirofumi Tanaka, PhD
Gerardo Heiss, MD, PhD Dalane W. Kitzman, MD Scott D. Solomon, MD
Correspondence to: Scott D. Solomon, MD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
BACKGROUND: Cigarette smoking has been associated with higher risk of incident heart failure independent of coronary artery disease, but the impact of tobacco use on cardiac structure and function in the general population is uncertain. This study evaluated the relationship between smoking and echocardiographic measures in a large elderly cohort.
METHODS AND RESULTS: We studied 4580 participants free of overt coronary artery disease, heart failure, and significant valvular disease from the fifth visit of the ARIC study (Atherosclerosis Risk in Communities) who underwent transthoracic echocardiography. Participants were classified into 3 categories based on self-reported smoking habits: never (43.2%), former (50.5%), and current smokers (6.3%). Pack-years and years of smoking were also estimated. Compared with never smokers, current smokers had greater left ventricular (LV) mass index (80.4±1.1 versus 76.7±0.4 g/m2; P<0.001), LV mass/volume ratio (1.93±0.03 versus 1.83±0.03 g/mL; P<0.001), higher prevalence of LV hypertrophy (15% versus 9%; P=0.008), and worse diastolic function, as reflected by higher E/E′ ratio (11.7±0.2 versus 10.9±0.1; P<0.001), after adjusting for potential confounding factors. In contrast, former smokers showed similar echocardiographic features when compared with never smokers. Furthermore, estimated pack-years and years of smoking, measures of cumulative cigarette exposure, were associated with greater LV mass index, LV mass/volume ratio, and worse diastolic function (higher E/E′ ratio) in current smokers after multivariable analysis (all P<0.01).
CONCLUSIONS: Active smoking and cumulative cigarette exposure were associated with subtle alterations in LV structure and function in an elderly, community-based population free of overt coronary artery disease and heart failure.
Circ Cardiovasc Imaging. 2016;9:e004950. DOI: 10.1161/CIRCIMAGING.116.004950.
Circulation: Cardiovascular Interventions
The SYNTAX score is a clinically relevant tool to assess the extent and complexity of coronary disease and to guide revascularization decisions. Recently, it has been shown that the “residual” SYNTAX score, reassessed after revascularization, provides important adjunctive information about the completeness of revascularization and subsequent risk. This study analyzes the value of reassessment of the SYNTAX after percutaneous coronary intervention (PCI), in patients who previously had undergone CABG surgery. The residual SYNTAX score proved to have long-term prognostic value, suggesting that incomplete revascularization with PCI among patients with prior CABG is associated with higher risk.
Validation of the Coronary Artery Bypass Graft SYNTAX Score (Synergy Between Percutaneous Coronary Intervention With Taxus) as a Prognostic Marker for Patients With Previous Coronary Artery Bypass Graft Surgery After Percutaneous Coronary Intervention
Tadayoshi Miyagi, MD Yasuhide Asaumi, MD, PhD Kunihiro Nishimura, MD, PhD Takahiro Nakashima, MD Hiroki Sakamoto, MD Kazuhiro Nakao, MD Tomoaki Kanaya, MD Toshiyuki Nagai, MD, PhD Yuji Shimabukuro, MD Yoshihiro Miyamoto, MD PhD Tomoyuki Fujita, MD, PhD Kengo Kusano, MD, PhD Toshihisa Anzai, MD, PhD Junjirou Kobayashi, MD, PhD Teruo Noguchi, MD, PhD Hisao Ogawa, MD, PhD Satoshi Yasuda, MD, PhD
Correspondence to: Yasuhide Asaumi, MD, PhD, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center Hospital, 5-7-1 Fujishiro-dai, Suita, Osaka, Japan 565–8565. E-mail
BACKGROUND: The efficacy and prognosis of percutaneous coronary intervention (PCI) as secondary revascularization in patients with previous coronary artery bypass graft surgery remain uncertain.
METHODS AND RESULTS: We retrospectively evaluated 434 consecutive patients with previous coronary artery bypass graft surgery hospitalized for PCI between 2004 and 2011 (men 84%, age 71 (interquartile range, 66–76) years) and calculated the coronary artery bypass graft Synergy Between Percutaneous Coronary Intervention With Taxus score (CSS) before (baseline CSS) and after PCI (post-PCI CSS). Patients were divided into 2 groups based on median post-PCI CSS: low-score (≤23; n=217) and high-score groups (>23; n=217). Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, myocardial infarction, and unplanned repeat revascularization for myocardial ischemia. The median baseline and post-PCI CSS were 30 (interquartile range, 21–40) and 23 (interquartile range, 14.5–33.5), respectively. During a median follow-up of 69 months, the prevalence of MACE and cardiac death differed significantly between the 2 post-PCI CSS groups (MACE: low, 13.8%; high, 28.6%; P<0.001; cardiac death: low, 6.2%; high, 16.7%; P=0.002). In multivariable analysis, the high post-PCI CSS divided by the median was associated with substantially greater cumulative MACE (hazard ratio, 2.09; 95% confidence interval, 1.31–3.34; P=0.002) and cardiac death (hazard ratio, 2.02; 95% confidence interval, 1.03–3.98; P=0.042) compared with the low post-PCI CSS. Net reclassification improvement analysis revealed that post-PCI CSS resulted in significantly improved prediction of MACE and cardiac death compared with baseline CSS.
CONCLUSIONS: In this external validation study, the CSS was a potential prognostic factor after subsequent PCI, even for previous coronary artery bypass graft surgery patients.
Circ Cardiovasc Interv. 2016;9:e003459. DOI: 10.1161/CIRCINTERVENTIONS. 115.003459.
Circulation: Cardiovascular Quality and Outcomes
Although high-sensitivity troponin assays have been widely implemented, data supporting improvements in outcomes with conversion to high sensitivity assays are limited mostly to observational studies. This randomized clinical trial evaluated the performance outcomes and effectiveness of providing high-sensitivity troponin assay results for the diagnosis and exclusion of myocardial infraction. In comparison to standard troponin assays, high-sensitivity troponin assays led to only very small changes in practice patterns and outcomes.
Randomized Comparison of High-Sensitivity Troponin Reporting in Undifferentiated Chest Pain Assessment
Derek P. Chew, MBBS, MPH Christopher Zeitz, MBBS, PhD Matthew Worthley, MBBS, PhD Hugh Grantham, MBBS, John Beltrame, BMBS, PhD Margaret Arstall, MBBS, PhD Penelope Coates, MBBS Carolyn Astley, DrPH Stephen Quinn, PhD Julie Ratcliffe, PhD Matthew Horsfall, RN Philip G. Aylward, BMBCh, PhD
Correspondence to: Derek P. Chew, MBBS, MPH, Flinders Medical Centre, Flinders Dr, Bedford Park, South Australia, 5042, Australia. E-mail
BACKGROUND: High-sensitivity troponin T (hs-TnT) assays promise greater discrimination of evolving myocardial infarction, but the impact of unguided implementation on the effectiveness of care is uncertain.
METHODS AND RESULTS: We evaluated the impact of hs-TnT reporting on care and outcome among chest pain patients presenting to 5 emergency departments within a multicenter randomized trial. Patients were allocated to hs-TnT reporting (hs-report) or standard reporting (std-report; Roche Elecys). The primary end point was death and new or recurrent acute coronary syndrome by 12 months. A total of 1937 patients without ST-segment elevation were enrolled between July 2011 and March 2013. The median age was 61 (interquartile range, 48–74) years, and 46.3% were women. During the index hospitalization, 1466 patients (75.7%) had maximal troponin <30 ng/L within 24 hours. Randomization to hs-report format did not alter the admission rate (hs-report: 57.7% versus std-report: 58.0%; P=0.069). There was no difference in angiography (hs-report: 11.9% versus std-report: 10.9%; P=0.479). The hs-reporting did not reduce 12-month death or new/recurrent acute coronary syndrome in the overall population (hs-report: 9.7% versus std-report: 7.2% [hazard ratio, 0.83 (0.57–1.22); P=0.362]). However, among those with troponin levels <30 ng/L, a modest reduction in the primary end point was observed (hs-report: 2.6% versus std-report: 4.4%, [hazard ratio, 0.58; 95% confidence interval, 0.34–0.1.00; P=0.050).
CONCLUSIONS: High-sensitivity troponin reporting alone is associated with only modest changes in practice. Clinical effectiveness in the adoption of high-sensitivity troponin may require close coupling with protocols that guide interpretation and care.
Circ Cardiovasc Qual Outcomes. 2016;9:542-553. DOI: 10.1161/CIRCOUTCOMES.115.002488.
Circulation: Heart Failure
Individual sites participating in clinical trials vary widely with regard to measures of performance such as participant recruitment and protocol completion. In a large international trial in acute heart failure (AHF), the impact of varying site enrollment and protocol execution on trial performance was assessed. The data suggest that site enrollment volume, as an additional domain of AHF trial heterogeneity, is associated with protocol completion, and with higher patient acuity, but lower short term morbidity and mortality. These findings have important implications for future study design, execution, and cost.
Influence of Clinical Trial Site Enrollment on Patient Characteristics, Protocol Completion, and End Points
Stephen J. Greene, MD Adrian F. Hernandez, MD, MHS Jie-Lena Sun, MS Marco Metra, MD Javed Butler, MD, MPH, MBA Andrew P. Ambrosy, MD Justin A. Ezekowitz, MBBCh, MSc Randall C. Starling, MD, MPH John R. Teerlink, MD Phillip J. Schulte, PhD Adriaan A. Voors, MD, PhD Paul W. Armstrong, MD, Christopher M. O’Connor, MD Robert J. Mentz, MD
Correspondence to: Stephen J. Greene, MD, Division of Cardiology, Duke University Medical Center, 2301 Erwin Rd, Suite 7400, Durham, NC 27705. E-mail
BACKGROUND: Most international acute heart failure trials have failed to show benefit with respect to key end points. The impact of site enrollment and protocol execution on trial performance is unclear.
METHODS AND RESULTS: We assessed the impact of varying site enrollment volume among all 7141 acute heart failure patients from the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). Overall, 398 sites enrolled ≥1 patient, and median enrollment was 12 patients (interquartile range, 5–23). Patients from high enrolling sites (>60 patients/site) tended to have lower ejection fraction, worse New York Heart Association functional class, and lower utilization of guideline-directed medical therapy but fewer comorbidities and lower B-type natriuretic peptide level. Every 10 patient increase (up to 100 patients) in site enrollment correlated with lower likelihood of protocol noncompletion (odds ratio, 0.93; 95% confidence interval [CI], 0.89–0.98). After adjustment, increasing site enrollment predicted higher risk of persistent dyspnea at 6 hours (per 10 patient increase: odds ratio 1.02; 95% CI, 1.01–1.03) but not at 24 hours (odds ratio, 0.99; 95% CI, 0.98–1.00). Higher site enrollment was independently associated with lower risk of 30-day death or rehospitalization (per 10 patient increase: odds ratio, 0.98, 95% CI, 0.96–0.99) but not 180-day mortality (hazard ratio, 0.99; 95% CI, 0.98–1.01). The influence of increasing site enrollment on clinical end points varied across geographic regions with strongest associations in Latin America and Asia-Pacific (all interaction P<0.01).
CONCLUSIONS: In this large, acute heart failure trial, site enrollment correlated with protocol completion and was independently associated with trial end points. Individual and regional site performance present challenges to be considered in design of future acute heart failure trials.
Circ Heart Fail. 2016;9:e002986. DOI: 10.1161/CIRCHEARTFAILURE.116.002986.
- © 2016 American Heart Association, Inc.