Katarzyna Mitręga

Comparison of Thiopental, Urethane, and Pentobarbital in the Study of Experimental Cardiology in Rats In Vivo

Background: Despite earlier research studying the influence of anesthetics in arrhythmia models, a lot of controversy remains. The aim was to compare the influence of three anesthetics (60 mg/kg thiopental, 1200 mg/kg urethane, 60 mg/kg pentobarbital intraperitoneally) on ventricular arrhythmias and to combine it with measured hemodynamic parameters to find the most suitable agent for such experiments. Method: In the model of ischemia- and reperfusion-induced arrhythmias in Sprague-Dawley rats, after left anterior descending coronary artery occlusion (7 minutes) and reperfusion (15 minutes), the following parameters have been measured or calculated: mortality index; ventricular fibrillation and tachycardia incidence and duration; systolic, diastolic, and mean arterial blood pressure; heart rate; myocardial index of oxygen consumption; and plasma creatine kinase concentration. Results: Evident depressive action of urethane on heart rate, blood pressures, and myocardial index of oxygen consumption should be reason enough to exclude it from use in such studies. Pentobarbital had no effect on arrhythmias, whereas thiopental was antiarrhythmic. Conclusions: Pentobarbital is the most suitable anesthetic offering stable hemodynamic values during arrhythmia studies. These hemodynamic values, which were similar to physiological values in awake rats, the long arrhythmia duration during reperfusion and approximately 50% mortality index are crucial parameters for evaluating antiarrhythmic drugs.

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.

Cardioprotective effects of an active metabolite of furnidipine in 2 models of isolated heart and on in vivo ischemia–induced and reperfusion-induced arrhythmias in rats.

Dihydropyridines are known not only to have antiarrhythmic effects but also to exert a significant cardiac depressive influence. We previously showed that M-2, an active and final metabolite of furnidipine, had cardioprotective effects without the marked cardiac depression seen with this dihydropyridine. We studied the influence of M-2 infusion (10−7 M) on hemodynamics during low-flow and regional ischemia in the rat working heart. We examined the protection conferred by M-2 infusion (10−7 M) against effects of veratridine-induced intracellular calcium overload in the Langendorff heart. Additionally, we performed an in vivo study to explore the effects of oral administration of M-2 at different times and doses, in the ischemia- and reperfusion-induced arrhythmias model. M-2 improved coronary flow during low-flow and regional ischemia while favorably maintaining aortic pressure parameters. M-2 provided outstanding protection against deleterious effects of calcium overloading by significantly preventing rise in left ventricular diastolic pressure and decrease in coronary flow. M-2 reduced mortality and incidence and duration of severe arrhythmias while exhibiting differential influence on blood pressure, which depended on dose and time of administration and could suggest its clinical indication. The results of our entire study establish a beneficial cardioprotective role of M-2, which exhibited pleiotropic effects on the ischemic heart by imparting protection in various ways. This combined with good tolerance, long duration of action, low toxicity, and relatively large therapeutic window makes M-2 a promising candidate as a precursor for a new chemical class of cardioprotective drugs.

Polish and European management strategies in patients with atrial fibrillation. Data from the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase (EORP-AF Pilot).

INTRODUCTION Despite continued efforts of the European Society of Cardiology (ESC) to unify management of patients with atrial fibrillation (AF) across Europe, interregional differences in guideline adherence are likely. OBJECTIVES The aim of the study was to compare treatment strategies depending on baseline characteristics of AF patients between Poland and other members of the European Union (EU). PATIENTS AND METHODS We analyzed the baseline data and treatment strategies in participants of the ESC registry: the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase. A total of 3119 consecutive patients with AF diagnosed within the last year were included in 67 centers from 9 countries, including 419 patients enrolled in 15 Polish centers. RESULTS A rhythm control strategy was more frequent in Poland than in other EU countries (20.8% vs 11.9%; P <0.0001). Catheter ablation for AF was also used more frequently in Polish cardiology wards (13.9% vs 8.3%; P = 0.0017), while amiodarone at discharge was used less frequently (12.0% vs 22.7%; P <0.0001). In-hospital use of vitamin K antagonists (VKAs) and non-VKA anticoagulants was less frequent in Polish patients with a CHA2DS2-VASc score of 2 or higher than in patients from other EU countries (61.1% vs 79.0%; P <0.0001), but overall anticoagulation rates at discharge were similar to those in other countries (83.3% vs 82.6%). CONCLUSIONS A rhythm control-oriented strategy in patients with AF with the use of ablation in cardiology wards is more frequent in Poland than in other EU countries. Similar to other EU countries, compliance with the ESC guidelines regarding anticoagulation in AF patients is suboptimal in Poland. Undertreatment was observed in a significant proportion of patients at high risk of stroke, while a large group of low-risk patients are overtreated. Differences between the types of recruiting centers in Poland and other EU countries might have influenced the results.

Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 μg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Differential Effects of Furnidipines’ Metabolites on Reperfusion-Induced Arrhythmias in Rats In Vivo

We previously established that furnidipine (FUR) and oxy dihydropyridines prevent rats mortality by strong reduction of the lethal arrhythmias in reperfusion. Therefore we decided to study the influence of three main metabolites (M-2, M-3, M-8) of FUR on ischemia-and reperfusion- induced arrhythmias and hemodynamic parameters in rat model to examine their independent activity. The metabolites (M-2, M-3, M-8) were given orally 20 mg/kg (24 and 1 h before ischemia). Mortality was significantly diminished in M-2 and M-3 treated groups with M-3 preventing animal mortality entirely. All three examined substances significantly reduced the duration and incidence of ventricular fibrillation (VF) with M-3, once again, completely preventing VF. Moreover, only M-3 significantly decreased the duration of ventricular tachycardia but had no influence on their incidence. Through the occlusion and reperfusion periods, M-2 and M-3 were markedly less hypotensive than M-8 and did not influence on heart rate. We conclude that two tested metabolites of FUR, M-3 and M-2 exhibited the most pronounced anti-arrhythmic effect being at the same time the most normotensive and therefore caused the most beneficial effects.

Prognostic value of collagen turnover biomarkers in cardiac resynchronization therapy: A subanalysis of the TRUST CRT randomized trial population

BACKGROUND A substantial proportion of patients do not respond to cardiac resynchronization therapy (CRT). Various echocardiographic and biochemical markers including collagen turnover biomarkers were suggested to predict CRT results. However, pathological significance of collagen turnover biomarkers in CRT remains controversial. OBJECTIVE The aim of the present study was to evaluate the relationship between levels of collagen turnover biomarkers (amino-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III [PIIINP]), N-terminal of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, and matrix metalloproteinases (metalloproteinase-2 and metalloproteinase-9) and echocardiographic response to CRT and clinical outcomes. METHODS The study population consisted of patients enrolled in the Triple Site Versus Standard Cardiac Resynchronization Therapy trial. Blood samples were obtained before implantation of a CRT with defibrillator. The levels of PIIINP, amino-terminal propeptide of procollagen type I, metalloproteinase-2, and metalloproteinase-9 were determined using commercially available ELISA kits. High-sensitivity C-reactive protein and NT-proBNP levels were determined in a standard way. RESULTS Samples were collected from 74 of 100 enrolled patients. The multivariate logistic regression analysis demonstrated that low PIIINP levels (odds ratio [OR] 3.56; 95% confidence interval [CI] 1.23-10.24; P = .017) and baseline ejection fraction (OR 2.14; 95% CI 1.11-4.11; P = .02) were favorably associated with echocardiographic response. PIIINP and NT-proBNP levels appeared to be independent predictors of all-cause mortality (PIIINP: OR 3.11; 95% CI 1.21-7.89; P = .033; NT-proBNP: OR 2.05; 95% CI 1.11-4.96; P = .039) and risk of major cardiac adverse event (PIIINP: OR 3.56; 95% CI 1.53-9.15; P = .007; NT-proBNP: OR 4.51; 95% CI 1.75-11.6; P = .001). PIIINP levels showed significant additive value in predicting mortality as compared with NT-proBNP levels, but they were not superior to ejection fraction in predicting response. Survival analysis with cutoff values identified by receiver operating characteristic analysis confirmed a significant benefit associated with low baseline PIIINP levels. CONCLUSION Low PIIINP levels are associated with favorable echocardiographic response and long-term survival in CRT recipients.

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.

Quality of life in patients with severe left ventricle dysfunction due to coronary artery disease

AbstractBackgroundThe majority of randomized trials comparing surgical treatment with percutaneous coronary intervention exclude patients with severe left ventricle dysfunction, resulting in the lack of a clear strategy for treatment.AimRetrospective post treatment evaluation of New York Heart Association classification (NYHA) and quality of life (QOL) in patients submitted to different methods of treatment.MethodologyPatients with Left Ventricle Ejection Fraction (LVEF) ≤ 30% and verified atherosclerotic lesions in their coronary arteries were divided into groups depending on the method of treatment: 1.Pharmacological Treatment (PT).2.Coronary Artery Bypass Graft (CABG).3.Percutaneous Coronary Intervention (PCI). NYHA classification and the quality of life were assessed during follow-up examination performed after the mean time of 28,16 months in all three groups. All patients received pharmacological treatment of heart failure according to current guidelines.ResultsFinally, 120 consecutive patients with severe dysfunction of left ventricle were enrolled in the study. Quality of Life was assessed after the mean time of 28,16 months in all three groups. QOL improved in the 58 percent of the patients in the pharmacological treatment group, 40 percent of the patients in the CABG group and 48 percent of the patients in the PCI group. Comparison between the groups did not reveal statistically significant differences: group 1 vs. 2 (p=0.48), 2 vs. 3 (p=1.0), 1 vs. 3 (p=0.11). The improvement of NYHA class in group of patients submitted to CABG treatment comparing to those patients who were only pharmacologically treated occurred in 8 patients and was statistically significant (p=0.00256). Improvement of NYHA class was achieved in 20 patients from the Pharmacological comparing to PCI group (p=0.055) and in 19 patients from the CABG comparing to PCI group (p=0.044) however these differences were not statistically significant.ConclusionsImprovement of NYHA functional class in patients with severe left ventricular dysfunction was statistically significant in patients submitted to CABG comparing to pharmacological treatment (p=0.00256). Improvement of QOL in particular groups was not statistically significant.

Usefulness of N-terminal-pro B-type natriuretic peptide as a heart failure marker in patients undergoing percutaneous left atrial appendage occlusion

BACKGROUND The left atrial appendage is involved in secretion of N-terminal-pro B-type natriuretic peptide (NT-proBNP). Percutaneous left atrial appendage occlusion (LAAO) for prevention of stroke may cause variations in NT-proBNP release. AIM This study aimed to assess the diagnostic value of NT-proBNP after LAAO. METHODS The study group comprised 53 patients in whom LAAO was performed. The patients with heart failure (HF) and reduced ejection fraction (EF) were allocated to group I (n = 16) whereas patients with no HF symptoms and EF > 40% were allocated to group II (n = 37). The symptomatic patients with EF > 40% were excluded. NT-proBNP values were measured prior to LAAO, at one-two days, and at three-month follow-up. EF, six-minute walk test (6MWT), and peak oxygen consump¬tion (VO2max) were assessed 24 h prior to LAAO and after three months. RESULTS Prior to LAAO the NT-proBNP level was higher in group I, when compared to group II (3084.74 ± 559.53 pg/mL vs. 808.02 ± 115.83 pg/ml, p < 0.01). In both groups there was a nonsignificant increase in NT-proBNP level at one-two days after LAOO (3100.14 ± 690.08 pg/mL in group I and 1012.09 ± 166.71 pg/mL in group II). At the three-month follow-up a fur¬ther increase of NT-proBNP level in group I (3852.73 ± 1025.78 pg/mL) and a decrease in group II (855.03 ± 107.49 pg/mL) was observed. The pairwise comparison between the means of 6MWT and VO2max showed no significant changes during follow-up. At baseline, NT-proBNP level of 988 pg/mL presented 87.5% sensitivity and 75.7% specificity for prediction of HF. Three months after LAAO, it increased to 1358 pg/mL (sensitivity 81.2%, specificity 78.4%). CONCLUSIONS When diagnosing HF in atrial fibrillation patients, the higher cut-off value of NT-proBNP should be used. NT-proBNP remains an appropriate diagnostic marker of HF in patients after LAAO.