Cardiac hemodynamics and proinflammatory cytokines during biatrial and right atrial appendage pacing in patients with interatrial block.

PURPOSE: Interatrial block (IAB) frequently coexists with sinus node disease and is considered a risk factor of left atrial dysfunction, atrial arrhythmias, and heart failure development. Conventional right atrial appendage (RAA) pacing impairs intra- and interatrial conductions and consequently prolongs P wave duration. Biatrial (BiA) pacing helps correct IAB, but its advantageous influence remains controversial. The aim of the study was to compare the effects of BiA and RAA pacing on cardiac hemodynamics and serum concentrations of inflammatory markers and neuropeptides. METHODS: Twenty-eight patients with IAB and preserved atrio-ventricular conduction treated with BiA pacing were studied. Standard invasive hemodynamic measurements were performed during BiA and RAA pacings. Furthermore, the influence of 1 week of BiA and RAA pacing on neuropeptides: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and markers of inflammation: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and neopterin was examined. RESULTS: BiA pacing resulted in significant increase of cardiac output (CO) and reduction of pulmonary capillary wedge pressure. We demonstrated significantly lower concentrations of ANP, hs-CRP, IL-6, and neopterin after 1 week of BiA in comparison to RAA pacing. BNP levels remained unchanged. CONCLUSIONS: BiA pacing in comparison to RAA pacing improves hemodynamic performance in patients with IAB and preserved atrio-ventricular conduction. BiA pacing is associated with reduction of ANP and markers of inflammation (hs-CRP, IL-6, and neopterin).

Inflammatory activation following interruption of long-term cardiac resynchronization therapy.

Previous observations suggest that cardiac resynchronization therapy (CRT) may exert an anti-inflammatory effect. The objective of this study was to evaluate the effect of temporary interruption of long-term CRT on plasma concentrations of proinflammatory cytokines and brain natriuretic peptide (BNP). The study group consisted of 54 patients (32 male and 22 female, mean age 64 years) with chronic heart failure (HF) treated with CRT. BNP, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and neopterin were measured three times: after 26-28 weeks of continuous CRT (CRT-on), 48 h after its cessation (CRT-off), and 48 h after switching the CRT-on again. CRT interruption resulted in a significant worsening of left ventricular systolic function: reduction of cardiac output (CO), dP/dt, and left ventricular ejection fraction (LVEF), as well as deterioration of mitral regurgitation in the CRT responder group. A significant increase in serum concentrations of hs-CRP, neopterin, IL-6, and BNP was noted in this subpopulation. In CRT nonresponders, no significant changes were observed. In responders the changes in serum concentrations of hs-CRP, IL-6, neopterin, and BNP, following CRT interruption, significantly correlated with the respective changes in thoracic fluid content (TFC) and inversely correlated with LVEF changes. Even short (48 h) interruption of long-term CRT led to a significant increase of proinflammatory cytokines and BNP concentrations in responders. The changes in hs-CRP, IL-6, neopterin, and BNP concentrations correlated with the change in TFC-marker of pulmonary congestion and inversely correlated with the change in LVEF.

Effect of polyamidoamine dendrimer G3 and G4 on skin permeation of 8-methoxypsoralene--in vivo study.

In the present study we have assessed the ability of (PAMAM) dendrimers G3 and G4 to facilitate transdermal delivery of 8-methoxypsoralen (8-MOP) in vivo. In vitro study using Franz diffusion cell revealed an enhanced transdermal flux for 8-MOP in complex with G3 and G4 dendrimer in relation to standard 8-MOP solution. In present study in vivo skin permeation potential of 8-MOP complex with G3 and G4 PAMAM dendrimer was assessed using confocal laser scanning microscopy (CLSM), which revealed an enhanced permeation of the 8-MOP to the deeper layers of the skin and significantly higher concentration in comparison with standard 8-MOP solution. Skin tissue 8-MOP concentration, evaluated by HPLC indicates that G3 and G4 PAMAM application significantly increase 8-MOP skin deposition in comparison with standard 8-MOP solutions after 1 and 2h. G4 appeared to be a more effective 8-MOP penetration enhancer than G3 PAMAM. Our results suggest the feasibility of G3 and G4 PAMAM dendrimers for transdermal delivery of 8-MOP resulting in better skin permeation and higher concentration of 8-MOP in epidermis and dermis of the drug that could help to improve effectiveness and safety of PUVA therapy.

Analysis of ventricular late potentials in signal-averaged ECG of people with epilepsy.

PURPOSE: There has been growing interest in cardiac disturbances in epilepsy patients and their etiologic role in the context of sudden death. Ventricular late potentials (VLPs) recorded on signal-averaged electrocardiography (SAECG) reflects delayed ventricular depolarization and identifies the structural or functional substrate for the ventricular tachycardia in the reentry mechanism. Therefore, abnormal SAECG poses the potential of identifying patients at increased risk of malignant ventricular arrhythmias and sudden cardiac death. The aim of this exploratory study was to screen epilepsy patients who were treated with established doses of antiepileptic drugs (AEDs) on the presence of VLPs. METHODS: Forty-five consecutive patients with the diagnosis of epilepsy and 19 healthy volunteers, aged younger than 46 years, participated in the study. Exclusion criteria included symptoms or signs of diseases other than epilepsy, in particular relating to heart disease or medication influencing the cardiovascular system, as well as seizure reported by patients that occurred <3 days before the ECG examination. The electrocardiogram was recorded according to the standard protocol. The seizure frequency was calculated based on the available data of epileptic events within the preceding 3 months. Disease duration was estimated by determining the time from the first reported seizure to the present. KEY FINDINGS: There were 22 patients (48%) in the epilepsy group and only one patient (5%) in the control group fulfilling the criteria for VLP (p = 0.0005). Subsequently, epilepsy patients were divided into two subgroups according to VLP presence. Patients with VLP had longer disease duration (p = 0.03) compared to those without VLP. Similarly, patients with VLP more frequently had refractory epilepsy (p = 0.03) and had higher monthly seizure frequency (p = 0.02). Analysis of the proportions of generalized seizures (GS) and focal seizures (FS) showed a tendency for higher number of generalized tonic-clonic seizures in the VLP group, but this did not reach statistical significance (p = 0.06). VLP patients tended to be more often on polytherapy (defined as more than one AED per patient) (p = 0.07) as compared to epilepsy patients without VLP. However, if the numbers of AEDs per patients among the subgroups were compared, patients with VLP were treated with more AEDs than patients without VLP (p = 0.01). The study was not sufficiently powered to pinpoint any particular drug or AED combination to influence the appearance of VLP in epileptic patients. In particular, there was no difference in valproate or carbamazepine exposure, considering the percentage of patients exposed or the total daily dose administered. SIGNIFICANCE: Epilepsy patients more frequently display abnormal SAECGs with VLPs as compared to the control population, and their presence correlates with the disease duration, uncontrolled seizures, and polytherapy. Further longitudinal studies are needed in order to stratify the risk of life-threatening ventricular events in epilepsy patients with VLPs.

Comparison of the acute hemodynamic effect of right ventricular apex, outflow tract, and dual-site right ventricular pacing.

BACKGROUND: We studied the acute effect of pacing at the right ventricular outflow tract (RVOT), right ventricular apex (RVA) and simultaneous RVA and RVOT-dual-site right ventricular pacing (DuRV) in random order on systolic function using impedance cardiography. METHODS: Seventy-three patients (46 males), aged 52-89 years (mean 71.4 years) subjected to routine dual chamber pacemaker implantation with symptomatic chronic II or atrioventricular block, were included to the study. RESULTS: DuRV pacing resulted in significantly higher cardiac index (CI) in comparison to RVOT and RVA and CI at RVOT was higher than at RVA pacing (2.46 vs 2.35 vs 2.28; P < 0.001). In patients with ejection fraction >50% significantly higher CI was observed during DuRV pacing when compared to RVOT and RVA pacing and there was no difference of CI between RVOT and RVA pacing (2.53 vs 2.41 vs 2.37; P < 0.001). In patients with ejection fraction <50%, DuRV and RVOT pacing resulted in significantly higher CI in comparison to RVA pacing while no difference in CI was observed between RVOT and DuRV pacing (2.28 vs 2.21 vs 2.09; P < 0.001). CONCLUSION: Dual-site right ventricular pacing in comparison to RVA pacing improved cardiac systolic function. RVOT appeared to be more advantageous than RVA pacing in patients with impaired, but not in those with preserved left ventricular function. No clear hemodynamic benefit of DuRV in comparison to RVOT pacing in patients with impaired systolic function was observed.

B-type natriuretic peptide as a marker of subclinical heart injury during mitoxantrone therapy in MS patients--preliminary study.

The aim of this study was to evaluate the plasma level changes of B-type natriuretic peptide (BNP), biochemical marker of heart failure, and echocardiographic parameters during mitoxantrone treatment in 22 multiple sclerosis (MS) patients (8 males, 14 females, mean age 37.1+/-6.6). Mitoxantrone (after mean cumulative dose of 58.0+/-7.0 mg/m(2)) did not alter left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), posterior wall thickness (PWT) and left ventricular end-diastolic volume (LVEDV). However, mean plasma level of BNP raised from 14.53+/-3.29 pg/ml at the baseline to 16.79+/-3.05 pg/ml and 18.83+/-4.90 pg/ml (P<0.01) after mean mitoxantrone dose of 30.7+/-5.9 mg/m(2) and 58.0+/-7.0 mg/m(2), respectively. These results strongly suggest subclinical myocardial dysfunction in mitoxantrone-treated group. We assume, that low-cost, repeated BNP measurements may be a good alternative for detection of early subtle myocardial injury in MS patients during routine mitoxantrone therapy.

[Influence of the antagonist of adenosine A1 receptors, 8-cyclopentyl-1 ,3-dipropylxanthine, upon the anticonvulsant activity of antiepileptic drugs in mice]. / Wplyw antagonisty receptorów adenozynowych A1, 8-cyklopentylo-1,3-dipropyloksantyny, na przeciwdrgawkowe dzialanie leków przeciwpadaczkowych u myszy.

BACKGROUND: Methylxanthine derivatives (theophylline, caffeine), nonselective antagonists of adenosine receptors, impair the anticonvulsant activity of antiepileptic drugs in experimental models of epilepsy. THE AIM OF THE STUDY: To answer a question whether the selective antagonist of adenosine A1 receptors, 8-cyclopentyl-1,3-dipropylxanthine (CPX), shares this negative propensity of methylxanthines upon the protective activity of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate) against maximal electroshock-induced seizures in mice. RESULTS: Acute CPX (up to 10 mg/kg) did not affect the electroconvulsive threshold but administered chronically for two weeks, it significantly lowered the threshold at 2.5 and 5 mg/kg. CPX (2.5 mg/kg) given acutely reduced only the protection offered by phenobarbital whilst injected chronically in the same dose, it did not only decrease the anticonvulsant action of carbamazepine. Acute CPX did not affect the brain concentration of phenobarbital but, interestingly, the selective adenosine A1 antagonist given chronically elevated the brain concentrations of phenobarbital and valproate, being only ineffective upon that of phenytoin. CONCLUSIONS: When given chronically, CPX is somewhat similar to theophylline and caffeine, however, these non-selective xanthine derivatives reduced the protective activity of all conventional antiepileptic drugs. Acute CPX expressed weaker negative effects when compared to theophylline or caffeine.

Pharmacotherapy changes following pacemaker implantation in patients with bradycardia-tachycardia syndrome.

The management of bradycardia-tachycardia syndrome (BTS) includes bradycardia and tachyarrhythmia therapy. At present, the treatment for symptomatic bradycardia in BTS patients is permanent cardiac pacing. The pharmacological treatment of atrial tachyarrhythmias comprises of rhythm and rate control, and prevention of thromboembolism. Patients with BTS often require both pacemaker and drug therapy. This article reviews the interactions of pacing and drug therapies in BTS. Drugs that alter cardiac electrophysiological properties may influence pacemaker indications, pacing mode selection, efficacy of pacing algorithms and pacing performance. Pacing by preventing drug-induced bradycardia increases the safety of pharmacotherapy and, thus, allows the intensification of those treatments. Pacing therapy and antiarrhythmic drugs used together as a hybrid therapy have a synergistic effect in the prevention of atrial tachyarrhythmias. Atrial-based pacing may reduce atrial tachyarrhythmia burden, allowing reduction of rhythm and rate control. Contemporary pacemakers' memory functions may help guide rhythm and rate control, as well as anticoagulation pharmacotherapy.

Biventricular versus right ventricular pacing decreases immune activation and augments nitric oxide production in patients with chronic heart failure.

INTRODUCTION: Immune system activation and oxidative stress are involved in the pathogenesis of heart failure (HF). We aimed to test the hypothesis that upgrading from right ventricular pacing (RVp) to biventricular pacing (BiVp) can counteract these phenomena. METHODS: 28 HF patients, with BiVp were switched to RVp for one week, and then returned to BiVp. Immediately prior to, and 48 h after the return to BiVp, left ventricular (LV) systolic function was evaluated by echocardiography, and serum N-terminal pro-brain natriuretic peptide (NTproBNP), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL6), nitric oxide metabolites (NO(x)) and malondialdehyde (MDA) were assayed. RESULTS: LV systolic function significantly improved 48 h after switching from RVp to BiVp: Ao-VTI (p<0.001), SV (p<0.001) and CO (p<0.001), and mitral regurgitation significantly decreased (p=0.003). At the same time, indices of peripheral immune activation decreased: TNF-alpha (p=0.02) and IL6 (p<0.001). MDA decreased (p<0.001), whereas NO(x) increased (p=0.04). NTproBNP and CRP did not change. In addition, in "responders" (i.e. CO increase >10% during BiVp vs. RVp) NTproBNP decreased and NO(x) increased. However, during BiVp, the decreases in TNF-alpha, IL6, and MDA occurred both in responders and in non-responders and were accompanied by a reduction in mitral regurgitation. CONCLUSION: The beneficial effect of BiVp compared to RVp extends beyond improving cardiac haemodynamics and comprises a decrease in immune activation accompanied by an increase in serum NO(x) and decrease in serum MDA.

The influence of adenosine A3 receptor agonist: IB-MECA, on scopolamine- and MK-801-induced memory impairment.

The effects of adenosine A3 agonist IB-MECA on scopolamine- and MK-801-induced impairment of spontaneous alternation and learning abilities were examined using Y-maze and passive avoidance tasks in mice. IB-MECA given 20 min before test had no effect on spontaneous alternation performance. Similarly learning abilities tested in passive avoidance were not disturbed after IB-MECA administration before training session. IB-MECA significantly diminished scopolamine- and MK-801-induced impairment of spontaneous alternation in Y-maze and learning abilities in passive avoidance task as well as reduced higher locomotor activity in MK-801-treated group. This ameliorating effect of IB-MECA was not antagonised by adenosine A1 antagonists CPX. Obtained results indicate that adenosine A3 receptor stimulation may ameliorate spatial memory and long term memory impairments in terms of cholinergic and glutamatergic deficits induced by scopolamine and MK-801, respectively.

The epileptogenic effect of seizures induced by hypoxia: the role of NMDA and AMPA/KA antagonists.

Hypoxia of the brain may alter further seizure susceptibility in a different way. In this study, we tried to answer the question how episode of convulsion induced by hypoxia (HS) changes further seizure susceptibility, and how N-methyl-D-aspartic acid (NMDA) and AMPA/KA receptor antagonists influence this process. Adult Albino Swiss mice exposed to hypoxia (5% O(2)) developed clonic/tonic convulsions after about 340 s. Mice which underwent 10 s but not 5 s seizures episode subsequently exhibited significantly increased seizure susceptibility to low doses (equal ED(16)) of bicuculline (BCC) and NMDA during a 3-week observation period. No morphological signs of brain tissue damage were seen in light microscope on the third day after a hypoxia-induced seizure (HS). Learning abilities assessed in passive avoidance test as well as spontaneous alternation were not disturbed after an HS episode. Pretreatment with AMPA/KA receptor antagonist NBQX effectively prolonged latency to HS and given immediately after seizure episode also attenuated subsequent convulsive susceptibility rise, however, NMDA receptor antagonist, MK-801, appeared to be ineffective. These results suggest that a seizure episode induced by hypoxia, depending on its duration, may play an epileptogenic role. The AMPA/KA receptor antagonist prolongs the latency to HS, and given after this episode, prevents the long-term epileptogenic effect.

Nociceptin, OP4 receptor ligand in different models of experimental epilepsy.

The anticonvulsive activity of nociceptin, endogenous OP4 receptors agonist was investigated in pentylenetetrazole (PTZ), N-methyl D-aspartic acid (NMDA), bicucculine (BCC) and electrically evoked seizure models of experimental epilepsy. Nociceptin, at the dose of 10 nmol, suppressed the clonic seizures induced by PTZ, NMDA and BCC. [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which has been proposed to be selective antagonist OP4 receptors, did not prevent the action of nociceptin. The effect of [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 on seizures induced by PTZ, NMDA and BCC was very similar to that of nociceptin. These data support the hypothesis that it possesses agonistic properties. Naloxone did not reverse the anticonvulsive action of nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which excludes the participation of opioid receptor in this action. On the other hand in the electroconvulsive model of generalized seizures, nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 influenced neither the electroconvulsive threshold nor the maximal electroshock test. The data suggest that nociceptin and [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 can exert anticonvulsive action. These properties depend on OP4 but not opioid receptors activation.