Type of Anemia, Chronic Non-cardiovascular Illnesses, and Outcomes of Patients with ST-segment Elevation Myocardial Infarction.

OBJECTIVES: To assess the impact of different types of anemia and of concomitant non-cardiovascular chronic illnesses on outcomes of patients with ST-segment elevation myocardial infarction (STEMI) and baseline anemia admitted to the Intensive Cardiac Care Unit. METHODS: Based on the mean corpuscular volume, anemia was stratified into: microcytic (<80 fL), normocytic (≥80, <96 fL), and macrocytic (≥96 fL). Data on concomitant chronic non-cardiovascular illnesses including malignancies were carefully collected. Endpoints included in-hospital bleeding as well as all-cause mortality at long-term follow-up. RESULTS: Of 1,390 patients with STEMI, 294 patients had baseline anemia (21.2%), in whom normocytic, microcytic, and macrocytic anemia was present in 77.2%, 17.0%, and 5.8% patients, respectively. In-hospital bleeding occurred in 25 (8.5%) of the study population without significant differences between the three groups. At a mean follow-up of 5.5±3.5 years, 104 patients (35.4%) had died. Mortality was the highest in patients with macrocytic anemia, followed by patients with normocytic anemia and microcytic anemia (58.8%, 37.0%, and 20.0%, respectively; P=0.009). Chronic non-cardiovascular condition was identified as an independent predictor of both in-hospital bleeding (odds ratio=2.57, P=0.01) and long-term mortality (hazard ratio [HR] 1.54, P=0.019). Performance of coronary angiography within index hospitalization was associated with lower long-term mortality (HR 0.38, P=0.001). Mean corpuscular volume did not predict either in-hospital bleeding or mortality. CONCLUSIONS: Chronic non-cardiovascular illnesses are highly prevalent among patients with STEMI and baseline anemia, and are strongly associated with higher in-hospital bleeding and long-term mortality. Type of anemia is not related to prognosis post-STEMI.

Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice.

BACKGROUND AND AIMS: Increased oxidative stress is associated with accelerated atherosclerosis. Emerging evidence highlights the role of heparanase in atherogenesis, where heparanase inhibitor PG545 reduces oxidative stress in apolipoprotein E deficient mice (E0 mice). Herein, we studied the effects of PG545 on atherosclerosis progression in E0 mice. METHODS: Male E0 mice fed a high-fat diet (n = 20) were divided into 3 groups treated with weekly intraperitoneal injections of either low (0.2 mg/mouse) or high dose (0.4 mg/mouse)PG545 or normal saline (controls) for twelve weeks. Body weight and food intake were measured weekly. At the end of the treatment period, blood pressure was measured, animals were sacrificed and serum samples were collected and assessed for biochemical parameters and oxidative stress. Aortic vessels and livers were collected for atherosclerotic plaques and histopathological analysis, respectively. RESULTS: Blood pressure decreased in mice treated with low, but not high dose of PG545. In addition, heparanase inhibition caused a dose-dependent reduction in serum oxidative stress, total cholesterol, low-density lipoproteins, triglycerides, high-density lipoproteins, and aryl esterase activity. Although food intake was not reduced by PG545, body weight gain was significantly attenuated in PG545 treated groups. Both doses of PG545 caused a marked reduction in aortic wall thickness and atherosclerosis development, and liver steatosis. Liver enzymes and serum creatinine were not affected by PG545. CONCLUSIONS: Heparanase inhibition by PG545 caused a significant reduction in lipid profile and serum oxidative stress along with attenuation of atherosclerosis, aortic wall thickness, and liver steatosis. Moreover, PG545 attenuated weight gain without reducing food intake. Collectively, these findings suggest that heparanase blockade is highly effective in slowing atherosclerosis formation and progression, and decreasing liver steatosis.

Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545.

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-ß, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-ß) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI.