Faculty Bibliography

Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by heterogeneity of presentation, an undulating course, and elevated risk for premature cardiovascular disease. Platelets have been understudied as a relevant contributor. Yet, these cells, which contain transcripts and the necessary molecular machinery to conduct translation, are intercellular regulators of inflammation and immune activation and play a key role in atherothrombosis. Platelets express low affinity type 2 receptors (FcgammaRIIA) whose ligand is the Fc portion of IgG. A single amino acid substitution, H131R, in the extracellular ligand binding domain increases the affinity for IgG and may account for individual variation in platelet activation, specifically an increase of function. Accordingly, this study addressed the hypothesis that FcyRIIA genotype associates with preclinical atherosclerosis and platelet hyperreactivity. Methods: Genotyping at rs1801274 (allelic discrimination, HWE P=NS) was performed in 71 SLE patients and 30 healthy controls. In 49 of the SLE patients and 30 healthy controls, carotid ultrasound for plaque (>50% increase over background IMT in any arterial segment); levels of soluble E-selectin as a proxy of endothelial cell activation; and C3, C4 to reflect complement activation were assessed. In 22 SLE patients, monocyteplatelet (MPA) and leukocyte-platelet aggregates (LPA), and light transmission aggregometry (LTA) in response to submaximal concentrations of collagen and arachidonic acid were evaluated. Results: Overall genotyping for FcgammaRIIA revealed 43 SLE patients carrying at least one copy of the variant allele and 28 patients who were homozygous for the ancestral allele. For the 49 with IMT, carotid plaque was reported in 22. A significant enrichment of carotid plaque was identified in patients with a variant compared to those who were homozygous ancestral (58% vs 25%, p=0.039). In contrast, among 30 healthy controls, the presence of carotid plaque was not associated with the variant or ancestral genotype (15% vs 15%). Soluble Eselectin (mean + 2SD, shown as dichotomous being above normal controls) was significantly increased in those patients with the variant vs ancestral (64% vs 23%, p=0.013). Complement levels, a proxy of circulating immune complexes, were lower in patients with the variant vs ancestral (64% vs 40%). With regard to platelet reactivity, among 22 SLE subjects evaluated, there was a significant increase in MPA and LPA (above controls, mean + 2SD) in those carrying at least one variant compared to the ancestral group (86% vs 37%, p=0.02 and 46% vs 12%, p=0.05, respectively). Platelet aggregation was more robust for those patients with the variant vs ancestral in response to 160 uM arachidonic acid and 1 ug/mL collagen (47% vs 19% and 47% vs 14%, respectively). Conclusion: These data suggest a model in which an FcgammaRIIA polymorphism associates with preclinical atherosclerosis and confers increased platelet activity in the setting of SLE, a disease characterized by circulating immune complexes

BACKGROUND: Type 2 myocardial infarction (MI) is defined as myocardial necrosis (myonecrosis) due to an imbalance in supply and demand with clinical evidence of ischemia. Some clinical scenarios of supply-demand mismatch predispose to myonecrosis but limit the identification of symptoms and ECG changes referable to ischemia; therefore, the MI definition may not be met. Factors that predispose to type 2 MI and myonecrosis without definite MI, approaches to treatment, and outcomes remain poorly characterized. METHODS: Patients admitted to an academic medical center with an ICD-9 diagnosis of secondary myocardial ischemia or non-primary diagnosis of non-ST-elevation MI were retrospectively reviewed. Cases were classified as either MI (n=255) or myonecrosis without definite MI (n=220) based on reported symptoms, ischemic ECG changes, and new wall motion abnormalities. RESULTS: Conditions associated with type 2 MI or myonecrosis included non-cardiac surgery (38%), anemia or bleeding requiring transfusion (32%), sepsis (31%), tachyarrhythmia (23%), hypotension (22%), respiratory failure (23%), and severe hypertension (8%). Inpatient mortality was 5%, with no difference between patients with MI and those with myonecrosis (6% vs. 5%, p=0.41). At discharge, only 43% of patients received aspirin and statin therapy. CONCLUSIONS: Type 2 MI and myonecrosis occur frequently in the setting of supply-demand mismatch due to non-cardiac surgery, sepsis, or anemia. Myonecrosis without definite MI is associated with similar in-hospital mortality as type 2 MI; both groups warrant further workup for cardiovascular disease. Antiplatelet and statin prescriptions were infrequent at discharge, reflecting physician uncertainty about the role of secondary prevention in these patients.

AIM: Left ventricular (LV) transient ischemic dilatation (TID) is not clear how it relates to inducible myocardial ischemia during stress echocardiography (SE). METHODS AND RESULTS: Eighty-eight SEs were examined from the site certification phase of the ISCHEMIA Trial. LV end-diastolic volume (EDV) and end-systolic volume (ESV) were measured at rest and peak stages and the percent change calculated. Moderate or greater ischemia was defined as >/=3 segments with stress-induced severe hypokinesis or akinesis. Optimum cut points in stress-induced percent EDV and ESV change that identified moderate or greater myocardial ischemia were analyzed. Analysis from percentage distribution identified a > 13% LV volume increase in EDV or a > 9% LV volume increase in ESV as the optimum cutoff points for moderate or greater ischemia. Using these definitions for TID, there were 27 (31%) with TIDESV and 12 (14%) with TIDEDV . By logistic regression analysis and receiver operating characteristic curves, the percent change in ESV had a stronger association with moderate or greater myocardial ischemia than that of EDV change. Compared to those without TIDESV , cases with TIDESV had larger extent of inducible wall-motion abnormalities, lower peak stress LVEF, and higher likelihood of moderate or grater ischemia. For moderate or greater myocardial ischemia detection, TIDESV had a sensitivity of 46%, specificity of 83%, positive predictive value of 70%, and negative predictive value of 64%. CONCLUSION: Transient ischemic dilatation by SE is a marker of extensive myocardial ischemia and can be used as an additional marker of higher risk.