Michał Żorniak

Beneficial effects of l-leucine and l-valine on arrhythmias, hemodynamics and myocardial morphology in rats.

Branched chain amino acids (BCAA) have been shown to have a general protective effect on the heart in different animal models as well as in humans. However, so far no attempt has been made to specifically elucidate their influence on arrhythmias. Our study was performed to evaluate whether an infusion of either l-leucine or l-valine in a dose of 1mgkg(-1)h(-1) 10min before a 7-min period of left anterior descending artery occlusion followed by 15min of reperfusion, had an effect on arrhythmias measured during the reperfusion phase in the ischemia- and reperfusion-induced arrhythmias model in rats in vivo. The effect of the infusion of these substances on mean arterial blood pressure was monitored throughout the experiment. Both of the tested amino acids exhibited significant antiarrhythmic properties. l-Leucine reduced the duration of ventricular fibrillation (P<0.05) and l-valine decreased the duration of ventricular fibrillation (P<0.001) and ventricular tachycardia (P<0.05). The two amino acids were generally hypotensive. l-Valine lowered blood pressure in all phases of the experiment (P<0.05) while l-leucine lowered this parameter mainly towards the end of occlusion and reperfusion (P<0.05). In addition, 30min infusion of the amino acids in the used dose did not produce any apparent adverse histological changes that were remarkably different from control. In summary, the results of our study suggest that l-leucine and l-valine in the dose that was used attenuates arrhythmias and are hypotensive in their influence. Our findings lend support to the many ongoing investigations into the benefit of the application of l-leucine and l-valine in cardiology like their addition to cardioplegic solutions.

Portal vein thrombosis in cirrhosis is not associated with intestinal barrier disruption or increased platelet aggregability.

OBJECTIVE Portal vein thrombosis (PVT) is a common complication of cirrhosis, but its pathogenesis is unclear. We tested the hypotheses that PVT is the result of platelet hyperactivity or intestinal barrier disruption. METHODS This study included 49 patients with cirrhosis (15 females) of mixed etiology. Based on spiral computed-tomography, the patients were divided into two groups: with PVT (n=16) and without PVT (n=33). Serum biomarkers of intestinal barrier integrity were endotoxins and zonulin, and platelet activity was assessed with multiple electrode aggregometry. RESULTS The levels of endotoxin (43.5±18.3ng/ml vs. 36.9±7.5ng/ml; P=0.19) and zonulin (56.3±31.1ng/ml vs. 69.3±63.1ng/ml; P=0.69) were not different between the patients with and without PVT. Moreover, endotoxin and zonulin did not correlate with the coagulation and platelet parameters. The platelet aggregability measured with the TRAP and the ADP tests was decreased in PVT patients. In the logistic regression analysis the PVT incidence was related to the levels of D-dimer and bilirubin as well as the TRAP test results. Patients with PVT presented with significantly higher levels of D-dimer (4.45±2.59 vs. 3.03±2.97mg/l; P<0.05) and prothrombin levels (175±98.8μg/ml vs. 115±72.9μg/ml; P<0.05) than patients without thrombosis. PVT could be excluded with a 90% negative predictive value when the D-dimer level was below 1.82mg/l. CONCLUSIONS Endotoxemia and platelet activity are not determinants of PVT in patients with cirrhosis. The D-dimer measurement has diagnostic significance for PVT in patients with liver cirrhosis.

Serum omentin and vaspin levels in cirrhotic patients with and without portal vein thrombosis

AIM To investigate serum omentin and vaspin levels in cirrhotic patients; and to assess the relationship of these levels with hemostatic parameters, metabolic abnormalities, cirrhosis severity and etiology. METHODS Fifty-one cirrhotic patients (17 with portal vein thrombosis) were analyzed. Serum omentin and vaspin levels were measured with commercially available direct enzyme-linked immunosorbent assays (ELISAs). To assess platelet activity, the following tests were performed using a MULTIPLATE®PLATELET FUNCTION ANALYZER: (1) an ADP-induced platelet activation test; (2) a cyclooxygenase dependent aggregation test (ASPI test); (3) a von Willebrand factor and glycoprotein Ib-dependent aggregation (using ristocetin) test (RISTO test); and (4) a test for thrombin receptor-activating peptide-6 induced activation of the thrombin receptor, which is sensitive to IIb/IIIa receptor antagonists. RESULTS Omentin, but not vaspin, serum concentrations were significantly decreased in patients with portal vein thrombosis (PVT) (P = 0.01). Prothrombin levels were significantly increased in patients with PVT (P = 0.01). The thrombin receptor activating peptide (TRAP) test results were significantly lower in the PVT group (P = 0.03). No significant differences in adipokines serum levels were found regarding the etiology or severity of liver cirrhosis assessed according to the Child-Pugh or Model of End-Stage Liver Disease (MELD) scores. There was a significant increase in the TRAP (P = 0.03), ASPI (P = 0.001) and RISTO high-test (P = 0.02) results in patients with lower MELD scores. Serum omentin and vaspin levels were significantly down-regulated in patients without insulin resistance (P = 0.03, P = 0.02, respectively). A positive relationship between omentin and vaspin levels were found both when all of the patients were analyzed (r = 0.41, P = 0.01) and among those with PVT (r = 0.94, P < 0.001). CONCLUSION Serum omentin levels are increased in patients without PVT. Cirrhosis origin and grade do not affect omentin and vaspin levels. The analyzed adipokines do not influence platelet activity.

Differential action of two prolactin isoforms on ischemia-and re-perfusion-induced arrhythmias in rats in vivo

Background: The different influences of one of the PRL isoforms (PRL I) on the cardiovascular system have been described in the past. Aim: Our goal was to establish an appropriate iv dose of 2 PRL isoforms (PRL I and PRL II) in intact rats. After establishing this dose, PRL I (0.01 mg/kg) or PRL II (0.001 mg/kg) was administered in bolus 10 min before left anterior descending coronary artery occlusion (7 min) followed by re-perfusion (15 min). We then aimed to study and compare the effects of these isoforms on ischemia- and re-perfusion-induced arrhythmias in the ischemia and re-perfusion-induced arrhythmias model in rats. Materials and methods: Mortality index, ventricular fibrillation and tachycardia (VF, VT) incidence and duration, systolic, diastolic, and mean arterial blood pressure, heart rate and myocardial index of oxygen consumption [pressure rate product (PRP)] were measured and calculated. Results: Both PRL isoforms reduced animal mortality (from 50 to 18.75 and 25%, respectively). PRL II significantly reduced VF incidence (to 25%) as well as VT duration (18.21±3.09) and these effects were markedly different from PRL I and from the control group (p<0.05). Both PRL reduced PRP in the recovery phase (p<0.05). Conclusions: We proved that supra-physiological doses of PRL isoforms administered in bolus could protect against sudden cardiac death as well as severe arrhythmias episodes during re-perfusion. Because of PRL’s positive influence on the cardiovascular system and as an endogenous, well-tolerated substance, it might be of potential clinical use.

Vaspin mRNA levels in the liver of morbidly obese women with nonalcoholic fatty liver disease

The aim of this study was to evaluate hepatic vaspin mRNA in morbidly obese women with nonalcoholic fatty liver disease (NAFLD) and to look for its relationships with metabolic and histopathological features. The study included 56 severely obese women who underwent intraoperative wedge liver biopsy during bariatric surgery. Hepatic vaspin mRNA was assessed by quantitative real-time PCR. Vaspin mRNA found in all included patients was markedly higher in patients with body mass index (BMI) ≥ 40 kg/m2 (4.59 ±3.09 vs. 0.44 ±0.33; p = 0.05). An evident but statistically insignificant difference in vaspin mRNA levels was observed between patients with and without hepatocyte ballooning (4.77 ±4.23 vs. 0.45 ±0.29, respectively), with and without steatosis (4.80 ±4.20 vs. 0.41 ±0.29, respectively), without and with fibrosis (0.25 ±0.80 vs. 6.23 ±7.2, respectively), and those without and with lobular inflammation (0.27 ±1.0 vs. 5.55 ±10.1, respectively). There was marked difference in vaspin mRNA between patients with simple steatosis/borderline nonalcoholic steatohepatitis (NASH) compared to those with definite NASH (0.24 ±0.96 vs. 10.5 ±10.4). Adiposity is an undoubted confounding factor influencing vaspin levels. Hepatic vaspin mRNA seems to be markedly elevated in morbidly obese patients with more advanced NAFLD and when hallmarks of NASH were observed. Pointing to non-linear mRNA levels within the NAFLD spectrum and an evident increase in patients with fibrosis and definite NASH, the detrimental action of vaspin cannot be excluded.

New approach to molsidomine active metabolites coming from the results of 2 models of experimental cardiology

Molsidomine is a well-known vasodilatating, antianginal drug. Despite earlier studies with its metabolites (3-morpholino-syndnonimine (SIN-1) and N-nitroso-N-morpholino-amino-acetonitrile (SIN-1A)), which indicated a potential favorable cardioprotective activity, a lot of controversy remains. The aim of our research was to compare molsidomine, SIN-1, SIN-1A, and lidocaine influence on arrhythmias and hemodynamic parameters in 2 experimental models in rats. In the Langendorff heart study, SIN-1A markedly elevated left ventricular systolic pressure, maximum rise and fall of the first pressure derivative, coronary flow, and myocardial oxygen consumption. In addition, SIN-1A more so than SIN-1 significantly lowered creatine kinase release. The antiarrhythmic action of SIN-1 was observed, while lidocaine significantly diminished ventricular arrhythmias duration in comparison with the control. In the ischemia-reperfusion-induced arrhythmias model, hypotensive action of molsidomine was observed as well as the reduction in pressure rate product. Molsidomine also prolonged ventricular tachycardia duration. On the other hand, no significant effects on hemodynamic parameters as well as on ventricular arrhythmias were found in any of the SIN-1 and SIN-1A groups. In conclusion, our research suggests a possible direct, cardioprotective action of SIN-1A. It seems worthwhile to further investigate molsidomine derivatives, especially SIN-1A, because of its potential use in invasive cardiology procedures such as percutaneous transluminal coronary angioplasty.