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Motivation Making sense of networked multivariate association patterns is vitally important to many areas of high-dimensional analysis. Unfortunately, as the data-space dimensions grow, the number of association pairs increases in O(n2); this means that traditional visualizations such as heatmaps quickly become too complicated to parse effectively. Results Here, we present associationSubgraphs: a new interactive visualization method to quickly and intuitively explore high-dimensional association datasets using network percolation and clustering. The goal is to provide an efficient investigation of association subgraphs, each containing a subset of variables with stronger and more frequent associations among themselves than the remaining variables outside the subset, by showing the entire clustering dynamics and providing subgraphs under all possible cutoff values at once. Particularly, we apply associationSubgraphs to a phenome-wide multimorbidity association matrix generated from an electronic health record and provide an online, interactive demonstration for exploring multimorbidity subgraphs. Availability and implementation An R package implementing both the algorithm and visualization components of associationSubgraphs is available at https://github.com/tbilab/associationsubgraphs. Online documentation is available at https://prod.tbilab.org/associationsubgraphs_info/. A demo using a multimorbidity association matrix is available at https://prod.tbilab.org/associationsubgraphs-example/.

Objective We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list. Materials and Methods To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature. Results DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available. Conclusions In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.

Objective Developing algorithms to extract phenotypes from electronic health records (EHRs) can be challenging and time-consuming. We developed PheMap, a high-throughput phenotyping approach that leverages multiple independent, online resources to streamline the phenotyping process within EHRs. Materials and Methods PheMap is a knowledge base of medical concepts with quantified relationships to phenotypes that have been extracted by natural language processing from publicly available resources. PheMap searches EHRs for each phenotype’s quantified concepts and uses them to calculate an individual’s probability of having this phenotype. We compared PheMap to clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network for type 2 diabetes mellitus (T2DM), dementia, and hypothyroidism using 84 821 individuals from Vanderbilt Univeresity Medical Center's BioVU DNA Biobank. We implemented PheMap-based phenotypes for genome-wide association studies (GWAS) for T2DM, dementia, and hypothyroidism, and phenome-wide association studies (PheWAS) for variants in FTO, HLA-DRB1, and TCF7L2. Results In this initial iteration, the PheMap knowledge base contains quantified concepts for 841 disease phenotypes. For T2DM, dementia, and hypothyroidism, the accuracy of the PheMap phenotypes were >97% using a 50% threshold and eMERGE case-control status as a reference standard. In the GWAS analyses, PheMap-derived phenotype probabilities replicated 43 of 51 previously reported disease-associated variants for the 3 phenotypes. For 9 of the 11 top associations, PheMap provided an equivalent or more significant P value than eMERGE-based phenotypes. The PheMap-based PheWAS showed comparable or better performance to a traditional phecode-based PheWAS. PheMap is publicly available online. Conclusions PheMap significantly streamlines the process of extracting research-quality phenotype information from EHRs, with comparable or better performance to current phenotyping approaches.

The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called ‘real-world’, and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease.

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10−54; CES1 G143E, P = 1.3 × 10−16; CYP2C19*17, P = 9.5 × 10−10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10−4; CYP2B6 516 G > T, P = 1.0 × 10−3; CYP2C9*2, P = 1.2 × 10−3; and CYP2C9*3, P = 1.5 × 10−3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14–2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35–14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. Conclusion Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Background Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis. Purpose The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury. Methods We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I. Results Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p Conclusions Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466

Background Abiraterone and enzalutamide are recently approved androgen deprivation therapies (ADT) for metastatic prostate cancer. The cardiac safety profile for the two drugs is unknown. Methods Using French and World Health Organization (WHO) pharmacovigilance databases, we performed a disproportionality-analysis of suspected adverse-drug-reactions (ADR) to evaluate the reporting-odds-ratio (ROR) of cardiac ADR associated with abiraterone compared to enzalutamide, other ADT used in prostate cancer, and entire database. Clinical and demographic characterization of patients with ADT-induced cardiac ADR was performed. Results In the 5,759,781 ADR reports in men, 55,070 pertained to ADT. The ROR of AT for abiraterone was of 4.1 [3.1–5.3] vs. enzalutamide, 3.7 [3–4.5] vs. other ADT, and 3.2 [2.7–3.7] vs. entire database. The corresponding ROR for HF were of 2.5 [2–3], 1.5 [1.3–1.7], and 2 [1.7–2.3], respectively. Mean time to AT and HF onset was shorter on abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) vs. other ADT (13.3±3.2 and 9.2±1.1 months; p Table 1 Number (available data) AT HF Hypokalemia Edema Hypertension Age (y) 5989 r: 0.03, p: 0.02 r: 0.05, p≤0.0001 r: 0.06, p≤0.0001 r: 0.04, p≤0.01 ns Dose of hydrocortisone equivalent (mg/day) 3828 ns ns ns r: −0.07, p≤0.001 r: −0.12, p≤0.0001 Dose of abiraterone (mg/day) 6285 ns ns ns ns ns Details concerning correlation (r) between clinical covariates and reporting for AT, HF, hypokalemia, edema and hypertension within overall adverse drug reaction on abiraterone (n: 9203) extracted from VigiBase (through 08/2017). Time to onset Conclusion Compared to other ADT, abiraterone was associated with a higher reporting of AT and HF associated with hypokalemia, hypertension and edema. These findings are consistent with the hyper-mineralocorticism induced by abiraterone and not with other ADT.

Aim Male hypogonadism, arising from various etiologies including androgen-deprivation therapies (ADT), has been reported as a risk-factor for acquired long-QT (aLQT) and Torsades de pointe (TdP). A full description of clinical features of aLQTS associated with ADT and of underlying mechanisms are lacking. Method and results We searched the WHO pharmacovigilance database for men (n=6,560,565) presenting with aLQT, TdP or sudden death (SD) associated with ADT. We identified 184 cases of aLQTS and/or TdP (11% fatal), and 99 with SD. Of the 10 ADT examined, 7 had a disproportional association (reporting-OR=1.4–4.7, p Table 1 ndeath/ntotal (%) aLQT TdP SD n/naLQTS±TdP±SD (%) with ADT considered suspect by reporter Leuprorelin 1,871/22,113 (8.5%) 33 16 18 28/55 (50.9%) Goserelin 471/5,821 (8.1%) 8 2 15 17/22 (77.3%) Triptorelin 52/1,517 (3.4%) 6 3 2 5/8 (62.5%) Degarelix 82/2,787 (2.9%) 7 4 3 10/11 (90.9%) Bicalutamide 724/10,144 (7.1%) 23 16 11 28/41 (68.3%) Flutamide 163/4075 (4%) 4 2 3 3/7 (42.9%) Enzalutamide 5,430/31,896 (17%) 19 4 13 30/32 (93.8%) Abiraterone 1,240/14,261 (8.7%) 19 7 10 29/31 (92.5%) Finasteride 1,062/33,877 (3.1%) 52 20 32 20/87 (23%) Dutasteride 248/15,177 (1.6%) 26 7 11 5/38 (13.2%) Total ADT* 10,540/127,385 (8.3%) 168 68 99 137/283 (48.4%) Number (n) of case reports in men in the WHO international pharmacovigilance database (VigiBase) by ADT through 08/09/2018. *Some patients were on combination ADT. Enzalutamide electrophysiology IPS-CMs Conclusion ADT is a risk factor for aLQT and TdP. Androgens may be useful in TdP treatment of hypogonadic men. Acknowledgement/Funding INSERM

Importance Ibrutinib, a first in class Bruton tyrosine kinase inhibitor, has revolutionized treatment for several B-cell malignancies. However, early data suggested that ibrutinib was associated with supra-ventricular arrhythmias (SVA) and bleeding. Other types of cardiovascular adverse drug reactions (CV-ADR) induced by ibrutinib have been sporadically reported. Objective To determine the full spectrum of CV-ADR associated with ibrutinib and provide data concerning their clinical characteristics. Design An observational, retrospective, pharmacovigilance study Setting VigiBase, the World Health Organization's pharmacovigilance database. Main outcomes and measures A disproportionality analysis using reporting odds-ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and ADR using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) >0 is considered statistically significant. Exposures Exposure to ibrutinib versus entire database. Results Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVA; ROR: 23.1 [21.6–24.7]; IC025:3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7 [3.4–4.1]; IC025:1.63), heart failure (HF; ROR: 3.5 [3.1–3.8]; IC025:1.46), ventricular arrhythmias (VA; ROR: 4.7 [3.7–5.9]; IC025:0.96), conduction disorders (CD; ROR: 3.5 [2.7–4.6]; IC025:0.76), CNS ischemic events (ROR: 2.2 [2.0–2.5]; IC025:0.73) and hypertension (ROR: 1.7 [1.5–1.9]; IC025:0.4). CV-ADR occurred early after ibrutinib administration, as soon as after the first dose, with a shorter median time to onset of 27.5 days (IQR: 1–138.5 days) for CD (p Conclusions Severe and occasionally fatal cardiac events related to cardiac SVA, VA, CD, HF, hypertension, CNS hemorrhagic and ischemic events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs.

Objective: Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often iterative, depends on fallible investigator intuition, and is time- and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites.Materials and Methods: We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best-performing algorithms at the Marshfield Clinic.Results: Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non-NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar.Conclusion: This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision.

Objective Health care generated data have become an important source for clinical and genomic research. Often, investigators create and iteratively refine phenotype algorithms to achieve high positive predictive values (PPVs) or sensitivity, thereby identifying valid cases and controls. These algorithms achieve the greatest utility when validated and shared by multiple health care systems. Materials and Methods We report the current status and impact of the Phenotype KnowledgeBase (PheKB, http://phekb.org ), an online environment supporting the workflow of building, sharing, and validating electronic phenotype algorithms. We analyze the most frequent components used in algorithms and their performance at authoring institutions and secondary implementation sites. Results As of June 2015, PheKB contained 30 finalized phenotype algorithms and 62 algorithms in development spanning a range of traits and diseases. Phenotypes have had over 3500 unique views in a 6-month period and have been reused by other institutions. International Classification of Disease codes were the most frequently used component, followed by medications and natural language processing. Among algorithms with published performance data, the median PPV was nearly identical when evaluated at the authoring institutions (n = 44; case 96.0%, control 100%) compared to implementation sites (n = 40; case 97.5%, control 100%). Discussion These results demonstrate that a broad range of algorithms to mine electronic health record data from different health systems can be developed with high PPV, and algorithms developed at one site are generally transportable to others. Conclusion By providing a central repository, PheKB enables improved development, transportability, and validity of algorithms for research-grade phenotypes using health care generated data.

Large-scale biorepositories that couple biologic specimens with electronic health records containing documentation of phenotypic expression can accelerate scientific research and discovery. However, differences between those subjects who participate in biorepository-based research and the population from which they are drawn may influence research validity. While an opt-out approach to biorepository-based research enhances inclusiveness, empirical research evaluating voluntariness, risk, and the feasibility of an opt-out approach is sparse, and factors influencing patients' decisions to opt out are understudied. Determining why patients choose to opt out may help to improve voluntariness, however there may be ethical and logistical challenges to studying those who opt out. In this perspective paper, the authors explore what is known about research based on the opt-out model, describe a large-scale biorepository that leverages the opt-out model, and review specific ethical and logistical challenges to bridging the research gaps that remain.

Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.

Objective: Despite the primacy of the sodium current in cardiac electrophysiology and evidence that decreased sodium current is arrhythmogenic in humans, little is known about transcriptional regulation of the underlying gene, SCN5A . Methods: We have cloned a 2.7 kb segment of 5′-flanking region of SCN5A and identified multiple transcription initiation sites by primer extension and RNase protection. Transient transfection assays in neonatal mouse myocytes and in Chinese Hamster Ovary (CHO) cells were employed to identify promoter activities. PCR-single stranded conformational polymorphism (SSCP) analysis was used to screen DNA variants in the promoter region. Results: The fragment includes >2 kb of upstream sequence, the 173-bp non-coding exon 1, and a portion of the 16-kb intron 1; the region is highly GC-rich and TATA-less. Transient transfection assays in neonatal mouse myocytes and in CHO cells identified (1) a core promoter in the −261/+140 segment, (2) regions conferring ∼3-fold decreases from core promoter activity in the 5′ upstream region (−261/−454 and −1020/−2109), and ∼3-fold increases in intron 1 (+255/+410 and+539/+613), and (3) a very strong negative regulatory region between +613 and +754 in intron 1. A core promoter polymorphism, present in 6/142 (4%) of normal alleles screened, increased reporter activity ∼50% in myocytes but not in CHO cells. Conclusion: The SCN5A promoter includes multiple positive and negative cis-acting elements extending into intron 1. A common polymorphism in this region modulates channel expression in vitro.

Objective: Co-expression of the KvLQT1 and minK potassium channel subunits is required to recapitulate I Ks, the slow component of the cardiac delayed rectifier current, and mutations in either gene cause the congenital Long QT syndrome. It is becoming increasingly well-recognized that multiprotein channel complexes containing proteins capable of modulating channel function assemble at the plasma membrane. Thus, the aim of our study was to identify proteins involved in I Ks modulation. Methods and results: Using a yeast-two-hybrid screen with the intracytoplasmic C-terminus of minK as bait, we identified the cardiac-enriched four-and-a-half LIM domain-containing protein (fhl2) as a potential minK partner. We show interaction between the two proteins in GST pulldown assays and demonstrate overlapping subcellular localization using immunocytochemistry of transfected cells supporting a potential interaction. At the functional level, expression of KvLQT1and minK in HEK cells, which lack endogenous fhl2 protein, generated I Ks only when fhl2 was co-expressed. By contrast, in CHO-K1 cells, which express fhl2 endogenously, I Ks was suppressed by anti-fhl2 antisense which did not affect the currents generated by KvLQT1alone. Conclusion: These data indicate that at least in heterologous cells, the generation of I Ks requires fhl2 as an additional protein component.

Drugs are widely recognized to vary in the beneficial and undesirable effects they produce in human subjects. The understanding that variants (polymorphisms and mutations) in the human genome are common and may well modulate both disease and its response to drugs, is a critical new concept in understanding mechanisms of drug action and their variability in human subjects. Variability can arise because of variability in genes encoding molecules of drug disposition, in genes encoding molecules that drugs target, or in genes that modulate the overall activity of the complex biological systems within which drugs act. The evolving understanding of the genetic basis of variability in response to drugs used in the treatment of sudden cardiac death has important implications not only for the treatment of patients who have survived an episode, but also for helping formulate a framework for further understanding mechanisms of drug action at the genetic level.

Clinical cardiologists who manage arrhythmias are increasingly faced with new complexities in management decisions. The once obscure science and jargon of medical genetics is assuming a much more prominent position in the mainstream medical literature, with seemingly weekly reports of new mutations to explain what once seemed very obscure diseases. This rapidly expanding knowledge base places the clinician — who usually trained when the concepts were not a major component of the medical school or fellowship training curricula — at a disadvantage in making day-to-day decisions with respect to managing common symptoms, such as unexplained syncope or heart failure. Even entertaining a diagnosis such as the congenital long QT syndrome or hypertrophic cardiomyopathy used to be a medical curiosity. Now, with increased public and physician awareness of these and even more esoteric conditions, the questions on patient management have become more common, and more complex. They include not only broad questions like ‘How can I establish (or better yet, rule out) a diagnosis?’ but also more specific issues such as ‘Should this patient undergo genetic testing? Where? How? And how can I interpret the results?’ The first and second parts of this article attempt to answer these questions. They neither teach molecular genetics nor do they provide an exhaustive review of the current state-of-the-art of molecular and genetic cardi

The uncommon congenital syndromes of QT prolongation associated with a high risk of sudden death (SD) were first described in the 1950s and 1960s,1–3 and the term torsade de pointes (TdP) was coined in the mid-1960s to describe the peculiar polymorphic ventricular tachycardia that can arise at slow heart rates when the QT is very long.4 The notion that drugs could produce a very similar clinical syndrome, with striking QT prolongation and polymorphic tachycardia, was first noted in the same era,5,6 and became increasingly well recognized with antiarrhythmic therapies during the 1970s and 1980s. The idea that ‘non-cardiovascular’ drugs could prolong the QT interval, and trigger TdP (or even SD), remained an arrhythmia curiosity until the initial report of terfenadine-associated TdP in the late 1980s.7 Review of the extant safety data, and a series of clinical and in vitro mechanistic studies, identified inhibition of CYP3A4-mediated terfenadine biotransformation to an antihistamine metabolite (fexofenadine) as the major mechanism.8–10 Terfenadine itself turned out to be a very potent QT prolonging agent, and that is now well recognized as a reflection of its ability to block the rapid component of the cardiac delayed rectifier I Kr. Indeed, block of I Kr, or in occasional instances reduction of the current by other mechanisms,11,12 is the major mechanism underlying virtually all forms of drug-induced TdP.13 The reason the terfenadine incident proved so important for drug development was not only the elucidation of underlying mechanisms, but also the recognition that even a small risk of a very serious side effect, such as drug-induced TdP, could upset the balance between risk and benefit that goes into the prescription of any drug. In the case of terfenadine, regulatory agencies viewed the benefit …

The effect of a polyvinyl chloride (PVC) i.v. administration system on the availability of quinidine gluconate was studied. Quinidine gluconate diluted in 5% dextrose injection was administered intravenously to five healthy volunteers via conventional PVC infusion sets, and the subjects received oral quinidine sulfate two days later. The mean +/- S.D. oral bioavailability of quinidine was, unexpectedly, greater than 100% (147 +/- 44%). To test the possibility that this occurred because of reduced delivery of i.v. quinidine, the percentage of drug delivered via two systems was evaluated in simulation studies, one involving a conventional PVC administration set and the other a glass syringe attached to shorter PVC tubing and a winged i.v. catheter. Spectrophotometric analysis revealed a 5-7% reduction in absorbance associated with loss of quinidine in the PVC infusion bag and a further 34-38% reduction in absorbance attributable to quinidine loss in the PVC tubing. However, with the winged i.v. catheter system the loss was reduced to less than 3%. More than 40% of a dose of quinidine gluconate was lost when the drug was administered with a conventional PVC i.v. administration set. Drug loss was reduced by using a winged i.v. catheter and shorter tubing.

Common clinical features in drug-induced torsade de pointes include hypokalemia and cycle-length prolongation just prior to initiation of the arrhythmia. In canine Purkinje fibres, drugs known to be associated with torsade de pointes, such as quinidine, sotalol or N-acetylprocainamide, consistently produce early after-depolarizations (EADs) and triggered activity at slow drive rates; for quinidine, these abnormalities are exaggerated by low extracellular potassium. Triggered activity can be abolished in vitro in two ways. First, action-potential shortening with abolition of EADs can be accomplished by increasing stimulation rates, beta-stimulation and action-potential shortening antiarrhythmics such as lidocaine. Second, triggered activity can be suppressed, with less prominent effects on EADs, by magnesium, alpha- and/or beta-adrenergic blockade and calcium-channel blockers. The parallels between these in vitro findings and clinical torsade de pointes suggest that EADs and triggered activity play a role in the genesis of the clinical arrhythmia. Further research directed at determining the mechanisms underlying the cellular abnormalities and their propagation to the whole heart should yield information that will increase the safety of antiarrhythmic therapy.

Background: Long QT (LQTS) and Brugada syndromes (BrS) are inherited arrhythmia syndromes characterised by risk of sudden cardiac death (SCD) and highly variable penetrance. Mutations in SCN5A, which encodes the Nav1.5 cardiac ion channel responsible for the inward cardiac sodium current, are responsible for 5-10% of LQTS and associated with 20% of BrS. The E1784K mutation in SCN5A is the most commonly identified SCN5A mutation in both LQTS and BrS, and causes the Long QT type 3 (LQT3)/BrS overlap disease with variable phenotypic expression. Carriers within the same pedigree may exhibit LQT3 phenotype, BrS phenotype or both. The aim of this international project was to determine if there are any associations between phenotype and ethnicity within a unique cohort of E1784K mutation carriers. Methods: 93 E1784K mutation carriers belonging to 33 families from 6 different countries including Japan were included. Data was collected on age, gender, symptoms, family history and the ECG. Non-digital and digital ECG data were analysed using proprietary software. Automatic readings and measurements from 2 observers were taken. A 3rd observer reviewed the ECGs where there was inter-observer discrepancy between the measurements. Statistical significance was determined using either the 2-tailed t-test or Chi-squared test as appropriate. Results: QTc intervals were significantly longer amongst Japanese E1784K mutation carriers, who were more symptomatic albeit with a lower incidence of SCD. Results are summarised in Table [1][1]. The spontaneous type 1 BrS ECG pattern also appeared to be more prevalent in the Japanese compared to Caucasian mutation carriers although the numbers were small. Mean QRS duration was longer amongst Caucasian mutation carriers. Drug-induced BrS phenotype was unmasked in 63% of Caucasians (34/54) who underwent a test. A family history of SCD was present in 50% of Caucasian families compared to only 13.6% of Japanese families (p=0.015). | | Total (n=93) | Caucasian (n=64) | Japanese (n=29) | p-value | | ------------------------- | ------------ | ---------------- | --------------- | ------- | | Age (years, mean, range) | 28, 1-67 | 30, 1-67 | 23, 6-62 | 0.0826 | | Sex-male (n,%) | 47, 51 | 32, 50 | 15, 52 | 0.8776 | | Spontaneous BrS (n,%) | 4, 4 | 1, 2 | 3, 10 | 0.0531 | | QTc (ms, mean, range) | 480, 404-579 | 472, 404-533 | 499, 430-579 | 0.0001 | | PR (ms, mean, range) | 167, 116-302 | 167, 116-302 | 166, 149-180 | 0.8952 | | QRS (ms, mean, range) | 96, 60-139 | 99, 68-139 | 90, 60-120 | 0.0145 | | Pre-syncope/syncope (n,%) | 17, 18 | 8, 13 | 9, 31 | 0.0741 | | Aborted SCD (n,%) | 6, 6 | 6, 9 | 0, 0 | 0.0882 | Table 1 Clinical characteristics Conclusions: There is variation in expression of E1784K between ethnicities with ethnic differences in severity and risk of sudden death. These results support a strong role for genetic modifiers of phenotype and risk which deserves further study. [1]: #T1

The electrocardiographic phenomenon of cardiac memory results from aberrant ventricular activation and causes transient ECG features that can mimic ischaemia. We present the case of a patient with ischaemic cardiomyopathy who exhibited evidence of T-wave memory in the setting of multiple episodes of non-sustained ventricular tachycardia that were triggered by an insect bite.