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Circulation on the Run

Feb 10, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week relates to an international multi-center evidence-based reappraisal of genes reported to cause congenital long QT syndrome. But, before we get to that, how about if we grab a cup of coffee and start on our other papers? Do you have one you'd like to discuss?

Dr Carolyn Lam: Yes. My favorite part of the week. So this first paper really asks the question, "What's the association between HDL functional characteristics, as opposed to HDL cholesterol levels, and acute coronary syndrome?" The paper comes from Dr Hernáez from IDIBAPS in Barcelona, Spain and colleagues who conducted a case control study nested within the PREDIMED cohort.

Originally a randomized trial where participants followed a Mediterranean or low-fat diet. Cases of incident acute coronary syndrome were individually matched one is to two to controls by sex, age, intervention group, body mass index, and follow-up time. The authors measure it the following functional characteristics, which were HDL cholesterol concentration, cholesterol efflux capacity, antioxidant ability, phospholipase A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and A4, serum amyloid A and complement 3 protein.

Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they find?

Dr Carolyn Lam: They found that low values of cholesterol efflux capacity, and levels of sphingosine-1-phosphate and apolipoprotein A1 in HDL or all associated with a higher risk of acute coronary syndrome in high cardiovascular risk individuals, irrespective of HDL cholesterol levels and other cardiovascular risk factors. Low cholesterol efflux capacity values and sphingo-1-phosphate levels were particularly associated with an increased risk of myocardial infarction, whereas HDL antioxidant or anti-inflammatory capacity was inversely related to unstable angina.

Now this is significant because it's the first longitudinal study to comprehensively examine the association of several HDL function related biomarkers with incident acute coronary syndrome beyond HDL cholesterol levels in a high-risk cardiovascular risk population.

Greg Hundley: Very nice. Carolyn. It sounds like function over just the levels is important.

Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've got another paper and I want to pick your brain first. Is it your impression that type 2 myocardial infarction, the type that occurs due to acute imbalance in myocardial oxygen supply versus demand in the absence of atherothrombosis, do you think that this type of MI is on the rise? It seems more and more common in my country.

Dr Greg Hundley: Do we want to say it's on the rise? Certainly by measuring all these high sensitivity troponins, et cetera, we're finding, I think, more evidence of type 2 MI. So, all in all, yeah it probably is on the rise, but likely related to some of our measurement techniques.

Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper that I'm about to tell you about really addresses some of these issues and it's from corresponding author Dr Gulati from Mayo Clinic in Rochester, Minnesota. And they really start by acknowledging that despite being frequently encountered in clinical practice, the population base incidents and trends of type 2 myocardial infarction is unknown and long-term outcomes are incompletely characterized. So they prospectively recruited 5,640 residents of Olmsted County, Minnesota who experienced an event associated with cardiac troponin T greater than 99th percentile of a normal reference population, which is greater than or equal to 0.01 nanograms per milliliter. And this was between 2003 and 2012, so very careful to talk about which Troponin T assay exactly to the point you discussed earlier, Greg. The events were retrospectively classified into type 1 versus type 2 MI using the universal definition.

Dr Greg Hundley: So Carolyn, what did they find?

Dr Carolyn Lam: They found that there was an evolution in the types of MI occurring in the community over a decade with the incidence of type 2 MI now being similar to type 1 MI. Adjusted long-term mortality following type 2 MI is markedly higher than after type 1 MI and that's driven by early and non-cardiovascular deaths. Mortality of type 2 MI is associated with a provoking factor and is more favorable when the principle provoking mechanism was an arrhythmia compared with postoperative status, hypotension, anemia or hypoxia. And these findings really underscore the healthcare burden of type 2 MI and provide benchmarks for clinical trial design.

Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from type 5 long QT syndromes and an analysis. And it's from Dr Jason Roberts from Western University. Through an international, multi-center collaboration, improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in long QT 5 was sought across 22 genetic arrhythmia clinics and four registries from nine countries that included 229 subjects with autosomal dominant long QT five. So there were 229 of those subjects. And then 19 individuals with the recessive type 2 Jervell and Lang-Nielsen syndrome. The authors compared the effects of clinical and genetic predictors on a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter defibrillators shocks, aborted cardiac arrest, and sudden cardiac death.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Well, several things, Carolyn. First, rare loss of function KCNE1 variants are weakly penetrant and do not manifest with a long QT syndrome phenotype in a majority of individuals. That's a little bit of a surprise. Second, QT prolongation and arrhythmic risk associated with type 2 Jervell and Lang-Nielsen syndrome is mild in comparison with the more malignant phenotype observed for type 1 Jervell and Lang-Nielsen syndrome. And then number three, all individuals possessing a rare loss of function KCNE1 variant should be counseled to avoid QT prolonging medications and should undergo a meticulous clinical evaluation to screen for long QTS phenotype.

And then finally, Carolyn, the last finding, in the absence of a long QTS phenotype, more intensive measures, such as beta blockade and exercise restriction, may not be merited.

Dr Carolyn Lam: Oh, very interesting. Well, I've got one more original paper and in this, authors describe a new cellular mechanism linking ischemia-reperfusion injury to the development of donor specific antibody, a pathologic feature of chronic antibody-mediated rejection, which mediates late graph loss. This paper is from corresponding author Dr Jane Witt from Yale University School of Medicine and colleagues who use humanized models and patient specimens to show that ischemia-reperfusion injury promoted elaboration of interleukin 18 from endothelial cells to selectively expand alloreactive interleukin 18 receptor 1 positive T peripheral helper cells in allograph tissues and this promoted donor specific antibody formation.

Dr Greg Hundley: Carolyn, here's the famous question. What does that mean clinically for us?

Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against endothelial cell derived factors like interleukin 18 may therefore block late complications of ischemia-reperfusion injury.

Dr Greg Hundley: Very nice. Sounds like more research to come. Well, how about other articles in the issue?

Dr Carolyn Lam: Well, I'd love to talk about a white paper from Dr Al-Khatib, and it's about the research needs and priorities for catheter ablation of atrial fibrillation and this is a report from the National Heart, Lung, and Blood Institute Virtual Workshop.

Dr Greg Hundley: Well, I've got another arrhythmia paper, so this is from Professor Michael Ackerman at the Mayo Clinic and its minor long QT gene disease associations by coupling the genome aggregation database. It's a harmonized database of 140,000 or more exomes and genome derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large long QT syndrome registry to reassess the strength of these minor long QT syndrome gene disease associations. Next, Carolyn, in an on my mind piece, Professor Gerd Heusch from University of Essen Medical School discusses, how can the many positive preclinical and clinical proof of concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes.

The author discusses the important differences between animal models that have been used a lot in this ischemia reperfusion and infarct size reduction science, and then the clinical scenarios of STEMI in humans as well as the many aspects of coronary reperfusion. How is that affecting the myocytes? How is that affecting the microcirculation, et cetera, that must be addressed? And then finally Carolyn, there is a series of letters, one from Professor Oliver Weingärtner from Universitätsklinikum Jena and another from Professor Yasuyoshi Ouchi from Toranomon Hospital. They're exchanging letters debating the utility of lipid lowering with Ezetimibe in individuals over the age of 75 years.

Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now move to our future discussion.

Dr Greg Hundley: You bet.

Well, welcome everyone. This is our feature discussion and today we're going to hear more about long QT syndrome. We have Dr Michael Gollob from University of Toronto and our own associate editor, Dr Sami Viskin from Tel Aviv Medical Center. Good morning. Good afternoon, gentlemen. Before we get started with a discussion of some of the study findings and results, Michael, could you tell us a little bit about why you performed the study and what were some of the hypotheses you wanted to test?

Dr Michael Gollob: As you know, long QT syndrome is probably the most recognized channelopathy associated with sudden cardiac death in young individuals and adults. And at the present time, there are 17 genes available for clinical genetic testing in cases of suspected long QT syndrome. We simply ask the question, "Is there sufficient scientific evidence to support that each of these genes are single gene causes of long QT syndrome based on our contemporary knowledge of genetics and the human genome?

Dr Greg Hundley: Great, Michael. So, can you tell us a little bit about your study population? How did you go about this and what was your study design?

Dr Michael Gollob: We designed a methods approach that would assure that any conclusions that were made from our working group were not based on the opinions of one or two individuals. We wanted to ensure that this was a consensus conclusion with multiple experts in the field including genomic scientists, genetic counselors, inherited arrhythmia experts, and researchers in the field. We created three independent teams of genetic experts to curate the genetic evidence reported in the medical literature for each of these 17 reported causes of long QT syndrome. This was essentially an evidence-based approach using a pre-specified evidence-based matrix or scoring system depending on the level of evidence, genetic primarily, in the reported literature for each gene.

Each of these curation teams worked independently of each other and they were blinded to each other's work and they were tasked with concluding whether a gene, based on the medical literature and the resource methodologies, had sufficient evidence for disease causation. Their classifications would be one of disputed evidence, limited evidence, moderate evidence, strong or definitive evidence for claims towards disease causation. Remarkably, independently, all of these teams reached the same conclusion. In the end, their summary data was reviewed by a clinical domain expert panel with individuals with expertise, particularly in long QT syndrome and other channelopathies. So in total 19 individuals reviewed all of the literature and the data presented and came to unanimous conclusions for each gene.

Dr Greg Hundley: Out of the 17, were there some that were more important than others or was it uniformly all 17 were relevant?

Dr Michael Gollob: Well, I think the most relevant conclusions of our study are that nine of these genes, more than half of these genes, were felt not to have sufficient evidence to support their causation as a single gene cause for typical long QT syndrome. So nine genes that are currently tested by clinical genetic testing providers do not have enough evidence to support their testing in patients with suspected long QT. And to us, that is the most relevant observation because testing genes that do not have sufficient evidence for disease causation poses a significant risk to patient harm and family harm. We concluded that only three genes had very definitive evidence for causation of long QT syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There were another four genes that were concluded to have strong or definitive evidence for unusual presentations of long QT syndrome. And by that, I mean presentations that typically occur in the neonatal period and are associated with heart block seizures or developmental delay or in the case of one of these genes, Triadin, an autosomal recessive form of the disease.

Dr Greg Hundley: So helping us perhaps what types of genes to screen for when we have someone with this condition or suspected. So Sami, can you help us put this into perspective? How does this study help us in management of this clinical situation.

Dr Sami Viskin: In Circulation, we immediately recognize the importance of the manuscript, the importance of the study because unfortunately, there are too many physicians all over who will accept the results of genetic testing essentially like gospel. Now it's in the DNA, it's in the genes, so whatever you find must be true. And too often, clinical decisions on treatment including ICD implantation have been undertaken based on results of genetic testing’s; thus are wrongly interpreted. So we recognize immediately the importance of this paper. We already had a different study by Dr Gollob and his associates. Again, reassessing the role of genes in Brugada syndrome. So we were familiar with this type of analysis.

We recognize the importance and we moved ahead to accept this paper, it went fairly easily, I think only one revision. At the same time, we were getting additional paper by other groups. So in the same issue, we have two more papers, one from Jason Roberts with the International Long QT Registry of long QT 5, reaching similar conclusions that this is a gene with very limited penetrants and another study by the Mayo clinic also showing that many of the genes who are not the major genes are overrepresented in the healthy population. So we put all these three papers together with a very nice editorial by Chris Semsarian in the same issue. So everything is put in the right perspective of how we should be looking at all the genes of these disease in a different way.

Dr Greg Hundley: So as a clinician quickly, how can I use this information in the issue, perhaps this paper and all three, in management of patients with either suspected or long QT syndrome?

Dr Michael Gollob: First off, I would emphasize that the diagnosis of long QT syndrome or any genetic base disease for that matter, should be based on clinical phenotype and not the observation of a genetic change, particularly if genes are being tested that do not have strong evidence for disease causation, as is the case for the nine genes that we've pointed out in this manuscript.

So I think clinicians need to be wary of the genetic testing panels that they are requesting be screened or used in the assessment of their patients and be knowledgeable that at this point in time, we really only have three genes with very strong evidence to support disease causation of the typical form of long QT syndrome. And that for the most part, these other genes should not be tested or should only remain in the realm of research.

I think that responsibility extends further than just the clinician taking care of the patient, but also clinical genetic testing providers, companies that offer these genetic testing services. I think they should assume a responsibility to ensure that they are only offering services for genes that have strong evidence for disease causation because when they report results in genes that are not valid for the disease, that only confuses the care of the patient and that creates a risk of harm to them if that information is misinterpreted by a physician.

As Dr Viskin or Sami pointed out, we do see patients who are inappropriately diagnosed. We remove the diagnosis of roughly 10 to 20% of cases in our own clinic. And unfortunately, many of these patients and their families have suffered undue anxiety. Some of them have ICDs in place that should not have been there. So I think overall, the field needs to be aware of what genes are relevant and what genes still are within the realm of research.

Dr Greg Hundley: Can you tell us just quickly Michael and then also Sami, what do you see as the next study in this field?

Dr Michael Gollob: We're taking a step back now. The first decade of this century saw an exponential growth in reported gene disease associations. And now in the last five or six years, we've learned a lot about human genetic variation, which has provided us an opportunity to reflect back on some of these previous and reported genes as causes for long QT and other diseases.

So I think many individuals in our field may say, "Well, you know, this is disappointing. We believed in these genes. We really thought these genes were causes of long QT." And to that point I would say, we need more research. If you believe in some of these genes that have now been considered to have limited or disputed evidence, research should continue if these remain plausible candidates for the disease.

So I think future research has to continue. There are probably still a few other genes that have not yet been discovered. I think we've got the vast majority. I think in most cases, at least in our experience, 90 to 95% of cases are explained by the top three genes. But there are probably other genes out there and it's always fascinating to learn or discover new genes, but those sorts of studies have to be done with the correct methodologies and rigid protocols. Lastly, I think in the future us clinicians and geneticists and genetic counselors need to work closely with genetic testing providers to ensure that they are offering responsible genetic testing services.

Dr Greg Hundley: Sami, do you have anything to add?

Dr Sami Viskin: Just congratulate the authors. I think they did a very great service to the medical community by pointing out the limitations of the genetic testing and the way we interpret the results, and they deserve to be applauded for reminding us that we have to be careful when we read papers about genetic results or when we get genetic testing results ourselves.

Dr Greg Hundley: I want to thank Michael from University of Toronto and Sami from Tel Aviv Medical Center for participating. And on behalf of both Carolyn and myself, wish you all a great week and look forward to chatting with you next week.

This program is copyright, the American Heart Association 2020.