Effect of COVID-19 Pandemic Lockdown on Emergency Medical Service Utilisation, and Percutaneous Coronary Intervention Volume-An Australian Perspective.

BACKGROUND: Acute coronary syndrome (ACS) admissions and percutaneous coronary intervention (PCI) volume declined during periods of COVID-19 lockdown internationally in 2020. The effect of lockdown on emergency medical service (EMS) utilisation, and PCI volume during the initial phase of the pandemic in Australia has not been well described. METHOD: We analysed data from the Victorian Cardiac Outcomes Registry (VCOR), a state-wide PCI registry, linked with the Ambulance Victoria EMS registry. PCI volume, 30-day major adverse cardiovascular and cerebrovascular events (MACCE; composite of mortality, myocardial infarction, stent thrombosis, unplanned revascularisation, and stroke), and EMS utilisation were compared over four time periods: lockdown (26 Mar 2020-12 May 2020); pre-lockdown (26 Feb 2020-25 Mar 2020); post-lockdown (13 May 2020-10 Jul 2020); and the year prior (26 Mar 2019-12 May 2019). Interrupted time series analysis was performed to assess PCI trends within and between consecutive periods. RESULTS: The EMS utilisation for ACS during lockdown was higher compared with other periods: lockdown 39.4% vs pre-lockdown 29.7%; vs post-lockdown 33.6%; vs year prior 27.1%; all p<0.01. Median daily PCI cases were similar: 31 (IQR 10, 38) during lockdown; 39 (15, 49) pre-lockdown; 39.5 (11, 44) post-lockdown; and, 42 (10, 49) the year prior; all p>0.05. Median door-to-procedure time for ACS indication during lockdown was shorter at 3 hours (1.2, 20.6) vs pre-lockdown 3.9 (1.7, 21); vs post-lockdown 3.5 (1.5, 21.26); and, the year prior 3.5 (1.5, 23.7); all p<0.05. Lockdown period was associated with lower odds for 30-day MACCE compared to pre-lockdown (odds ratio [OR] 0.55 [0.33-0.93]; p=0.026); post-lockdown (OR 0.66; [0.40-1.06]; p=0.087); and the year prior (OR 0.55 [0.33-0.93]; p=0.026). CONCLUSIONS: Contrary to international trends, EMS utilisation for ACS increased during lockdown but PCI volumes remained similar throughout the initial stages of the pandemic in Victoria, with no observed adverse effect on 30-day MACCE during lockdown. These data suggest that the public health response in Victoria was not associated with poorer quality cardiovascular care in patients receiving PCI.

Prevalence and outcomes of patients with SMuRF-less acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: There is increasing awareness that patients without standard modifiable risk factors (SMuRFs; diabetes, hypercholesterolaemia, hypertension and smoking) may represent a unique subset of patients with acute coronary syndrome (ACS). We aimed to investigate the prevalence and outcomes of patients with SMuRF-less ACS undergoing percutaneous coronary intervention (PCI) compared with those with SMuRFs. METHODS: We analysed data from the Melbourne Interventional Group PCI Registry. Patients with coronary artery disease were excluded. The primary outcome was 30-day mortality. Secondary outcomes included in-hospital and 30-day events. Long-term mortality was investigated using Cox-proportional hazards regression. RESULTS: From 1 January 2005 to 31 December 2020, 2727/18 988 (14.4%) patients were SMuRF less, with the proportion increasing over time. Mean age was similar for patients with and without SMuRFs (63 years), and fewer females were SMuRF-less (19.8% vs 25.4%, p<0.001). SMuRF-less patients were more likely to present with cardiac arrest (6.6% vs 3.9%, p<0.001) and ST-elevation myocardial infarction (59.1% vs 50.8%, p<0.001) and were more likely to experience postprocedural cardiogenic shock (4.5% vs 3.6%, p=0.019) and arrhythmia (11.2% vs 9.9%, p=0.029). At 30 days, mortality, myocardial infarction, revascularisation and major adverse cardiac and cerebrovascular events did not differ between the groups. During median follow-up of 7 years, SMuRF-less patients had an adjusted 13% decreased rate of mortality (HR 0.87 (95% CI 0.78 to 0.97)). CONCLUSIONS: The proportion of SMuRF-less patients increased over time. Presentation was more often a devastating cardiac event compared with those with SMuRFs. No difference in 30-day outcomes was observed and SMuRF-less patients had lower hazard for long-term mortality.

Neutrophil NLRP3 promotes cardiac injury following acute myocardial infarction through IL-1ß production, VWF release and NET deposition in the myocardium.

NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta (IL-1ß). Permanent ligation of the left anterior descending artery was used to induce MI in WT and NLRP3-/- mice as well as in NLRP3-/- recipient mice transfused with either WT or NLRP3-/- neutrophils. NLRP3 deficiency reduced infarct size to roughly a third of WT heart injury and preserved left ventricular (LV) function at 12 h after MI as assessed by echocardiography and triphenyltetrazolium chloride staining of live tissue. Transfusion of WT but not NLRP3-/- neutrophils after MI increased infarct size in NLRP3-/- mice and significantly reduced LV function. The key features of myocardial tissue in WT neutrophil transfused recipients were increased H3Cit-positive deposits with NET-like morphology and increased tissue levels of IL-1ß and plasma levels of von Willebrand Factor (VWF). Flow cytometry analysis also revealed that neutrophil NLRP3 increased the number of labeled and transfused neutrophils in the bone marrow of recipient mice following MI. Our data suggest a key role for neutrophil NLRP3 in the production of IL-1ß and deposition of NETs in cardiac tissue exacerbating injury following MI. We provide evidence for a link between neutrophil NLRP3 and VWF release likely enhancing thromboinflammation in the heart. Neutrophil NLRP3 deficiency conferred similar cardioprotective effects to general NLRP3 deletion in MI rendering anti-neutrophil NLRP3 therapy a promising target for early cardioprotective treatment.

Generation of Rhesus Macaque Embryos with Expanded CAG Trinucleotide Repeats in the Huntingtin Gene.

Huntington's disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development of HD. A nonhuman primate (NHP) HD model would provide important insight into disease development and the generation of novel therapies due to their genetic and physiological similarity to humans. For this purpose, we tested CRISPR/Cas9 and a single-stranded DNA (ssDNA) containing expanded CAG repeats in introducing an expanded CAG repeat into the HTT gene in rhesus macaque embryos. Analyses were conducted on arrested embryos and trophectoderm (TE) cells biopsied from blastocysts to assess the insertion of the ssDNA into the HTT gene. Genotyping results demonstrated that 15% of the embryos carried an expanded CAG repeat. The integration of an expanded CAG repeat region was successfully identified in five blastocysts, which were cryopreserved for NHP HD animal production. Some off-target events were observed in biopsies from the cryopreserved blastocysts. NHP embryos were successfully produced, which will help to establish an NHP HD model and, ultimately, may serve as a vital tool for better understanding HD's pathology and developing novel treatments.

Multivessel Coronary Function Testing Increases Diagnostic Yield in Patients With Angina and Nonobstructive Coronary Arteries.

BACKGROUND: Invasive CFT is the gold standard for diagnosing coronary vasomotor dysfunction in patients with ANOCA. Most institutions recommend only testing the left coronary circulation. Therefore, it is unknown whether testing multiple coronary territories would increase diagnostic yield. OBJECTIVES: The aim of this study was to evaluate the diagnostic yield of multivessel, compared with single-vessel, invasive coronary function testing (CFT) in patients with angina and nonobstructive coronary arteries (ANOCA). METHODS: Multivessel CFT was systematically performed in patients with suspected ANOCA. Vasoreactivity testing was performed using acetylcholine provocation in the left (20 to 200 µg) and right (20 to 80µg) coronary arteries. A pressure-temperature sensor guidewire was used for coronary physiology assessment in all three epicardial vessels. RESULTS: This multicenter study included a total of 228 vessels from 80 patients (57.8 ± 11.8 years of age, 60% women). Compared with single-vessel CFT, multivessel testing resulted in more patients diagnosed with coronary vasomotor dysfunction (86.3% vs 68.8%; P = 0.0005), coronary artery spasm (60.0% vs 47.5%; P = 0.004), and CMD (62.5% vs 36.3%; P < 0.001). Coronary artery spasm (n = 48) predominated in the left coronary system (n = 38), though isolated right coronary spasm was noted in 20.8% (n = 10). Coronary microvascular dysfunction (CMD), defined by abnormal index of microcirculatory resistance and/or coronary flow reserve, was present 62.5% of the cohort (n = 50). Among the cohort with CMD, 27 patients (33.8%) had 1-vessel CMD, 15 patients (18.8%) had 2-vessel CMD, and 8 patients (10%) had 3-vessel CMD. CMD was observed at a similar rate in the territories supplied by all 3 major coronary vessels (left anterior descending coronary artery = 36.3%, left circumflex coronary artery = 33.8%, right coronary artery = 31.3%; P = 0.486). CONCLUSIONS: Multivessel CFT resulted in an increased diagnostic yield in patients with ANOCA compared with single-vessel testing. The results of this study suggest that multivessel CFT has a role in the management of patients with ANOCA.

Healthcare and economic cost burden of emergency medical services treated non-traumatic shock using a population-based cohort in Victoria, Australia.

OBJECTIVES: We aimed to assess the healthcare costs and impact on the economy at large arising from emergency medical services (EMS) treated non-traumatic shock. DESIGN: We conducted a population-based cohort study, where EMS-treated patients were individually linked to hospital-wide and state-wide administrative datasets. Direct healthcare costs (Australian dollars, AUD) were estimated for each element of care using a casemix funding method. The impact on productivity was assessed using a Markov state-transition model with a 3-year horizon. SETTING: Patients older than 18 years of age with shock not related to trauma who received care by EMS (1 January 2015-30 June 2019) in Victoria, Australia were included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome assessed was the total healthcare expenditure. Secondary outcomes included healthcare expenditure stratified by shock aetiology, years of life lived (YLL), productivity-adjusted life-years (PALYs) and productivity losses. RESULTS: A total of 21 334 patients (mean age 65.9 (±19.1) years, and 9641 (45.2%) females were treated by EMS with non-traumatic shock with an average healthcare-related cost of $A11 031 per episode of care and total cost of $A280 million. Annual costs remained stable throughout the study period, but average costs per episode of care increased (Ptrend=0.05). Among patients who survived to hospital, the average cost per episode of care was stratified by aetiology with cardiogenic shock costing $A24 382, $A21 254 for septic shock, $A19 915 for hypovolaemic shock and $A28 057 for obstructive shock. Modelling demonstrated that over a 3-year horizon the cohort lost 24 355 YLLs and 5059 PALYs. Lost human capital due to premature mortality led to productivity-related losses of $A374 million. When extrapolated to the entire Australian population, productivity losses approached $A1.5 billion ($A326 million annually). CONCLUSION: The direct healthcare costs and indirect loss of productivity among patients with non-traumatic shock are high. Targeted public health measures that seek to reduce the incidence of shock and improve systems of care are needed to reduce the financial burden of this syndrome.

Clinical Outcomes of Renal Transplant Recipients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Clinical outcomes of patients with renal transplant (RT) undergoing percutaneous coronary intervention (PCI) remain poorly elucidated. METHOD: Between 2014 and 2021, data were analysed for the following three groups of patients undergoing PCI enrolled in a multicentre Australian registry: (1) RT recipients (n=226), (2) patients on dialysis (n=992), and (3) chronic kidney disease (CKD) patients (estimated glomerular filtration rate [eGFR], 30‒60 mL/min per 1.73 m2) without previous RT (n=15,534). Primary outcome was 30-day major adverse cardiac and cerebrovascular events (MACCEs)-composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularisation, and stroke. RESULTS: RT recipients were younger than dialysis and patients with CKD (61±10 vs 68±12 vs 78±8.2 years, p<0.001). Patients with RT less frequently had severe left ventricular dysfunction compared with dialysis and CKD groups (6.7% vs 14% and 8.5%); however more, often presented with acute coronary syndrome (58% vs 52% and 48%), especially STEMI (all p<0.001). Patients with RT and CKD had lower rates of 30-day MACCE (4.4% and 6.8% vs 11.6%, p<0.001) than the dialysis group. Three-year survival was similar between RT and CKD groups, however was lower in the dialysis group (80% and 83% vs 60%, p<0.001). After adjustment, dialysis was an independent predictor of 30-day MACCE (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.44‒2.50, p<0.001), however RT was not (OR 0.91, CI 0.42‒1.96, p=0.802). Both RT (hazard ratio [HR] 2.07, CI 1.46‒2.95, p<0.001) and dialysis (HR 1.35, CI 1.02‒1.80, p=0.036) heightened the hazard of long-term mortality. CONCLUSIONS: RT recipients have more favourable clinical outcomes following PCI compared with patients on dialysis. However, despite having similar short-term outcomes to patients with CKD, the hazard of long-term mortality is significantly greater for RT recipients.

No-Reflow Prediction in Acute Coronary Syndrome During Percutaneous Coronary Intervention: The NORPACS Risk Score.

BACKGROUND: Suboptimal coronary reperfusion (no reflow) is common in acute coronary syndrome percutaneous coronary intervention (PCI) and is associated with poor outcomes. We aimed to develop and externally validate a clinical risk score for angiographic no reflow for use following angiography and before PCI. METHODS: We developed and externally validated a logistic regression model for prediction of no reflow among adult patients undergoing PCI for acute coronary syndrome using data from the Melbourne Interventional Group PCI registry (2005-2020; development cohort) and the British Cardiovascular Interventional Society PCI registry (2006-2020; external validation cohort). RESULTS: A total of 30 561 patients (mean age, 64.1 years; 24% women) were included in the Melbourne Interventional Group development cohort and 440 256 patients (mean age, 64.9 years; 27% women) in the British Cardiovascular Interventional Society external validation cohort. The primary outcome (no reflow) occurred in 4.1% (1249 patients) and 9.4% (41 222 patients) of the development and validation cohorts, respectively. From 33 candidate predictor variables, 6 final variables were selected by an adaptive least absolute shrinkage and selection operator regression model for inclusion (cardiogenic shock, ST-segment-elevation myocardial infarction with symptom onset >195 minutes pre-PCI, estimated stent length ≥20 mm, vessel diameter <2.5 mm, pre-PCI Thrombolysis in Myocardial Infarction flow <3, and lesion location). Model discrimination was very good (development C statistic, 0.808; validation C statistic, 0.741) with excellent calibration. Patients with a score of ≥8 points had a 22% and 27% risk of no reflow in the development and validation cohorts, respectively. CONCLUSIONS: The no-reflow prediction in acute coronary syndrome risk score is a simple count-based scoring system based on 6 parameters available before PCI to predict the risk of no reflow. This score could be useful in guiding preventative treatment and future trials.

Electrocardiographic patterns and clinical outcomes of acute coronary syndrome cardiogenic shock in patients undergoing percutaneous coronary intervention - A propensity score analysis.

OBJECTIVES: To determine the influence of presenting electrocardiographic (ECG) changes on prognosis in acute coronary syndrome cardiogenic shock (ACS-CS) patients undergoing percutaneous coronary angiography (PCI). BACKGROUND: The effect of initial ECG changes such as ST-elevation myocardial infarction (STEMI) versus non-STEMI among patients ACS-CS on prognosis remains unclear. METHODS: We analysed data from consecutive patients with ACS-CS enrolled in the Victorian Cardiac Outcomes registry between 2014 and 2020. Inverse probability of treatment weighting analysis (IPTW) was used to assess the effect of ECG changes on 30-day mortality. RESULTS: Of 1564 patients with ACS-CS who underwent PCI, 161 had non-STEMI and 1403 had STEMI on ECG. The mean age was 66 ± 13 years, and 74 % (1152) were males. Patients with non-STEMI compared to STEMI were older (70 ± 12 vs 65 ± 13 years), had higher rates of diabetes (34 % vs 21 %), prior coronary artery bypass graft surgery (14 % vs 3.3 %), peripheral arterial disease (10.6 % vs 4.1 %, p < 0.01), and lower baseline eGFR (53.8 [37.1, 75.4] vs 65.3 [46.3, 87.8] ml/min/1.73m2), all p ≤ 0.01. Non-STEMI patients were more likely to have a culprit left circumflex artery (29 % vs 20 %) and more often underwent multivessel percutaneous coronary intervention (30 % vs 20 %) but had lower rates of out-of-hospital cardiac arrest (21 % vs 39 %), all p ≤ 0.01. Propensity score analysis with IPTW confirmed that non-STEMI ECG was associated with lower odds for 30-day all-cause mortality (OR 0.47 [0.32, 0.69], p < 0.001), and 30-day major adverse cardiovascular and cerebrovascular events (OR 0.48 [0.33, 0.70]). CONCLUSIONS: In patients undergoing PCI, Non-STEMI as compared to STEMI on index ECG was associated with approximately half the relative risk of both 30-day mortality and 30-day MACCE and could be a useful variable to integrate in ACS-CS risk scores.

Structured Weaning From the Impella Left Ventricular Micro-Axial Pump in Acute Myocardial Infarction With Cardiogenic Shock and Protected Percutaneous Coronary Intervention: Experience From a Non-Cardiac Surgical Centre.

BACKGROUND: The Impella (Abiomed, Danvers, MA, USA) temporary percutaneous left ventricular assist device is increasingly used as mechanical circulatory support in patients with acute myocardial infarction-cardiogenic shock (AMICS) or those undergoing high-risk protected percutaneous coronary intervention (PCI). The optimal weaning regimen remains to be defined. METHOD: We implemented a structured weaning protocol in a series of 10 consecutive patients receiving Impella support for protected PCI or AMICS treated with PCI in a high volume non-cardiac surgery centre. Weaning after revascularisation was titrated to native heart recovery using both haemodynamic and echocardiographic parameters. RESULTS: Ten patients (eight male, two female; aged 43-70 years) received Impella support for AMICS (80%) or protected PCI (20%). Cardiogenic shock was of Society for Cardiac Angiography & Interventions grade C-E of severity in 80%, and median left ventricular end-diastolic pressure was 31 mmHg. Protocol implementation allowed successful weaning in eight of 10 patients with a median support time of 29 hours (range, 4-48 hours). Explantation was associated with an increase in heart rate (81 vs 88 bpm; p=0.005), but no significant change in Cardiac Index (2.9 vs 2.9 L/min/m2), mean arterial pressure (79 vs 82 mmHg), vasopressor requirement (10% vs 10%), or serum lactate (1.0 vs 1.0). Median durations of intensive care and hospital stay were 3 and 6 days, respectively. At 30 days, the mortality rate was 20%, with median left ventricular ejection fraction of 40%. CONCLUSIONS: A structured and dynamic weaning protocol for patients with AMICS and protected PCI supported by the Impella device is feasible in a non-cardiac surgery centre. Larger studies are needed to assess generalisability of such a weaning protocol.

Association of socioeconomic status in the incidence, quality-of-care metrics, and outcomes for patients with cardiogenic shock in a pre-hospital setting.

AIMS: The relationship between lower socioeconomic status (SES) and poor cardiovascular outcomes is well described; however, there exists a paucity of data exploring this association in cardiogenic shock (CS). This study aimed to investigate whether any disparities exist between SES and the incidence, quality of care or outcomes of CS patients attended by emergency medical services (EMS). METHODS AND RESULTS: This population-based cohort study included consecutive patients transported by EMS with CS between 1 January 2015 and 30 June 2019 in Victoria, Australia. Data were collected from individually linked ambulance, hospital, and mortality datasets. Patients were stratified into SES quintiles using national census data produced by the Australian Bureau of Statistics.A total of 2628 patients were attended by EMS for CS. The age-standardized incidence of CS amongst all patients was 11.8 [95% confidence interval (95% CI), 11.4-12.3] per 100 000 person-years, with a stepwise increase from the highest to lowest SES quintile (lowest quintile 17.0 vs. highest quintile 9.7 per 100 000 person-years, P-trend < 0.001). Patients in lower SES quintiles were less likely to attend metropolitan hospitals and more likely to be received by inner regional and remote centres without revascularization capabilities. A greater proportion of the lower SES groups presented with CS due to non-ST elevation myocardial infarction (NSTEMI) or unstable angina pectoris (UAP), and overall were less likely to undergo coronary angiography. Multivariable analysis demonstrated an increased 30-day all-cause mortality rate in the lowest three SES quintiles when compared with the highest quintile. CONCLUSION: This population-based study demonstrated discrepancies between SES status in the incidence, care metrics, and mortality rates of patients presenting to EMS with CS. These findings outline the challenges in equitable healthcare delivery within this cohort.

Real-world long-term survival after non-emergent percutaneous coronary intervention to unprotected left main coronary artery - From the Melbourne Interventional Group (MIG) registry.

BACKGROUND: Current evidence suggests that percutaneous coronary intervention for unprotected left main coronary artery disease (LMPCI) in selected patients is a safe alternative to coronary artery bypass grafting. However, real-world long-term survival data is limited. METHODS: We analyzed 24,644 patients from the MIG (Melbourne Interventional Group) registry between 2005 and 2020. We compared baseline clinical and procedural characteristics, in-hospital and 30-day outcomes, and long-term survival between unprotected LMPCI and non-LMPCI among patients without ST-segment elevation myocardial infarction, cardiogenic shock, or cardiac arrest. RESULTS: Unprotected LMPCI patients (n = 185) were significantly older (mean age 72.0 vs. 64.6 years, p < 0.001), had higher prevalence of impaired ejection fraction (EF <50 %; 27.3 % vs. 14.9 %, p < 0.001) and lower estimated glomerular filtration rate < 60 ml/min/1.73m2 (40.9 % vs. 21.5 %, p < 0.001), and had greater use of intravascular ultrasound (21 % vs. 1 %, p < 0.001) and drug-eluting stents (p < 0.001). LMPCI was associated with longer hospital stay (4 days vs. 2 days, p < 0.001). There was no significant difference in other in-hospital outcomes, 30-day mortality (0.6 % vs. 0.6 %, p = 0.90), and major adverse cardiac events (1.7 % vs. 3 %, p = 0.28). Although the unadjusted Kaplan-Meier survival to 8 years was significantly less with LMPCI compared to non-LMPCI (p < 0.01), LMPCI was not a predictor of long-term survival up to 8 years after Cox regression analysis (HR 0.67, 95 % CI 0.40-1.13, p = 0.13). CONCLUSION: In this study, non-emergent unprotected LMPCI was uncommonly performed, and IVUS was underutilized. Despite greater co-morbidities, LMPCI patients had comparable 30-day outcomes to non-LMPCI, and LMPCI was not an independent predictor of long-term mortality.

Novel therapeutic targets and emerging treatments for atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide. Even with excellent control of low-density lipoprotein cholesterol (LDL-C) levels, adverse cardiovascular events remain a significant clinical problem worldwide, including among those without any traditional ASCVD risk factors. It is necessary to identify novel sources of residual risk and to develop targeted strategies that address them. Lipoprotein(a) has become increasingly recognized as a new cardiovascular risk determinant. Large-scale clinical trials have also signalled the potential additive cardiovascular benefits of decreasing triglycerides beyond lowering LDL-C levels. Since CANTOS (Anti-inflammatory Therapy with Canakinumab for Atherosclerotic Disease) demonstrated that antibodies against interleukin-1ß may decrease recurrent cardiovascular events in secondary prevention, various anti-inflammatory medications used for rheumatic conditions and new monoclonal antibody therapeutics have undergone rigorous evaluation. These data build towards a paradigm shift in secondary ASCVD prevention, underscoring the value of targeting multiple biological pathways in the management of both lipid levels and systemic inflammation. Evolving knowledge of the immune system, and the gut microbiota may result in opportunities for modifying previously unrecognized sources of residual inflammatory risk. This review provides an overview of novel therapeutic targets for ASCVD and emerging treatments with a focus on mechanisms, efficacy, and safety.

Variability in Contemporary Heparin Prescription and Activated Clotting Time Monitoring During Percutaneous Coronary Intervention: Call for Up-To-Date Evidence-Based Guidelines.

BACKGROUND: Unfractionated heparin (UFH) is the preferred anticoagulant agent in percutaneous coronary intervention (PCI) procedures for minimising the risk of thrombotic complications. Because of the narrow therapeutic range of UFH, some society guidelines have advocated the use of the activated clotting time (ACT) test to monitor anticoagulation intensity during PCI to reduce thrombotic and bleeding complications. We aimed to assess the current practice of UFH prescription and its monitoring in Australia and New Zealand (ANZ). METHOD: We conducted an anonymous voluntary cross-sectional survey of interventional cardiologists (ICs) who were members of the Cardiac Society of Australia and New Zealand in 2022. The survey included 10 questions pertaining to the current practice of anticoagulation during PCI. RESULTS: Of 430 ICs surveyed, 148 responded (response rate, 34.4%). Most ICs (84.4%) prescribed 70-100 IU/kg of UFH for PCI. Over half of ICs (58.7%) routinely measured ACT during PCI, whereas only 22.2% routinely measured ACT after PCI to guide additional UFH prescription. Among ICs who prescribed additional UFH, approximately half (48%) aimed for ACT ≥250 seconds. Factors that influenced post-PCI UFH prescription included vascular access site and concomitant antiplatelet or anticoagulant therapy. CONCLUSIONS: The contemporary practice of UFH prescription during PCI and ACT monitoring in ANZ is variable and based on outdated evidence preceding current drug-eluting stents, antiplatelet therapies, and radial-first practice. Current society guideline recommendations lack clarity and agreement, reflecting the quality of the available evidence. Up-to-date clinical trials evaluating UFH prescription and ACT monitoring are needed to optimise clinical outcomes in contemporary PCI procedures.

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a case report.

BACKGROUND: Undifferentiated carcinomas of the pancreas with osteoclast-like giant cells (UCPOGC) are rare pancreatic neoplasms that account for less than 1% of all pancreatic malignancies. This case report of a 54-year-old male with metastatic UCPOGC adds to the existing literature and further ascertains the clinical and imaging features, treatment options, and prognosis of this rare entity. CASE PRESENTATION: We present the detailed clinical course of a 54-year-old Asian male patient with UCPOGC, with focus on the relevant clinical features and imaging findings that are characteristic of this disease entity. CONCLUSIONS: UCPOGC is an extremely rare pancreatic tumor with a unique histopathology and clinical course. It is often difficult to distinguish UCPOGCs from other pancreatic tumors, such as traditional pancreatic ductal adenocarcinomas (PDAC), on imaging, and it therefore remains a pathological diagnosis. Surgery is generally regarded as the first-line treatment option, and the roles of chemotherapy and radiation are unclear. Due to the exceeding rarity of this tumor, large-scale clinical studies are not feasible. Therefore, it is important to share individual insights and experiences to improve our understanding and care for patients with this devastating disease.

Activation of Chaperone-Mediated Autophagy Inhibits the Aryl Hydrocarbon Receptor Function by Degrading This Receptor in Human Lung Epithelial Carcinoma A549 Cells.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a substrate protein of a Cullin 4B E3 ligase complex responsible for diverse cellular processes. In the lung, this receptor is responsible for the bioactivation of benzo[a]pyrene during tumorigenesis. Realizing that the AHR function is affected by its expression level, we are interested in the degradation mechanism of AHR in the lung. Here, we have investigated the mechanism responsible for AHR degradation using human lung epithelial A549 cells. We have observed that the AHR protein levels increase in the presence of chloroquine (CQ), an autophagy inhibitor, in a dose-dependent manner. Treatment with 6-aminonicotinamide (6-AN), a chaperone-mediated autophagy (CMA) activator, decreases AHR protein levels in a concentration-dependent and time-dependent manner. This decrease suppresses the ligand-dependent activation of the AHR target gene transcription, and can be reversed by CQ but not MG132. Knockdown of lysosome-associated membrane protein 2 (LAMP2), but not autophagy-related 5 (ATG5), suppresses the chloroquine-mediated increase in the AHR protein. AHR is resistant to CMA when its CMA motif is mutated. Suppression of the epithelial-to-mesenchymal transition in A549 cells is observed when the AHR gene is knocked out or the AHR protein level is reduced by 6-AN. Collectively, we have provided evidence supporting that AHR is continuously undergoing CMA and activation of CMA suppresses the AHR function in A549 cells.

Clinical Features and Outcomes Among Patients With Refractory Out-of-Hospital Cardiac Arrest and an Initial Shockable Rhythm.

BACKGROUND: Clinical features among patients with refractory out-of-hospital cardiac arrest (OHCA) and initial shockable rhythms of ventricular fibrillation/pulseless ventricular tachycardia are not well-characterized. METHODS: We compared clinical characteristics and coronary angiographic findings between patients with refractory OHCA (incessant ventricular fibrillation/pulseless ventricular tachycardia after ≥3 direct-current shocks) and those without refractory OHCA. RESULTS: Between 2014 and 2018, a total of 204 patients with ventricular fibrillation/pulseless ventricular tachycardia OHCA (median age 62; males 78%) were divided into groups with (36%, 74/204) and without refractory arrest (64%, 130/204). Refractory OHCA patients had longer cardiopulmonary resuscitation (23 versus 15 minutes), more frequently required ≥450 mg amiodarone (34% versus 3.8%), and had cardiogenic shock (80% versus 55%) necessitating higher adrenaline dose (4.0 versus 1.0 mg) and higher rates of mechanical ventilation (92% versus 74%; all P<0.01). Of 167 patients (82%) selected for coronary angiography, 33% (n=55) had refractory OHCA (P=0.035). Significant coronary artery disease (≥1 major vessel with >70% stenosis) was present in >70% of patients. Refractory OHCA patients frequently had acute coronary occlusion (64% versus 47%), especially left circumflex (20% versus 6.4%) and graft vessel (7.3% versus 0.9%; all P<0.05) compared with those without refractory OHCA. Refractory OHCA group had higher in-hospital mortality (45% versus 30%, P=0.036) and greater new requirement for dialysis (18% versus 6.3%, P=0.011). After adjustment, refractory OHCA was associated with over 2-fold higher odds of in-hospital mortality (odds ratio, 2.28 [95% CI, 1.06-4.89]; P=0.034). CONCLUSIONS: Refractory ventricular fibrillation/pulseless ventricular tachycardia OHCA was associated with more intensive resuscitation, higher rates of acute coronary occlusion, and poorer in-hospital outcomes, underscoring the need for future studies in this extreme-risk subgroup.

Effect of Concomitant Cardiac Arrest on Outcomes in Patients With Acute Coronary Syndrome-Related Cardiogenic Shock.

Patients with acute coronary syndrome (ACS)-related cardiogenic shock (CS) with or without concomitant CA may have disparate prognoses. We compared clinical characteristics and outcomes of patients with CS secondary to ACS with and without cardiac arrest (CA). Between 2014 and 2020, 1,573 patients with ACS-related CS with or without CA who underwent percutaneous coronary intervention enrolled in a multicenter Australian registry were analyzed. Primary outcome was 30-day major adverse cardiovascular and cerebrovascular events (MACCE) (composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularization and stroke). Long-term mortality was obtained through linkage to the National Death Index. Compared with the no-CA group (n = 769, 49%), the CA group (n = 804, 51%) was younger (62 vs 69 years, p <0.001) and had fewer comorbidities. Patients with CA more frequently had ST-elevation myocardial infarction (92% vs 86%), occluded left anterior descending artery (43% vs 33%), and severe preprocedural renal impairment (49% vs 42%) (all p <0.001). CA increased risk of 30-day MACCE by 45% (odds ratio 1.45, 95% confidence interval 1.05 to 2.00, p = 0.024) after adjustment. CA group had higher 30-day MACCE (55% vs 42%, p <0.001) and mortality (52% vs 37%, p <0.001). Three-year survival was lower for CA compared with no-CA patients (43% vs 52%, p <0.001). In Cox regression, CS with CA was associated with a trend toward greater long-term mortality hazard (hazard ratio 1.19, 95% confidence interval 1.00 to 1.41, p = 0.055). In conclusion, concomitant CA among patients with ACS-related CS conferred a particularly heightened short-term risk with a diminishing legacy effect over time for mortality. CS survivors continue to exhibit high sustained long-term mortality hazard regardless of CA status.

State of Shock: Contemporary Vasopressor and Inotrope Use in Cardiogenic Shock.

Cardiogenic shock is characterized by tissue hypoxia caused by circulatory failure arising from inadequate cardiac output. In addition to treating the pathologic process causing impaired cardiac function, prompt hemodynamic support is essential to reduce the risk of developing multiorgan dysfunction and to preserve cellular metabolism. Pharmacologic therapy with the use of vasopressors and inotropes is a key component of this treatment strategy, improving perfusion by increasing cardiac output, altering systemic vascular resistance, or both, while allowing time and hemodynamic stability to treat the underlying disease process implicated in the development of cardiogenic shock. Despite the use of mechanical circulatory support recently garnering significant interest, pharmacologic hemodynamic support remains a cornerstone of cardiogenic shock management, with over 90% of patients receiving at least 1 vasoactive agent. This review aims to describe the pharmacology and hemodynamic effects of current pharmacotherapies and provide a practical approach to their use, while highlighting important future research directions.