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.

Dihydropyridines' metabolites-induced early apoptosis after myocardial infarction in rats; new outlook on preclinical study with M-2 and M-3.

Our previous studies established cardio-protective effects of furnidipine and its active metabolites called M-2 and M-3. The aim of current research was to compare the effects of single oral pretreatment with 20 mg kg(-1) of M-2 and M-3 on mortality, different forms of arrhythmias, blood pressures parameters and ST-segment changes during occlusion (for 90 min) and reperfusion in the model of myocardial infarction in rats evoked by left anterior descending coronary artery occlusion. Additionally, the development of programmed cell death and biochemical parameters in blood serum were studied at 4th day after infarction. Furnidipines' metabolites effectively reduced mortality index while did not markedly influence on blood pressures parameters, arrhythmias, ST-segment changes as well as biochemical parameters. Intriguingly, programmed cell death study (TUNEL) showed distinct increase in the amount of apoptotic nuclei in post-infarcted myocardium, granulation tissue and what is more in arteriolar walls after M-2 and M-3 application. Moreover, M-2 turned out to be more powerful in stimulation of apoptosis in granulation tissue surrounding infarcted area whereas M-3 presented balanced profile in this matter. Taking into account that programmed cell death plays positive role in post-infarcted heart healing, M-2 presents itself as more attractive agent for oral pretreatment in early stages of ischemia by non-stable individuals due to its more specific action in stimulation repairing processes in granulation tissue as well as in arteriolar walls. While M-2 and M-3 are common metabolites present in degradation pathways of many widely used dihydropyridines in clinic, this key fact put the new outlook on understanding additional mechanism and effects of not only furnidipines' metabolites but also other dihydropyridines.

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.

Risk stratification for complex ventricular arrhythmia complicating ST-segment elevation myocardial infarction.

OBJECTIVES: The primary aim of the study was to evaluate risk factors for ventricular fibrillation/sustained ventricular tachycardia (VF/VT) and to develop the risk score for prediction of VF/VT in patients with ST-segment elevation myocardial infarction (STEMI) treated invasively. The secondary aim was to assess the effect of VF/VT on mortality depending on timing of arrhythmia. PATIENTS AND METHODS: We analyzed 4363 consecutive patients with STEMI treated invasively. Among them, 163 patients with pre-reperfusion arrhythmia were excluded from the study. Group ventricular arrhythmias (VA) encompassed patients with VF/VT - those with reperfusion-induced arrhythmia were included into group VA1, whereas group VA2 consisted of patients with postreperfusion arrhythmia. The control group comprised patients free of VF/VT. RESULTS: VF or VT occurred in 313 (7.45%) patients - group VA1 encompassed 103 (32.9%) and group AV2 210 (67.1%) patients. Cardiogenic shock on admission [hazard ratio (HR) 3.5], new-onset atrial fibrillation (HR 2.1), incomplete revascularization (HR 1.7), prior myocardial infarction (HR 1.6) and symptom-to-balloon time more than 3 h (HR 1.3) were the independent predictors of VF/VT occurrence. In group VA2, the in-hospital and long-term mortality were 4- and 1.5-fold higher than in the arrhythmia-free population (20.5 vs. 4.5% and 36.2 vs. 22.6%, respectively; P<0.001). On the contrary, in group VA1, the long-term mortality was not significantly higher compared with the control group (26.2 vs. 22.6%; P=NS), whereas in-hospital mortality was almost three-fold increased (12.5 vs. 4.5%, respectively; P<0.001). CONCLUSION: The risk score based on simple clinical parameters might be useful for risk stratification for VF/VT in patients with STEMI. The predictive value of VF/VT was strongly dependent on timing of arrhythmia.

Cardiomyopathy development protection after myocardial infarction in rats: Successful competition for major dihydropyridines' common metabolite against captopril.

During the last 25 years angiotensin-converting enzyme inhibitors spectacularly conquered the field of cardiovascular diseases therapy. Nevertheless, lack of new studies concerning side effects associated with their chronic administration seems to be rather confusing. In our previous research, we proved that the main furnidipines' metabolite (M-2) possess multiple cardioprotective actions. Currently, we compared effects of post-infarction long-term oral treatment with M-2 and captopril on hemodynamic parameters and "ischemic cardiomyopathy" development in rats. Myocardial infarction was evoked by permanent left anterior descending coronary artery occlusion for 35 days. Surviving rats were treated with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6th- 35th day. At 35th day rats' hearts were tested on working heart setup, where following parameters were measured: heart rate, preload pressure, aortic systolic and diastolic pressures, aortic maximum rise and fall, aortic and coronary flow, myocardial oxygen consumption and oximetry in perfusate. Subsequently, heart tissue specimens were assessed during morphological estimation. Captopril caused significant heart rate increase and markedly diminished preload pressure in comparison to M-2. Both drugs evoked essential aortic pressure increase. Aortic flow was significantly decreased after M-2, whereas captopril increased this parameter in comparison to M-2. Both agents caused marked coronary flow increase. Morphologic examination in captopril revealed cardiomyopathic process in 70% of hearts, whereas in M-2 this value reached 30%. Neovascularization of post-infarcted myocardium was visible only after M-2 therapy. Concluding, M-2 presented itself as more attractive agent in long-term post-infarction treatment by preventing cardiomyopathy development, angiogenesis stimulation and preserving cardiac performance.

Fragmentation of the QRS complex in patients with acute coronary syndrome treated invasively.

BACKGROUND: Previous studies showed that the presence of fragmented QRS (f-QRS) in patients with acute coronary syndrome (ACS), who underwent complete revascularisation, is associated with worse prognosis and the possibility of arrhythmia occurrence. AIM: To assess the prognostic value of f-QRS in patients with ACS and complete revascularisation, in the context of cardiac ar-rhythmias. METHODS: We analysed 124 consecutive patients (66.1% males; mean age 62.38 ± 11.0 years) with ACS (STEMI 49%) treated invasively. Based on electrocardiogram (ECG) record, performed during the admission to the clinic, after the complete revascularisation (TIMI = 3) and during discharging from hospital (4th-5th days after ACS), we classified QRS as f-QRS based on generally accepted criteria (QRS < 120 ms, which included an additional R wave [R']) or notching in the nadir of the S wave, or > 1 R' (fragmentation) in two contiguous leads, corresponding to a major coronary artery territory. 24-h Holter ECG recording was performed on the fifth day after ACS to assess the frequency of conduction disturbances and others arrhythmias. RESULTS: There were no statistically significant differences between patients with and without f-QRS during hospitalisation. In the patients with f-QRS there were no statistically significant conduction disturbances and other arrhythmias compared to patients without f-QRS at discharge. CONCLUSIONS: In the patients with ACS, who underwent successful revascularisation (TIMI = 3), the presence of f-QRS is not correlated with a higher incidence of arrhythmias compared to patients without f-QRS in short-term follow-up.

Gender-dependent profile of heart rate turbulence parameters in patients after acute myocardial infarction treated invasively.

BACKGROUND AND AIM: The aim of this study was to determine whether gender is related to differences in heart rate turbulence (HRT) parameters and the authors' own predefined HRT categories comprising turbulence timing (TT) in patients at the early stage of acute myocardial infarction (AMI) treated invasively. METHODS: We analysed 489 consecutive patients (147 females and 342 males, aged 63.9 ± 11.7 years) with AMI admitted to our department and treated invasively on admission to the hospital. On the fifth day after MI 24-h digital Holter recordings were performed to assess HRT, and the following HRT parameters were calculated in all patients using the HRTView pro-gram: turbulence onset (TO, %), slope (TS, ms/RR interval), and TT. The following values of HRT parameters were considered abnormal: TO ≥ 0, TS ≤ 2.5, and TT ≥ 10. Based on the abovementioned parameters, the authors defined their own HRT categories (A, B, C): A - comprising three normal parameters, B - one abnormal parameter, C - three abnormal parameters. RESULTS: TT was significantly later in women than in men: 7.5 ± 3.1 vs. 6.8 ± 3.1 (p < 0.05), respectively. When analysing the authors' own predefined HRT categories, significant differences between women and men were present in the occurrence of the category C, including all three abnormal HRT parameters: TO, TS, and TT. CONCLUSIONS: In women worse TT was present and all three abnormal HRT parameters occurred more frequently. HRT in women after AMI is profoundly altered compared to in men. This indicates greater autonomic dysfunction and higher risk for sudden cardiac death in women after AMI.

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.