Clinical Updates of Interest to Providers
STATE OF GENETIC TESTING FOR CONGENITAL LONG QT SYNDROME
(LQTS): Recommendations from the Heart Rhythm Society (HRS) and the
European Heart Rhythm Association (EHRA)
Congenital long QT syndrome (LQTS) is a genetic disease characterized by its hallmark
electrocardiographic feature of QT prolongation, its trademark arrhythmia of torsades de
pointes (TdP), and its predisposition for syncope, “seizures,” and sudden cardiac death (SCD)
in young individuals with structurally normal hearts. The majority of LQTS cases manifest
diagnostic QT prolongation on their resting 12-lead ECG; but up to 40% of LQTS patients have
non-diagnostic QT intervals at rest and are referred to as “normal QT interval” or “phenotype
negative” LQTS. Besides needing to verify the computer derived QTc value manually, careful
inspection of T wave and U wave morphology is necessary to detect subtle clues regarding
the possible presence of LQTS. Exercise testing and Holter monitoring may increase the
diagnostic sensitivity in some patients. A clinical diagnostic score (Schwartz Score), developed
before genetics entered the field of LQTS, still is used to help establish the diagnosis. With an
estimated incidence of at least 1 in 2,500 people, LQTS is underscored by marked clinical
heterogeneity ranging from a lifelong asymptomatic state to sudden death during infancy.
LQTS is more likely to express itself before puberty in males and after puberty in females.
Besides age and sex, the degree of QTc prolongation is associated with likelihood of a first
LQT-triggered cardiac event (syncope or aborted cardiac arrest) while occurrence of such
cardiac events, particularly while on therapy, is a strong predictor of recurrences and the
possibility of sudden cardiac death. Among symptomatic index cases, the untreated 10-year
mortality is approximately 50% among all types of LQTS. Since the sentinel discovery of the
first LQTS-causative gene in 1995, at least 1000 mutations in 13 LQTS genes have been
reported. Genotyping yields LQTS-associated mutations in 75% of patients with clinically
definite LQTS. Thus, approximately 25% of LQTS remains genetically elusive following
comprehensive genetic testing. The majority of LQTS is inherited as an autosomal dominant
trait. LQTS genetic testing should not be performed solely in response to a past history of
fainting without cardiology consultation. It must not be performed as part of pre-sports
participation or as a universal screening protocol. The significant rate of rare variants of
uncertain significance (4% in whites and 6% to 8% in non-whites) in the LQT1–3 genes
complicates correct mutation assignment and mandates that LQTS genetic testing be
sought based upon clinical suspicion rather than ordered indiscriminately.
Numerous genotype–phenotype relationships in LQTS have been discovered in the past 15
years, including genotype- suggestive ECG patterns, genotype-suggestive arrhythmogenic
triggers, genotype-based natural histories, and genotype-specific responses to therapy.
The majority of these relationships pertain to the major LQTS genotypes: LQT1, LQT2, and
LQT3. The genetic test result has joined traditional risk factors as independent prognostic risk
factors. Compared with the more common potassium channel loss-of-function subtypes (LQT1
and LQT2), patients with LQT3 appear to have the highest mortality per event. In addition,
within each of the two major LQTS genotypes (LQT1 and LQT2), the mutation’s location within
the gene and its functional properties seem to be independent risk factors with hazard ratios
similar to the QTc > 500 ms risk factor. Lastly, the results of genotyping have therapeutic
implications. For example, LQTS1 is very sensitive to β-blocker therapy whereas other genetic
abnormalities might warrant alternative therapies.
In August, 2011, the HRS and EHRA made the following recommendations with regard to
genetic screening for LQTS:
1. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A ) targeted LQTS genetic testing is
recommended (Class I indication) for any patient in whom a cardiologist has established a
strong clinical index of suspicion for LQTS based on examination of the patient’s clinical
history, family history, and ECG.
2. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A ) targeted LQTS genetic testing is
recommended for any asymptomatic patient with QT prolongation in the absence of other
clinical conditions that might prolong the QT interval (such as electrolyte abnormalities,
ventricular hypertrophy, bundle branch block, etc) on serial 12-lead ECGs defined as QTc >
480 ms (prepuberty) or > 500 ms (adults).
3. Mutation-specific genetic testing is recommended for first-degree family members and other
appropriate relatives following the identification of the LQTS-causative mutation in an index
case.
4. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A ) targeted LQTS genetic testing may
be considered (Class IIB indication) for any asymptomatic patient with otherwise idiopathic
QTc values > 460 ms (prepuberty) or > 480 ms (adults) on serial 12-lead ECGs.
POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME
Postural Orthostatic Tachycardia Syndrome (POTS) is a disabling disease first described in the
1940s and is probably the most common reason for referral for chronic orthostatic intolerance.
Symptoms of autonomic dysfunction (chronic fatigue, dizziness, abdominal discomfort and
chronic pain) frequently dominate the syndrome. POTS is an orthostatic disorder
characterized by dizziness, lightheadedness, palpitations and blurred vision which are
particularly evident in the upright position. Nonorthostatic symptoms, including dry
eyes/mouth, bloating, nausea, vomiting, constipation, diarrhea and migraine headaches, also
have been documented in this disorder, and occur frequently. POTS is diagnosed when heart
rate increases by greater than 30 beats per minute or increases to a sustained heart rate of
greater than 120 beats per minute within 10 minutes of a head-up tilt test or after assuming
an upright posture. POTS is not uncommon, but is often misdiagnosed or unrecognized. It
affects millions of individuals and occurs predominantly in female patients (80%) ages 12 to
50 years, often with onset after a viral infection, other inflammatory condition or surgical
procedure. Although initially described as an “adult” entity, POTS is widely seen in the
pediatric population, most frequently in adolescents. In pediatric patients, POTS has been
shown to coexist with chronic fatigue syndrome (CFS) and functional gastrointestinal
disorders (FGIDs), and has been associated with fatigue, chronic pain, and altered
temperature sensation.
Because the range of symptoms is so wide and involves many different organ systems, one
unifying cause is unlikely to be found. Most studies to date, however, support the notion that
POTS likely is caused by either dysfunction or dysregulation of the autonomic nervous system.
Current evidence indicates that the related symptoms are the result of excessive central
hypovolemia. The signature tachycardia, therefore, may result from related reflex
parasympathetic withdrawal and sympathetic activation. Studies of heart rate and blood
pressure variability indicate vagal withdrawal and at least relative cardiac sympathetic excess.
Many patients with POTS report gastrointestinal symptoms, such as nausea, vomiting, and
bloating and a subset of patients with FGID complain of lightheadedness, dizziness and
fatigue.
The January, 2011 issue of The Journal of Pediatrics contains two retrospective studies of
adolescent pediatric populations with POTS. One study (Ojha A, et al. Journal of Pediatrics
2011; 1548: 20-23) looked at the comorbidities in pediatric and adults patients with POTS. In
the pediatric group, average age was 15 ± 2 years. More than 3 episodes of syncope were
reported by 32% of the pediatric patients and 30% of the adult patients. Gastrointestinal
complaints occurred in 79% of the pediatric patients and 71% of the adults. Most complained
of abdominal pain and nausea. Nearly half of the pediatric patients reported headache that,
when untreated, persisted for more than 4 hours but less than 72 hours. Most also reported
photophobia and or phonophobia. Sleep abnormality was the most prevalent comorbidity in
the pediatric group, occurring in 98% of subjects. More than half of the pediatric subjects
(61%) complained of unexplained, severe fatigue lasting at least 1 month.
The second study, from the Mayo Clinic, evaluated exercise performance in 202 adolescents
with POTS and autonomic dysfunction (chronic fatigue, dizziness, abdominal discomfort, and
pain). Although most (2/3) of the adolescents with POTS showed evidence for deconditioning,
the lower than normal stroke volume and slower heart rate recovery after exercise were
related to reduced cardiac output and decreased blood volume (relative hypovolemia). The
authors emphasized that exercise training, by increasing cardiac size and mass and
expanding blood volume, can improve or, in some instances, cure POTS.
TRICYCLIC ANTIDEPRESSANT (TCA) TOXICITY: STILL COMMON AFTER
ALL THESE YEARS
Case Presentation: A 16 year old girl presented to the emergency department with
somnolence, respiratory depression, hypotension, poor perfusion and tachycardia. A portion
of her ECG is shown.
Although she was originally thought to be in ventricular tachycardia, a history of purposeful
TCA (nortryptyline) overdose was obtained from a parent and the patient was appropriately
managed with ventilatory support, intravenous hydration and intravenous alkalinization with
sodium bicarbonate. Within a few hours, her ECG started to normalize and she made a full
recovery.
Discussion: TCAs inhibit the reuptake of serotonin and epinephrine, block cardiac sodium
channels and phase 3 cardiac potassium channels, increase anticholinergic activity and
produce peripheral vascular α-adrenergic blockade. In toxic concentrations, the effects include
sinus tachycardia, significant cardiac conduction abnormalities (increased PR and QRS
durations), prolonged QT interval, ST segment and T-wave changes, hypotension, altered
mentation, seizures and the possibility of malignant and potentially fatal cardiac arrhythmias.
The classic electrocardiogram shows sinus tachycardia with long PR interval, wide QRS
duration, prolonged QT interval (which is what the above ECG shows; this is not ventricular
tachycardia) and a ‘classic’ large R wave in AVR (see above). A QRS duration >100ms predicts
a higher risk for ventricular arrhythmias and seizures and demands immediate attention.
There is no antidote for TCA overdose. Treatment includes rapid alkalinization of the serum to
a pH > 7.45, which counteracts the sodium channel blocking effects and quickly normalizes the
ECG. Fluid resuscitation, assisted ventilation and sedation to prevent seizures are utilized as
needed. Correct ECG interpretation is essential, since inappropriate use of antiarrhythmics
can easily increase sodium channel blockade (worsen conduction) and further prolong the QT
interval, thereby facilitating severe ventricular arrhythmias.
STATE OF GENETIC TESTING FOR CONGENITAL LONG QT SYNDROME
(LQTS): Recommendations from the Heart Rhythm Society (HRS) and the
European Heart Rhythm Association (EHRA)
Congenital long QT syndrome (LQTS) is a genetic disease characterized by its hallmark
electrocardiographic feature of QT prolongation, its trademark arrhythmia of torsades de
pointes (TdP), and its predisposition for syncope, “seizures,” and sudden cardiac death (SCD)
in young individuals with structurally normal hearts. The majority of LQTS cases manifest
diagnostic QT prolongation on their resting 12-lead ECG; but up to 40% of LQTS patients have
non-diagnostic QT intervals at rest and are referred to as “normal QT interval” or “phenotype
negative” LQTS. Besides needing to verify the computer derived QTc value manually, careful
inspection of T wave and U wave morphology is necessary to detect subtle clues regarding
the possible presence of LQTS. Exercise testing and Holter monitoring may increase the
diagnostic sensitivity in some patients. A clinical diagnostic score (Schwartz Score), developed
before genetics entered the field of LQTS, still is used to help establish the diagnosis. With an
estimated incidence of at least 1 in 2,500 people, LQTS is underscored by marked clinical
heterogeneity ranging from a lifelong asymptomatic state to sudden death during infancy.
LQTS is more likely to express itself before puberty in males and after puberty in females.
Besides age and sex, the degree of QTc prolongation is associated with likelihood of a first
LQT-triggered cardiac event (syncope or aborted cardiac arrest) while occurrence of such
cardiac events, particularly while on therapy, is a strong predictor of recurrences and the
possibility of sudden cardiac death. Among symptomatic index cases, the untreated 10-year
mortality is approximately 50% among all types of LQTS. Since the sentinel discovery of the
first LQTS-causative gene in 1995, at least 1000 mutations in 13 LQTS genes have been
reported. Genotyping yields LQTS-associated mutations in 75% of patients with clinically
definite LQTS. Thus, approximately 25% of LQTS remains genetically elusive following
comprehensive genetic testing. The majority of LQTS is inherited as an autosomal dominant
trait. LQTS genetic testing should not be performed solely in response to a past history of
fainting without cardiology consultation. It must not be performed as part of pre-sports
participation or as a universal screening protocol. The significant rate of rare variants of
uncertain significance (4% in whites and 6% to 8% in non-whites) in the LQT1–3 genes
complicates correct mutation assignment and mandates that LQTS genetic testing be
sought based upon clinical suspicion rather than ordered indiscriminately.
Numerous genotype–phenotype relationships in LQTS have been discovered in the past 15
years, including genotype- suggestive ECG patterns, genotype-suggestive arrhythmogenic
triggers, genotype-based natural histories, and genotype-specific responses to therapy.
The majority of these relationships pertain to the major LQTS genotypes: LQT1, LQT2, and
LQT3. The genetic test result has joined traditional risk factors as independent prognostic risk
factors. Compared with the more common potassium channel loss-of-function subtypes (LQT1
and LQT2), patients with LQT3 appear to have the highest mortality per event. In addition,
within each of the two major LQTS genotypes (LQT1 and LQT2), the mutation’s location within
the gene and its functional properties seem to be independent risk factors with hazard ratios
similar to the QTc > 500 ms risk factor. Lastly, the results of genotyping have therapeutic
implications. For example, LQTS1 is very sensitive to β-blocker therapy whereas other genetic
abnormalities might warrant alternative therapies.
In August, 2011, the HRS and EHRA made the following recommendations with regard to
genetic screening for LQTS:
1. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A ) targeted LQTS genetic testing is
recommended (Class I indication) for any patient in whom a cardiologist has established a
strong clinical index of suspicion for LQTS based on examination of the patient’s clinical
history, family history, and ECG.
2. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A ) targeted LQTS genetic testing is
recommended for any asymptomatic patient with QT prolongation in the absence of other
clinical conditions that might prolong the QT interval (such as electrolyte abnormalities,
ventricular hypertrophy, bundle branch block, etc) on serial 12-lead ECGs defined as QTc >
480 ms (prepuberty) or > 500 ms (adults).
3. Mutation-specific genetic testing is recommended for first-degree family members and other
appropriate relatives following the identification of the LQTS-causative mutation in an index
case.
4. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A ) targeted LQTS genetic testing may
be considered (Class IIB indication) for any asymptomatic patient with otherwise idiopathic
QTc values > 460 ms (prepuberty) or > 480 ms (adults) on serial 12-lead ECGs.
POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME
Postural Orthostatic Tachycardia Syndrome (POTS) is a disabling disease first described in the
1940s and is probably the most common reason for referral for chronic orthostatic intolerance.
Symptoms of autonomic dysfunction (chronic fatigue, dizziness, abdominal discomfort and
chronic pain) frequently dominate the syndrome. POTS is an orthostatic disorder
characterized by dizziness, lightheadedness, palpitations and blurred vision which are
particularly evident in the upright position. Nonorthostatic symptoms, including dry
eyes/mouth, bloating, nausea, vomiting, constipation, diarrhea and migraine headaches, also
have been documented in this disorder, and occur frequently. POTS is diagnosed when heart
rate increases by greater than 30 beats per minute or increases to a sustained heart rate of
greater than 120 beats per minute within 10 minutes of a head-up tilt test or after assuming
an upright posture. POTS is not uncommon, but is often misdiagnosed or unrecognized. It
affects millions of individuals and occurs predominantly in female patients (80%) ages 12 to
50 years, often with onset after a viral infection, other inflammatory condition or surgical
procedure. Although initially described as an “adult” entity, POTS is widely seen in the
pediatric population, most frequently in adolescents. In pediatric patients, POTS has been
shown to coexist with chronic fatigue syndrome (CFS) and functional gastrointestinal
disorders (FGIDs), and has been associated with fatigue, chronic pain, and altered
temperature sensation.
Because the range of symptoms is so wide and involves many different organ systems, one
unifying cause is unlikely to be found. Most studies to date, however, support the notion that
POTS likely is caused by either dysfunction or dysregulation of the autonomic nervous system.
Current evidence indicates that the related symptoms are the result of excessive central
hypovolemia. The signature tachycardia, therefore, may result from related reflex
parasympathetic withdrawal and sympathetic activation. Studies of heart rate and blood
pressure variability indicate vagal withdrawal and at least relative cardiac sympathetic excess.
Many patients with POTS report gastrointestinal symptoms, such as nausea, vomiting, and
bloating and a subset of patients with FGID complain of lightheadedness, dizziness and
fatigue.
The January, 2011 issue of The Journal of Pediatrics contains two retrospective studies of
adolescent pediatric populations with POTS. One study (Ojha A, et al. Journal of Pediatrics
2011; 1548: 20-23) looked at the comorbidities in pediatric and adults patients with POTS. In
the pediatric group, average age was 15 ± 2 years. More than 3 episodes of syncope were
reported by 32% of the pediatric patients and 30% of the adult patients. Gastrointestinal
complaints occurred in 79% of the pediatric patients and 71% of the adults. Most complained
of abdominal pain and nausea. Nearly half of the pediatric patients reported headache that,
when untreated, persisted for more than 4 hours but less than 72 hours. Most also reported
photophobia and or phonophobia. Sleep abnormality was the most prevalent comorbidity in
the pediatric group, occurring in 98% of subjects. More than half of the pediatric subjects
(61%) complained of unexplained, severe fatigue lasting at least 1 month.
The second study, from the Mayo Clinic, evaluated exercise performance in 202 adolescents
with POTS and autonomic dysfunction (chronic fatigue, dizziness, abdominal discomfort, and
pain). Although most (2/3) of the adolescents with POTS showed evidence for deconditioning,
the lower than normal stroke volume and slower heart rate recovery after exercise were
related to reduced cardiac output and decreased blood volume (relative hypovolemia). The
authors emphasized that exercise training, by increasing cardiac size and mass and
expanding blood volume, can improve or, in some instances, cure POTS.
TRICYCLIC ANTIDEPRESSANT (TCA) TOXICITY: STILL COMMON AFTER
ALL THESE YEARS
Case Presentation: A 16 year old girl presented to the emergency department with
somnolence, respiratory depression, hypotension, poor perfusion and tachycardia. A portion
of her ECG is shown.
Although she was originally thought to be in ventricular tachycardia, a history of purposeful
TCA (nortryptyline) overdose was obtained from a parent and the patient was appropriately
managed with ventilatory support, intravenous hydration and intravenous alkalinization with
sodium bicarbonate. Within a few hours, her ECG started to normalize and she made a full
recovery.
Discussion: TCAs inhibit the reuptake of serotonin and epinephrine, block cardiac sodium
channels and phase 3 cardiac potassium channels, increase anticholinergic activity and
produce peripheral vascular α-adrenergic blockade. In toxic concentrations, the effects include
sinus tachycardia, significant cardiac conduction abnormalities (increased PR and QRS
durations), prolonged QT interval, ST segment and T-wave changes, hypotension, altered
mentation, seizures and the possibility of malignant and potentially fatal cardiac arrhythmias.
The classic electrocardiogram shows sinus tachycardia with long PR interval, wide QRS
duration, prolonged QT interval (which is what the above ECG shows; this is not ventricular
tachycardia) and a ‘classic’ large R wave in AVR (see above). A QRS duration >100ms predicts
a higher risk for ventricular arrhythmias and seizures and demands immediate attention.
There is no antidote for TCA overdose. Treatment includes rapid alkalinization of the serum to
a pH > 7.45, which counteracts the sodium channel blocking effects and quickly normalizes the
ECG. Fluid resuscitation, assisted ventilation and sedation to prevent seizures are utilized as
needed. Correct ECG interpretation is essential, since inappropriate use of antiarrhythmics
can easily increase sodium channel blockade (worsen conduction) and further prolong the QT
interval, thereby facilitating severe ventricular arrhythmias.
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| PEDIATRIX CARDIOLOGY ASSOCIATES OF NEW MEXICO |
