Arrhythmia Risk Stratification in a Clinical Patient Cohort and Correlation with Genotype and Environmental Modulators

Numerous noninvasive ECG derived methodologies have been proposed to risk
stratify patients for ventricular arrhythmias, and sudden cardiac death. Some
of them, like T-wave alternans and signal averaging are commercially available,
others, like beat-to-beat variability
of repolarisation, are clinically still in their testing or developmental
phase. Both T-wave alternans and BVR are repolarisation dependent biomarkers
that have been associated with disturbed intracellular calcium handling. Where
BVR can be determined at resting or slow heart rates, the use of micro-voltage
T wave alternans has been limited to heart rates above 110 beats/min. Still a
common aetiology (disturbed intracellular calcium handling) may exist, because
experimentally the frequency dependency of BVR shows increasing values at the
two extremes of the heart rate spectrum. In this clinical study, a direct link
between these various risk markers of repolarisation pathophysiology will be
assessed.

1) To electrophysiologially characterise a selected, large cohort of patients
prone to malignant ventricular arrhythmias (ICD recipients)
2) To exactly quantitate outcome by total mortality as well as malignant
arrhythmia risk through number of adequate ICD shocks and pacing induced
ventricular tachyarrhythmias at electrophysiological testing
3) To reassess the predictive value of all typical noninvasive risk
stratification techniques in a specific population deemed at high risk of
arrhythmias, with or without a history of myocardial infarction - with
particular emphasis to temporal dispersion of repolarisation, including T-wave
alternans and BVR
4) To establish a link between phenotype, clinical risk assessment and genotype
for selected candidate genes involved in the pathophysiology of ventricular
arrhythmias
5) To establish a link between arrhythmia risk and environmental factors such
as obesity and diabetes
6) To establish a direct link between various risk markers of repolarisation
pathophysiology - T wave alternans, T wave morphology and beat-to-beat
variability of repolarisation (BVR)

The study is designed as an observational study involving genetic testing and
noninvasive and invasive diagnostics. No therapeutic intervention or
randomisation is performed. No medicinal products, medical devices or drugs are
evaluated.

1. blood sampling - Possible individual benefits for he individual study
participant (benefits): none. - Possible risks fort he individual study
participant (risks): not study-related, because blood sample is taken at same
time as clinical routine blood sample is taken. In general, occasionally
haematoma, extreme rare infection or injury of nerves).
2. digital resting ECG - Benefits: analysis of heart rhythm, PQ time, QRS
complex (e. g. bundle-branch blocks), repolarisation incl. QT time. - Risks:
wrong ECG due to reverse polarity (no risk for patient, but for exactness of
study data).
3. signal averaging ECG - - Benefits: no specific benefit for individual
patient. - Risks: wrong ECG due to reverse polarity (no risk for patient, but
for exactness of study data).
4. T-wave-alternans-test - Benefits: 1. additional diagnostic tests may be
recommended (e. g. in case of myocardial ischaemia). 2. adjust patients
medication - Risks: rare allergic reaction on electrodes. The risk of occurring
of a dangerous arrhythmia is the same like activity of daily life, e. g.
climbing stairs and lower than clinical routine stress ECG because of much more
effort for the patient.
5a. In case of invasive electrophysiological study (new ICD implant patients) -
Benefits: 1. improve programming of the ICD device to avoid unnecessary ICD
therapy, 2. adjust patients medication - Risks: Sustained and continuous heart
rhythm disturbances from the heart chamber such as VT and VF are dangerous and
life threatening or potentially life threatening. In contrast, heart rhythm
disturbances from the atria are never dangerous, albeit annoying. Any of the
induced heart rhythm disturbances can be terminated by the doctor, if necessary
immediately. For this purpose there is fast and painless overstimulation as
well as electric shocks in short narcosis. There is no risk that an arrhythmia
cannot be terminated. The risk of haematoma at the puncture site is about 1%,
nerve irritation and serious damage of blood vessels by the catheter is
extremely rare. Thrombosis, embolism, damage to the heart with pericardial
effusion and tamponade have been described but are extremely rare. All other
complications together are estimated to occur with less than 0.5 %, each
complication alone is extremely rare. Heart rhythm disturbances may be induced
by mechanical manipulation of the heart by the catheter during placement, and
usually end spontaneously. An additional risk due to the additional
measurements of the EUTrigTreat Study can be ruled out.
5b. In case of non-invasive electrophysiological study (chronic ICD patients) -
Benefits: 1. improve programming of the ICD device to avoid unnecessary ICD
therapy, 2. adjust patients medication. - Risks: Sustained and continuous heart
rhythm disturbances from the heart chamber such as VT and VF are dangerous and
life threatening or potentially life threatening. In contrast, heart rhythm
disturbances from the atria are never dangerous, albeit annoying. Any of the
induced heart rhythm disturbances can be terminated by the doctor, if necessary
immediately. For this purpose there is fast and painless overstimulation as
well as electric shocks in short narcosis. There is no risk that an arrhythmia
cannot be terminated.
6. 24h ECG - Benefits: monitoring for atrial fibrillation, ventricular
arrhythmias so important modification of patient medication can be performed
(e. g. starting anticoagulation to prevent stroke in patients with new detected
atrial fibrillation) - Risks: rare allergic reaction on electrodes, wrong ECG
due to reverse polarity or lowbattery (no risk for patient, but for exactness
of study data).