meaning and determination of the qt-interval : clinical ... · pdf filemeaning and...
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K. SeidlHerzzentrum Ludwigshafen
Meaning and Determination of the QT-Interval : Clinical Aspects
APF workshop on QT/QTc prolongation TrialsHeidelberg 2005
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Background of the QT-interval
• QT interval is used as a surrogate marker for the prediction of serious adverse drug effects like
- VT/ TDP- syncope- sudden cardiac death
• HR is an important factor affecting QT. Drugs may independently affect QT and HR and the successful treatment of a disease may itself change the HR
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Background LQTS
• Molecular genetic aspects: Channelopathy- 7 genes have been linked to LQTS- mutations of the fast and slow K+ - channel (loss of function, reduces repolarizing K currents)- mutations of the Na+-channel (gain of function, increases inward INacurrents)
prolongation of the repolarization
• congenital QT-syndrome • acquired QT-syndrome (drug induced)
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• 7 Genes on chromosoms 3, 4, 7, 11 and 21 identified
• Most frequent are mutations on KCNQ1-gene (LQT1 30%) and on KCNH2-gene (LQT2 30%).
LQT1-Syndrom: KCNQ1, mutations slow K-channelLQT2-Syndrom: KCNQ2 mutations fast K-channelLQT3-Syndrom: SCN5A, mutations Na-channel
LQT4-Syndrom: ankyrin B, mutations unknownLQT5-Syndrom: KCNQ1, mutations slow K-channelLQT6-Syndrom: KCNQ2, mutations fast K-channel
Background LQTS: Genetic
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LQTS1:7000 bis 1:10000 all newborn
Congenital (60 %) Sporadic (40 %)
Romano Ward (99%)Autosomal dominantLQT1 (25%), LQT2 (25%), LQT3 (10%)Mild-severeLQT5 (1%), LQT6 (1%)MildAutosomal rezessivLQT1-3 (1%)severe
Jervell-Lange-Nielsen-syndrome (<1%)Autosomal rezessivLQT1 (75%), LQT5 (25%)
Anderson-syndrome Autosomal dominant with extracardiac involvementLQT7
New mutations (LQT1-3)
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Typical episode of drug induced VT or TDP associated with QT-
prolongation
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Measurement of the QT-intervalguidelines
• manually measured by using one of the limb leads
• Beginning of QRS – end of T – wave (3-5 beats)
• U-wave only included if large and merging with T-wave
• Measured during peak plasma levels of the QT prolonging drugs
• QT intervall should be adjusted for heart rate
Al Khatib et al., JAMA 2003: 289 ; 2120-2127
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ECG in LQTS (QTc 550ms)
QT
incision
RR
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Measurement of the QT-interval•SR vs atrial fibrillation
• narrow QRS vs wide QRS vs pacemaker QRS
RR
RR1 RR2
Bazett Formula (60-100 bpm)RR
QTQTc =
1
11
RRQT
QTc =2
22
RRQT
QTc =
221 QTcQTc
QTc+
=
RRQT
QTc =
Fridericia Formula (> 80-100 bpm)
2
3
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Interpretation of the QT-interval
• QT interval > 500 ms is commonly regarded as conferring an increased risk
• QTc Interval > 450 ms in male• QTc interval > 460 ms in female
• However, in family members of pts with LQTS (registry) 5 % had TDP or SCD with QTc < 440 msas QT interval is inconstant
• Exercise testing: no reduction of QT duration during HR increase
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Typical ECG findings in LQTS• QT-prolongation, QT-dispersion• T wave changes, U - wave • Bradycardia• polymorphic VT/TDP
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Criteria for the diagnosis of LQTS• QTc interval points
- > 480 ms 3- 460 - 470 ms 2- 450 ms 1- TDP 2-T-wave alternas 1- incision in T wave in 3 leads 1- bradycardia 0.5
- syncope- during exercise 2- without exercise 1
- deafness 0.5- Family history for LQTS 1- SCD <30 yrs of age 0.5
< 1 point probability low ; 2-3 points moderate, > 4 points high
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Inherited Long QT syndrome (LQTS-Registry)
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
7%
45%43%
0%
25%
50%
LQTS1 LQTS2 LQTS3
frequ
ency
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Clinical aspects for thedifferent forms of LQTS
Genotype-phenotype correlations and risk stratification
16 yrs.12 yrs.9 yrs.Mean age at 1. event2044Mortality (%)53637< 1 event (%)184662> 1 event (%)
Cardiac event until 40 yrs
delayedSmallProlonged, QT not shortened by exercise
T-wave
Sleep,restEmotional stress, acoustic stimuli
Exercise,physical activity, swimmingInduction
LQT3LQT2LQT1
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Survival free events in LQTS
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
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< 446 ms
447-468 ms
469-498 ms
>498 ms
Survival free events in LQTS according to QT-durations
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
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Priori et al., N Engl J Med 2003: 348 ; 1866-1874
Survival free events in LQT1 according to sex and QTc
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Survival free events in LQT2 according to sex and QTc
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
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Survival free events in LQT3 according to sex and QTc
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
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Incidence of first event before the age of 40 yrs in different forms of LQTS
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
30%
46%
42%
0%
25%
50%
LQTS1 LQTS2 LQTS3
card
iace
vent
bef
ore
the
age
40 y
rs
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QTc duration is associated with the event rate in the LQTS
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
25%
40%
70%
0%
25%
50%
75%
100%
< 470 ms 470-500ms > 500 ms
even
t rat
e be
fore
40
yrs
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Risk stratification for LQTS
Priori et al., N Engl J Med 2003: 348 ; 1866-1874
QTc < 500 msecMale sex, LQT2
LQT1
QTc < 500 msecFemale sex, LQT2Female sex, LQT3
Male sex, LQT3QTc > 500 msec
Female sex, LQT3
QTc > 500 msecLQT1, LQT2
Male sex, LQT3
Low risk < 30%
Intermediate Risk (30-49%)
High Risk > 50%
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Background LQTS (drug induced)
• In the past decade the single most common cause of the withdrawel or the restriction of the use of drugs that have already been marketed has been the prolongation of the QT-interval
• QT interval prolongation is associated with poly-morphic VT or TDP.
• Current predictors of this serious side effect are imperfect, both for individual pts and for populations of pts who are exposed to a given drug
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Drugs that may cause TDP
• Drugs commonly involved (Loss of function K+)• by more than 50 ms, risk for TDP 2-4%, monitoring required
- Quinidine- Sotalol - Dofetelide- Ibutilide- Disopyramide- Bepridil- Amiodarone (risk for TDP < 1%)
• Other drugs • mean increase about 5-20 ms. risk for TDP < 1%
- Cisapride (gain of function)- Antiinfective agents: claritromycin, erythromycin - antiemetic agents: domperidone, droperidol- antipsychotic agents: chlorpromazine, haloperidol etc- Methadone
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Risk factors for drug induced TDP
• female gender• family history od SCD• Hypokalemia• Bradycardia• Recent CV of atrial fibrillation in SR (eg AAD)
• congestive heart failure• digitalis therapy• High drug concentrations (exception quinidine)
• rapid iv infusion with a QT prolonging drug • baseline QT prolongation• Ion channel polymorphisms• severe Hypomagnesemia
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Hereditäre Susceptibilityfor a subclinical LQTS
• subclinical SCN5A-mutation, which manifests after Cisaprid administation
• sotalol unmasks drug induced QT polongation
Kääb et al., European Heart Journal 2003:24 ; 649-657
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Precautions if QT prolonging drug is administered
• minimal program- carefully taken history for risk predictors- ECG
• Patient should be informed to report promptly the new-onset of symptoms like
- palpitations- near syncope- syncope
• or intercurrent conditions or therapies that can cause hypokalemia
•Control ECG during treatment
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Treatment options
• No/withdrawel of QT prolonging drugs
• betablocker (recurrence rate 25%, SCD 10%) plus pacemaker
• contraindication for BB: Ca-antagonist (EAD)
• pacemaker (increase of the intrinsic heart rate)
• ganglion stellatum blockade
• ICD
• acute treatment if VT/TDP persists after KV- withrawel of QT prolonging drugs- Mg 2 iv in 2 min (2x) K > 4,5 mmol/l- BB, Lidocain, Ca-antagonist
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Recomodations for clinical practice
• Physicans have to be informed about the problem with QT-prolonging drugs (not only cardiologists)
• adequate dosage of the drug, reduce dosage, if renal or hepatic failure
• use potassium saving diuretics, if necessary
• control the ECG, E‘lyte
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Weighing risk and benefits
• Drug effectiveness in an otherwise fatal disease- Arsenic trioxide. acute promyeolytic leukemia
- Antiarrhythmic drug
• A drug that causes even a very low incidence of TDP would be unacceptable if safer alternative were available or if the indication were not itself serious.