Coronary Atherosclerosis Clinical Trial
Official title:
DNA Damage and Repair Proteins In Patients With Atherosclerotic Coronary Artery Disease
The purpose of this study is:
1. To examine the association between stable and unstable coronary artery disease (CAD)
with markers of DNA damage and repair,
2. To examine the association between plaque morphology as assessed by frequency-domain
optical coherence tomography (FD-OCT) and markers of DNA damage and repair in order to
identify potential markers of plaque instability,
3. To examine the association between markers of DNA damage and repair and major adverse
cardiovascular events defined as death, MI and unplanned percutaneous or surgical
revascularization,
Hypotheses ----------------
We hypothesise that defective DNA damage response is an important aetiological factor in the
development of CAD, underlying CAD severity and development. If this hypothesis is true,
then we predict that:
1. There is differential expression of markers of DNA damage and repair in patients with
stable angina, a model of stable CAD, and patients with non ST-elevation myocardial
infarction (NSTEMI), a model of unstable CAD.
2. Differential expression of markers of DNA damage and repair correlate with plaque
morphology and stability as defined by FD-OCT,
3. Markers of DNA damage and repair can serve as distinguishing markers of stable and
unstable CAD,
Methodology
Study Population:
Patients presenting with stable angina undergoing percutaneous revascularization at
Ashford and St. Peter's Hospitals Foundation Trust will be prospectively enrolled. Data
regarding demographic, clinical, and procedural characteristics of patients will be
collected by the Ashford and St. Peter's Hospitals Foundation Trust research personnel
and entered into a secure, encrypted, dedicated database.
Pre-defined clinical and angiographic inclusion and exclusion criteria will be met as
per the DECODE study protocol.
FD-OCT (St. Jude Medical ILUMIEN OCT System) will be performed in all the three main
epicardial coronary arteries prior to target vessel PCI after administration of
glyceryl trinitrate. Data will be acquired in a designated, secure compute and sent to
a corelab for analysis. Quantitative measurements will include endoluminal area, plaque
area, as well as plaque parameters including thin- capped fibroatheromas (TCFA),
fibrous tissue, lipid core and calcium. TCFA will be defined by lipid-rich plaque with
cap thickness ≤ 65μm.
Culprit lesions will be defined according to electrocardiographic criteria (ST-segment
shift or T-wave inversion) and angiographic appearances (luminal irregularities
consistent with lesion ulceration, filling defect(s) consistent with thrombus, or point
of angiographic maximal stenosis) in patients with NSTEMI and angiographic stenosis ≥
70% in patients with stable angina not responding to at least two anti-anginal
medications.
Blood will be drawn immediately prior to percutaneous coronary intervention. In
addition to routine haematological and biochemical parameters (complete blood count,
white cell count, platelet count, creatinine, urea, sodium, potassium, cholesterol,
glucose, troponine I, creatinine phosphokinase, liver function tests and clotting
screen) one additional blood sample will be taken and separated into plasma and serum.
Polymorphonuclear leukocytes will be used for measurements of DNA damage and repair
proteins.
Clinical follow-up will occur at 30-day and 12-month from enrolment by telephone
interview and clinic visits. A repeat blood sample will be taken for analysis of DNA
damage and repair proteins.
DNA Damage
DNA damage will be analysed by measuring DNA strand breaks in cell pellets using the
comet assay. Serum oxidised purines will also be measured using an ELISA based assay.
The transcriptional activation of DNA damage proteins will be assessed by real time
PCR. For this, RNA will be isolated using a Roche High Pure Isolation kit. The RT2
First Strand Kit (SABioscience) will be utilised for reverse transcription of total
RNA. Automated PCR will be set up and the raw data will be normalised using the average
cycle threshold (ct) value of four housekeeping genes (B2M, RPL13A, GAPDH, and ACTB).
Whether differential gene expression leads to differential protein expression will be
determined by Western blotting. Moreover, the phosphorylation status of DNA damage
proteins will also be assessed.
DNA repair activity will also be assessed for several DNA repair enzymes important for
the repair of base damage generated by reactive oxygen and nitrogen species. DNA repair
activity will be measured by using in-vitro oligonucleotide-based cleavage assays.
Finally, we will then correlate measures of DNA damage and repair with patient
presentation (stable angina vs. NSTEMI), MACE, and FD-OCT derived parameters including
the number of TCFA, plaque volume and percentage of plaque components.
Statistical analysis
Statistical analysis will be performed using SAS version 8.2 (SAS institute Inc., Cary,
North Carolina). Biomarker parameters will be tested for an association with patient
presentation (stable angina vs. NSTEMI) and MACE using a log-rank test. OCT derived
parameters will be tested for an association with biomarkers using univariate Cox
proportional hazard regression. Parameters with a significance level of ≤0.1 on
univariate analysis will undergo multivariate Cox proportional hazard analysis. A p
value <0.05 will be considered statistically significant.
The recruitment period is anticipated to last 15-18 months, with data collation and
interpretation throughout recruitment and analysis anticipated to be complete by 24
months.
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