Describe the electrocardiographic changes and areas of late myocardial activation encountered in PLN and PKP2 mutation carriers during ajmaline provocation and the relation of these differences to the development for early stages of arrhythmogenic…
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Source
Brief title
Condition
- Myocardial disorders
- Cardiac and vascular disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The mean difference in local Activation Time Duration before ajmaline
administration and at the maximal amount of ajmaline administration in the
subtricuspid area, the mid right ventricle area, right ventricular outflow
tract, the left ventricle anterior area and left ventricle posterolateral area
as calculated by ECG imaging.
Secondary outcome
Mean differences in epicardial and endocardial Activation Time Duration before
and at the maximal amount of ajmaline administration in these specified areas
(subtricuspid area, the mid RV area, RVOT, the LV anterior and LV
posterolateral) as calculated by ECG imaging.
Electrocardiographic parameters (PQ, QRS and QTc intervals, the occurrence of
the type I Brugada pattern, terminal activation duration) before, during and
directly after ajmaline provocation.
Other study parameters:
Patient demographics: Sex, Age, Past medical history (including previous
episodes of ventricular tachycardia and the results of cardiovascular
diagnostic test, for example cardiac holters, cardiac MRI and
echocardiography), Allergies, Family history of sudden cardiac death, the
amount of 2010 Task Force Criteria points for arrhythmogenic cardiomyopathy
(ACM) currently used medication, Weight (kg), Length (cm), Body mass index.
Laboratory parameters: Before ajmaline provocation: Creatinine and GFR, Sodium,
Potassium, ALAT, ASAT, GGT, AF, bilirubin.
Two weeks after ajmaline provocation: ALAT, ASAT, GGT, AF, bilirubin.
Background summary
Arrhythmogenic Cardiomyopathy (ACM) is a disease with a genetic origin and
involves cardiac desmosomes dysfunction and fibrofatty replacement of the
myocardium. Clinically, patients present with ventricular arrhythmias or sudden
cardiac death. Genetic testing in family members of patients with ACM shows
incomplete penetrance and variable expression, especially in the early disease
state. Unfortunately, currently used diagnostic test are unable to predict the
development of ACM in asymptomatic mutation carriers. This is bothersome, since
life threatening arrhythmias and sudden cardiac death might be the first signs
of disease progression.
Studies have shown that plakophilin-2 (PKP2) insufficiency due to PKP2 mutation
leads to down regulation of cardiac sodium channels along with the desmosomes.
This down regulation of sodium channels results in conduction slowing due to
dysfunction of the cardiac desmosomes and gap junctions. Earlier imaging
studies have shown that the electromechanical interval and RV deformation
imaging is abnormal in the subtricuspid area of the right ventricle (RV) even
in the early stage of disease. We hypothesize that provocation with a sodium
blocker such as ajmaline induces more pronounced electrical dysfunction of
those myocardial areas that are affected in the early stage of ACM. Therefore,
this ajmaline challenge could identify those mutation carriers who are at risk
for the development of ACM, arrhythmias and/or sudden cardiac death.
Study objective
Describe the electrocardiographic changes and areas of late myocardial
activation encountered in PLN and PKP2 mutation carriers during ajmaline
provocation and the relation of these differences to the development for early
stages of arrhythmogenic cardiomyopathy.
Study design
Multicentre, diagnostic trial and cohort study.
T0. Inclusion of patients ((1) patients with arrhythmogenic cardiomyopathy, (2)
asymptomatic mutation carriers, (3) controls.)
T1. Ajmaline provocation (T1): Electrocardiographic imaging will be performed
before and after ajmaline infusion.
T2. Laboratory follow up (T2) Two weeks after the ajmaline challenge the liver
parameters will be tested using a single peripheral blood sample.
Intervention
Ajmaline (class 1c sodium channel blocker, with a short half-life) infusion in
fractions of 10mg every minute up to a target dose of 1mg/kg.
Study burden and risks
Participants will undergo an ajmaline provocation test with a duration of
approximately 2 hours. During the provocation, electrocardiographic imaging and
the standard 12 lead ECG will be used to record cardiac activation times and
the effects of ajmaline on de- and repolarization parameters. This test will be
scheduled together with the other outpatients appointments. The risks of this
intervention are low when using the generally accepted infusion protocol and
the cardiac monitoring protocol, although there is a small risk of ventricular
arrhythmias. This risk is short term (during infusion and cardiac monitoring)
and minimalized with the protocol used for the ajmaline challenge. Ajmaline
provocation is widely used and has been proven to be safe in patients with the
suspicion of the Brugada syndrome.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
Age >=18 years
Pathogenic PLN mutation, pathogenic PKP2 mutation or patients without structural heart disease who are referred for ajmaline provocation to exclude Brugada syndrome.
Referral for cardiac MRI during routine clinical practice
New York Heart Association functional class <= 1.
Exclusion criteria
Severe hepatic impairment (Child-Pugh class C)
Severe renal dysfunction (eGFR <30 ml/min/kg)
Symptomatic heart failure, NYHA >= 2
Women who are currently pregnant
Known intolerance or contraindication to Ajmaline
Sick sinus syndrome, second or third degree AV block
Recent myocardial infarction
Known strong allergic reaction to ECG electrodes
Current use of anti-arrhythmic drugs (Bruagdadrugs.org list class I, IIa, IIb)
Current or recent use of amiodarone (within 6 months)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000752-18-NL |
| CCMO | NL65196.041.18 |