Genetic Pickup Rate Not Trivial in Cardiac-Arrest Survivors

Patrice Wendling

June 21, 2017

VANCOUVER, BC — Genetic testing identified a pathogenic variant in one out of six survivors of seemingly unexplained sudden cardiac arrest (SCA)—all of whom had normal left ventricular function and normal coronary arteries at entry in the CASPER registry[1].

Among the 174 SCA survivors tested, a clinical phenotype was identified in only 41%.

"The key thing is to start with the recognition that in these patients, the cause of cardiac arrest was not obvious and historically we would put in an ICD and just observe," senior study author Dr Andrew Krahn (University of British Columbia, Vancouver, Canada) told|Medscape Cardiology.

"When you do genetic testing, particularly broad genetic testing, you have the opportunity to find things that explain or are major contributors to their cardiac arrest in one out of six, or 17%," he continued. "That has important implications because of course those inherited things are potentially carried by other family members, who can then be screened and protected from the implications of that genetic predisposition."

Focused genetic testing performed in 21 relatives from nine families identified variants in 57%, while in an earlier analysis the yield for clinical testing in family members was about 20%, Krahn said.

The study, which was published online June 9, 2017 in Circulation Cardiovascular Genetics, contains interesting data nuggets but is also an object lesson in the complexity of cardiac genetic testing.

In an accompanying editorial[2], Dr Christopher Semsarian (University of Sydney, Australia) and Dr Arthur AM Wilde (University of Amsterdam, the Netherlands) highlight several key aspects of genetic testing that clinicians wrestle with and conclude, as do the investigators, that genetic testing should be limited to specialist cardiac genetic clinics.

Semsarian and Wilde write that the study also "brings into sharp focus a fundamental question—that is, should a cardiac-arrest survivor be considered a living sudden cardiac death? In other words, is a young person who dies from a cardiac arrest different from the one who survives in terms of etiology?"

They note that despite prompt resuscitation, some young patients still die from SCA while others survive, and point to new research suggesting the genetic pickup rate in relatives of young sudden cardiac death victims is almost twice as high as in young cardiac-arrest survivors, despite inherited cardiac diseases being the predominant cause in both groups.

An Ongoing, National Registry

Genetic testing in the 13-year-old Canadian-based CASPER registry was restricted to limited research testing prior to 2007 and thereafter performed through local hospitals or commercial laboratories using direct Sanger sequencing or next-generation sequencing. Testing ranged from single phenotype or single gene tests to broad multiphenotype panels including <150 genes associated with arrhythmias or cardiomyopathies.

SCA survivors also underwent clinical testing, including high-lead ECG, signal-averaged ECG, exercise stress testing, ambulatory monitoring, cardiac MRI, and procainamide and epinephrine provocation testing.

Genetic testing identified 29 unique pathogenic variants in 15 genes (60% channelopathy-associated and 40% cardiomyopathy-associated genes) in 29 patients and 70 unique variants of unknown significance (VUS) in 30 genes in 32 patients.

Most of the pathogenic variants were found in genes known to be implicated in long-QT syndrome (LQTS), Brugada syndrome, and arrhythmogenic RV cardiomyopathy. But in three unrelated survivors, there was a single variant in the calcium-channel gene CACNA1C (c.2570C>T, p.Pro857Leu), which only recently was associated with autosomal dominant LQTS with a history of sudden death in the family.

Cardiomyopathy genes were implicated in 11 SCA survivors (mean age 31 years), almost half of whom (45%) had no apparent clinical phenotype.

Krahn noted that this is in line with a recent molecular sudden cardiac death autopsy study[3] that identified 36 pathogenic and probable pathogenic variants in cardiomyopathy genes among children and young adults, 40% of whom had structurally normal hearts at post mortem.

"The notion that pathogenic variants in cardiomyopathy genes may result in sudden death without manifest structural change both prompts a reassessment of the accepted mechanisms of arrhythmia in such cases and supports a humble approach to investigation of sudden death, where the limitations of phenotyping are recognized and genetic testing is undertaken with an open mind," the investigators write.

Semsarian and Wilde speculate that the arrhythmic phenotype in these survivors may precede the development of structural changes, or the variant may contribute to disease not as a pathogenic cause but as a disease modifier in tandem with other genetic or environmental influences.

"At the other end of the spectrum," it's also possible the pathogenic variant in the cardiomyopathy gene may represent an unrelated incidental finding of little clinical significance.

"Disentangling how a mutation in a cardiomyopathy gene leads to cardiac arrest in the absence of a structural phenotype in the cardiac-arrest survivor remains a major next step of the current study," the editorialists write.

Indeed, some of the variants implicated as pathogenic in the study may in fact reside in a place called 'Genetic Purgatory' and may still require further evidence before declaring them as the disease-causative mutation, said Dr Michael Ackerman (Mayo Clinic's Genetic Heart Rhythm Clinic, Rochester, MN), whose lab discovered the aforementioned CACNA1C variant.

"Curiously, among the 72 patients who were said to be phenotype positive, 25 were diagnosed as LQTS and eight were diagnosed as [catecholaminergic polymorphic ventricular tachycardia] CPVT," Ackerman told in an email. "Yet the yield of genetic testing among those two phenotype-positive subgroups was only 20% and 25%, respectively.

"If these diagnoses were 'rock solid,' the yield should have been 75% to 80% and 60% to 65%, respectively, suggesting that these phenotype-positive cases may not be so positive after all."

Independent Predictors

In multivariate analysis, prior syncope (odds ratio [OR] 4.0; 95% CI 1.6–9.7) and a family history of sudden death (OR 3.2; 95% CI 1.1–9.4) were independent predictors of a pathogenic variant.

Identification of a clinical phenotype, which is thought to improve the pickup rate for pathogenic variants because it allows for directed genetic testing, was associated with a higher yield for pathogenic variants in univariate analysis (P=0.01) but was of only borderline significance after full adjustment (OR 2.3; 95% CI 0.9–5.5).

Among phenotype-negative patients, use of broad multiphenotype panels increased the yield for pathogenic variants from 8% with other tests to 21% (P=0.04) but also increased the number of VUS findings from 5% to 55% (P<0.01).

Krahn said limitations of the study are the lack of systematic testing across all cardiac-arrest patients and sites and that only half of the 375 SCA survivors in CASPER got tested. Biobanking is currently under way and more comprehensive testing including whole-exome sequencing is planned.

The study was supported by the Heart and Stroke Foundation of Canada and an unrestricted research grant from Boston Scientific. Krahn receives support from the Heart and Stroke Foundation of Canada, the Sauder Family and Heart and Stroke Foundation Chair in Cardiology, and the Paul Burnes Chair in Heart Rhythm Disorders. The authors reports they have no relevant financial relationships. Semsarian is the recipient of a National Health and Medical Research Council Practitioner Fellowship. Wilde receives support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences.

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