Dataset Information

Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets.

ABSTRACT: A reliable method for the diagnosis of minimal cardiac ischemia would meet a strong demand for the sensitive diagnosis of coronary artery disease in cardiac stress testing and risk stratification in patients with chest pain but unremarkable ECGs and biomarkers. We hypothesized that platelets accumulate early on in ischemic myocardium and a newly developed technology of non-invasive molecular PET imaging of activated platelets can thus detect minimal degrees of myocardial ischemia. To induce different degrees of minimal cardiac ischemia, the left anterior descending artery (LAD) was ligated for 10, 20 or 60?min. Mice were injected with a newly generated scFv_{anti-GPIIb/IIIa}-⁶⁴CuMeCOSar radiotracer, composed of a single-chain antibody that only binds to activated integrin GPIIb/IIIa (?_IIb?_III) and thus to activated platelets, and a sarcophagine cage MeCOSar complexing the long half-life PET tracer copper-64. A single PET/CT scan was performed. Evans Blue/TTC staining to detect necrosis as well as classical serological biomarkers like Troponin I and heart-type fatty acid-binding protein (H-FABP) were negative, whereas PET imaging of activated platelets was able to detect small degrees of ischemia. Taken together, molecular PET imaging of activated platelets represents a unique and highly sensitive method to detect minimal cardiac ischemia.

SUBMITTER: Ziegler M

PROVIDER: S-EPMC5133579 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets.

Ziegler Melanie M Alt Karen K Paterson Brett M BM Kanellakis Peter P Bobik Alex A Donnelly Paul S PS Hagemeyer Christoph E CE Peter Karlheinz K

Scientific reports 20161202

A reliable method for the diagnosis of minimal cardiac ischemia would meet a strong demand for the sensitive diagnosis of coronary artery disease in cardiac stress testing and risk stratification in patients with chest pain but unremarkable ECGs and biomarkers. We hypothesized that platelets accumulate early on in ischemic myocardium and a newly developed technology of non-invasive molecular PET imaging of activated platelets can thus detect minimal degrees of myocardial ischemia. To induce diff ...[more]

PMID: 27909290

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:BACKGROUND:Prior studies with single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) have shown a survival benefit with early revascularization in patients with >10% to 12.5% ischemic myocardium. The relationship among positron emission tomography (PET)-derived extent of ischemia, early revascularization, and survival is unknown. OBJECTIVES:The purpose of this study was to evaluate the association among percent ischemia on PET MPI, revascularization, and survival. METHODS:A total of 16,029 unique consecutive patients who were undergoing Rubidium-82 rest-stress PET MPI from 2010 to 2016 were included. Patients with known cardiomyopathy and nondiagnostic perfusion results were excluded. Percent ischemic myocardium was estimated from a 17-segment model. Propensity scoring was used to account for nonrandomized referral to early revascularization (90 days of PET). A Cox model was developed, adjusting for propensity scores for early revascularization and percent ischemia, and an interaction between ischemia and early revascularization was tested. RESULTS:Median follow-up was 3.7 years. Overall, 1,277 (8%) patients underwent early revascularization and 2,493 (15.6%) died (738 cardiac). Nearly 37% of patients (n = 5,902) had ischemia, with 13.5% (n = 2,160) having ≥10%. In propensity-adjusted analyses, there was a significant interaction between ischemia and early revascularization (p < 0.001 for all-cause and cardiac death), such that patients with greater ischemia had improved survival with early revascularization, with a potential ischemia threshold at 5% (upper limit 95% confidence interval at 10%). There was no differential association between ischemia and early revascularization on death based on history of known coronary artery disease (interaction p = 0.72). CONCLUSIONS:In a contemporary cohort of patients undergoing PET MPI, patients with greater ischemia had a survival benefit from early revascularization. On exploratory analyses, this threshold was lower than that previously reported for SPECT. These findings require future validation in prospective cohorts or trials.

Dataset Information

Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets.

Publications

Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets.

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