New Research in Long QT Syndrome: Interview With Dr. Michael Ackerman

In this interview EP Lab Digest speaks with Michael J. Ackerman, MD, PhD about his recent research on treadmill stress testing to unmask patients with concealed long QT syndrome (LQTS).¹ Dr. Ackerman is the director of Mayo Clinic’s Long QT Syndrome Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory in Rochester, Minnesota.

Tell us about the different diagnostic methods used for evaluating LQTS.

Long QT syndrome is the most common of the so-called channelopathies; it affects about 1 in 2,000 individuals. It is characterized by QT prolongation on the 12-lead electrocardiogram, and its trademark dysrhythmia is Torsades de pointes. In terms of the different diagnostic methods, the most important element is the history. There is a sort of detective-like tenacity in understanding the circumstances of a possible cardiac event, trying to figure out whether you think it is cardiac in origin or mediated elsewhere. If the event is suspicious, one can proceed with the various electrocardiographic tests such as a 12-lead electrocardiogram, 24-hour Holter monitor, treadmill stress testing, other means of provocative stress testing including an epinephrine QT stress test, and then finally, genetic testing for long QT syndrome.

What are some of the challenges in diagnosing LQTS? How often is LQTS misdiagnosed or overdiagnosed?

I think the challenge comes with the fact that LQTS is not common. The most common symptom is a fainting spell, and fainting spells, or what I call “vanilla faints,” are extraordinarily common — about 20 to 25 percent of all of us on the planet will faint by the age of 25. So deciphering the sudden death warning faint from the ordinary faint is not always easy, especially in a rushed clinical setting where clinicians may not take the time (or have the time) to meticulously dissect the features of the faint. I think that is what sets the misdiagnosis and the overdiagnosis into motion, starting with the assessment of the spell. We’re in a phase in which this condition is still misdiagnosed as epilepsy or as an ordinary faint because the faint wasn’t investigated properly. It’s also being overdiagnosed because of the increase in ECG screening programs or because of a premature rush to judgment for someone who has an ordinary-sounding fainting spell but their QTc is so-called borderline, and all of a sudden it’s viewed as long QT syndrome, when all they might have been was a vasovagal fainter with a 90th percentile QTc value. I think we’re making progress with awareness; only 4 years ago, we published a paper in Circulation showing that 40 percent of the unrelated patients who came with a diagnosis of long QT syndrome to Mayo Clinic’s Long QT Syndrome Clinic left with that diagnosis. The vast majority had the diagnosis reversed all the way back to otherwise normal or healthy. Therefore, I think the challenges come from: 1) correct and tenacious assessment of the story; 2) elucidating the family history; and 3) studying the electrocardiogram and assessing the QT interval and the T wave profile with your own eyes rather than relying on the computer, and then based upon your experience and your reference point, deciding whether you have amounted a sufficient index of suspicion that compels you toward or away from that diagnosis. If you’re at a place that sees maybe 1 or 5 long QT cases a year, you will probably have a different vantage point than if you’re located somewhere that is very familiar with the various ways that long QT shows itself.

Discuss your study’s purpose and elements of its design.

The field has known for quite some time that about 30 to 40 percent of all long QT syndrome patients — this includes mostly the relatives, not the index cases — but a good percentage of long QT patients live with what we call “concealed long QT syndrome” or others call “normal QT interval long QT syndrome,” in which the patient has long QT, but their 12-lead electrocardiogram does not show it. Several years ago, our program at the Mayo Clinic and Dr. Shimizu’s program in Japan developed the epinephrine QT stress test as a way to see if we could ‘catch’ long QT syndrome or unmask its presence when the QT interval was normal at rest. We’ve shown how the epinephrine stress test can do that, but the epinephrine QT stress test is a test that cannot be done everywhere, and it probably should not be done everywhere because, again, if you are doing one stress test a year versus having done many of them, you may not know exactly how to delineate a true positive from a false positive, and so forth.

Many programs have been looking at the treadmill stress test to see if that can unmask long QT syndrome, and this has been around for decades — everybody has a treadmill exercise facility, or at least most programs do — and treadmill stress testing has been a standard part of the evaluation of long QT syndrome for a long time. However, the new revelations have come with knowing the different genetic subtypes of long QT syndrome, and then realizing that one of the reasons why the treadmill stress test has shown all kinds of different patterns is because the different genetic subtypes give different treadmill test responses. This provided an opportunity to delineate what are the characteristic treadmill stress test responses of the three most common genetic flavors of long QT syndrome. Basically, we are searching to identify what part of the treadmill stress test has the most diagnostically useful information to catch long QT syndrome. This work is very similar to some great research by Dr. Andrew Krahn in Canada. Our study provided the largest study of patients with genetically proven long QT syndrome in which we could delineate the characteristic reaction of type 1, type 2, and type 3 long QT syndrome during the exercise stress test, and as it turns out, more importantly, during the recovery phase from the treadmill stress test — meaning, what happens after they reach their peak heart rate and have cooled down. This is where we and others have shown that this is where the greatest information resides with how the stress test can catch long QT syndrome.

Describe the gene-specific QTc changes seen during peak exercise and recovery in LQT1 patients and the subcohort of concealed LQT1 patients.

This is exactly where we and others have seen now that the test’s greatest power is to unmask type 1 long QT syndrome. To unmask it, it will give you a suspicion that you’re dealing with it in a patient who already has manifest QT prolongation, and it will unmask or catch type 1 long QT syndrome in a person who has a normal QT interval at rest. For most of us, when we exercise, our heart rate speeds up, and as our catecholamines are released, our repolarization system should become more and more efficient. However, if you have type 1 long QT syndrome, which is due to a defect in one of the key potassium channels of the heart that responds to adrenaline, what those individuals show is a maladaptive response in their recharging system during exercise, and more importantly, during the recovery phase. So instead of the corrected QT interval shortening, it actually paradoxically lengthens during the exercise stress test, and this is especially in the recovery phase, such that, during the recovery phase, the first 5 minutes after the heart rate has reached its peak, for normal individuals and LQT2 and 3 individuals, their QTc is still shorter than it was at baseline. But if you have type 1 long QT syndrome, you display a paradoxically prolonged QTc in that recovery phase, and that was true whether you had shown QT prolongation at rest or had a normal QT interval at rest. In fact, we showed that the 3-minute recovery point overall had the single greatest diagnostic utility, where if that QTc was over 470 milliseconds, that suggested the presence of type 1 long QT syndrome with a positive predictive value of around 75 percent. So that is really the key response during the treadmill stress test — that sort of ‘aha’ moment — I think we’ve caught long QT 1 if there was a normal QT interval at rest, or for the patient with diagnostic QT prolongation at rest, that kind of recovery phase reaction could make the physician strongly suspect that they’re dealing with the most common genetic subtype of flavor number 1 while they’re securing genetic testing and confirming that suspicion. Thus, it can provide a pre-genetic test suspicion as to what genetic subtype they are dealing with, and then be able to begin a LQT1-directed treatment program.

What makes this study significant? How will these results benefit long QT patients?

I think these results provide clarity, showing the aspect of the treadmill stress test where the most valuable information resides. Hopefully, it will help decrease the misuse of the treadmill stress test and the way that this test has been invoked to overdiagnose the condition. I think it also provides another tool for the patient and family, and will help physicians advance the case for the presence of the disease. I think it should help make us better at diagnosing the condition if it’s there, and better at refraining from the diagnosis by overreaching with an observation if we just don’t have the evidence.

Describe your work as director of Mayo Clinic’s Long QT Syndrome Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory. Tell us about the population of patients you treat there, including the number of cases and the types of treatments available.

I’ve had the real privilege over the last 10 years of directing those clinics. The two entities provide a hand-glove relationship, if you will, to try to get smarter about the genetic underpinnings of long QT syndrome for our LQTS patients. We’re trying to understand the various genotype and phenotype relationships for long QT syndrome, and we also take care of these patients in Mayo’s Long QT Syndrome Clinic. In the clinic, we try to correctly diagnose the entity when it is there, and to remove the diagnosis when it is deemed to have been placed prematurely or erroneously. For those who have the disease, we do the best we can to risk stratify so that we don’t overtreat or undertreat their entity. We try to individualize and tailor their therapy according to evidence-based insights from the published literature as well as drawing from our clinic’s rich experience. I have treated approximately 800 patients with genetically proven long QT syndrome, and we’ve evaluated over 1,400 patients in Mayo’s Long QT Syndrome Clinic. Despite the fact that this is a potentially lethal condition, we view it as being a highly treatable one, and have developed all of the treatment options in our program — whether it is medication therapy, device therapy with an implantable defibrillator, or denervation surgery with videoscopic left cardiac sympathetic denervation. With this combined bench-to-bedside approach, we have come to fully expect our patients to not only live but to thrive despite their diagnosis. 

On the research side, while we view each patient as an individual where the needs of the patient come first, we also try to view them as a possible research subject who has the potential to help us get smarter about their disease. That is when we would bring their blood sample and genetic material into the Windland Smith Rice Sudden Death Genomics Laboratory, and try to identify new LQTS-causing genes for the 20–25 percent of patients who will escape genetic detection with the tests that we currently have. About 25 percent of all long QT patients are currently genetically elusive, meaning that they will have a negative clinically available genetic test. So for that subset, we’re still trying to find their cause. For those who have a findable cause, we’re trying to figure out the other genetic variants that modify their risk and make them a more severe QT case or, conversely, why that person seems so well protected despite their QT substrate.

I see that identification of the subset of patients with a negative genetic test has enabled the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory to discover 4 of the last 5 LQTS-susceptibility genes. What can you tell us about this?

The key is that if there is a negative genetic test for a family, that doesn’t mean that the game is over — there’s still work to be done, and fortunately (or unfortunately), that work now needs to be done in a research environment because all of the known genes have been interrogated. So for those families with a negative genetic test who have partnered with us and our Sudden Death Genomic Laboratory, that has helped us to build what we would call our discovery cohort of patients who have the disease, but whose clinical genetic test is negative. From among such patients, we have been able to identify 4 new long QT syndrome-susceptibility genes. All 4 of them are extremely uncommon, but nevertheless, these 4 genes have revealed new insights about biology, about structure-function relationships in the protein complexes that govern the heart’s electrical system, and have provided important clues as to where to look for additional causes of long QT syndrome. So these discoveries go both ways — they go back to the bedside and help us give an answer to the patient, and they also further the scientific exploration as to understanding why a mutation in that gene that encodes that protein causes an abnormality in cardiac recharging, which then sets the individual up for the possibility of sudden cardiac death. Thus, it teaches us more about structure-and-function of the proteins and the proteins that interact with each other, and illustrates how clinical practice and research is a hand in glove relationship.

Reference

1. Horner JM, Horner MM, Ackerman MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm 2011;8:1698-1704.