Persistent circulating platelet and endothelial derived microparticle signature may explain on-going pro-thrombogenicity after acute coronary syndrome.

AIMS: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. METHODS & RESULTS: Circulating total annexin v + (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) origin were quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls. The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p = 1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. CONCLUSIONS: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of on-going inflammation, endothelial injury and may explain on-going pro-thrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy.

Association of systemic inflammatory biomarkers with morphological characteristics of coronary atherosclerotic plaque by intravascular optical coherence tomography.

Despite significant advances in preventive, medical, and interventional management, coronary artery disease remains the leading cause of death worldwide. We now know that in the majority of acute coronary syndromes, a thrombotic event is triggered either by the rupture or erosion of the so-called high-risk or 'vulnerable' plaque. However, accurately identifying the individual who is at significant risk of acute event remains the holy grail of preventive cardiology. To better stratify an individual's risk of developing and suffering a cardiovascular event, biomarkers are needed that can accurately predict coronary events and, if possible, monitor disease activity in response to medical or interventional therapies. In order to be able to understand the association of these biomarkers with the morphological substrate of high-risk plaques, intravascular imaging modalities can provide invaluable assistance. Novel imaging tools such as optical coherence tomography (OCT) have not only helped in identifying atherosclerotic plaque characteristics that are unstable but also in estimating global plaque burden. In this study, we provide an overview of our current knowledge of association of various inflammatory markers with atherosclerotic plaque characteristics seen on OCT.

Dynamic physiological temperature and pressure sensing with phase-resolved low-coherence interferometry.

We report the development and characterisation of highly miniaturised fibre-optic sensors for simultaneous pressure and temperature measurement, and a compact interrogation system with a high sampling rate. The sensors, which have a maximum diameter of 250 µm, are based on multiple low-finesse optical cavities formed from polydimethylsiloxane (PDMS), positioned at the distal ends of optical fibres, and interrogated using phase-resolved low-coherence interferometry. At acquisition rates of 250 Hz, temperature and pressure changes of 0.0021 °C and 0.22 mmHg are detectable. An in vivo experiment demonstrated that the sensors had sufficient speed and sensitivity for monitoring dynamic physiological pressure waveforms. These sensors are ideally suited to various applications in minimally invasive surgery, where diminutive lateral dimensions, high sensitivity and low manufacturing complexities are particularly valuable.

Reducing time to angiography and hospital stay for patients with high-risk non-ST-elevation acute coronary syndrome: retrospective analysis of a paramedic-activated direct access pathway.

OBJECTIVE: To assess whether a novel 'direct access pathway' (DAP) for the management of high-risk non-ST-elevation acute coronary syndromes (NSTEACS) is safe, results in 'shorter time to intervention and shorter admission times'. This pathway was developed locally to enable London Ambulance Service to rapidly transfer suspected high-risk NSTEACS from the community to our regional heart attack centre for consideration of early angiography. METHODS: This is a retrospective case-control analysis of 289 patients comparing patients with high-risk NSTEACS admitted via DAP with age-matched controls from the standard pan-London high-risk ACS pathway (PLP) and the conventional pathway (CP). The primary end point of the study was time from admission to coronary angiography/intervention. Secondary end point was total length of hospital stay. RESULTS: Over a period of 43 months, 101 patients were admitted by DAP, 109 matched patients by PLP and 79 matched patients through CP. Median times from admission to coronary angiography for DAP, PLP and CP were 2.8 (1.5-9), 16.6 (6-50) and 60 (33-116) hours, respectively (p<0.001). Median length of hospital stay for DAP and PLP was similar at 3.0 (2.0-5.0) days in comparison to 5 (3-7) days for CP (p<0.001). CONCLUSIONS: DAP resulted in a significant reduction in time to angiography for patients with high-risk NSTEACS when compared to existing pathways.

Intracoronary platelet and monocyte activation status within platelet-monocyte complexes are determinants of inflammation in ST elevation myocardial infarction1.

INTRODUCTION: Platelet Monocyte Complexes (PMCs) are commonly expressed in coronary artery disease but their pathologic significance in ST elevation myocardial infarction (STEMI) is unclear. This study evaluates the relationship between locally activated PMCs and intracoronary inflammation in stable and unstable coronary disease. MATERIAL AND METHODS: Micro catheter aspirated blood samples of 15 STEMI and 7 stable angina patients are collected from the coronary artery (CA), aorta (AO) and right atrium (RA). Samples are labelled with monoclonal antibodies and prepared for flow cytometry. CD 14 and CD 61 double positive cells are identified as PMC. P-selectin expression is identified by additional CD62P positivity and TF expression by additional CD142 positivity. Plasma TNF-alpha and IL-6 are measured using ELISA and CRP is measured in plasma using a high sensitivity automated microparticle enhanced latex turbidimetric immunoassay. RESULTS: No site-specific difference is seen in overall PMC expression in STEMI or stable angina. Surface P-selectin expression in STEMI [median (IQR)] is significantly higher in CA [35.01 (23.15-56.99)] compared with AO [15.99 (10.3-18.85)] or RA [14.02 (10.42-26.08)] (p = 0.003). Intracoronary PMC correlates significantly with intracoronary TNF-alpha (r = 0.87, p = 0.001) and intracoronary IL-6 (r = 0.76, p = 0.03). Bound monocytes within P-selectin positive and tissue factor positive complexes correlate positively with intracoronary TNF-alpha (r = 0.81, p = 0.008 & r = 0.80, p = 0.009 respectively) and IL-6 (r = 0.54, p = 0.16 & r = 0.71, p = 0.05 respectively). No such correlation is observed in the peripheral circulation of STEMI and stable angina patients. CONCLUSION: Inflammation is not attributable to PMC formation per se. However, increased intracoronary P-selectin expression by activated platelets and tissue factor expression by activated monocytes within the complexes are determinants of local intracoronary inflammatory burden in STEMI.

Pacemaker placement and shoulder surgery: is there a risk?

INTRODUCTION: Surgery to the anterior aspect of the shoulder is performed by many surgical specialties but the techniques used by our cardiology colleagues for insertion of cardiac pacemaker wires are often not appreciated by the surgical community. The deltopectoral approach has been used for open pacemaker wire insertion for many years by cardiologists. METHODS: We surveyed a group of subspecialty shoulder surgeons as well as orthopaedic trainees to see if this approach for pacemakers is well recognised. We tried to assess what level of knowledge exists regarding pacemaker placement in general as well as specific risks. RESULTS: There appears to be a paucity of knowledge regarding pacemaker placement and related patient safety issues in both surveyed groups. There was no difference between the two groups, suggesting that the level of knowledge does not increase with experience and specialisation. CONCLUSIONS: There is the potential to cause harm to patients if the insertion site and type of device is not identified before commencing surgery in this region and steps must be taken to minimise any intra-operative risk. There is a risk from direct injury to the pacemaker and/or leads as well as the hazards of using diathermy in close proximity to a pacemaker. There must be more widespread dissemination of this information in order to minimise risks to patients with pacemakers in situ.

Antithrombotic and interventional treatment options in cardioembolic transient ischaemic attack and ischaemic stroke.

Peer-reviewed data pertaining to anti-thrombotic and interventional therapy for transient ischaemic attack (TIA) or ischaemic stroke patients with non-valvular atrial fibrillation, atrial flutter, interatrial septal abnormalities, or left ventricular thrombus were reviewed. Long-term oral anticoagulant therapy with warfarin is the treatment of choice for secondary stroke prevention following TIA or minor ischaemic stroke in association with persistent or paroxysmal non-valvular atrial fibrillation or atrial flutter. If warfarin is contraindicated, long-term aspirin is a safe, but much less effective alternative treatment option in this subgroup of patients with cerebrovascular disease. Management of young patients with TIA or stroke in association with an interatrial septal defect is controversial. Various treatment options are outlined, but readers are encouraged to include these patients in one of the ongoing randomised clinical trials in this area. It is reasonable to consider empirical anticoagulation in patients with TIA or ischaemic stroke in association with left ventricular thrombus formation following myocardial infarction or in association with idiopathic dilated cardiomyopathy. If warfarin is prescribed, one should aim for a target international normalised ratio of 2.5 (range 2-3) to achieve the best balance between adequate secondary prevention of cardioembolic events and the risk of major haemorrhagic complications.

Antiarrhythmic and anti-ischaemic effects of angina in patients with and without coronary collaterals.

OBJECTIVE: To determine whether the changes in the manifestations of myocardial ischaemia during sequential angina episodes caused by exercise or coronary artery occlusion are collateral dependent. METHODS: 40 patients awaiting percutaneous transluminal coronary angioplasty for an isolated left anterior descending artery stenosis underwent three sequential treadmill exercise tests, with the second exertion separated from the first by 15 minutes, and from the third by 90 minutes; 28 patients subsequently completed two (> 180 s) sequential intracoronary balloon inflations with measurement of collateral flow index from mean coronary artery wedge, aortic, and coronary sinus pressures. RESULTS: On second compared with first exercise, time to 0.1 mV ST depression (mean (SD): 340 (27) v 266 (25) s) and rate-pressure product at 0.1 mV ST depression (22 068 (725) v 19 586 (584) beats/min/mm Hg) were increased (all p < 0.005), while angina and ventricular ectopic beat frequency were diminished (p < 0.05). This advantage, which had waned by the third effort, was independent of collateral flow index. Similarly, at the end of the second compared with the first coronary occlusion, ventricular tachycardia (21% v 0%, p < 0.05), ST elevation (0.47 (0.07) v 0.33 (0.05) mV, p < 0.005), and angina severity (6.1 (0.7) v 4.6 (0.7) units, p < 0.005) were reduced despite similar collateral flow indices. CONCLUSIONS: In patients with coronary artery disease, ventricular arrhythmias, ST deviation, and angina are reduced during a second exertion or during a second coronary occlusion. This protective effect can occur independently of collateral recruitment. These characteristics, together with the breadth and temporal pattern of protection, are consistent with ischaemic preconditioning.

Local and systemic expression of basic fibroblast growth factor in a patient with familial glomangioma.

Glomangiomas are rare cutaneous tumours composed of glomus cells, which are modified smooth muscle cells. The aetiology of this condition is thought to involve a mutation in a novel gene acting to regulate angiogenesis. We report a patient from a large family with three generations affected by familial multiple glomangiomas. We hypothesized that the growth factors basic fibroblast growth factor and vascular endothelial growth factor, which stimulate/regulate angiogenesis could be involved in the pathogenesis of these lesions. Therefore, using enzyme-linked immunosorbent assays and immunohistochemistry, respectively, we measured systemic and tissue levels of these growth factors in a patient with familial glomangiomas. In addition, we investigated endothelial mitogenicity of the patient's serum as a functional assay of systemic growth factor activity.

Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury.

Protein kinase C (PKC)-mediated regulation of the mitogen-activated protein kinases (MAPK) may play a role in the protection afforded by ischemic preconditioning (PC). Nitric oxide (NO) can influence MAPK activation via interaction with PKC or farnesylation of low-molecular-weight (LMWT) G proteins. However, we have recently reported the mechanism of NO-induced cardioprotection to be a PKC-independent process. Therefore, we investigated the role of LMWT G proteins and MAPK signaling in NO-induced cardioprotection against simulated ischemia-reoxygenation (SI-R) injury. Neonatal rat cardiomyocytes treated for 90 min with the NO donor S-nitroso-N-acetyl-l,l-penicillamine (SNAP) 1 mM were protected against 6 h of SI (hypoxic conditions at 37 degrees C with 20 mM lactate, 16 mM KCl at pH 6.2) and 24 h reoxygenation under normal culture conditions. NO-induced protection was blocked by the G protein inhibitor alpha-hydroxyfarnesylphosphonic acid (alphaHFP) 10 microM. We studied the time course of p42/44 and p38 MAPK dual-phosphorylation hourly during SI using phospho-specific antibodies. p38 was phosphorylated during SI and the peak phosphorylation was significantly delayed by SNAP pretreatment. The p38 inhibitor SB203580 1 microM, given during SI, protected against injury. Thus the delay in peak p38 activation may contribute to, rather than be the effect of, NO-induced cardioprotection. We have shown that p38beta does not contribute to the total p38 signal in our extracts. Thus there is no detectable beta isoform. We conclude that the main isoform present in these cells and thought to be responsible for the observed phenomenon, is the alpha isoform.

Mitochondria as targets for nitric oxide-induced protection during simulated ischemia and reoxygenation in isolated neonatal cardiomyocytes.

BACKGROUND: As shown previously, exposure to NO donors initiates protective mechanisms in cardiomyocytes that persist after removal of the donor, a form of pharmacological preconditioning. Because NO also affects mitochondrial respiration, we studied the effect of NO on mitochondrial Ca(2+) uptake. METHODS AND RESULTS: Neonatal rat ventricular myocytes in primary culture were exposed to 1 hour of simulated ischemia and 1 hour of reoxygenation (sI/R). Pretreatment with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) (1 mmol/L for 90 minutes), followed by washing and incubation for 10 to 30 minutes, reduced sI/R-induced cell death to 25.4% compared with control (propidium iodide exclusion assay, P<0.001). Short (10-second) exposures to SNAP reversibly suppressed mitochondrial respiration without a detectable change in mitochondrial potential. In contrast, treatment with SNAP for 90 minutes caused a modest but sustained mitochondrial depolarization, as judged by JC-1 fluorescence. SNAP pretreatment limited cellular Ca(2+) overload during ischemia (fura-2 ratio rose to 226+/-40% versus 516+/-170% of baseline, n=5, P<0.05) and prevented loss of cell membrane integrity during reoxygenation. SNAP pretreatment also significantly reduced the ability of mitochondria to accumulate Ca(2+) in the face of a similar cytosolic Ca(2+) load (peak rhod-2 fluorescence 133+/-4% versus 166+/-7% of baseline at similar fluo-3 levels, P=0.0004, n=52 and 25, respectively). CONCLUSIONS: Pretreatment with an NO donor induces a modest, sustained mitochondrial depolarization and protects cardiomyocytes from sI/R injury. The demonstrated reduction in mitochondrial Ca(2+) uptake possibly reduces cytosolic Ca(2+) overload, providing a likely mechanism for NO-induced protection.

Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes.

The aim of this study was to investigate the role of nitric oxide (NO) in a cellular model of early preconditioning (PC) in cultured neonatal rat ventricular myocytes. Cardiomyocytes "preconditioned" with 90 min of stimulated ischemia (SI) followed by 30 min reoxygenation in normal culture conditions were protected against subsequent 6 h of SI. PC was blocked by N(G)-monomethyl-L-arginine monoacetate but not by dexamethasone pretreatment. Inducible nitric oxide synthase (NOS) protein expression was not detected during PC ischemia. Pretreatment (90 min) with the NO donor S-nitroso-N-acetyl-L,L-penicillamine (SNAP) mimicked PC, resulting in significant protection. SNAP-triggered protection was completely abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) but was unaffected by chelerythrine or the presence of glibenclamide and 5-hydroxydecanoate. With the use of RIA, SNAP treatment increased cGMP levels, which were blocked by ODQ. Hence, NO is implicated as a trigger in this model of early PC via activation of a constitutive NOS isoform. After exposure to SNAP, the mechanism of cardioprotection is cGMP dependent but independent of protein kinase C or ATP-sensitive K(+) channels. This differs from the proposed mechanism of NO-induced cardioprotection in late PC.

Differential nitric oxide synthase activity in ischemic and idiopathic dilated cardiomyopathy.

We measured plasma nitrite and interleukin 1beta levels in patients with idiopathic dilated cardiomyopathy, ischemic cardiomyopathy, and in normal controls. Nitrite levels were abnormally high in both ischemic and idiopathic dilated cardiomyopathy, suggesting increased nitric oxide activity in these conditions.

Restrictive pericarditis.

BACKGROUND: Pericardial thickening is an uncommon complication of cardiac surgery. OBJECTIVES: To study pericardial thickening as the cause of severe postoperative venous congestion. SUBJECTS: Two men, one with severe aortic stenosis and single coronary artery disease, and one with coronary artery disease after an old inferior infarction. Both had coronary artery bypass grafting surgery. METHODS: Magnetic resonance imaging (MRI), Doppler echocardiography, and cardiac catheterisation. RESULTS: Venous pressure was raised in both patients. MRI showed mildly thickened pericardium, and cardiac catheterisation indicated diastolic equalization of pressures in the four chambers. Jugular venous pulse showed a dominant "Y" descent coinciding with early diastolic flow in the superior vena cava, and mitral and tricuspid Doppler forward flow proved restrictive physiology. The clinical background suggested pericardial disease so both patients had pericardiectomy. This proved the pericardium to be thickened; the extent of fibrosis also involved the epicardium. CONCLUSIONS: Although rare, restrictive pericarditis (restrictive ventricular physiology resulting from pericardial disease) should be considered to be a separate diagnostic entity because its pathological basis and treatment are different from intrinsic myocardial disease. This diagnosis may be confirmed by standard investigational techniques or may require diagnostic thoracotomy.