Modern Diagnosis and Evaluation of Long QT Syndrome
Modern Diagnosis and Evaluation of Long QT Syndrome
Long QT syndrome (LQTS) is the prototypic cardiac channelopathy underscored by profound genetic and phenotypic heterogeneity. In 1991, the first LQTS chromosome locus was identified and subsequently more than 400 mutations in nine cardiac channel/channel associated-encoding genes have been identified (LQT 1-9).
Michael J. Ackerman, MD, PhD, FACC, said: "We used to think that long QT syndrome was extraordinarily rare – 1 in 20,000. Then the estimate became 1 in 10,000, 1 in 5,000, and the latest data coming out of Italy and presented last fall suggests it may be as high as 1 in 2,000 or 1 in 3,000 persons." It is one of the most common causes of autopsy negative, sudden unexplained death. Contributing to its lack of identification is the fact that individuals may or may not show QT prolongation; indeed as many as half have no QT prolongation.
Since May 2004, genetic testing has been available as a clinical diagnostic test from Genaissance Pharmaceuticals IPR (now Clinical Data, Inc.). According to Dr. Ackerman, Director of the Long QT Syndrome Clinic and Sudden Death Genomics Laboratory at Mayo Clinic, it is now critical to carefully scrutinize the relationships between genotype and phenotype as they pertain to clinical practice.
The most common presentation of LQTS in a child, adolescent, or young adult is without warning; it is usually an unexplained episode of fainting that may be triggered by exertion or auditory startle or an episode that gets wrongly diagnosed as an epileptic event. If the physician considers LQTS in the differential diagnosis, then the work-up includes an electrocardiogram to look at the QT interval; since only half of all patients will have QT prolongation, Holter monitoring or stress testing with exercise or adrenaline may be necessary to try to provoke or unmask the long QT heart.
Dr. Ackerman said, "We routinely use what we call an epinephrine QT stress test; we give the patient adrenaline and try to detect an abnormal QT response. Then there is also genetic testing, looking for genetic evidence of the LQT substrate."
The extent of diagnostic testing, said Dr. Ackerman, is driven by the patient's story. "If the patient's story is boring – no symptoms, no family history, no nothing – then the evaluation for whatever reason the ECG was obtained, is a fairly limited evaluation. But if there is a suspicious story – an unexplained death, an unexplained faint, an exercise-triggered faint, a doorbell-triggered faint, a seizure, or a family history – those are the kind of families where you press very hard, far beyond just a resting electrocardiogram."
"You look at the electrocardiogram and decide the QT interval; that's the key first step because the computer is notoriously poor at measuring correctly the QT interval. Unfortunately, even the cardiology community is not good at measuring the QT interval and picking up the subtleties of LQTS (Slide 1)."
(Enlarge Image)
Figure 1.
ECG Characteristics of LQTS Source: Clinical image provided by the American College of Cardiology Foundation
According to Dr. Ackerman, "Once you identify an index case, you have an obligation to realize that you're dealing with a potentially inherited syndrome, so your patient quickly becomes a family rather than an individual. And so the evaluation needs to extend to all first-degree relatives to see if you are dealing with inherited long QT syndrome."
According to a recent report by Ackerman and colleagues, genetic testing is more cost-effective than not testing for symptomatic index cases at an estimated cost of $2,500 (US) per year of life saved. The primary benefit of testing is to more accurately diagnose and treat individuals based on a combination of clinical scores and test results.
If a genetic mutation is detected, its type and location can assist the physician in making treatment selections that could include life-style modification, prescription or avoidance of specific classes of drugs, or the implantation of a defibrillator. The most common form, LQT1, affects about one-third of individuals and is due to a defective potassium channel. "Beta-blockers are extraordinarily protective," said Dr. Ackerman. Whereas in type 3 LQTS, which affects only about 5% to 10% of patients, there is much less protective effect from beta-blockers. "In fact, there are some who would view beta-blockers as being relatively contraindicated in that form," he said.
Who should undergo genetic testing? "The place to start is in the index case," he said. "That's the most informative individual and the person who needs to be tested." One of the developers and early evaluators of the genetic test, Dr. Ackerman said, "Currently LQT genetic testing will catch 75% of the syndrome. If you identify the biomarker and identify the LQT genetic defect in the index case, then you have what we call the gold standard diagnostic biomarker for the rest of the family, who by and large will be asymptomatic and whose corrected QT interval will be in a very difficult range for deciphering. In these cases, genetic testing of the index case provides a definitive test to determine the have's and the have not's in the rest of the family."
Of course, when there is a sudden death there is no genetic testing of the index case and the challenge then is how to approach testing the rest of the family. "If the sudden death is associated with a completely normal autopsy, if the circumstances (of the death) were in the setting of exertion or of a suspicious nature, then you start looking for LQT because that's one of many different conditions that could have caused the person's sudden death," said Dr. Ackerman. "A screening ECG is the standard. If there are no signals on the screening ECG and no story of concern in the family members left behind, then I think the role of genetic testing for the rest of family doesn't make great sense right now."
Instead, he suggests a molecular autopsy on the decedent to probe for LQT genes or genes related to inherited arrhythmia syndrome. "We have solid evidence that about one-third of unexplained sudden deaths after the first year of life are channelopathies like LQTS and Brugada syndrome. So, that's the best person to start with."
Dr. Ackerman is working to educate medical examiner and coroner offices to retain a sample of tissue that would allow a post-mortem genetic test to be completed in the event of unexplained sudden death. "Many of us have been annual speakers at the National Association of Medical Examiners," he said, "alerting them that even though their traditional autopsy could not explain the cause and manner of death, genetic testing or a molecular autopsy has the ability to explain it in a portion of these sudden death cases. Over time, I think we're going to start seeing the standard of include retention of a blood spot card that would allow DNA to be extracted or freezing of tissue specimens to allow DNA to be archived and potentially analyzed in the future."
In terms of physician education, he cites two critical components. The first is better awareness of these potentially lethal syndromes that should be considered during the differential diagnosis of a patient presenting with unexplained fainting or seizure. Dr. Ackerman said this is especially important, but not well appreciated, at the front lines among pediatricians and family physicians. Second, once the physician is aware, they flag a patient as potentially having LQTS, and get the patient referred, "Cardiologists are not uniformly aware of LQTS," he said. If they do order an ECG, Dr. Ackerman emphasized, "The ECG is not the report given across the top of the ECG. They have to look at the ECG themselves, they have to measure the QT interval themselves, and then make the decision: am I still concerned about the possibility of QT interval, yes or no?"
As to the future, "We need to figure out who's really at risk and who really has a quiescent form that we should leave fairly enough alone except for preventative measures. We're not great yet at risk stratification (Slide 2). One of the things we're seeing in the United States is an over-zealous approach to treating these patients with an implantable defibrillator. So the pendulum has swung way too far to the right; we need to bring that back and recognize that much of LQTS can be treated very, very effectively without the sledge hammer, so to speak."
(Enlarge Image)
Figure 2.
Proposed Schema for Risk Stratification among Patients with the Long-QT Syndrome According to Genotype and Sex Description: Proposed Scheme for Risk Stratification among Patients with the Long-QT Syndrome According to Genotype and Sex. The risk groups have been defined on the basis of the probability of a first cardiac event (syncope, cardiac arrest, or sudden death) before the age of 40 years and before therapy. A probability of 50 percent or higher defines the high-risk group, a risk of 30 to 49 percent the intermediate-risk group, and a risk below 30 percent the low-risk group. Citation: Reproduced with permission from Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-74. Copyright © 2003, Massachusetts Medical Society. All rights reserved. Source: Clinical image provided by the American College of Cardiology Foundation
Alfred A. Bove, MD, FACC: Dr. Ackerman has made important contributions to our understanding of LQTS and channelopathies in general. We now understand that they are more common than once thought, that many drugs can affect the QT interval and put the patient at risk for a lethal arrhythmia, and that many environmental conditions can provoke serious arrhythmias in LQTS patients.
Graham TP Jr, Driscoll DJ, Gersony WM, Newburger JW, Rocchini A, Towbin JA. Task Force 2: congenital heart disease. J Am Coll Cardiol 2005;45:1326-33.
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Cardiol. 2002;40(9):1703-19. Full text guidelines are at ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices. http://www.cardiosource.com/guidelines/guidelines/pacemaker/index.htm
The Challenge
Long QT syndrome (LQTS) is the prototypic cardiac channelopathy underscored by profound genetic and phenotypic heterogeneity. In 1991, the first LQTS chromosome locus was identified and subsequently more than 400 mutations in nine cardiac channel/channel associated-encoding genes have been identified (LQT 1-9).
Michael J. Ackerman, MD, PhD, FACC, said: "We used to think that long QT syndrome was extraordinarily rare – 1 in 20,000. Then the estimate became 1 in 10,000, 1 in 5,000, and the latest data coming out of Italy and presented last fall suggests it may be as high as 1 in 2,000 or 1 in 3,000 persons." It is one of the most common causes of autopsy negative, sudden unexplained death. Contributing to its lack of identification is the fact that individuals may or may not show QT prolongation; indeed as many as half have no QT prolongation.
Since May 2004, genetic testing has been available as a clinical diagnostic test from Genaissance Pharmaceuticals IPR (now Clinical Data, Inc.). According to Dr. Ackerman, Director of the Long QT Syndrome Clinic and Sudden Death Genomics Laboratory at Mayo Clinic, it is now critical to carefully scrutinize the relationships between genotype and phenotype as they pertain to clinical practice.
The Data
The most common presentation of LQTS in a child, adolescent, or young adult is without warning; it is usually an unexplained episode of fainting that may be triggered by exertion or auditory startle or an episode that gets wrongly diagnosed as an epileptic event. If the physician considers LQTS in the differential diagnosis, then the work-up includes an electrocardiogram to look at the QT interval; since only half of all patients will have QT prolongation, Holter monitoring or stress testing with exercise or adrenaline may be necessary to try to provoke or unmask the long QT heart.
Dr. Ackerman said, "We routinely use what we call an epinephrine QT stress test; we give the patient adrenaline and try to detect an abnormal QT response. Then there is also genetic testing, looking for genetic evidence of the LQT substrate."
The extent of diagnostic testing, said Dr. Ackerman, is driven by the patient's story. "If the patient's story is boring – no symptoms, no family history, no nothing – then the evaluation for whatever reason the ECG was obtained, is a fairly limited evaluation. But if there is a suspicious story – an unexplained death, an unexplained faint, an exercise-triggered faint, a doorbell-triggered faint, a seizure, or a family history – those are the kind of families where you press very hard, far beyond just a resting electrocardiogram."
"You look at the electrocardiogram and decide the QT interval; that's the key first step because the computer is notoriously poor at measuring correctly the QT interval. Unfortunately, even the cardiology community is not good at measuring the QT interval and picking up the subtleties of LQTS (Slide 1)."
(Enlarge Image)
Figure 1.
ECG Characteristics of LQTS Source: Clinical image provided by the American College of Cardiology Foundation
Interpretation
According to Dr. Ackerman, "Once you identify an index case, you have an obligation to realize that you're dealing with a potentially inherited syndrome, so your patient quickly becomes a family rather than an individual. And so the evaluation needs to extend to all first-degree relatives to see if you are dealing with inherited long QT syndrome."
According to a recent report by Ackerman and colleagues, genetic testing is more cost-effective than not testing for symptomatic index cases at an estimated cost of $2,500 (US) per year of life saved. The primary benefit of testing is to more accurately diagnose and treat individuals based on a combination of clinical scores and test results.
If a genetic mutation is detected, its type and location can assist the physician in making treatment selections that could include life-style modification, prescription or avoidance of specific classes of drugs, or the implantation of a defibrillator. The most common form, LQT1, affects about one-third of individuals and is due to a defective potassium channel. "Beta-blockers are extraordinarily protective," said Dr. Ackerman. Whereas in type 3 LQTS, which affects only about 5% to 10% of patients, there is much less protective effect from beta-blockers. "In fact, there are some who would view beta-blockers as being relatively contraindicated in that form," he said.
Who should undergo genetic testing? "The place to start is in the index case," he said. "That's the most informative individual and the person who needs to be tested." One of the developers and early evaluators of the genetic test, Dr. Ackerman said, "Currently LQT genetic testing will catch 75% of the syndrome. If you identify the biomarker and identify the LQT genetic defect in the index case, then you have what we call the gold standard diagnostic biomarker for the rest of the family, who by and large will be asymptomatic and whose corrected QT interval will be in a very difficult range for deciphering. In these cases, genetic testing of the index case provides a definitive test to determine the have's and the have not's in the rest of the family."
Of course, when there is a sudden death there is no genetic testing of the index case and the challenge then is how to approach testing the rest of the family. "If the sudden death is associated with a completely normal autopsy, if the circumstances (of the death) were in the setting of exertion or of a suspicious nature, then you start looking for LQT because that's one of many different conditions that could have caused the person's sudden death," said Dr. Ackerman. "A screening ECG is the standard. If there are no signals on the screening ECG and no story of concern in the family members left behind, then I think the role of genetic testing for the rest of family doesn't make great sense right now."
Instead, he suggests a molecular autopsy on the decedent to probe for LQT genes or genes related to inherited arrhythmia syndrome. "We have solid evidence that about one-third of unexplained sudden deaths after the first year of life are channelopathies like LQTS and Brugada syndrome. So, that's the best person to start with."
Dr. Ackerman is working to educate medical examiner and coroner offices to retain a sample of tissue that would allow a post-mortem genetic test to be completed in the event of unexplained sudden death. "Many of us have been annual speakers at the National Association of Medical Examiners," he said, "alerting them that even though their traditional autopsy could not explain the cause and manner of death, genetic testing or a molecular autopsy has the ability to explain it in a portion of these sudden death cases. Over time, I think we're going to start seeing the standard of include retention of a blood spot card that would allow DNA to be extracted or freezing of tissue specimens to allow DNA to be archived and potentially analyzed in the future."
In terms of physician education, he cites two critical components. The first is better awareness of these potentially lethal syndromes that should be considered during the differential diagnosis of a patient presenting with unexplained fainting or seizure. Dr. Ackerman said this is especially important, but not well appreciated, at the front lines among pediatricians and family physicians. Second, once the physician is aware, they flag a patient as potentially having LQTS, and get the patient referred, "Cardiologists are not uniformly aware of LQTS," he said. If they do order an ECG, Dr. Ackerman emphasized, "The ECG is not the report given across the top of the ECG. They have to look at the ECG themselves, they have to measure the QT interval themselves, and then make the decision: am I still concerned about the possibility of QT interval, yes or no?"
As to the future, "We need to figure out who's really at risk and who really has a quiescent form that we should leave fairly enough alone except for preventative measures. We're not great yet at risk stratification (Slide 2). One of the things we're seeing in the United States is an over-zealous approach to treating these patients with an implantable defibrillator. So the pendulum has swung way too far to the right; we need to bring that back and recognize that much of LQTS can be treated very, very effectively without the sledge hammer, so to speak."
(Enlarge Image)
Figure 2.
Proposed Schema for Risk Stratification among Patients with the Long-QT Syndrome According to Genotype and Sex Description: Proposed Scheme for Risk Stratification among Patients with the Long-QT Syndrome According to Genotype and Sex. The risk groups have been defined on the basis of the probability of a first cardiac event (syncope, cardiac arrest, or sudden death) before the age of 40 years and before therapy. A probability of 50 percent or higher defines the high-risk group, a risk of 30 to 49 percent the intermediate-risk group, and a risk below 30 percent the low-risk group. Citation: Reproduced with permission from Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-74. Copyright © 2003, Massachusetts Medical Society. All rights reserved. Source: Clinical image provided by the American College of Cardiology Foundation
Second Opinion
Alfred A. Bove, MD, FACC: Dr. Ackerman has made important contributions to our understanding of LQTS and channelopathies in general. We now understand that they are more common than once thought, that many drugs can affect the QT interval and put the patient at risk for a lethal arrhythmia, and that many environmental conditions can provoke serious arrhythmias in LQTS patients.
Guidelines
Graham TP Jr, Driscoll DJ, Gersony WM, Newburger JW, Rocchini A, Towbin JA. Task Force 2: congenital heart disease. J Am Coll Cardiol 2005;45:1326-33.
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Cardiol. 2002;40(9):1703-19. Full text guidelines are at ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices. http://www.cardiosource.com/guidelines/guidelines/pacemaker/index.htm
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