Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
Condition: Long QT Syndrome
MeSH terms: Tachycardia; Long QT Syndrome; Syndrome
Study type: Interventional

Summary: 
      The drug-induced long QT syndrome (diLQTS) describes a clinical entity in which
      administration of a drug produces marked prolongation of the QT interval of the
      electrocardiogram, associated with the development of a polymorphic ventricular tachycardia,
      termed torsades de pointes (TdP). The heart rate is an important variable affecting the QT
      interval. The QT interval normally shortens as the heart rate accelerates; however, the
      adaptation of the QT interval to sudden heart rate acceleration is not instantaneous.
      Interestingly, Holter studies show that the speed of response of the QT interval to sudden
      changes in heart rate (that is, the time it takes the QT interval of a given person to reach
      a new steady-state QT/RR relation) in healthy persons is highly individual and independent of
      the basic QTc. The investigators and others recently proposed the "quick standing" test as a
      simple bedside test that facilitates the diagnosis of congenital LQTS. The test takes
      advantage of the fact that as one stands up, the heart rate acceleration is abrupt while the
      associated QT-interval shortening is gradual. As the R-R interval shortens faster than the QT
      interval, the QT appears to "stretch" toward the next P wave and the corrected QT interval
      (QTc) for heart rate actually increases momentarily. The phenomenon of "QT stretching" is
      universal but is exaggerated in patients with LQTS, allowing for a simple but accurate
      diagnostic test. There is no data on the effects of quick standing on drug-associated form of
      the long QT syndrome. The investigators therefore propose the present study to better
      understand who these patients with drug-associated form of the long QT syndrome are and what
      the significance of their abnormal QT-response is.
    

Detailed description: 
      The drug-induced long QT syndrome (diLQTS) describes a clinical entity in which
      administration of a drug produces marked prolongation of the QT interval of the
      electrocardiogram, associated with the development of a polymorphic ventricular tachycardia,
      termed torsades de pointes (TdP). Drugs that produce diLQTS block the repolarizing current,
      IKr, encoded by KCNH2, the disease gene for type 2 congenital LQTS (cLQTS) . Some risk
      factors are drug-specific (pharmacokinetic factors such as cytochrome P450 variants) whereas
      others (pharmacodynamic factors) seem more related to myocardial sensitivity across drugs.
      Studies of the congenital syndrome demonstrated variable penetrance in the congenital
      syndrome; that is, there is variability in the extent to which mutation carriers display long
      QT intervals, syncope, and sudden death. Thus, one pharmacogenetic hypothesis is that persons
      displaying diLQTS represent an atypical form of the congenital form of the syndrome. In fact,
      a minority of subjects with diLQTS have rare mutations in cLQTS disease genes and can thus be
      labeled as having the congenital syndrome. In a given family, some persons with a LQTS
      mutation have clearly long QT intervals, whereas others with the same mutation have normal QT
      intervals at baseline. In some cases, these latter people, often referred to as "latent" or
      "subclinical" LQTS, experience TdP only after therapy with a QT-prolonging drug. Indeed, when
      cLQTS disease genes have been screened, mutations are identified in about 10% of subjects
      with diLQTS. The heart rate is an important variable affecting the QT interval. The QT
      interval normally shortens as the heart rate accelerates; however, the adaptation of the QT
      interval to sudden heart rate acceleration is not instantaneous. Animal and clinical studies
      have shown that following an abrupt increase in ventricular pacing rate, it takes up to 2
      minutes until the ventricular refractory period and the QT interval shorten to a new steady
      state that is appropriate for the new (faster) rate. Interestingly, Holter studies show that
      the speed of response of the QT interval to sudden changes in heart rate (that is, the time
      it takes the QT interval of a given person to reach a new steady-state QT/RR relation) in
      healthy persons is highly individual and independent of the basic QTc. The investigators and
      others recently proposed the "quick standing" test as a simple bedside test that facilitates
      the diagnosis of congenital LQTS. The test takes advantage of the fact that as one stands up,
      the heart rate acceleration is abrupt while the associated QT-interval shortening is gradual.
      As the R-R interval shortens faster than the QT interval, the QT appears to "stretch" toward
      the next P wave and the corrected QT interval (QTc) for heart rate actually increases
      momentarily. The phenomenon of "QT stretching" is universal but is exaggerated in patients
      with LQTS, allowing for a simple but accurate diagnostic test. There is no data on the
      effects of quick standing on drug-associated form of the long QT syndrome. The investigators
      therefore propose the present study to better understand who these patients with
      drug-associated form of the long QT syndrome are and what the significance of their abnormal
      QT-response is.
    

Intervention name(s): tilt table
Intervention type(s): Device
Intervention description(s): Participating individuals will be instructed to rest supine for 10 minutes while repeat electrocardiograms are recorded. They will then be instructed to stand up quickly and remain standing still for 10 minutes.
Individuals with inability to stand up quickly will be tested with tilt table test used in our hospital
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: QT interval prolongation