Serum amyloid A receptor blockade and incorporation into high-density lipoprotein modulates its pro-inflammatory and pro-thrombotic activities on vascular endothelial cells.

The acute phase protein serum amyloid A (SAA), a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF) in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction-a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC). HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1), WRW4; receptor for advanced glycation-endproducts (RAGE), (endogenous secretory RAGE; esRAGE) and toll-like receptors-2/4 (TLR2/4) (OxPapC), before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL), a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.

Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury.

Treatments to inhibit or repair neuronal cell damage sustained during focal ischemia/reperfusion injury in stroke are largely unavailable. We demonstrate that dietary supplementation with the antioxidant di-tert-butyl-bisphenol (BP) before injury decreases infarction and vascular complications in experimental stroke in an animal model. We confirm that BP, a synthetic polyphenol with superior radical-scavenging activity than vitamin E, crosses the blood-brain barrier and accumulates in rat brain. Supplementation with BP did not affect blood pressure or endogenous vitamin E levels in plasma or cerebral tissue. Pre-treatment with BP significantly lowered lipid, protein and thiol oxidation and decreased infarct size in animals subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. This neuroprotective action was accompanied by down-regulation of hypoxia inducible factor-1α and glucose transporter-1 mRNA levels, maintenance of neuronal tissue ATP concentration and inhibition of pro-apoptotic factors that together enhanced cerebral tissue viability after injury. That pre-treatment with BP ameliorates oxidative damage and preserves cerebral tissue during focal ischemic insult indicates that oxidative stress plays at least some causal role in promoting tissue damage in experimental stroke. The data strongly suggest that inhibition of oxidative stress through BP scavenging free radicals in vivo contributes significantly to neuroprotection. We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection.

Medical graduates becoming rural doctors: rural background versus extended rural placement.

OBJECTIVES: To determine whether recruitment of rural students and uptake of extended rural placements are associated with students' expressed intentions to undertake rural internships and students' acceptance of rural internships after finishing medical school, and to compare any associations. DESIGN, SETTING AND PARTICIPANTS: Longitudinal study of three successive cohorts (commencing 2005, 2006, 2007) of medical students in the Sydney Medical Program (SMP), University of Sydney, New South Wales, using responses to self-administered questionnaires upon entry to and exit from the Sydney Medical School and data recorded in rolls. MAIN OUTCOME MEASURES: Students' expressed intentions to undertake rural internships, and their acceptance of rural internships after finishing medical school. RESULTS: Data from 448 students were included. The proportion of students preferring a rural career dropped from 20.7% (79/382) to 12.5% (54/433) between entry into and exit from the SMP. A total of 98 students took extended rural placements. Ultimately, 8.1% (35/434) accepted a rural internship, although 14.5% (60/415) had indicated a first preference for a rural post. Students who had undertaken an extended rural placement were more than three times as likely as those with rural backgrounds to express a first preference for a rural internship (23.9% v 7.7%; χ(2) = 7.04; P = 0.008) and more than twice as likely to accept a rural internship (21.3% v 9.9%; χ(2) = 3.85; P = 0.05). CONCLUSION: For the three cohorts studied, rural clinical training through extended placements in rural clinical schools had a stronger association than rural background with a preference for, and acceptance of, rural internship.

Stroke risk and antithrombotic strategies in atrial fibrillation.

BACKGROUND AND PURPOSE: Although the stroke rate associated with atrial fibrillation has declined over the last 10 years, the emerging atrial fibrillation epidemic threatens to increase the incidence of cardioembolic stroke. Summary of Review-Oral anticoagulants are superior antithrombotic agents but are underused due to fear of bleeding and uncertainty about which patients will benefit. Individualized decisions on antithrombotic therapy require balancing the competing risks of thromboembolism and bleeding. The CHADS2 (Congestive heart failure, Hypertension, Age > 75 years, and Diabetes mellitus, and 2 points for prior Stroke/transient ischemic attack) score and other schemes provide an estimate of thromboembolic risk; however, the external validity of these estimates in the context of well-controlled risk factors, or a hypercoagulable state, is uncertain. Moreover, it is very difficult to estimate bleeding risk. Recent studies highlight the need for meticulous international normalized ratio control to achieve optimal outcomes hampered by the high bleeding risk during oral anticoagulant inception and other limitations of warfarin. Dabigatran is at least as efficacious as warfarin in preventing stroke and systemic embolism for patients in whom the risk of thromboembolism outweighs bleeding risk. In addition, the results of ongoing trials evaluating alternative anticoagulants such as oral anti-Xa agents are awaited. In this review, we discuss emerging therapies including available and completed trials of direct antithrombins and anti-Xa agents, including ximelagatran, idraparinaux, and dabigatran; and new device therapies including left atrial appendage occlusion devices. CONCLUSIONS: In light of these promising new therapies, it is likely that atrial fibrillation thromboembolism guidelines will need to be rewritten and frequently updated.

Twelve-lead ambulatory electrocardiographic monitoring in Brugada syndrome: Potential diagnostic and prognostic implications.

BACKGROUND: Patients with Brugada syndrome (BrS) are diagnosed and risk stratified on the basis of a spontaneous or drug-induced type 1 electrocardiographic (ECG) pattern, often at single time points not accounting for variation throughout the day. OBJECTIVES: The purpose of this study was to prospectively assess the overall burden of type 1 Brugada ECG changes using 12-lead 24-hour Holter monitoring and evaluate association with cardiac events. METHODS: From July 1, 2013 to December 31, 2015, patients with BrS were recruited from 3 Australian centers and the Australian Genetic Heart Disease Registry. All patients underwent clinical review, baseline ECG, and 12-lead 24-hour Holter assessment with precordial leads placed in the left and right second, third, and fourth intercostal spaces. The frequency, temporal, and spatial burden of type 1 BrS ECG pattern were analyzed and assessed for association with cardiac events. RESULTS: A total of 54 patients with BrS were recruited (n=44, 81% men; mean age 44 ± 13 years); the mean follow-up was 2.3 ± 2.5 years. Eleven of 32 patients (34%) initially classified as "drug-induced BrS" demonstrated a spontaneous type 1 pattern at least once over 24 hours. Patients with cardiac events had a significantly higher temporal burden of type 1 ST-segment elevation in the 24-hour monitoring period (total area under the curve 21% vs 15%; P = .008), being most pronounced between the hours of 1600 and 2400 (P = .027). CONCLUSION: Patients with BrS traditionally classified as drug-induced can exhibit spontaneous ECG changes with longer-term monitoring, particularly in the evening. Temporal burden on 12-lead Holter monitor was associated with cardiac events. Ambulatory 12-lead ECG monitoring may have potential utility in the diagnosis and risk stratification of patients with BrS.

Influence of history of heart failure on diagnostic performance and utility of B-type natriuretic peptide testing for acute dyspnea in the emergency department.

BACKGROUND: The aim of this study was to assess the impact of a history of heart failure (HF) on emergency department (ED) B-type natriuretic peptide (BNP) testing and impact of feedback of BNP level to ED physicians. METHODS: Admission BNP was measured in 143 patients (mean age 79 +/- 10 years) presenting to the ED with dyspnea. Emergency department physicians scored probability of HF as cause of dyspnea and categorized cause of dyspnea. An independent cardiologist determined cause of dyspnea after chart review. In 83 patients, ED physicians rescored and reclassified patients after BNP measurement and evaluated test utility. RESULTS: The area under the receiver operating characteristic curve for BNP diagnosis of HF cause of dyspnea was significantly worse in patients with history of HF than those without (0.74 vs 0.94, P < .01) and in those with left ventricular ejection fraction <50% (0.64 vs 0.87, P < .05). A BNP cut point of 100 pg/mL had 100% sensitivity but only 41% specificity for diagnosing acute HF, whereas a cut point of 400 pg/mL had 87% sensitivity and 76% specificity. Emergency department physicians rated BNP useful in 64% of patients, and diagnostic uncertainty was reduced from 53% to 25% (P < .001). CONCLUSION: B-type natriuretic peptide test performance for diagnosis of dyspnea cause is significantly reduced in patients with a history of HF and must be taken into consideration in the evaluation of such patients in the ED.

Development and testing of innovative patient resources for the management of coronary heart disease (CHD): a descriptive study.

BACKGROUND: Although heart disease is a major cause of morbidity and mortality the majority of patients do not access existing rehabilitation programs and patient resources are not designed to facilitate patient choice and decision-making. The objective of this study was to develop and test a series of risk factor modules and corresponding patient information leaflets for secondary prevention of CHD. METHODS: In phase one, a series of risk factor modules and management options were developed following analysis of literature and interviews with health professionals. In phase two, module information leaflets were developed using published guidelines and interviews of people with CHD. In phase three, the leaflets were tested for quality (DISCERN), readability (Flesch) and suitability (SAM) and were compared to the existing cardiac rehabilitation (CR) information leaflet. Finally, the patients assessed the leaflets for content and relevance. RESULTS: Four key risk factors identified were cholesterol, blood pressure, smoking and physical inactivity. Choice management options were selected for each risk factor and included medical consultation, intensive health professional led program, home program and self direction. Patient information needs were then identified and leaflets were developed. DISCERN quality scores were high for cholesterol (62/80), blood pressure (59/80), smoking (62/80) and physical activity (62/80), all scoring 4/5 for overall rating. The mean Flesch readability score was 75, representing "fairly easy to read", all leaflets scored in the superior category for suitability and were reported to be easy to understand, useful and motivating by persons with CHD risk factors. The developed leaflets scored higher on each assessment than the existing CR leaflets. CONCLUSION: Using a progressive three phase approach, a series of risk factor modules and information leaflets were successfully developed and tested. The leaflets will contribute to shared-decision making and empowerment for persons with CHD.

Atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disorder, and increases in prevalence with increasing age and the number of cardiovascular comorbidities. AF is characterized by a rapid and irregular heartbeat that can be asymptomatic or lead to symptoms such as palpitations, dyspnoea and dizziness. The condition can also be associated with serious complications, including an increased risk of stroke. Important recent developments in the clinical epidemiology and management of AF have informed our approach to this arrhythmia. This Primer provides a comprehensive overview of AF, including its epidemiology, mechanisms and pathophysiology, diagnosis, screening, prevention and management. Management strategies, including stroke prevention, rate control and rhythm control, are considered. We also address quality of life issues and provide an outlook on future developments and ongoing clinical trials in managing this common arrhythmia.

The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon.

OBJECTIVES: The aim of the study was to assess the angiographic and clinical benefits of the calcium T-channel blocker, mibefradil, in the coronary slow flow phenomenon (CSFP). BACKGROUND: The CSFP is characterized by delayed vessel opacification on angiography (Thrombolysis In Myocardial Infarction [TIMI]-2 flow) in the absence of obstructive epicardial coronary disease and is often associated with recurrent chest pain. METHODS: A total of 10 CSFP patients (46 +/- 9 years) underwent angiography before and 30 min after 50 mg mibefradil; off-line blinded analysis of angiographic data included comparisons of epicardial vessel diameter, TIMI flow grade and TIMI frame count. We also performed a randomized, double-blind, placebo-controlled, cross-over study to examine the long-term efficacy of mibefradil 100 mg/day on the frequency of total angina, prolonged angina (i.e., persisting >20 min) episodes, and sublingual nitrate consumption, during consecutive one-month treatment periods in 20 patients (age 51 +/- 12 years) with the CSFP. RESULTS: Without changing epicardial vessel diameter or rate-pressure product, mibefradil reduced the number of vessels exhibiting TIMI-2 flow from 18 to 5; furthermore, mibefradil significantly improved the TIMI frame count only in those vessels exhibiting TIMI-2 flow (28 +/- 18%, p < 0.005). Compared with placebo, mibefradil significantly reduced total angina frequency by 56% (p < 0.001), prolonged episodes of angina by 74% (p < 0.001), and sublingual nitrate consumption by 59% (p < 0.01); furthermore, mibefradil improved physical quality of life as assessed by the Health Outcome Study Short Form-36. CONCLUSIONS: These angiographic and clinical improvements produced by mibefradil support a microspastic pathogenesis of the CSFP.

Isolated hypertrophy of the basal ventricular septum: characteristics of patients with and without outflow tract obstruction.

BACKGROUND: Isolated basal septal hypertrophy (IBSH) of the left ventricle (LV) is not a well understood phenomenon, particularly in the presence of concomitant left ventricular outflow tract obstruction (LVOTO). We evaluated the prevalence of IBSH and compared those with and without LVOTO. METHODS: Retrospective observational study of 4104 consecutive patients undergoing echocardiography at a community cardiology practice and a hospital without specialized Hypertrophic Cardiomyopathy (HCM) service to determine prevalence of IBSH, defined as isolated hypertrophy (>15 mm) of the basal LV septum (BS) without hypertrophy elsewhere. Clinical, ECG and echocardiographic characteristics were compared in IBSH with and without LVOTO. RESULTS: Prevalence of IBSH was 5.8% (240/4104): mean (SD) age was 76.0y (10.4) with equal gender distribution. Prevalence increased with age (p<0.001 for trend), reaching 7.8% over 70y. None had a family history of HCM, and HCM-associated ECG changes were uncommon. Mean BS thickness (SD) was 17.8mm (0.24) with a BS/posterior wall ratio (SD) of 1.76 (0.31). Resting peak LVOT gradient (>20mmHg) was present in 8/240 (3.3%), mean (SD) 69.6mmHg (59.3). Patients with LVOTO had hypercontractile LV function (fractional shortening [SD] 51.8% [9.5] vs. 40.5% [10.9], p=0.012) compared to those without LVOTO, but had similar BS thickness [SD] (17.8mm [3.0] vs. 17.8mm [2.8], p=0.996) and ECG characteristics. Greater apical and septal displacements of the mitral valve co-aptation point characterized those with IBSH and LVOTO. CONCLUSIONS: IBSH is common in elderly patients referred for echocardiography. LVOTO occurs only when concomitant mitral valve co-aptation and LV hypercontractility facilitate development of a gradient, rather than through differences in the degree of BS myocardial hypertrophy.

Supraventricular tachycardia.

Supraventricular tachycardia (SVT) is a common cardiac rhythm disturbance; it usually presents with recurrent episodes of tachycardia, which often increase in frequency and severity with time. Although SVT is usually not life-threatening, many patients suffer recurrent symptoms that have a major impact on their quality of life. The uncertain and sporadic nature of episodes of tachycardia can cause considerable anxiety - many patients curtail their lifestyle as a result, and many prefer curative treatment. SVT often terminates before presentation, and episodes may be erroneously attributed to anxiety. Sudden-onset, rapid, regular palpitations characterise SVT and, in most patients, a diagnosis can be made with a high degree of certainty from patient history alone. Repeated attempts at electrocardiographic documentation of the arrhythmia may be unnecessary. Treatment of SVT may not be necessary when the episodes are infrequent and self-terminating, and produce minimal symptoms. When episodes of tachycardia occur frequently, are prolonged or are associated with symptoms that affect quality of life, catheter ablation is the first choice of treatment; it is a low-risk procedure with a high success rate. Long-term preventive pharmacotherapy is an alternative approach in some patients.

Acute coronary syndromes: consensus recommendations for translating knowledge into action.

A systematic, integrated national approach is needed to implement 2006 Australian guidelines for management of acute coronary syndromes (ACS). Clinical outcomes can be improved by closing the current gaps between evidence and practice. In 2007, the National Heart Foundation of Australia, the Cardiac Society of Australia and New Zealand, and the Australasian College for Emergency Medicine held a national forum to identify current gaps in ACS management and priority strategies to improve outcomes. Consensus recommendations were based on evidence and expert opinion. Prompt reperfusion for patients with ST-segment-elevation myocardial infarction should be ensured by establishing protocols for single-call activation of primary percutaneous coronary intervention, or, where unavailable, enabling health care workers to initiate thrombolysis. Accuracy of risk stratification of non-ST-segment-elevation ACS (NSTEACS) should be improved using clinical pathways that integrate ambulance, medical and nursing care. Rates of early invasive management for patients with high-risk NSTEACS should be increased using efficient systems for transfer to revascularisation facilities. All patients with an ACS should be referred to rehabilitation and secondary prevention programs, including alternative models of care where appropriate. Equal access to recommended care for all Australians with an ACS - including those in rural, remote and Aboriginal and Torres Strait Islander communities - should be achieved by improving workforce capacity in under-resourced regions and ensuring access to third-generation fibrinolytic agents, defibrillation, timely essential pathology tests and invasive revascularisation facilities. National standards for data collection and clinical outcomes should be established, and performance should be monitored.

Patient-centered modular secondary prevention following acute coronary syndrome: a randomized controlled trial.

PURPOSE: Cardiac rehabilitation (CR) is beneficial for those who attend, but alternative models for nonattenders need investigation. We tested the effectiveness of modular prevention on risk factors in survivors of acute coronary syndrome (ACS) not accessing CR. METHODS: We randomly allocated ACS survivors not accessing CR to a control group (n = 72) receiving conventional care or modular group (n = 72) who participated in risk factor modules on the basis of patient-centered care and collaborative goal setting to systematically lower risk factors. We also recruited a consecutive reference group of ACS survivors participating in CR (n = 64). Blinded measurements of risk factors and global risk were completed at baseline and 3 months. RESULTS: Although well matched for risk factor level and prevalence at baseline, by 3 months, the modular group had significantly reduced risk factor level in comparison with controls for most risk factors including total cholesterol (158 +/- 3.9 vs 186 +/- 3.9 mg/dL, P < .001), systolic blood pressure (133.5 +/- 2.0 vs 144.4 +/- 2.4 mm Hg, P < .01), body mass index (28.9 +/- 0.7 vs 31.0 +/- 0.7 kg/m, P = .02), and physical activity (1,187 +/- 164 vs 636 +/- 115 metabolic equivalents [METS]/kg/min, P < .01). Also at 3 months, fewer patients in the modular group smoked than in the control group (6% vs 23%, P < .01) and were in the moderate to high-risk category of the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) score (40% vs 59%, P = .02). Although the modular group had higher risk factors at baseline, they achieved similar mean levels as the CR group at 3 months. CONCLUSIONS: Patient-centered modular prevention significantly improves coronary risk profile in comparison with conventional care and provides an effective alternative for the large numbers of ACS survivors not accessing CR.

Antithrombotic therapy in patients treated with oral anticoagulation undergoing coronary artery stenting. An expert consensus document with focus on atrial fibrillation.

Dual antiplatelet treatment with aspirin and clopidogrel is recommended after coronary stenting (PCI-S). There is scant evidence defining optimal post-PCI-S antithrombotic therapy in patients with atrial fibrillation (AF) in whom oral anticoagulation (OAC) is mandated. To evaluate the safety and efficacy of the antithrombotic strategies for this population, we conducted a systematic review of the available evidence in patients treated with OAC undergoing PCI-S. AF was the most frequent indication for OAC. Post-PCI-S management was highly variable, and triple therapy with warfarin, aspirin, and clopidogrel was the most frequent and effective combination. Warfarin plus aspirin alone was not sufficiently effective in the early period after PCI-S and should not be prescribed. While acknowledging that the optimal antithrombotic treatment for patients with AF at medium or high thromboembolic risk undergoing PCI-S is currently undefined, triple therapy of warfarin, aspirin, and clopidogrel is currently recommended, although associated with an increased risk of major bleeding. Restrictive use of drug-eluting stent is also recommended, due to the need for prolonged multiple-drug antithrombotic therapy which may increase the bleeding risk. Whether the combination of warfarin and clopidogrel (without aspirin) will preserve efficacy and produce less bleeding is an important issue still needing to be addressed.

Atrial fibrillation.

The incidence and prevalence of atrial fibrillation are increasing because of both population ageing and an age-adjusted increase in incidence of atrial fibrillation. Deciding between a rate control or rhythm control approach depends on patient age and comorbidities, symptoms and haemodynamic consequences of the arrhythmia, but either approach is acceptable. Digoxin is no longer a first-line drug for rate control: beta-blockers and verapamil and diltiazem control heart rate better during exercise. Anti-arrhythmic drugs have only a 40%-60% success rate of maintaining sinus rhythm at 1 year, and have significant side effects. The selection of optimal antithrombotic prophylaxis depends on the patient's risk of ischaemic stroke and the benefits and risks of long-term warfarin versus aspirin, but is independent of rate or rhythm control strategy. Ischaemic stroke risk is best estimated with the CHADS2 score (Congestive heart failure, Hypertension, Age > or = 75 years, Diabetes, 1 point each; prior Stroke or transient ischaemic attack, 2 points). For patients with valvular atrial fibrillation or a CHADS(2) score > or = 2, anticoagulation with warfarin is recommended (INR 2-3, higher for mechanical valves) unless contraindicated or annual major bleeding risk > 3%. Aspirin or warfarin may be used when the CHADS(2) score = 1. Aspirin, 81-325 mg daily, is recommended in patients with a CHADS(2) score of 0 or if warfarin is contraindicated. Stroke rate is similar for paroxysmal, persistent, and permanent atrial fibrillation, and probably for atrial flutter.

What do we know about perioperative ischaemic cardiac events in patients undergoing non-cardiac surgery?

A recent review shows how much more we need to find out about this important problem.