Frequently-Asked
Questions on Ventricular Repolarization
1. Ion
Channels
1.1.
How does the chemical environment differ between
the inside of a cell and the outside?
1.2.
Do the chemical differences balance out
electrically, or is there an electrical potential difference between the inside
and outside of the cell?
1.3.
What is an ion channel?
1.4.
How might an ion channel malfunction?
2. Action Potentials
2.1.
What is an action potential?
2.2.
Why don't the depolarizing channels re-open as
soon as the repolarizing flux has moved the transmembrane potential back into
the range in which the depolarizing channels are normally open?
2.3.
Why does one action potential follow another?
2.4.
How can malfunctioning ion channels affect
the action potential?
2.5.
Do all cardiac cells have the same mix of
ion channels, and thus the same sort of action potentials?
3. Cell-Cell Interactions
3.1.
How can one cell's electrical activity affect the
electrical activity of another cell?
4. Electrical Development of Each Heartbeat
4.1.
How do the action potentials of the various
cardiac cells combine to produce a normal heartbeat?
4.2.
What can go wrong with this process?
5. Electrocardiograms
5.1.
What is measured by an electrocardiogram?
5.2.
What is the electrocardiographic appearance of a
typical cardiac beat?
5.3.
To what action potentials do the various portions of
the ECG complex correspond?
5.4.
How are the durations of the various intervals
affected by heart rate?
6. The QT Interval
6.01.
How do we decide whether a biometric datum is
“normal”?
6.02.
What is meant by QT “correction”?
6.03.
What formula is used for QT correction?
6.04.
Is the Bazett correction unbiased?
6.05.
When the heart
rate is close to 60, so that QTcB is
close to QT, need I be concerned about the failings of the Bazett formula?
6.06.
Hasn't the Bazett formula been validated by
years of use?
6.07.
Would it be better to use a similar formula with a
around 0.32?
6.08.
Would it be better yet to obtain sufficient
baseline data to fit a separate formula for each subject?
6.09.
When the heart rate changes, does the QT interval
change right away?
6.10.
What is meant by "QT dispersion"?
7. Torsade de Pointes
7.1.
Is it torsade or torsades?
7.2.
What is torsade de pointes?
7.3.
Why is torsade de pointes important?
7.4.
Who are at risk for torsade de pointes?
8. Congenital Long-QT Syndromes
8.1.
What are the congenital long-QT syndromes?
8.2.
How common are these syndromes?
8.3.
How important are they to people who have them?
8.4.
Are similar syndromes known to occur in animals?
8.5.
Do people with the same hereditary long-QT
syndrome all have the same mutation?
8.6.
Do people with the same ion-channel mutation all
have equally prolonged QT intervals?
8.7.
Do people with the same ion-channel mutation
all have an equal likelihood of arrhythmic events?
8.8.
What happens to people with congenitally short
QT intervals?
9. Drug-Induced Changes in Ion-Channel
Function
9.1.
How is a drug's propensity to cause changes in ion-channel function tested?
9.2.
How are the results described?
9.3.
Is alteration of ion-channel function ever
an intended drug effect?
9.4.
Are some ion channels more susceptible to
drug-induced interference than others?
9.5.
What drugs have ion-channel effects, and which
channels are affected?
9.6.
Do ion-channel studies provide close analogies to
distortions of human electrocardiograms?
9.7.
Do ion-channel studies provide close analogies to
human torsade de pointes?
9.8.
Has in vitro
ion-channel testing been validated as a means of predicting drug-induced torsade
de pointes in humans?
10. Drug-Induced
Changes in the Action Potential
10.1.
How is a drug's propensity to cause changes in action potentials tested?
10.2.
How are the results described?
10.3.
Do action-potential studies provide close analogies to
distortions of human electrocardiograms?
10.4.
Do action-potential studies provide close analogies to
human torsade de pointes?
10.5.
Does prolongation
of action potentials in vitro reliably
predict drug-induced torsade de pointes in
humans?
11. The Wedge Preparation
11.1.
What is the wedge preparation, and what studies
are done with it?
11.2.
How are the results described?
11.3.
Do wedge-preparation studies provide close
analogies to distortions of human electrocardiograms?
11.4.
Do wedge-preparation studies provide close
analogies to human torsade de pointes?
11.5.
Have wedge-preparation studies been validated
as a means of predicting drug-induced torsade de pointes in
humans?
12. Drug-Induced QT Prolongation in Animals
12.1.
How is a drug's propensity to cause QT prolongation in animals tested?
12.2.
How are the results described?
12.3.
Do QT prolongation and other ECG abnormalities in animals closely resemble these
phenomena in humans?
12.4.
Have studies
of drug-induced QT prolongation in animals been validated as a means of
predicting drug-induced torsade de pointes in
humans?
13. Drug-Induced Torsade
de Pointes in Animals
13.1.
How is a drug's propensity to cause torsade de pointes
in animals tested?
13.2.
How are the results described?
13.3.
Have studies
of drug-induced torsade de pointes
in animals been validated as a means of predicting drug-induced torsade
de pointes in humans?
14. Drug-Induced QT Prolongation in Humans
14.1.
Is prolongation of the human QT interval ever an intended drug effect?
14.2.
What drugs prolong the QT interval?
14.3.
If a given dose of a drug prolongs the QT interval
by a certain amount, will a higher dose of the drug prolong the QT interval by
the same amount or greater?
14.4.
Does drug-induced QT prolongation cause torsade
de pointes?
15. Drug-Induced Torsade de Pointes
15.1.
What drugs are known to cause torsade de
pointes?
15.2.
Do all of the true culprit drugs interfere
with the function of ion channels?
15.3.
Which ion channels are involved?
15.4.
How often is a patient with drug-induced
torsade found to have been unusually susceptible because of a subclinical
congenital channel dysfunction?
15.5.
Do all drugs that block IKr cause torsade
de pointes if given in sufficient
dose?
15.6.
Do all of the drugs known to cause torsade
de pointes prolong the QT interval?
15.7.
Conversely, will any drug that prolongs the QT
interval cause torsade de pointes if it
is given in sufficient dose?
15.8.
Are there drugs that cause torsade de
pointes even though they prolong the QT interval only slightly?
16. Drug Development and Regulation
16.1.
How important are metabolic effects during human
trials of drugs that might affect repolarization?
16.2.
What is the goal of Phase 1 trials?
16.3.
How important is the non-occurrence of torsade
de pointes during human drug trials?
16.4
What is FDA doing now (late 2013)?
16.5
How old are the data that are now leading FDA to
change its position?
16.6
How does my company get reimbursed for the
millions of dollars wasted on Thorough QT Studies?
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