Body mass index related electrocardiographic findings in healthy young individuals with a normal body mass index.

INTRODUCTION: An increased body mass index (BMI) (>25 kg/m2) is associated with a wide range of electrocardiographic changes. However, the association between electrocardiographic changes and BMI in healthy young individuals with a normal BMI (18.5-25 kg/m2) is unknown. The aim of this study was to evaluate the association between BMI and electrocardiographic parameters. METHODS: Data from 1,290 volunteers aged 18 to 30 years collected at our centre were analysed. Only subjects considered healthy by a physician after review of collected data with a normal BMI and in sinus rhythm were included in the analysis. Subjects with a normal BMI (18.5-25 kg/m2) were divided into BMI quartiles analysis and a backward multivariate regression analysis with a normal BMI as a continuous variable was performed. RESULTS: Mean age was 22.7 ± 3.0 years, mean BMI was 22.0, and 73.4% were male. There were significant differences between the BMI quartiles in terms of maximum P-wave duration, P-wave balance, total P-wave area in lead V1, PR-interval duration, and heart axis. In the multivariate model maximum P-wave duration (standardised coefficient (SC) = +0.112, P < 0.001), P-wave balance in lead V1 (SC = +0.072, P < 0.001), heart axis (SC = -0.164, P < 0.001), and Sokolow-Lyon voltage (SC = -0.097, P < 0.001) were independently associated with BMI. CONCLUSION: Increased BMI was related with discrete electrocardiographic alterations including an increased P-wave duration, increased P-wave balance, a leftward shift of the heart axis, and decreased Sokolow-Lyon voltage on a standard twelve lead electrocardiogram in healthy young individuals with a normal BMI.

Intracoronary infusion of mononuclear cells after PCI-treated myocardial infarction and arrhythmogenesis: is it safe?

To reduce long-term morbidity after revascularised acute myocardial infarction, different therapeutic strategies have been investigated. Cell therapy with mononuclear cells from bone marrow (BMMC) or peripheral blood (PBMC) has been proposed to attenuate the adverse processes of remodelling and subsequent heart failure. Previous trials have suggested that cell therapy may facilitate arrhythmogenesis. In the present substudy of the HEBE cell therapy trial, we investigated whether intracoronary cell therapy alters the prevalence of ventricular arrhythmias after 1 month or the rate of severe arrhythmogenic events (SAE) in the first year. In 164 patients of the trial we measured function and infarct size with cardiovascular magnetic resonance (CMR) imaging. Holter registration was performed after 1 month from which the number of triplets (3 successive PVCs) and ventricular tachycardias (VT, ≥4 successive PVCs) was assessed. Thirty-three patients (20%) showed triplets and/or VTs, with similar distribution amongst the groups (triplets: control n = 8 vs. BMMC n = 9, p = 1.00; vs. PBMC n = 10, p = 0.67. VT: control n = 9 vs. BMMC n = 9, p = 0.80; vs. PBMC n = 11, p = 0.69). SAE occurred in 2 patients in the PBMC group and 1 patient in the control group. In conclusion, intracoronary cell therapy is not associated with an increase in ventricular arrhythmias or SAE.

The pharmacokinetics and effects of a long-acting preparation of superoxide dismutase (PC-SOD) in man.

AIM: To study the pharmacokinetics (PK), safety and tolerability of single rising doses up to 80 mg of superoxide dismutase covalently linked to lecithin (PC-SOD) in healthy White volunteers. METHODS: This double-blind, placebo-controlled, four-period cross-over study was performed in eight healthy volunteers (four male/four female). Three doses of PC-SOD (20, 40 and 80 mg) and placebo were administered intravenously in randomized order. Serum and urinary PC-SOD concentrations were measured predose and up to 96 h after dosing. In addition to standard safety measurements, the urinary excretion of N-acetyl-beta-glucosaminidase, alpha-glutathione S-transferase (alpha-GST) and pi-GST was measured to evaluate renal function. The PK of PC-SOD was analysed using noncompartmental and compartmental methods. RESULTS: All treatments were well tolerated, and no obvious relationship between adverse events and treatment was observed. No effects of PC-SOD on renal function could be detected. Dose normalized C(max) and AUC were not different between the different dosages, indicating linearity of plasma concentrations with dose. Estimated PC-SOD clearance was 2.54 ml min(-1)[95% confidence interval (CI) 2.07, 2.83]. The terminal half-life was estimated to be 1.54 days (95% CI 0.93, 2.15). SOD activity was elevated above baseline for 19 +/- 6 h after the 80-mg dose. CONCLUSIONS: Single intravenous administrations of PC-SOD in doses up to 80 mg were well tolerated in healthy White male and female volunteers. With the doses used, SOD activity was linearly related to the dose; after the 80-mg dose it was present for an appreciable period. These findings suggest that it is worthwhile to investigate PC-SOD in clinical conditions characterized by a high radical overload.

Disagreement between bedside and laboratory activated partial thromboplastin time and international normalized ratio for various novel anticoagulants.

During studies on warfarin, heparin and various anticoagulants with novel mechanisms of action, the activated partial thromboplastin time (aPTT) and the (apparent) international normalized ratio (INR) from a bedside monitor (Coagucheck Plus(R)) were compared with laboratory assay results. Data were compared using the Bland and Altman method of comparison where systematic differences result in significant slopes of the regression line. During heparin treatment, the bedside monitor largely underestimated the aPTT (slope = -0.80). During treatment with the direct thrombin inhibitor napsagatran (slope = 0.99), the pentasaccharides Org31540/SR90107A (slope = 0.77) and SanOrg34006 (slope = 0.35), and warfarin (slope = 0.60), the bedside monitor underestimated the aPTT at lower aPTT levels, while at higher aPTT levels it overestimated the laboratory values. The bedside monitor slightly overestimated the INR during treatment with warfarin (slope = 0.33). Apparent INR was largely overestimated during treatment with Org31540/SR90107A (slope = 1.38), SanOrg34006 (slope = 0.97), Napsagatran (slope = 1.23), and recombinant tissue factor pathway inhibitor (slope = 1.48, P < 0.001 for all regression lines). These results indicate that a substantial disagreement in aPTT or (apparent) INR exists between the bedside monitor and laboratory assay during treatment with the studied 'classic' and novel anticoagulants. The amount of disagreement depended on the anticoagulant given.

No Influence of acute hypertriglyceridemia on plasma t-PA in healthy male volunteers.

Dietary effects on liver blood flow may have biased the previously observed effects of hypertriglyceridemia on systemic tissue-type plasminogen activator (t-PA) concentrations. Therefore, in this study the effects of hypertriglyceridemia on plasma t-PA were determined by inducing hypertriglyceridemia with an intravenous fat emulsion (Intralipid) infusion. In a randomised crossover fashion, eight healthy male volunteers received Intralipid 10% (1.5 ml/min) or 0.9% saline for 2 h and 45 min. After 2 h of infusion, t-PA antigen, t-PA activity, t-PA/plasminogen activator inhibitor (PAI-1) complex, and PAI-1 activity were determined. Concomitantly, the effects of Intralipid t-PA clearance were determined from steady-state t-PA antigen concentrations of a 45-min recombinant tissue-type plasminogen activator (rt-PA) infusion (31.25 microg/min). Liver blood flow was assessed from steady-state concentrations of a continuous sorbitol infusion. Differences between treatments were calculated using the prevalue as the covariate. No significant differences were observed in mean+/-S.D. endogenous concentrations of t-PA antigen, 4.5+/-0.9/4.1+/-0.9 ng/ml (Intralipid vs. saline infusion; difference of 0.3 ng/ml, 95% confidence interval, CI: -0.2, 0.8); t-PA activity, 0.69+/-0.21/0.68+/-0.21 U/ml (difference of 0.04 U/ml, CI: -0.17, 0.25); t-PA/PAI-1 complex, 2.0+/-1.3/1.6+/-1.0 ng/ml (difference of 0.1 ng/ml, CI: -0.8, 0.6); and PAI-1 activity, 7.3+/-5.1/7.1+/-5.1 U/ml (difference of 0.26 U/ml, CI: -3.7, 4.3). Mean t-PA clearance and liver blood flow were unaffected by the Intralipid infusion. These results indicate that acute hypertriglyceridemia does not alter plasma fibrinolytic parameters in healthy male volunteers.

Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics.

PURPOSE: The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil-in-water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method. METHODS: Dermal delivery of lidocaine was estimated by microdialysis in 8 volunteers. Absorption coefficients and lag times were determined by pharmacokinetic modelling of the microdialysis data. Subsequently, the anaesthetic effect of the treatments was assessed by mechanical stimuli using von Frey hairs in 12 volunteers. RESULTS: The microemulsion formulation increased the cutaneous absorption coefficient of lidocaine 2.9 times (95% confidence interval: 1.9/4.6) compared with the O/W emulsion-based cream. Also, lag time decreased from 110 +/- 43 min to 87 +/- 32 min (P = 0.02). The compartmental pharmacokinetic model provided an excellent fit of the concentration-time curves with reliable estimation of absorption coefficient and lag time. A significant anaesthetic effect was found for both active treatments compared to placebo (P < 0.02), but the effect did not diverge significantly between the two formulations. CONCLUSIONS: The microemulsion vehicle can be applied to increase dermal drug delivery of lipophilic drugs in humans. The microdialysis technique combined with an appropriate pharmacokinetic model provides a high sensitivity in bioequivalence studies of topically applied substances.

No evidence for functional involvement of 5-HT2B receptors in serotonin-induced vasodilatation in the human forearm.

The receptor involved in the serotonin (5-hydroxytryptamine [5-HT])-induced vasodilatation in the human forearm has not yet been identified. Experimental data point to the 5-HT2B receptor located on the endothelium. RS-127445 (2-amino-4-(4-fluoronaphthyl-1-yl)-6-isopropylpyrimidine) is a novel potent and selective 5-HT2B receptor antagonist. The effect of oral RS-127445 (500 mg) on 5-HT-induced vasodilatation was studied in a double-blind, randomized, placebo-controlled, crossover study in six healthy volunteers. On each study day 5-HT (0.5 ng/kg/min) was infused into the brachial artery for 8 min, before drug administration and at intervals of 20, 65, 110, 230, and 470 min after oral ingestion. At each infusion, plasma samples for study drug assay were taken and forearm blood flow was assessed using venous occlusion plethysmography. Although (log) drug concentrations exceeded pKi, there was no correlation between RS-127445 concentrations and 5-HT-induced vasodilatation. 5-HT-induced vasodilatation did not differ between treatments and time points. It appears that there is no functional involvement of 5-HT2B receptors in 5-HT-mediated vasodilatation in the human forearm.

The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor.

OBJECTIVES: Recombinant tissue factor pathway inhibitor (rTFPI) has been shown to be an effective treatment in animal models of sepsis and is under investigation for human use. Reduced liver blood flow during septic shock may substantially alter the pharmacokinetics of rTFPI because clearance of rTFPI approaches liver blood flow. The aim of this study was to examine the effect of exercise-induced reduction in liver blood flow on the pharmacokinetics and pharmacodynamics of rTFPI. METHODS: This was a two-way, open-label, randomized crossover study in eight healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with intravenous sorbitol (50 mg/min) for 4 hours. Sorbitol was used as a biomarker for liver blood flow. The subjects were randomized to remain supine or to exercise on a bicycle ergometer for 30 minutes starting at the beginning of the third hour of the infusion. RESULTS: Exercise reduced liver blood flow (mean +/- SEM) from 1.44 +/- 0.06 L/min to 0.40 +/- 0.03 L/min. The average clearance of rTFPI decreased from 0.73 +/- 0.04 L/min in the supine position to 0.25 +/- 0.02 L/min during exercise. This decrease in rTFPI clearance resulted in an 80% (95% confidence interval [CI], 60% to 102%) increase in plasma rTFPI levels during exercise. The average maximal prothrombin time and activated partial thromboplastin time values during exercise were 1.4 (95% CI, 0.4 to 2.5) and 4.4 (95% CI, 2.7 to 6.1) seconds higher compared with the supine steady-state level. CONCLUSIONS: Reduction in liver blood flow by exercise markedly increased rTFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied.

The influence of the hand circulation on the assessment of venous distensibility of the human forearm with venous occlusion plethysmography.

AIMS: To determine the influence of the hand circulation on the determination of venous distensibility with venous occlusion plethysmography. METHODS: In a randomised study, duplicate measurements of forearm venous distensibility, with and without a wrist cuff, were made over occlusion periods of 3 and 12 min in eight volunteers. Treatments were compared with paired Student's t-tests and differences are presented as 95% confidence intervals (CI). Intra-subject variability was assessed with analysis of variance. RESULTS: Non-significant differences in increases in forearm volume between the occlusions with and without wrist cuff were found for the 3 min occlusion (CI: -0.4, + 0.2%) and the 12 min occlusion period (CI: -0.7, + 0.2%). However, the coefficient of variation was lower with the use of a wrist cuff; after 3 min occlusion (12% vs 19%) and after 12 min of occlusion (14% vs 24%). Forearm volume after 12 min of venous occlusion was 0.5% (CI: + 0.4, + 0.7) higher than after 3 min. CONCLUSIONS: Although venous distensibility was equal when assessed with and without wrist cuff, exclusion of the hand circulation reduces intraindividual variability. Equilibrium in forearm volume is not reached after 3 min period of venous occlusion, as often assumed. The magnitude of the additional increase after prolonged occlusion stresses the need for well-controlled studies.

Calculation of plasma concentrations of intra-arterially infused compounds in forearm plethysmography.

OBJECTIVE: Forearm blood flow plethysmography is a widely accepted in vivo technique for pharmacologic and functional studies in peripheral resistance vessels and veins. Pharmacological effects on forearm blood flow (FBF) are usually expressed by means of dose-response relationships. This approach does not consider the influence of variations in FBF on the actual plasma concentrations of compounds infused, and is less suitable for quantitative comparison of the pharmacologic characteristics of different compounds. The aim of this study was to validate an equation to estimate the plasma concentrations of intra-arterially infused compounds. This was done at different levels of FBF, using an indicator dilution technique with constant rate infusions of indocyanine green (ICG) and inulin. METHODS: ICG (0.5 mg/min) and insulin (5 mg/min) were infused into the brachial artery in the presence of sodium nitroprusside (10 ng/kg/min; to obtain high FBF), vehicle (0.9% saline; for intermediate FBF), and methoxamine (1 microgram/kg/min; for low FBF), FBF was measured using venous occlusion plethysmography in six healthy male volunteers. Plasma concentrations of the indicators, measured in venous blood samples, were compared with the calculated values. RESULTS: Excellent correspondence was observed between calculated and measured plasma concentrations for both ICG and inulin. Venous plasma concentrations of ICG (> or = 95% protein binding) reached steady-state within four min independent of FBF. Alternatively, the time required for venous plasma concentrations of inulin (not bound to protein) to reach steady-state appeared dependent on FBF. CONCLUSION: Total plasma concentrations of intra-arterially infused drugs can be appropriately estimated at the level of the arterioles by the proposed equation.

Comparison of cholinergic vasodilator responses to acetylcholine and methacholine in the human forearm.

In order to study the contribution of the nitric oxide (NO)-pathway to cholinergic vasodilatation in the resistance vessels of the human forearm, we infused acetylcholine (ACh; 0.1 1000 ng/kg/min) or methacholine (MCh; 0.1 A 100 ng/kg/min) in the presence of saline, the NO-scavenger and guanylate cyclase inhibitor methylene blue (MB; 1000 ng/kg/min), or the NO-synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 30 micrograms/kg/min) into the brachial artery of normotensive volunteers (n = 32), using venous occlusion plethysmography. We calculated the plasma concentrations of the infused compounds to obtain EC50-values (-log mol/l). ACh and MCh both caused concentration-dependent vasodilatation (EC50-values of 6.43 +/- 0.05 and 7.24 +/- 0.08, respectively). MB (13 mumol/l) did not change basal forearm blood flow (FBF) when administered alone, but it markedly potentiated the vasodilator response to ACh, shifting the concentration-response curve (CRC) leftwards by 1.5 log-step (p < 0.001). MB did not affect MCh-induced vasodilatation. L-NMMA (1 mmol/l) alone caused dose-dependent vasoconstriction that was subject to tachyphylaxis. In addition, L-NMMA caused a steepening of the slopes of the CRCs of ACh, and MCh L-NMMA attenuated the ACh-/MCh-induced vasodilator responses in the lowest concentration ranges (p < 0.05) only, but did not alter the response at higher concentrations. The 10-fold higher potency of MCh compared to ACh can be explained by the more rapid degradation of ACh by cholinesterases. The observation that high concentrations of L-NMMA only affect vasodilation mediated by low concentrations of ACh or MCh, suggests a second mechanism in cholinergic vasodilatation, such as a direct effect on smooth muscle cells or the release of a relaxing factor other than NO.

Cholinergic receptor-mediated responses in the arteriolar and venous vascular beds of the human forearm.

In arterioles, acetylcholine (ACh) is a well known vasodilator. However, in veins a wide variation in responses to ACh has been reported. In the present study the effects of the cholinergic agonists acetylcholine and methacholine (MCh) were determined simultaneously both in arterial and venous vasculature in the forearm vascular bed of healthy volunteers by means of venous occlusion plethysmography. The vasodilator sodium nitroprusside (SNP) served as an endothelium-independent control agent. The vascular beds were preconstricted by the selective alpha 1-adrenoceptor agonist methoxamine. Atropine, a non-selective muscarinic receptor antagonist, was used to antagonize the dilator effect of MCh. Overall we observed a weaker relaxant effect of ACh, MCh and SNP in the veins compared with their dilator responses in the arteries. ACh, which is highly sensitive to the hydrolytic inactivation by choline esterases, failed to induce a significant vasodilation in the venous vascular bed. Atropine blocked the dilator effects of MCh, indicating the involvement of muscarinic receptors. In arteries, MCh did not induce a significantly stronger vasodilatation than SNP on a molar basis. However, in veins, MCh had a weaker relaxant effect (p < 0.05).