Daria Orszulak-Michalak

Elevated resistin opposed to adiponectin or angiogenin plasma levels as a strong, independent predictive factor for the occurrence of major adverse cardiac and cerebrovascular events in patients with stable multivessel coronary artery disease over 1-year follow-up.

Summary Background Adipokines such as adiponectin and resistin, as well as angiogenin, may be associated with inflammation and atherosclerosis. The relationship between their levels and prognosis in high risk patients is, however, still unclear. The aim of this study was to evaluate the prognostic value of these adipokines in patients with stable multivessel coronary artery disease (MCAD). Material/Methods The study group comprised 107 MCAD patients (74% males, mean age 63±8 years). Adiponectin, resistin and angiogenin plasma levels were measured at admission and after 1-year follow-up. Primary end point (major adverse cardiac and cerebrovascular events – MACCE) was defined as cardiac death, nonfatal myocardial infarction, stroke, and hospitalization for angina or heart failure over a 1-year period. Results After 1-year follow-up, 9 (8%) patients died, all from cardiovascular causes. Primary end point was experienced by 32% of patients. Surgical treatment (CABG) was received by 51% of patients, while 49% were treated medically alone. Total cholesterol concentration levels ≥173 mg/dl were associated with a 7-fold increase (OR 7.3; 95% CI, 1.6–33.0); LDL ≥93.5 mg/dl with a 16-fold increase (OR 16.3; 95% CI, 2.8–93.8), and resistin ≥17.265 ng/ml with a 13-fold increase in MACCE risk (OR 13.5; 95% CI, 2.3–80.3). In multivariate analysis, a medical treatment strategy (p=0.001), a higher CCS class (p=0.004), resistin levels (p=0.003) and a higher Gensini score (p=0.03) were independent predictors of MACCE. Conclusions In stable patients with MCAD, elevated plasma resistin (as opposed to adiponectin or angiogenin) is a strong, independent predictive factor for the occurrence of MACCE over 1-year follow-up.

The beneficial impact of fasudil and sildenafil on monocrotaline-induced pulmonary hypertension in rats: a hemodynamic and biochemical study.

Pulmonary arterial hypertension (PAH) still cannot be cured effectively, hence the search for novel treatments continues. The effects of sildenafil (25 mg/kg body weight) and fasudil (30 mg/kg body weight) given alone or in combination, on normalization of right ventricular pressure (RVP), right ventricle mass, as well as the levels of several biomarkers (HDL-C, BNP, VEGF-A), were assessed in a rat model of monocrotaline (MCT)-induced PAH. MCT (60 mg/kg body weight) induced clear PAH in male Wistar rats. After 21 days, a significant decrease in RVP accompanied by a reduction of right ventricular hypertrophy - a significant decrease in the right ventricle/left ventricle plus septum ratio - as a result of sildenafil or fasudil administration was assessed. The administration of fasudil and sildenafil alone or in combination caused a significant decrease in plasma BNP level as compared to MCT-treated rats. Fasudil alone or with sildenafil, but not sildenafil alone, significantly increased HDL-C level as compared to MCT-treated rats. Fasudil and sildenafil given alone or in combination caused a significant increase in plasma VEGF-A level as compared to rats exposed to MCT.

Novel mechanistic and clinical implications concerning the safety of statin discontinuation

The beneficial effects of statins have been discussed widely, and their preventative role has been confirmed in cardiovascular disorders, primary and secondary prevention settings, and in asymptomatic subjects with a high cardiovascular risk. Despite these benefits, discontinuation of statins is frequent in cardiac patients and might be associated with adverse outcomes in several conditions involving acute coronary syndromes or acute stroke. In this review, we focus on the mechanistic background of statins that might contribute to such negative changes and that extend beyond cholesterol-lowering effects, including the so-called pleiotropic statin activity. In particular, findings regarding the detrimental impact of statin withdrawal on endothelial function, inflammation, platelet activity or AT1 signaling are discussed, along with the possible clinical implications for statin safety.

Differences in plasma gastrin, CEA, and CA 19-9 concentration in patients with proximal and distal colorectal cancer

SummaryAim. We investigated whether there are differences in plasma gastrin, as compared with carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 between patients with proximal and distal colorectal cancer. Gastrin concentration has also been analyzed, dependent on the tumor stage, in order to evaluate the possible prognostic role of this measurement.Methods. In 50 patients with colon cancer-fasting gastrin, CA 19-9 and CEA levels were evaluated.Results. Mean plasma-gastrin level in patients with distal tumor yielded 105.31 ± 12.5 µU/L and was significantly higher than in patients with the proximal tumor site (42.2 ± 3.1 µU/L) as well as in controls (p<0.001). No significant difference was observed between mean plasma gastrin in patients with proximal tumors and the control group. The mean CEA plasma level was significantly higher (p<0.01) in patients with distal tumors (9.1 ± 1.1 ng/mL) than in those with proximal tumors (1.48 ± 0.1 ng/mL). Similarly, the mean CA 19-9 plasma level was significantly higher (p<0.01) in patients with distal tumor (19.9 ± 2.1 U/mL) than in those with proximal tumor: 1.8 ± 0.2 U/mL. The mean gastrin plasma, CA 19-9, and CEA level was significantly higher in group of Duke’s stage C and D as compared to A and B.Conclusion. We speculate that observed differences in gastrin concentration in patients with distal and proximal tumors may contribute to the distinct pathogenesis and biological properties of those cancers. The significance of gastrin as a marker for diagnostic or prognostic purposes in colorectal cancer requires further study.

The current approach into signaling pathways in pulmonary arterial hypertension and their implication in novel therapeutic strategies.

Many mediators and signaling pathways, with their downstream effectors, have been implicated in the pathogenesis of pulmonary hypertension. Currently approved drugs, representing an option of specific therapy, target NO, prostacyclin or ET-1 pathways and provide a significant improvement in the symptomatic status of patients and a slower rate of clinical deterioration. However, despite such improvements in the treatment, PAH remains a chronic disease without a cure, the mortality associated with PAH remains high and effective therapeutic regimens are still required. Knowledge about the role of the pathways involved in PAH and their interactions provides a better understanding of the pathogenesis of the disease and may highlight directions for novel therapeutic strategies for PAH. This paper reviews some novel, promising PAH-associated signaling pathways, such as RAAS, RhoA/ROCK, PDGF, PPAR, and TGF, focusing also on their possible interactions with well-established ones such as NO, ET-1 and prostacyclin pathways.

Rosuvastatin, sildenafil and their combination in monocrotaline- -induced pulmonary hypertension in rat

Abstract There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline-induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development.

Concurrent Rho-Kinase and Tyrosine Kinase Platelet-Derived Growth Factor Inhibition in Experimental Pulmonary Hypertension

Background: We hypothesized that inhibition of Rho-kinase by fasudil, together with tyrosine kinase platelet-derived growth factor (PDGF) receptor inhibition by imatinib, results in greater pulmonary arterial hypertension (PAH) improvement. Methods: The effects of such regimens were investigated on hemodynamics, right ventricle hypertrophy, PDGF and ROCK in experimental monocrotaline (MCT)-induced pulmonary hypertension. Fourteen days after MCT injection, male rats were treated orally for another 14 days with imatinib, fasudil or their combination. Results: Concurrent imatinib and fasudil administration reversed an MCT-induced increase in right ventricular pressure more than either drug alone and decreased right ventricle hypertrophy (right ventricle weight to left ventricle plus septum weight ratio) significantly. The simultaneous administration of fasudil and imatinib caused a further decrease in plasma PDGF-BB levels compared to either drug alone. Conclusions: Inhibition of Rho-kinase by fasudil in addition to tyrosine kinase PDGF inhibition by imatinib can result in further PAH improvement. Such outcome may result from additional impact of the Rho-kinase inhibitor on the decrease in PDGF-induced effects.

The use of biodegradable polymers in design of cellular scaffolds.

The objective of this work was to demonstrate the usage of biodegradable polymers, made of calcium alginate and dibutyrylchitin, in the design of cellular scaffolds having broad application in reconstructive therapy (dentistry, orthopedics). To visualize cells seeded on calcium alginate and dibutyrylchitin polymers DAPI staining of fibroblasts nuclei was used. The cytotoxicity of the materials and microscopic evaluation of the viability of seeded cells was tested with a PKH 67 fluorescent dye. To assess the cellular toxicity the proliferation of fibroblasts adjacent to the tested polymers was examined. The vitability of cells seeded on polymers was also evaluated by measuring the fluorescence intensity of calcein which binds only to live cells. The conducted experiments (DAPI and PKH 67 staining) show that the tested materials have a positive influence on cell adhesion crucial for wound healing - fibroblasts. The self-made dibutyrylchitin dressing do not cause the reduction of viability of cells seeded on them. The in vitro study illustrated the interactions between the tested materials, constructed of calcium alginate or dibutyrylchitin and mouse fibroblasts and proved their usefulness in the design of cellular scaffolds. Examined polymers turned out to be of great interest and promise for cellular scaffolds design.

HMG-COA reductase inhibitors: An opportunity for the improvement of imatinib safety. An experimental study in rat pulmonary hypertension

BACKGROUND Co-administration of statin with imatinib is thought to result in greater improvement in pulmonary arterial hypertension (PAH) than imatinib treatment alone, and hence may allow greater effectiveness of imatinib therapy at lower doses. METHODS The effects of imanitib at dose of 20 and 50mg/kg bw given together with rosuvastatin or simvastatin were investigated with respect to right ventricle pressure (RVP), arterial blood pressure and right ventricle hypertrophy (RVH) in experimental monocrotaline (MCT)-induced pulmonary hypertension. Fourteen days after MCT injection, male rats were treated orally for another 14 days with imatinib, statin or a combination of the two. RESULTS Concurrent administration of statin (lipophilic simvastatin, hydrophilic rosuvastatin) and higher dose imatinib reversed the MCT-induced increase in RVP more than each drug alone and decreased RV hypertrophy (RV/LV+S ratio), significantly. The increased RVP and RV hypertrophy was found to be reversed when a lower dose of imatinib was co-administered with rosuvastatin or simvastatin. CONCLUSIONS Statins may intensify the beneficial effects of imatinib in PAH, which may be due to the additional influence of statin on the decrease of platelet-derived growth factor (PDGF)-induced effects. These properties allow the dose of imatinib used in PAH treatment to be reduced and thereby might improve its safety profile.

Effects of 4-week administration of simvastatin in different doses on heart rate and blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats

Introduction Statins and β1-adrenergic antagonists are well established in cardiovascular events therapy and prevention. The previous study showed that statins might impact on β-adrenergic signalling and blood pressure in a dose-dependent manner. The aim of the study was to evaluate the impact of 4-week administration of simvastatin given at different doses on the heart rate and blood pressure after injection of metoprolol in rats. Material and methods The experiments were performed in normocholesterolaemic and normotensive Wistar rats. Rats received simvastatin in doses of 1, 10 and 20 mg/kg body weight (bw) for 4 weeks. The control group received 0.2% methylcellulose. For the further estimation of the heart rate and blood pressure, metoprolol at 5 mg/kg bw or 0.9% NaCl was injected intraperitoneally. Results Simvastatin at doses of 1, 10 and 20 mg/kg bw did not influence the heart rate or blood pressure as compared to the control group. Metoprolol injection statistically significantly decreased the heart rate (439.29±14.03 min−1 vs. 374.41±13.32 min−1; p<0.05). In rats receiving simvastatin during the 4-week period after metoprolol injection, heart rate and blood pressure (mean, systolic, diastolic) were similar as compared to the group receiving metoprolol alone. Conclusions Simvastatin administration during a 4-week period in different doses did not influence the heart rate or blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.