Merriam-Webster's online dictionary defines purgatory as "an intermediate state after death for expiatory purification" or more specifically as "a place or state of punishment wherein according to ...Roman Catholic doctrine the souls of those who die in God׳s grace may make satisfaction for past sins and so become fit for heaven." Alternatively, it is defined as "a place or state of temporary suffering or misery." Either way, purgatory is a place where you are stuck, and you don't want to be stuck there. It is in this context that the term genetic purgatory is introduced. Genetic purgatory is a place where the genetic test-ordering physician and patients and their families are stuck when a variant of uncertain/unknown significance (VUS) has been elucidated. It is in this dark place where suffering and misery are occurring because of unenlightened handling of a VUS, which includes using the VUS for predictive genetic testing and making radical treatment recommendations based on the presence or absence of a so-called maybe mutation. Before one can escape from this miserable place, one must first recognize that one is stuck there. Hence, the purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticists/genetic counselors who order such genetic tests believers in genetic purgatory. Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant.
As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as ...hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.
The mind-boggling progress in the understanding of the molecular mechanisms underlying the long QT syndrome (LQTS) has been the subject of many articles and reviews. Still, when it comes to the ...management of the patients affected by this life-threatening disorder, too many errors still take place, both in the diagnostic process and in the therapeutic choices. The price of these errors is paid by the patients and their families. This review is not directed to the relatively small number of LQTS experts who know what to do. It does not deal with genetics, with epidemiology, or with the well-known clinical manifestations. We have focused solely on the approach to diagnosis and therapy and we have directed this review to the average clinical cardiologist who, in his/her practice, sees occasionally patients affected or suspected to be affected by LQTS; the cardiologist who may know enough to manage them but not enough to be completely confident on his/her most critical choices. We have provided our personal views without making any attempt to blend differences whenever present. On most issues we agree fully but where we do not, we make it clear to the reader by indicating who is thinking what. The result may be unconventional, but it mirrors the challenges, often severe, that we all face in managing and protecting these patients from sudden death while also helping them live and thrive despite their diagnosis. We trust that this unabashed presentation of our clinical approach will be useful for both cardiologists and patients.
There are few areas in cardiology in which the impact of genetics and genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin ...related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, 3 are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these 3 diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing, including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important it is to understand the ways that genotype can affect clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these heritable arrhythmia syndromes and the proper use and interpretation of clinical genetic testing should remain the standard of care.
ACC/AHA Task Force Members Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, MACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair¶ Sana M. Al-Khatib, MD, ...MHS, FACC, FAHA Joshua A. Beckman, MD, MS, FAHA Kim K. Birtcher, MS, PharmD, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA¶ Ralph G. Brindis, MD, MPH, MACC¶ Joaquin E. Cigarroa, MD, FACC Anita Deswal, MD, MPH, FACC, FAHA Lesley H. Curtis, PhD, FAHA¶ Lee A. Fleisher, MD, FACC, FAHA Federico Gentile, MD, FACC Samuel Gidding, MD, FAHA¶ Zachary D. Goldberger, MD, MS, FACC, FAHA Mark A. Hlatky, MD, FACC, FAHA John Ikonomidis, MD, PhD, FAHA José A. Joglar, MD, FACC, FAHA Laura Mauri, MD, MSc, FAHA Barbara Riegel, PhD, RN, FAHA Susan J. Pressler, PhD, RN, FAHA¶ Duminda N. Wijeysundera, MD, PhD¶Former Task Force member; current member during the writing effort.Table of Contents Preamblee93 Introductione95 1.1.Methodology and Evidence Reviewe95 1.2.Organization of the Writing Committeee95 1.3.Document Review and Approvale95 1.4.Scope of the Guidelinee97 1.5.Abbreviationse99 2. Evidence Gaps and Future Research Needse182 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)e214 Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)e216 Preamble Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. Adherence to recommendations can be enhanced by shared decision-making between healthcare providers and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities.Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modifies guideline methodology on the basis of published standards from organizations including the Institute of Medicine (P-1,P-2) and on the basis of internal reevaluation. Publication of new, potentially practice-changing study results that are relevant to an existing or new medication, device, or management strategy will prompt evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned.
Hypertrophic cardiomyopathy (HCM) is an uncommon but important cause of sudden cardiac death.
This study sought to develop an artificial intelligence approach for the detection of HCM based on ...12-lead electrocardiography (ECG).
A convolutional neural network (CNN) was trained and validated using digital 12-lead ECG from 2,448 patients with a verified HCM diagnosis and 51,153 non-HCM age- and sex-matched control subjects. The ability of the CNN to detect HCM was then tested on a different dataset of 612 HCM and 12,788 control subjects.
In the combined datasets, mean age was 54.8 ± 15.9 years for the HCM group and 57.5 ± 15.5 years for the control group. After training and validation, the area under the curve (AUC) of the CNN in the validation dataset was 0.95 (95% confidence interval CI: 0.94 to 0.97) at the optimal probability threshold of 11% for having HCM. When applying this probability threshold to the testing dataset, the CNN’s AUC was 0.96 (95% CI: 0.95 to 0.96) with sensitivity 87% and specificity 90%. In subgroup analyses, the AUC was 0.95 (95% CI: 0.94 to 0.97) among patients with left ventricular hypertrophy by ECG criteria and 0.95 (95% CI: 0.90 to 1.00) among patients with a normal ECG. The model performed particularly well in younger patients (sensitivity 95%, specificity 92%). In patients with HCM with and without sarcomeric mutations, the model-derived median probabilities for having HCM were 97% and 96%, respectively.
ECG-based detection of HCM by an artificial intelligence algorithm can be achieved with high diagnostic performance, particularly in younger patients. This model requires further refinement and external validation, but it may hold promise for HCM screening.
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Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in ...patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
Of 17 genes reported as being causative for LQTS, 9 (
) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (
) were curated as definitive genes for typical LQTS. Another 4 genes (
) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (
) had moderate level evidence for causing LQTS.
More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
Abstract Objective To perform long QT syndrome and catecholaminergic polymorphic ventricular tachycardia cardiac channel postmortem genetic testing (molecular autopsy) for a large cohort of cases of ...autopsy-negative sudden unexplained death (SUD). Methods From September 1, 1998, through October 31, 2010, 173 cases of SUD (106 males; mean ± SD age, 18.4±12.9 years; age range, 1-69 years; 89% white) were referred by medical examiners or coroners for a cardiac channel molecular autopsy. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, a comprehensive mutational analysis of the long QT syndrome susceptibility genes ( KCNQ1 , KCNH2 , SCN5A, KCNE1, and KCNE2 ) and a targeted analysis of the catecholaminergic polymorphic ventricular tachycardia type 1–associated gene ( RYR2 ) were conducted. Results Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%). Females had a higher yield (26/67 38.8%) than males (19/106 17.9%; P <.005). Among SUD cases with exercise-induced death, the yield trended higher among the 1- to 10-year-olds (8/12 66.7%) compared with the 11- to 20-year-olds (4/27 14.8%; P =.002). In contrast, for those who died during a period of sleep, the 11- to 20-year-olds had a higher yield (9/25 36.0%) than the 1- to 10-year-olds (1/24 4.2%; P =.01). Conclusion Cardiac channel molecular autopsy should be considered in the evaluation of autopsy-negative SUD. Several interesting genotype-phenotype observations may provide insight into the expected yields of postmortem genetic testing for SUD and assist in selecting cases with the greatest potential for mutation discovery and directing genetic testing efforts.
Over the last 2 decades, the pathogenic basis for the most common heritable cardiovascular disease, hypertrophic cardiomyopathy (HCM), has been investigated extensively. Affecting approximately 1 in ...500 individuals, HCM is the most common cause of sudden death in young athletes. In recent years, genomic medicine has been moving from the bench to the bedside throughout all medical disciplines including cardiology. Now, genomic medicine has entered clinical practice as it pertains to the evaluation and management of patients with HCM. The continuous research and discoveries of new HCM susceptibility genes, the growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM make it essential that the modern-day cardiologist understand the diagnostic, prognostic, and therapeutic implications of HCM genetic testing.
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