The incidence of airway haemorrhage in manual versus mechanical cardiopulmonary resuscitation.

OBJECTIVE: The aim of this study was to compare the incidence of airway haemorrhage between participants who received manual cardiopulmonary resuscitation (CPR) and those who had received mechanical CPR using the LUCAS device. METHODS: A retrospective cohort study was conducted by means of a medical chart review. All non-traumatic cardiac arrest patients that presented to the ED, from May 2014 to February 2018, were recruited. The groups were stratified according to those who had the majority of CPR performed using the LUCAS and those who had the majority of CPR performed manually. The primary outcome was the proportion of participants with airway haemorrhage, defined as blood observed in the endotracheal tube, pharynx, trachea or mouth, and documented in the doctor or nursing notes. Logistic regression analysis was performed to adjust for confounders. RESULTS: 12 of 54 (22%) participants in the majority LUCAS CPR group had airway haemorrhage, compared with 20 of 215 (9%) participants in the majority manual CPR group, a difference of 13% (95% CI 3% to 26%, p=0.02). The unadjusted odds for developing airway haemorrhage in the majority LUCAS CPR group was 2.8 (95% CI 1.3 to 6.1). After adjusting for confounders, the odds for developing airway haemorrhage in the majority LUCAS CPR group was 2.5 (95% CI 1.1 to 5.7). CONCLUSIONS: The LUCAS mechanical CPR device is associated with a higher incidence of airway haemorrhage compared with manual CPR. Limitations in the study design mean this conclusion is not robust.

Human macrophage cathepsin B-mediated C-terminal cleavage of apolipoprotein A-I at Ser228 severely impairs antiatherogenic capacity.

Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I, such as chlorination, nitration, oxidation, and proteolysis, can impair its antiatherogenic function, although it is unknown whether macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDMs) were incubated with human apoA-I under conditions used to induce cholesterol export. Two-dimensional gel electrophoresis and Western blot analysis identified that apoA-I is cleaved (∼20-80%) by HMDMs in a time-dependent manner, generating apoA-I of lower MW and isoelectric point. Mass spectrometry analysis identified a novel C-terminal cleavage site of apoA-I between Ser228-Phe229 Recombinant apoA-I truncated at Ser228 demonstrated profound loss of capacity to solubilize lipid and to promote ABCA1-dependent cholesterol efflux. Protease inhibitors, small interfering RNA knockdown in HMDMs, mass spectrometry analysis, and cathepsin B activity assays identified secreted cathepsin B as responsible for apoA-I cleavage at Ser228 Importantly, C-terminal cleavage of apoA-I was also detected in human carotid plaque. Cleavage at Ser228 is a novel, functionally important post-translational modification of apoA-I mediated by HMDMs that limits the antiatherogenic properties of apoA-I.-Dinnes, D. L. M., White, M. Y., Kockx, M., Traini, M., Hsieh, V., Kim, M.-J., Hou, L., Jessup, W., Rye, K.-A., Thaysen-Andersen, M., Cordwell, S. J., Kritharides, L. Human macrophage cathepsin B-mediated C-terminal cleavage of apolipoprotein A-I at Ser228 severely impairs antiatherogenic capacity.

Cellular cholesterol regulates ubiquitination and degradation of the cholesterol export proteins ABCA1 and ABCG1.

The objective of this study was to examine the influence of cholesterol in post-translational control of ABCA1 and ABCG1 protein expression. Using CHO cell lines stably expressing human ABCA1 or ABCG1, we observed that the abundance of these proteins is increased by cell cholesterol loading. The response to increased cholesterol is rapid, is independent of transcription, and appears to be specific for these membrane proteins. The effect is mediated through cholesterol-dependent inhibition of transporter protein degradation. Cell cholesterol loading similarly regulates degradation of endogenously expressed ABCA1 and ABCG1 in human THP-1 macrophages. Turnover of ABCA1 and ABCG1 is strongly inhibited by proteasomal inhibitors and is unresponsive to inhibitors of lysosomal proteolysis. Furthermore, cell cholesterol loading inhibits ubiquitination of ABCA1 and ABCG1. Our findings provide evidence for a rapid, cholesterol-dependent, post-translational control of ABCA1 and ABCG1 protein levels, mediated through a specific and sterol-sensitive mechanism for suppression of transporter protein ubiquitination, which in turn decreases proteasomal degradation. This provides a mechanism for acute fine-tuning of cholesterol transporter activity in response to fluctuations in cell cholesterol levels, in addition to the longer term cholesterol-dependent transcriptional regulation of these genes.

Safety and efficacy of rescue angioplasty for ST-elevation myocardial infarction with high utilization rates of glycoprotein IIb/IIIa inhibitors.

BACKGROUND: Fibrinolytic therapies remain widely used for ST-elevation myocardial infarction, and for "failed reperfusion," rescue percutaneous coronary intervention (PCI) is guideline recommended to improve outcomes. However, these recommendations are based on data from an earlier era of pharmacotherapy and procedural techniques. METHODS AND RESULTS: To determine factors affecting prognosis after rescue PCI, we studied 241 consecutive patients (median age 55 years, interquartile range [IQR] 48-65) undergoing procedures between 2001 and 2009 (53% anterior ST-elevation myocardial infarction and 78% transferred). The median treatment-related times were 1.2 hours (IQR 0.8-2.2) from symptom onset to door, 2 hours (IQR 1.3-3.2) from symptom onset to fibrinolysis (93% tenecteplase), and 3.9 hours (IQR 3.1-5.2) from fibrinolysis to balloon. Procedural characteristics were stent deployment in 95% (11.6% drug eluting) and 78% glycoprotein IIb/IIIa inhibitor use, and Thrombolysis In Myocardial Infarction (TIMI) 3 flow rates pre-PCI and post-PCI were 41% and 91%, respectively (P < .001). At 30 days, TIMI major bleeding occurred in 16 (6.6%) patients, and 23 (9.5%) patients received transfusions; nonfatal stroke occurred in 4 (1.7%) patients (2 hemorrhagic). Predictors of TIMI major bleeding were female gender (odds ratio 3.194, 95% CI 1.063-9.597; P = .039) and pre-PCI shock (odds ratio 3.619, 95% CI,1.073-12.207; P = .038). Mortality at 30 days was 6.2%, and 3.2% in patients without pre-PCI shock. One-year mortality was 8.2% (5.3% in patients without pre-PCI cardiogenic shock), 5.2% had reinfarction, and the target vessel revascularization rate was 6.4% (2.6% in arteries ≥ 3.5 mm in diameter). Pre-PCI shock, female gender, and post-PCI TIMI flow grades ≤ 2 were significant predictors of 1-year mortality on multivariable regression modeling, but TIMI major bleeding was not. CONCLUSIONS: Rescue PCI with contemporary treatments can achieve mortality rates similar to rates for contemporary primary PCI in patients without pre-PCI shock. Whether rates of bleeding can be reduced by different pharmacotherapies and interventional techniques needs clarification in future studies.

Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent.

OBJECTIVE: Maintenance of cholesterol homeostasis in human macrophages is essential to prevent foam cell formation. We evaluated the relative contribution of the ABCA1 and ABCG1 transporters to cholesterol efflux from human macrophages, and of the capacity of LXR agonists to reduce foam cell formation by stimulating export of cellular cholesterol. METHODS AND RESULTS: ABCG1 mRNA levels were strongly increased in acLDL-loaded THP-1 macrophages and in HMDM on stimulation with LXR agonists. However, silencing of ABCG1 expression using ABCG1-specific siRNA indicated that ABCG1 was not essential for cholesterol efflux to HDL in cholesterol-loaded human macrophages stimulated with LXR agonists. Indeed, ABCA1 was solely responsible for the stimulation of cholesterol efflux to HDL on LXR activation, as this effect was abolished in HMDM from Tangier patients. Furthermore, depletion of cellular ATP indicated that the LXR-induced export of cholesterol was an ATP-dependent transport mechanism in human macrophages. Finally, use of an anti-Cla-1 blocking antibody identified the Cla-1 receptor as a key component in cholesterol efflux to HDL from cholesterol-loaded human macrophages. CONCLUSIONS: Our data indicate that stimulation of cholesterol efflux to HDL by LXR agonists in human foam cells involves an ATP-dependent transport mechanism mediated by ABCA1 that it appears to be independent of ABCG1 expression.

Heart Failure Integrated Care Project: overcoming barriers encountered by primary health care providers in heart failure management.

Objective Heart failure (HF) is associated with increased morbidity and mortality. A significant proportion of HF patients will have repeated hospital presentations. Effective integration between general practice and existing HF management programs may address some of the challenges in optimising care for this complex patient population. The Heart Failure Integrated Care Project (HFICP) investigated the barriers encountered by primary healthcare providers in providing care to patients with HF in the community. Methods Five general practices in the St George and Sutherland regions (NSW, Australia) that employed practice nurses (PNs) were enrolled in the project. Participants responded to a printed survey that asked about their perceived role in the management of HF patients and their current knowledge and confidence in managing this condition. Participants also took part in a focus group meeting and were asked to identify barriers to improving HF patient management in general practice, and to offer suggestions about how the project could assist them to overcome those barriers. Results Barriers to effective delivery of HF management in general practice included clinical factors (consultation time limitations, underutilisation of patient management systems, identifying patients with HF, lack of patient self-care materials), professional factors (suboptimal hospital discharge summary letters, underutilisation of PNs), organisation factors (difficulties in communication with hospital staff, lack of education regarding HF management) and system issues (no Medicare rebate for B-type natriuretic peptide testing, insufficient Medicare rebate for using PN in chronic disease management). Conclusions The HFICP identified several barriers to improving integrated management for HF patients in the Australian setting. These findings provide important insights into how an HF integrated care model can be implemented to strengthen the working relationship between hospitals and primary care providers in delivering better care to HF patients. What is known about the topic? Multidisciplinary HF programs are heterogeneous in their structures, they have low patient participation rates and a significant proportion of HF patients have further presentations to hospital with HF. Integrating the care of HF patients into the primary care system following hospital admission remains challenging. What does this paper add? This paper identified several factors that hinder the effective delivery of care by primary care providers to patients with HF. What are the implications for practitioners? The findings provide important insights into how an HF integrated care model can be implemented to strengthen the working relationship between tertiary health facilities and primary care providers in delivering better care to HF patients.

How Should We Treat Multi-Vessel Disease in STEMI Patients?

OPINION STATEMENT: Primary angioplasty of the culprit coronary artery lesion is the preferred reperfusion strategy for ST-elevation myocardial infarction (STEMI) when timely access to a catheterization laboratory is available. The presence of multi-vessel disease (MVD) in patients undergoing primary PCI is common, occurring in about 40 %-50 % of patients. The presence of MVD in patients who have undergone successful primary PCI substantially increases the risks of mortality and major adverse cardiac events, such as reinfarction or need for urgent revascularization. The current evidence supporting revascularization of non-culprit lesions is sparse, with no large, adequately powered randomized trials to guide clinical practice. An analysis combining observational data and small randomized trials suggests that complete revascularization with PCI to significant non-culprit lesions may afford a benefit compared with medical management alone. However, this benefit appears to be confined to when revascularization is performed as a separate, staged procedure. By contrast, when non-culprit lesion PCI is performed during the initial primary PCI procedure, the risk of death or cardiovascular events is higher than medical management alone or to staged revascularization. A large, adequately powered randomized trial is urgently needed to determine whether routine staged PCI plus optimal medical therapy is superior to optimal medical therapy alone for significant non-culprit coronary artery lesions in patients who have undergone successful primary PCI for STEMI.

Comparing radial and femoral access for coronary angiography and interventions.

Cardiac catheterization and coronary intervention via the radial approach is increasingly adopted as the preferred vascular access to avoid transfemoral vascular complications. Recent clinical trials have confirmed that radial access reduces vascular complications and local bleeding with similar procedural efficacy. Transradial access has inherent technical challenges, including smaller vessel size of the radial artery, arterial spasm and tortuosity involving the radial and subclavian arteries, which may undermine the procedural success of this approach. A number of strategies have been reported to minimize complications of radial access, including the use of hydrophilic introducer sheaths and smaller sheath sizes, administration of nitroglycerin and unfractionated heparin during the procedure, patent hemostasis of the radial artery and careful patient selection. Operators experienced in transradial percutaneous coronary intervention can achieve comparable clinical outcomes to the transfemoral approach and minimize vascular complications. Radial artery access is likely to become widely accepted as the preferred percutaneous coronary intervention approach.

Expression and stability of two isoforms of ABCG1 in human vascular cells.

OBJECTIVE: To evaluate the expression of two ABCG1 isoforms that differ in the presence or absence of a 12 amino acid (AA) peptide between the ABC cassette and the transmembrane region, termed ABCG1(+12) and ABCG1(-12), respectively, in human vascular cells and tissues. METHODS AND RESULTS: mRNA for both isoforms was expressed in human macrophages, vascular endothelial and smooth muscle cells as well as whole human spleen, lung, liver and brain tissue. However, ABCG1(+12) was not expressed in mouse tissues. 2D gel electrophoresis of ABCG1 protein indicated that both protein isoforms were expressed in human macrophages. Furthermore the half-lives of the two ABCG1 protein isoforms, stably expressed in CHOK1 cells, measured under basal conditions were different, suggesting the presence of a degradation or stabilising signal in or near the 12AA region of ABCG1(+12). CONCLUSION: ABCG1(+12) is an isoform of ABCG1 exclusively expressed in human cells at the RNA and protein level. As ABCG1(+12) is not expressed in mice, although mouse models are widely used to elucidate the function of ABCG1, further investigations into the importance of this human ABCG1 isoform are warranted.