Distribution of Cell-cell Junction Proteins in Arrhythmic Disorders
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age18+
SponsorSt. George's Hospital, London
About this trial
Every week in the UK, 12 apparently healthy and fit individuals under the age of 35 die suddenly, a tragic event known as sudden cardiac death (SCD). The investigators have shown that heritable cardiac disorders affect the distribution of proteins at the cardiac cell-cell junctions, the areas where cardiac cells are mechanically and electrically coupled. This knowledge has helped the investigators diagnose specific heart disorders in individuals thus reducing the risk and incidence of SCD. Yet, the primary material required is a heart sample. A heart biopsy is an invasive process that comes with risks and is not performed unless absolutely necessary. And it is impossible to obtain a heart sample from an individual that may be carrying a disease-causing mutation (and hence be at risk of SCD) but does not yet show evidence of disease manifestation. The investigators recently showed that buccal cells show changes in protein distribution equivalent to those exhibited by the heart,hence providing them with a surrogate tissue for the myocardium. The investigators aim to use buccal smears as a means to identify those at risk of SCD. Patients regularly seen at the cardiology clinics at St. George's Hospital can participate in the study. The investigators shall take a buccal smear simply by rubbing a soft brush at the inside of their cheek and smearing it on a slide. Most individuals willing to participate in the study will only have to provide the investigators with a sample once. However, in selected cases (for instance, if the patients show disease progression or have a change in medication) they may be asked to provide the investigators with a subsequent sample during one of their scheduled follow-up visits. The process takes only a few seconds, is totally risk- and pain-free and it is anticipated to have great implications in diagnosis and patient management.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Family members of victims of SCD evaluated at the same clinic for risk assessment and diagnosis. These groups include both individuals with clear disease manifestation (termed "affected") as shown by conventional diagnostic approaches (electrocardiography, echocardiography, cardiac MRI, Holter monitoring) as well as potential carriers of disease-causing mutations who, however, may not/not yet manifest any overt sign of cardiovascular abnormalities (termed "carriers"). These are typically family members of probands diagnosed with a heritable arrhythmic disorder or family members of a sudden cardiac death victim.
All individuals that fall in the above categories will be included regardless of their management (medication, devices, and surgical procedures).
Individuals with co-existing conditions will also be included and their medical history will be taken into account when interpreting the results of the immunohistochemical analysis.
Adult individuals (>18 years of age).
Disqualifiers
Individuals lacking decisional capacity.
Individuals with non-heritable, non-arrhythmic cardiac disorders (such as ischemic heart disease or inflammatory disorders) followed at St. George's University Hospitals NHS Foundation Trust.
Non-English speakers will be excluded from the study unless a translator is present who can thoroughly explain to them the research question/plan in order for them to provide an informed consent.
Trial population
Participants will include individuals that have arrhythmic disorders or are being evaluated for arrhythmic disorders due to a family history of sudden cardiac death at the cardiology center of St George's.
Trial design
Design model
Case-only
Time perspective
Retrospective
Treatments tested in this trial
obtaining a buccal smear sample
Diagnostic testA sample will be taken from the inside of the participants' cheeks using a soft brush
Treatment groups
26 Participants
are divided into 1 treatment groupGroup A: patients with arrhythmic disorders1 intervention
Trial outcomes
Primary outcomes
1
Alteration of Key Protein Distribution
We recruit individuals that have propensity to an arrhythmic disorder (ie. they are carriers of disease-causing mutations) or they have been already diagnosed with a heritable heart condition. The primary outcome measure is whether key proteins show altered localization in the eligible participants. We are reporting the number of participants that did show altered protein distribution at baseline. There is no unit of measurement for this outcome. Cheek smears are subjected to immunofluorescence staining and examined under a confocal microscope. The technique has been optimized to show a binary outcome: a protein is either at its normal location or not.
Time frame
This is a longitudinal study. Each participant will provide cheek smears at recruitment to assess baseline protein distribution. Thereafter, each participant will be asked to provide follow-up samples every 6 months for the duration of the study.Secondary outcomes
1
Correlation of Protein Distribution With Participants' Genotype
A potential secondary outcome of the research is whether the investigators can correlate protein distribution in the buccal mucosa with specific genotypes. The investigators' preliminary results on the cohort of patients with ACM suggest that mutations in different genes result in different protein distribution patterns within the buccal mucosa. Being able to predict the gene bearing the disease-causing mutation will significantly reduce the time and cost of genetic sequencing. Identifying the specific gene underlying a heritable arrhythmic disorder is of pivotal importance as increasingly developing genotype/phenotype correlations help individualized risk identification and patient management.
Time frame
This is a longitudinal study. Each participant will provide cheek smears at recruitment to assess baseline protein distribution. Thereafter, each participant will be asked to provide follow-up samples every 6 months for the duration of the study.2
Correlation of Treatments With Cx43 Distribution
Another potential outcome has to do with the effect changes in the patients' treatment plans may have on Cx43 distribution. Cx43 is the major gap junction protein responsible for the electrical coupling of the cells. It has been shown that patients with arrhythmic disorders show decreased distribution of Cx43 at the cell borders in their hearts and this has been associated with an increased risk for arrhythmias. The investigators' preliminary studies show that patients with cardiomyopathies show Cx43 remodeling in their buccal mucosa. If a patient seen at the arrhythmia service of St. George's shows Cx43 remodeling during initial sampling and in a follow-up visit his clinical care team deems necessary to change his treatment plan the investigators would like to study Cx43 distribution again during one of his/hers follow up visits. If the new treatment plan results in restoration of Cx43, this finding may be an indication of successful arrhythmia management.
Time frame
This is a longitudinal study. Each participant will provide cheek smears at recruitment to assess baseline protein distribution. Thereafter, each participant will be asked to provide follow-up samples every 6 months for the duration of the study.Sponsors and contacts
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Source ClinicalTrials.gov