Impact of coronary collaterals on outcome following percutaneous coronary intervention (from the National Heart, Lung, and Blood Institute Dynamic Registry)

Coronary collateral circulation is beneficial in patients with coronary artery disease, but controversy still exists regarding the association between angiographic collaterals and outcome after percutaneous coronary intervention (PCI). We compared the baseline characteristics and cumulative 1-year event rates of consecutive patients undergoing PCI by target vessel collateral status-no angiographic evidence of collateral circulation (NC; n = 5051), treated artery supplied collaterals (SC; n = 239), and treated artery received collaterals (RC; n = 893)-using the National Heart, Lung, and Blood Institute Dynamic Registry. Patients in the SC group were older and had more previous coronary bypass surgery, myocardial infarction, co-morbid illness, and heart failure than the NC and RC groups and had less often undergone revascularization for acute myocardial infarction (p <0.01 for all). The total angiographic PCI success was comparable for the SC and NC groups but higher than for the RC group (94.1% vs 94.4% vs 83.9%, respectively; p <0.001). Overall stent use was 77.5% and was highest in the SC group (82.4%, p <0.001). At 1 year, significant differences in outcome were observed by collateral status. Compared with the NC group, patients with PCI of a SC artery had higher adjusted mortality (relative risk [RR] 1.95, 95% confidence interval [CI] 1.27 to 3.01, p = 0.002) and death/myocardial infarction (RR 1.75, 95% CI 1.26 to 2.45, p <0.001) rates. Patients with PCI of a RC vessel, conversely, had lower adjusted death/myocardial infarction (RR 0.72, 95% CI 0.54 to 0.96, p = 0.02) and repeat revascularization (RR 0.73, 95% CI 0.59 to 0.91, p = 0.005) rates. In conclusion, our results suggest that PCI on collateralized vessels is warranted, but that patients with PCI in arteries that supply collaterals are a high-risk group that may benefit from closer follow-up and complete revascularization.     

Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI Dynamic Registry)

Advances in percutaneous coronary intervention (PCI) have reduced complications but expanded indications. We used the National Heart, Lung, and Blood Insitute Dynamic Registry to determine clinical outcomes up to 1 year after PCI in 2,839 patients with at least 1 treated complex lesion (defined as a lesion showing evidence of thrombus, calcification, bifurcation or ostial location, or chronic occlusion) and 1,790 patients with only simple lesions treated. Complex lesion interventions were associated (p <0.05) with more sustained major dissections, distal embolization, side branch occlusion, and persistent flow reduction. Patients with treated complex lesions had a lower procedural success rate (93.8% vs 97.3%, p <0.001) and increased in-hospital rates (p <0.001) of death (2.0% vs 0.6%), death/myocardial infarction [MI] (5.2% vs 2.4%), or death/MI/coronary artery bypass graft [CABG] surgery (6.5% vs 2.9%). After adjustment for potential confounders, patients treated for multiple complex lesions were more likely to experience the in-hospital combined end points of death/MI (odds ratio 3.22, 95% confidence interval 2.10 to 4.92), or death/MI/CABG (odds ratio 2.55, 95% confidence interval 1.71 to 3.80). At 1 year, patients with treated complex lesions were more likely (p <0.001) to die (6.2% vs 3.7%), suffer death/MI (11.7% vs 7.5%), or death/MI/CABG/repeat PCI (27.2% vs 23.4%). Patients treated for multiple complex lesions were approximately 50% more likely to die or to have major adverse events than with patients only treated for simple lesions. An increased in-hospital adverse clinical event rate was independently noted for thrombotic, bifurcation, and calcified lesions, and bifurcation lesions had worse long-term event rates.     

Unreliability of exercise-induced R wave changes as indexes of coronary artery disease

To investigate the diagnostic value of exercise-related QRS amplitude changes, the responses of 40 young normal subjects and 28 patients with chest pain and no significant coronary arterial obstruction were compared with those of 73 patients with coronary arterial narrowing of various degrees of severity. All underwent submaximal, multiple lead multistaged treadmill exercise testing. The combined normal group showed an average decrease in R wave amplitude between rest and exercise of 1.1 ± 2.8 mm (mean ± standard deviation) in lead V₅; those with coronary artery disease had an increase of 0.6 ± 3.4 mm (P = 0.001). Similar but less pronounced differences were observed in lead II (a decrease of 1.9 ± 2.3 mm in normal subjects versus a decrease of 0.5 ± 3.1 mm in those with coronary disease, P = 0.01). When derived R wave criteria were used, the test sensitivity averaged 52 percent and the specificity 63 percent; these values were inferior to the sensitivity of 88 percent and specificity of 72 percent of S-T segment criteria in the same group of patients. No significant relation was found between the extent of coronary artery disease and R wave changes, and an analysis of multiple variables suggested possible correlations with factors not directly related to ischemia. It is concluded that exercise-induced QRS amplitude changes are unreliable predictors of the presence, absence or severity of coronary artery disease.     

Inhibition of c-kit ligand/steel factor by antibodies reduces survival of lethally irradiated mice

Survival after irradiation with LD100/30 (radiation dose lethal to 100% of mice in 30 days) is based on recovery of impaired hematopoietic function. Our previous studies using antibodies to interleukin-1 receptor (IL-1R), tumor necrosis factor (TNF), and IL-6 demonstrated that endogenous production of these three cytokines is required for untreated mice as well as mice protected with lipopolysaccharide (LPS), IL-1, or TNF to survive lethal irradiation. In this report we show that anti-c-kit ligand/steel factor (SIF) antibody similarly abrogates LPS- and IL-1-induced radioprotection. Furthermore, administration of this antibody to unmanipulated mice increased LD50/30 radiation lethality from 50% to 100%. Such an effect was not obtained using anti-IL-3, anti- IL-4, or anti-granulocyte-macrophage colony-stimulating factor antibody. Thus, like IL-1, TNF, and IL-6, SIF is required for survival from lethal irradiation.     

CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin

Background

CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.

Design and Methods

We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined.

Results

As assessed by flow cytometry, stem cell-enriched CD34⁺/CD38⁻/CD123⁺ leukemic cells expressed significantly higher levels of CD33 compared to normal CD34⁺/CD38⁻ stem cells. Moreover, highly enriched leukemic CD34⁺/CD38⁻ cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34⁺/CD38⁻ cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells.

Conclusions

CD33 is expressed abundantly on immature CD34⁺/CD38⁻ stem cells and may serve as a stem cell target in chronic myeloid leukemia.