Increased generation of platelet-derived microparticles following percutaneous transluminal coronary angioplasty

Platelet-derived microparticles that are produced during platelet activation bind to traumatized endothelium. Such endothelial injury occurs during percutaneous transluminal coronary angioplasty. Approximately 20% of these patients subsequently develop restenosis, although this is improved by treatment with the anti-platelet glycoprotein IIb/IIIa receptor drug abciximab. As platelet activation occurs during angioplasty, it is likely that platelet-derived microparticles may be produced and hence contribute to restenosis. This study population consisted of 113 angioplasty patients, of whom 38 received abciximab. Paired peripheral arterial blood samples were obtained following heparinization and subsequent to all vessel manipulation. Platelet-derived microparticles were identified using an anti-CD61 (glycoprotein IIIa) fluorescence-conjugated antibody and flow cytometry. Baseline clinical characteristics between patient groups were similar. The level of platelet-derived microparticles increased significantly following angioplasty in the group without abciximab (paired t test, P 0.019). However, there was no significant change in the level of platelet-derived microparticles following angioplasty in patients who received abciximab, despite requiring more complex angioplasty procedures. In this study, we have demonstrated that the level of platelet-derived microparticles increased during percutaneous transluminal coronary angioplasty, with no such increase with abciximab treatment. The increased platelet-derived microparticles may adhere to traumatized endothelium, contributing to re-occlusion of the arteries, but this remains to be determined.

Cholesteryl ester transfer protein genotypes associated with venous thrombosis and dyslipoproteinemia in males

Although numerous genetic and acquired factors are appreciated as risk factors for venous thromboembolism (VTE) [1,2], only recently have male gender [3,4], dyslipoproteinemia [5], and silent atherosclerotic vascular disease [6] been linked to VTE. We recently found that high-density lipoprotein (HDL) deficiency is a key feature of a pattern of dyslipoproteinemia that is associated with VTE in males, and we found that the common TaqI B1 variation in the cholesteryl ester transfer protein (CETP) gene is significantly linked to VTE [5]. However, the TaqI B1/B2 single nucleotide polymorphism (SNP) itself is unlikely to affect directly CETP activity, but it is linked to nonsynonymous CETP SNPs Ala373Pro and Arg451Gln [7–9]. Here, we demonstrate that these two CETP variations are associated with VTE and low plasma HDL levels in males.

Reversal of acute coagulopathy during hypotensive resuscitation using small-volume 7.5% NaCl adenocaine and Mg2+ in the rat model of severe hemorrhagic shock

OBJECTIVE: : Acute traumatic coagulopathy occurs early in hemorrhagic trauma and is a major contributor to mortality and morbidity. Our aim was to examine the effect of small-volume 7.5% NaCl adenocaine (adenosine and lidocaine, adenocaine) and Mg on hypotensive resuscitation and coagulopathy in the rat model of severe hemorrhagic shock. DESIGN: : Prospective randomized laboratory investigation. SUBJECTS: : A total of 68 male Sprague Dawley Rats. INTERVENTION: : Post-hemorrhagic shock treatment for acute traumatic coagulopathy. MEASUREMENTS AND METHODS: : Nonheparinized male Sprague-Dawley rats (300-450 g, n = 68) were randomly assigned to either: 1) untreated; 2) 7.5% NaCl; 3) 7.5% NaCl adenocaine; 4) 7.5% NaCl Mg; or 5) 7.5% NaCl adenocaine/Mg. Hemorrhagic shock was induced by phlebotomy to mean arterial pressure of 35-40 mm Hg for 20 mins (~40% blood loss), and animals were left in shock for 60 mins. Bolus (0.3 mL) was injected into the femoral vein and hemodynamics monitored. Blood was collected in Na citrate (3.2%) tubes, centrifuged, and the plasma snap frozen in liquid N2 and stored at -80°C. Coagulation was assessed using activated partial thromboplastin times and prothrombin times. RESULTS: : Small-volume 7.5% NaCl adenocaine and 7.5% NaCl adenocaine/Mg were the only two groups that gradually increased mean arterial pressure 1.6-fold from 38-39 mm Hg to 52 and 64 mm Hg, respectively, at 60 mins (p < .05). Baseline plasma activated partial thromboplastin time was 17 ± 0.5 secs and increased to 63 ± 21 secs after bleeding time, and 217 ± 32 secs after 60-min shock. At 60-min resuscitation, activated partial thromboplastin time values for untreated, 7.5% NaCl, 7.5% NaCl/Mg, and 7.5% NaCl adenocaine rats were 269 ± 31 secs, 262 ± 38 secs, 150 ± 43 secs, and 244 ± 38 secs, respectively. In contrast, activated partial thromboplastin time for 7.5% NaCl adenocaine/Mg was 24 ± 2 secs (p < .05). Baseline prothrombin time was 28 ± 0.8 secs (n = 8) and followed a similar pattern of correction. CONCLUSIONS: : Plasma activated partial thromboplastin time and prothrombin time increased over 10-fold during the bleed and shock periods prior to resuscitation, and a small-volume (~1 mL/kg) IV bolus of 7.5% NaCl AL/Mg was the only treatment group that raised mean arterial pressure into the permissive range and returned activated partial thromboplastin time and prothrombin time clotting times to baseline at 60 mins.

GABAB receptors expressed in human aortic endothelial cells mediate intracellular calcium concentration regulation and endothelial nitric oxide synthase translocation

GABAB receptors regulate the intracellular Ca2+ concentration ([Ca2+]i) in a number of cells (e.g., retina, airway epithelium and smooth muscle), but whether they are expressed in vascular endothelial cells and similarly regulate the [Ca2+]i is not known. The purpose of this study was to investigate the expression of GABAB receptors, a subclass of receptors to the inhibitory neurotransmitter γ-aminobutyric acid (GABA), in cultured human aortic endothelial cells (HAECs), and to explore if altering receptor activation modified [Ca2+]i and endothelial nitric oxide synthase (eNOS) translocation. Real-time PCR, western blots and immunofluorescence were used to determine the expression of GABAB1 and GABAB2 in cultured HAECs. The effects of GABAB receptors on [Ca2+]i in cultured HAECs were demonstrated using fluo-3. The influence of GABAB receptors on eNOS translocation was assessed by immunocytochemistry. Both GABAB1 and GABAB2 mRNA and protein were expressed in cultured HAECs, and the GABAB1 and GABAB2 proteins were colocated in the cell membrane and cytoplasm. One hundred μM baclofen caused a transient increase of [Ca2+]i and eNOS translocation in cultured HAECs, and the effects were attenuated by pretreatment with the selective GABAB receptor antagonists CGP46381 and CGP55845. GABAB receptors are expressed in HAECs and regulate the [Ca2+]i and eNOS translocation. Cultures of HAECs may be a useful in vitro model for the study of GABAB receptors and vascular biology.

GABAB receptors are expressed in human aortic smooth muscle cells and regulate the intracellular Ca2+ concentration

The aim of this study was to investigate the expression of GABAB receptors, a subclass of receptors to the inhibitory neurotransmitter gamma-aminobutyric acid (GABAB), in human aortic smooth muscle cells (HASMCs), and to explore if altering receptor activation modified intracellular Ca(2+) concentration ([Ca(2+)]i) of HASMCs. Real-time PCR, western blots and immunofluorescence were used to determine the expression of GABABR1 and GABABR2 in cultured HASMCs. Immunohistochemistry was used to localize the two subunits in human left anterior descending artery (LAD). The effects of the GABAB receptor agonist baclofen on [Ca(2+)]i in cultured HASMCs were demonstrated using fluo-3. Both GABABR1 and GABABR2 mRNA and protein were identified in cultured HASMCs and antibody staining was also localized to smooth muscle cells of human LAD. 100 μM baclofen caused a transient increase of [Ca(2+)]i in cultured HASMCs regardless of whether Ca(2+) was added to the medium, and the effects were inhibited by pre-treatment with CGP46381 (selective GABAB receptor antagonist), pertussis toxin (a Gi/o protein inhibitor), and U73122 (a phospholipase C blocker). GABAB receptors are expressed in HASMCs and regulate the [Ca(2+)]i via a Gi/o-coupled receptor pathway and a phospholipase C activation pathway

Walking performance, oxygen uptake kinetics and resting muscle pyruvate dehydrogenase complex activity in peripheral arterial disease

In the present study, we tested the hypothesis that walking intolerance in intermittent claudication (IC) is related to both slowed whole body oxygen uptake (Vo(2)) kinetics and altered activity of the active fraction of the pyruvate dehydrogenase complex (PDCa) in skeletal muscle. Ten patients with IC and peripheral arterial disease [ankle/brachial index (ABI) = 0.73 +/- 0.13] and eight healthy controls (ABI = 1. 17 +/- 0.13) completed three maximal walking tests. From these tests, averaged estimates of walking time, peak Vo(2) and the time constant of Vo(2) (tau) during submaximal walking were obtained. A muscle sample was taken from the gastrocnemius medialis muscle at rest and analysed for PDCa and several other biochemical variables. Walking time and peak Vo(2) were approx. 50 % lower in patients with IC than controls, and tau was 2-fold higher (P < 0.05). r was significantly correlated with walking time (r = -0.72) and peak Vo(2) (r = -0.66) in patients with IC, but not in controls. PDCa was not significantly lower in patients with IC than controls; however, PDCa tended to be correlated with tau (r = -0.56, P = 0.09) in patients with IC, but not in controls (r = -0.14). A similar correlation was observed between resting ABI and tau (r = -0.63, P = 0.05) in patients with IC. These data suggest that the impaired Vo(2) kinetics contributes to walking intolerance in IC and that, within a group of patients with IC, differences in Vo(2) kinetics might be partly linked to differences in muscle carbohydrate oxidation.

Strengthening cardiac rehabilitation and secondary prevention for Aboriginal and Torres Strait Islander peoples

This article summarises the findings of a project funded and supported by a principal committee of the National Health and Medical Research Council, the Health Advisory Committee, chaired by Professor Adele Green.

Influence of arterial compliance on presence and extent of ischaemia during stress echocardiography

Objective: To seek an association between total arterial compliance (TAC) and the extent of ischaemia at stress echocardiography. Design: Cohort study. Setting: Regional cardiac centre. Methods: 255 consecutive patients (147 men; mean (SD) age 58 (8)) presenting for stress echocardiography for clinical indications were studied. Wall motion score index (WMSI) was calculated and ischaemia was defined by an inducible or worsening wall motion abnormality. Peak WMSI was used to reflect the extent of dysfunction (ischaemia or scar), and Delta WMSI was indicative of extent of ischaemia. TAC was assessed at rest by simultaneous radial applanation tonometry and pulsed wave Doppler in all patients. Results: Ischaemia was identified by stress echocardiography in 65 patients (25%). TAC was similar in the groups with negative and positive echocardiograms (1.08 (0.41) v 1.17 (0.51) ml/ mm Hg, not significant). However, the extent of dysfunction was associated with TAC independently of age, blood pressure, risk factors, and use of a beta blocker. Moreover, the extent of ischaemia was determined by TAC, risk factors, and use of a b blocker. Conclusion: While traditional cardiovascular risk factors are strong predictors of ischaemia on stress echocardiography, TAC is an independent predictor of the extent of ischaemia.

Relationship between myocardial perfusion and dysfunction in diabetic cardiomyopathy: A study of quantitative contrast echocardiography and strain rate imaging

Objective: To use quantitative myocardial contrast echocardiography (MCE) and strain rate imaging (SRI) to assess the role of microvascular disease in subclinical diabetic cardiomyopathy. Methods: Stress MCE and SRI were performed in 48 patients (22 with type II diabetes mellitus (DM) and 26 controls), all with normal left ventricular systolic function and no obstructive coronary disease by quantitative coronary angiography. Real-time MCE was acquired in three apical views at rest and after combined dipyridamole-exercise stress. Myocardial blood flow (MBF) was quantified in the 10 mid- and apical cardiac segments at rest and after stress. Resting peak systolic strain rate (SR) and peak systolic strain (epsilon) were calculated in the same 10 myocardial segments. Results: The DM and control groups were matched for age, sex and other risk factors, including hypertension. The DM group had higher body mass index and left ventricular mass index. Quantitative SRI analysis was possible in all patients and quantitative MCE in 46 (96%). The mean e, SR and MBF reserve were all significantly lower in the DM group than in controls, with diabetes the only independent predictor of each parameter. No correlation was seen between MBF and SR (r = -0.01, p = 0.54) or between MBF and epsilon ( r = -0.20, p = 0.20). Conclusions: Quantitative MCE shows that patients with diabetes but no evidence of obstructive coronary artery disease have impaired MBF reserve, but abnormal transmural flow and subclinical longitudinal myocardial dysfunction are not related.

Are echo techniques comparable for measurement of left ventricular dysynchrony? Comparison of real time 3D and tissue Doppler echocardiography in patients with ischaemic cardiomyopathy

Tissue Doppler (TD) assessment of dysynchrony (DYS) is established in evaluation for bi-ventricular pacing. Time to regional minimal volume by real-time 3D echo (3D) has been applied to DYS. 3D offers simultaneous assessment of all segments and may limit errors in localization of maximum delay due to off-axis images.We compared TD and 3D for assessment of DYS. 27 patients with ischaemic cardiomyopathy (aged 60±11 years, 85% male) underwent TD with generation of regional velocity curves. The interval between QRS onset and maximal systolic velocity (TTV) was measured in 6 basal and 6 mid-cavity segments. Onthe same day,3Dwas performed and data analysed offline with Q-Lab software (Philips, Andover, MA). Using 12 analogous regional time-volume curves time to minimal volume (T3D)was calculated. The standard deviation (S.D.) between segments in TTV and T3D was calculated as a measure ofDYS. In 7 patients itwas not possible to measureT3D due to poor images. In the remaining 20, LV diastolic volume, systolic volume and EF were 128±35 ml, 68±23 ml and 46±13%, respectively. Mean TTV was less than mean T3D (150±33ms versus 348±54 ms; p < 0.01). The intrapatient range was 20–210ms for TTV and 0–410ms for T3D. Of 9 patients (45%) with significantDYS (S.D. TTV > 32 ms), S.D. T3D was 69±37ms compared to 48±34ms in those without DYS (p = ns). In DYS patients there was concordance of the most delayed segment in 4 (44%) cases.Therefore, different techniques for assessing DYS are not directly comparable. Specific cut-offs for DYS are needed for each technique.