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Primary percutaneous coronary intervention (PCI) for patients with ST-elevation myocardial infarction (STEMI) is recommended within 90 min of first medical contact. Those without pre-hospital notification (PN) are less likely to meet reperfusion targets and are an understudied subset of the STEMI population.An observational cohort study from a multicentre PCI registry of consecutive patients undergoing primary PCI for STEMI between 2012 and 2017. Exclusion criteria included out-of-hospital cardiac arrest, prior thrombolysis, symptom onset12 h prior, and cardiogenic shock.2519 patients were included: 1392 (55.3%) without PN (no-PN group) and 1127 (44.7%) with PN (PN group). Those without PN had longer median DTBT (78 min vs 51 min, p0.001) and STBT (206 min vs 161 min, p0.001), with only 55% meeting DTBT targets out-of-hours in the no-PN group. No-PN patients had lower rates of AHA/ACC type B2/C lesions, GP IIb/IIIa use, aspiration thrombectomy and had smaller stent diameter (all p ≤ 0.003), suggesting smaller areas of ischemic myocardium. There were no significant differences in 30-day MACE (no-PN 5.6% vs PN 6.5%, p = 0.36) or long-term National Death Index linked mortality (no-PN 6.2% vs PN 7.9%, p = 0.09). Lack of PN did not independently predict long-term mortality.Despite comparably excellent outcomes overall, those without PN had longer ischemic times and were less likely to meet DTBT targets, especially after hours. Ischemic times may be a better evaluation of PN networks than hard clinical outcomes, and efficient systems of care tailored to the individual health service are essential to ensure timely reperfusion of patients with STEMI.

Approximately 5-10% of patients presenting for percutaneous coronary intervention (PCI) have concurrent atrial fibrillation (AF). To what extent AF portends adverse long-term outcomes in these patients remains to be defined.We analysed data from the multicentre Melbourne Interventional Group Registry from 2014-2018. Patients were identified as being in AF or sinus rhythm (SR) at the commencement of PCI. The primary endpoint was long-term mortality, obtained via linkage with the National Death Index.13,286 procedures were included, with 800 (6.0%) patients in AF and 12,486 (94.0%) in SR. Compared to SR, patients with AF were older (72.9±10.9 vs 64.1±12.0 p0.001) and more likely to have comorbidities including diabetes mellitus (31.3% vs 25.0% p0.001), hypertension (74.4% vs 65.1% p0.001) and moderate to severe left ventricular systolic dysfunction (36.6% vs 19.5% p0.001). Atrial fibrillation was associated with an increased risk of in-hospital mortality (11.0% vs 2.5% p0.001) and MACE (composite of all-cause mortality, myocardial infarction, or target vessel revascularisation) (11.9% vs 4.2% p0.001). In-hospital major bleeding was more common in the AF group (3.1% vs 1.0% p0.001). On Cox proportional hazards modelling, AF was an independent predictor of long-term mortality (adjusted HR 1.38 95% CI 1.11-1.72 p0.004) at a mean follow-up of 2.3±1.5 years.Preprocedural AF is common among patients presenting for PCI. Preprocedural AF is associated with high-rates of comorbid illnesses and portends higher risk of short- and long-term outcomes including mortality underscoring the need for careful evaluation of its risks prior to PCI.

BackgroundAn adverse interaction whereby opioids impair and delay the gastrointestinal absorption of oral P2Y12inhibitors has been established, however the clinical significance of this in acute coronary syndrome (ACS) is uncertain. We sought to characterise the relationship between prehospital opioid dose and clinical outcomes in patients with ACS.MethodsPatients given opioid treatment by emergency medical services (EMS) with ACS who underwent percutaneous coronary intervention (PCI) between 1 January 2014 and 31 December 2018 were included in this retrospective cohort analysis using data linkage between the Ambulance Victoria, Victorian Cardiac Outcomes Registry and Melbourne Interventional Group databases. Patients with cardiogenic shock, out-of-hospital cardiac arrest and fibrinolysis were excluded. The primary end point was the risk-adjusted odds of 30-day major adverse cardiac events (MACE) between patients who received opioids and those that did not.Results10 531 patients were included in the primary analysis. There was no significant difference in 30-day MACE between patients receiving opioids and those who did not after adjusting for key patient and clinical factors. Among patients with ST-elevation myocardial infarction (STEMI), there were significantly more patients with thrombolysis in myocardial infarction (TIMI) 0 or 1 flow pre-PCI in a subset of patients with high opioid dose versus no opioids (56% vs 25%, pConclusionsOpioid use was not associated with 30-day MACE. There were higher rates of TIMI 0/1 flow pre-PCI in patients with STEMI prescribed opioids. Future prospective research is required to verify these findings and investigate alternative analgesia for ischaemic chest pain.

Cytotoxic T lymphocytes (CTLs) and natural killer cells kill virus-infected and tumor cells through the polarized release of perforin and granzymes. Perforin is a pore-forming toxin that creates a lesion in the plasma membrane of the target cell through which granzymes enter the cytosol and initiate apoptosis. Endosomal sorting complexes required for transport (ESCRT) proteins are involved in the repair of small membrane wounds. We found that ESCRT proteins were precisely recruited in target cells to sites of CTL engagement immediately after perforin release. Inhibition of ESCRT machinery in cancer-derived cells enhanced their susceptibility to CTL-mediated killing. Thus, repair of perforin pores by ESCRT machinery limits granzyme entry into the cytosol, potentially enabling target cells to resist cytolytic attack.

Patients with stable ischemic heart disease (SIHD) may present with a variety of symptoms including typical angina, angina equivalents such as dyspnea or no symptoms. We sought to determine whether symptom status affects periprocedural safety and long-term mortality in patients undergoing PCI.Prospectively enrolled consecutive patients undergoing PCI for SIHD at six hospitals in Australia between 2005 to 2018 as part of the Melbourne Interventional Group registry. Symptom status was recorded at the time of PCI and patients undergoing staged PCI were excluded.Overall, 11,730 patients with SIHD were followed up for a median period of 5 years (maximum 14.0 years, interquartile range 2.2-9.0 years) with 1,317 (11.2%) being asymptomatic. Asymptomatic patients were older, and more likely to be male, have triple-vessel disease, with multiple comorbidities including renal failure, diabetes and heart failure (all P.01). These patients had significantly higher rates of periprocedural complications and major adverse cardiovascular events at 30-days. Long-term mortality was significantly higher in asymptomatic patients (27.2% vs 18.0%, P.001). On cox regression for long-term mortality, after adjustment for more important clinical variables, asymptomatic status was an independent predictor (Hazard ratio (HR) 1.39 95% CI 1.16-1.66, P.001).In a real-world cohort of patients undergoing revascularization for SIHD, absence of symptoms was associated with higher rates of periprocedural complications and, after adjustment for more important clinical variables, was an independent predictor of long-term mortality. As the primary goal of revascularization in SIHD remains angina relief, the appropriateness of PCI in the absence of symptoms warrants justification.

The short- and long-term implications of identifying totally occluded culprit coronary arteries (TOCCA) in patients presenting with non-ST-elevation myocardial infarction (NSTEMI) have not been well studied. This study compares clinical characteristics, short- and long-term outcomes of patients with NSTEMI identified with TOCCA to that of patients with non-TOCCA undergoing percutaneous coronary intervention (PCI). We analyzed data from patients with NSTEMI undergoing single-vessel PCI within the Melbourne Interventional Group multi-center registry between 2005 and 2017. Those with TOCCA were compared to those with non-TOCCA. The primary endpoint was 30-day major adverse cardiac events (MACE). Secondary endpoints included 12-month MACE and long-term mortality. A total of 6,829 patients with NSTEMI had single-vessel PCI of which 954 (14%) had TOCCA. Most TOCCA were non-left anterior descending (right coronary artery 39% versus circumflex 33% versus left anterior descending 26%; p

Background Patient selection and procedural characteristics continue to evolve in percutaneous coronary intervention (PCI). Australian data on long-term trends and outcomes are limited. This study aimed to identify long-term temporal trends in patient characteristics and outcomes in a large Australian PCI cohort. Methods We analysed data from 41,146 PCI procedures included in the multi-centre Melbourne Interventional Group registry to determine trends in patient characteristics, procedural practices and outcomes from 2005 to 2018. Procedures were divided into 2-yearly periods for trends analysis. Results Temporal trends in patient characteristics showed increases in age, proportion of males, rates of obesity, insulin-requiring diabetes mellitus, current smoking, obstructive sleep apnoea and prior PCI (all Ptrend Conclusions Over the last 14 years, Australian PCI procedural complexity and patient risk profiles have increased. Higher mortality rates appear to relate to increased patient risk profile rather than procedural factors.

BACKGROUND: Data on the patient characteristics and health outcomes of Indigenous Australians having revascularisation for treatment of coronary artery disease are scarce. The aim of this study was to assess differences in patient characteristics, presentations, and outcomes among Indigenous and non-Indigenous Australians having percutaneous coronary intervention (PCI) in urban and larger regional centres in Victoria, Australia. METHODS: In this multicentre, prospective, observational cohort study, data were prospectively collected from six government-funded tertiary hospitals in the state of Victoria, Australia. The Melbourne Interventional Group PCI registry was used to identify patients having PCI at Victorian metropolitan and large regional hospitals between Jan 1, 2005, and Dec 31, 2018. The primary outcome was long-term mortality. Secondary outcomes were 30 day mortality and 30 day major adverse cardiovascular events (MACE), defined as a composite endpoint of death, myocardial infarction, and target-vessel revascularisation. Regression analyses, adjusted for clinically relevant covariates and geographical and socioeconomic indices, were used to establish the influence of Indigenous status on these study outcomes. FINDINGS: 41 146 patient procedures were entered into the registry, of whom 179 (0·4%) were recorded as identifying as Indigenous Australian, 39 855 (96·9%) were not Indigenous Australian, and 1112 (2·7%) had incomplete data regarding ethnicity and were excluded. Compared with their non-Indigenous counterparts, Indigenous patients were younger, more often women, and more likely to have comorbidities. Indigenous Australians were also more likely to live in a regional community and areas of socioeconomic disadvantage. Procedural success and complication rates were similar for Indigenous and non-Indigenous patients having PCI. At 30 day follow-up, Indigenous Australians were more likely to be taking optimal medical therapy, although overall follow-up rates were lower and prevalence of persistent smoking was higher. Multivariable analysis showed that Indigenous status was independently associated with increased risk of long-term mortality (hazard ratio 2·49, 95% CI 1·79-3·48; p

Introduction The dual antiplatelet therapy (DAPT) score was developed to identify patients more likely to derive benefit (score ≥2) or harm (score Purpose We sought to examine long-term mortality after PCI by the DAPT score in patients treated with DAPT per local guidelines. Methods We examined data from the MIG PCI database from 2005 to 2018 in whom the DAPT score could be derived and grouped them as score ≥2 or Results Out of 27,740 patients in the study, 9,401 (33.9%) had DAPT score ≥2. They were younger and included more females and higher prevalence of renal impairment. DAPT score ≥2 patients had higher in-hospital major bleeding, 30-day mortality, MI and target vessel revascularisation. DAPT score ≥2 patients had lower long-term survival to 12 years (p Conclusion A third of all-comer PCI patients had DAPT score ≥2 with greater short-term risk of ischaemic and bleeding outcomes, as well as long-term mortality. Theoretically, those with DAPT score ≥2 would benefit from longer duration of DAPT as ischaemic risk outweighs bleeding risk. However, given our finding of increased short-term bleeding risk and long-term mortality, dynamic bleeding risk assessment should be undertaken to guide pharmacotherapy strategies. Funding Acknowledgement Type of funding sources: None.

To evaluate the effect of age in an all-comers population undergoing percutaneous coronary intervention (PCI).Age is an important consideration in determining appropriateness for invasive cardiac assessment and perceived clinical outcomes.We analysed data from 29,012 consecutive patients undergoing PCI in the Melbourne Interventional Group (MIG) registry between 2005 and 2017. 25,730 patients80 year old (78% male, mean age 62±10 years; non-elderly cohort) were compared to 3,282 patients ≥80 year old (61% male, mean age 84±3 years; elderly cohort).The elderly cohort had greater prevalence of hypertension, diabetes and previous myocardial infarction (all p0.001). Elderly patients were more likely to present with acute coronary syndromes, left ventricular ejection fraction45% and chronic kidney disease (p0.0001). In-hospital, 30-day and long-term all-cause mortality (over a median of 3.6 and 5.1 years for elderly and non-elderly cohorts, respectively) were higher in the elderly cohort (5.2% vs. 1.9%; 6.4% vs. 2.2%; and 43% vs. 14% respectively, all p0.0001). In multivariate Cox regression analysis, estimated glomerular filtration rate (eGFR)30 mL/min/1.73 mThe elderly cohort is a high-risk group of patients with increasing age being associated with poorer long-term mortality. Age, thus, should be an important consideration when individualising treatment in elderly patients.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is associated with increased risk of cardiovascular events and mortality. Evidence regarding outcomes following PCI is limited. This study aimed to assess differences in outcomes following percutaneous coronary intervention (PCI) between patients with and without RA. The Melbourne Interventional Group PCI registry (2005 to 2018) was used to identify 756 patients with RA. Outcomes were compared with the remaining cohort (n = 38,579). Patients with RA were older, more often female, with higher rates of hypertension, previous stroke, peripheral vascular disease, obstructive sleep apnea, chronic lung disease, myocardial infarction, and renal impairment, whereas rates of dyslipidemia and current smoking were lower, all p

OBJECTIVE: The aim of the review was to assess whether CHA2DS2-VASc score is predictive of mortality in patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI). BACKGROUND: The CHA2DS2-VASc score is validated in predicting stroke risk in atrial fibrillation. The optimum management strategy for these patients undergoing PCI is still debated. METHODS: The CHA2DS2-VASc score was calculated in consecutive patients with atrial fibrillation undergoing PCI in a large Australian registry between 2007 and 2013. Patients were divided into low (1-2), intermediate (3-4) and high (≥5) groups. Clinical and procedural data, 30-day, 1-year and long-term outcomes were compared between the groups. RESULTS: A total of 564 patients were included in our analysis. Patients with high CHA2DS2-VASc scores had higher mortality rates at 1-year (2, 8, 15; P = 0.002) and long-term (6, 20, 37; P

AimsThere is a paucity of evidence supporting routine beta blocker (BB) use in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). The aim of this study was to evaluate BB use post PCI and its association with mortality. Furthermore, the study aimed to evaluate the association between BB and mortality in the subgroups of patients with left ventricular ejection fraction (LVEF) 50%.MethodsUsing a large PCI registry, data from patients with ACS between January 2005 and June 2017 who were alive at 30 days were analysed. Those patients taking BB at 30 days were compared with those who were not taking BB. The primary outcome was all-cause mortality. The mean follow-up was 5.3±3.5 years.ResultsOf the 17 562 patients, 83.3% were on BB. Mortality was lower in the BB group (13.1% vs 19.5%, p=0.0001). Multivariable Cox proportional hazards model showed that BB use was associated with lower overall mortality (adjusted HR 0.87, 95% CI 0.78 to 0.97, p=0.014). In the subgroup analysis, BB use was associated with reduced mortality in LVEF 50% (adjusted HR 1.03, 95% CI 0.87 to 1.21, p=0.74).ConclusionBB use remains high and is associated with reduced mortality. This reduction in mortality is primarily seen in those with reduced ejection fraction, but not in those with preserved ejection fraction.

Systems of care have been established to ensure patients with ST-elevation myocardial infarction (STEMI) get timely access to primary percutaneous coronary intervention (PPCI). In this study, we evaluated whether patients undergoing PPCI both in-hours and out-of-hours experience similar care and clinical outcomes.Of 9,865 patients who underwent PCI for STEMI from 2005 to 2016 and were enrolled in the multi-centre Melbourne Interventional Group registry, patients who had initially presented to a non-PCI capable hospital, received thrombolysis or presented12hourspost-symptom onset were excluded. Our final study cohort of 4,590 patients were dichotomised by whether PPCI was performed in-hours or out-of-hours, and compared. The primary outcome was 30-day mortality.The in-hours group included 1,865 patients (40.6%) while 2,725 patients (59.4%) had out-of-hours PPCI. Patients presenting out-of-hours had longer median door-to-balloon time (DTBT; 83 [IQR 61-109] vs. 60 [IQR 41-88] mins, p0.01) and were more likely to receive a drug-eluting stent (p=0.001). Procedural characteristics were otherwise similar although rates of radial access were low overall (18.4%). No differences in in-hospital, 30-day or 12-month mortality were observed between the groups (p=NS). On Cox proportional hazards modelling, out-of-hours presentation was not an independent predictor of 30-day mortality (HR 0.94, 95% CI 0.71-1.22). A landmark analysis of data from 2012 did not change the primary outcome.Despite a slightly longer DTBT, patients undergoing PPCI out-of-hours experienced similar care and clinical outcomes to the in-hours group. Given the majority of patients with STEMI present out-of-hours, these data have implications for STEMI systems of care.

Background Stroke rates and risk factors may change as percutaneous coronary intervention practice evolves and no data are available comparing stroke incidence after percutaneous coronary intervention to the general population. Aims This study aimed to identify the incidence and risk factors for inpatient and subsequent stroke following percutaneous coronary intervention with comparison to age-matched controls. Methods Data were prospectively collected from 22,618 patients undergoing percutaneous coronary intervention in the Melbourne Interventional Group registry (2005–2015). The cohort was compared to the North-East Melbourne Stroke Incidence Study population-based cohort (1997–1999) and predefined variables assessed for association with inpatient or outpatient stroke. Results Inpatient stroke occurred in 0.33% (65.3% ischemic, 28.0% haemorrhagic, and 6.7% cause unknown), while outpatient stroke occurred in 0.55%. Inpatient and outpatient stroke were associated with higher rates of in-hospital major adverse cardiovascular outcomes ( p Conclusions Risk of inpatient stroke following percutaneous coronary intervention appears to be largely associated with clinical status at presentation, while outpatient stroke relates more to age and chronic disease. Compared to the general population, outpatient stroke rates following percutaneous coronary intervention are higher for younger, but not older, patients.

Previous large multi-centre randomised controlled trials have not provided clear benefit with routine intracoronary thrombus aspiration (TA) as an adjunct to primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI).To determine whether there is a difference in outcomes with the use of manual TA prior to PCI, compared with PCI alone in a cohort of patients with STEMI.We analysed data from 6270 consecutive patients undergoing primary PCI for STEMI prospectively enrolled in the Melbourne Interventional Group registry between 2007 and 2018. Multivariable analysis was performed to determine predictors of 30-day major adverse cardiovascular and cerebrovascular events (MACCE) and long-term mortality.We compared 1621 (26%) patients undergoing primary PCI with TA to 4649 (74%) patients undergoing PCI alone. Male gender (81% vs 78%; P 0.01), younger age (61 vs 63 years; P = 0.03), GP-IIb/IIIa use (76% vs 58%, P 0.01), and current smoking (40% vs 36%; P 0.01) were more common in the TA group. TA was more likely to be used in patients with complex lesions (83% vs 66%; P 0.01) with TIMI 0 flow (77% vs 56%; P 0.01). No significant difference in post-procedural TIMI flow, stroke, 30-day mortality, or long-term mortality were identified. Multivariable analysis demonstrated a reduction in 30-day MACCE (hazard ratio (HR) 0.75; confidence interval (CI) 0.63-0.89; P 0.01) in the TA group, but was not associated with long-term mortality (HR 0.98; CI 0.85-1.1; P = 0.73).The use of TA in patients undergoing primary PCI for STEMI was not associated with improved short or long-term mortality when compared with PCI alone.

International audience; Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical Gαq/11-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.

Background Myocardial infarction complicated by cardiogenic shock (MI-CS) has a poor prognosis, even with early revascularisation. Previously, intra-aortic balloon pump (IABP) use was thought to improve outcomes, but the SHOCK-II trial in 2012 found no survival benefit. Purpose This study aimed to determine the trends in IABP use in patients with MI-CS undergoing percutaneous intervention (PCI) over time and characteristics associated with use. Methods Between 2005–2018, patients presenting with MI-CS that underwent percutaneous coronary intervention (PCI) at a hospital participating in the Melbourne Interventional Group Registry were included. The primary outcome was the trend in IABP use over time. Secondary outcomes included mortality, 30-day MACCE (major adverse cardiovascular and cerebrovascular events) and predictors of outcome, determined via logistic regression. Results Of the 1,110 patients identified, IABP was used in 478 (43%). IABP was used more in patients with left main and left anterior descending culprit lesions (62% vs. 46%), lower ejection fraction ( Conclusions Consistent with the SHOCK II trial, IABP use is not associated with reduced short- or long-term mortality, but in this study was associated with increased short-term adverse events. IABP use is declining, but is still used in sicker patients with greater myocardium at risk, given limited alternatives. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Melbourne interventional group

Unprotected left main (LM) percutaneous coronary intervention (PCI) at centers without onsite cardiac surgery remains controversial. We aimed to evaluate the effect of onsite cardiac surgery on short-term and long-term outcomes in patients who had unprotected LM PCI. We analyzed Victorian Cardiac Outcomes Registry data on consecutive patients who had unprotected LM PCI at cardiac surgical centers (SCs) and non-SCs (NSCs) between January 2014 to December 2018. Compared with the SC group (n = 594, 81%), the NSC group (n = 136) were younger (69 vs 72 years) and presented with more ST-elevation myocardial infarction (35% vs 16%) and cardiogenic shock (25% vs 15%), with higher rates of preprocedural intubation (17% vs 11%) and mechanical circulatory support (20% vs 9.3%), all p 0.01. Unadjusted in-hospital mortality (23% vs 11.4%), and 30-day major adverse cardiac events (composite of mortality, myocardial infarction, stent thrombosis, or unplanned revascularization) (26% vs 16%) were higher in NSC patients, all p 0.01. However, following multivariable adjustment, SC was neither a predictor of in-hospital mortality (odds ratio 0.68, 95% confidence interval [CI] 0.32 to 1.43, p = 0.31), 30-day mortality (odds ratio 0.70, 95% CI 0.33 to 1.48, p = 0.35) nor long-term survival at 60 months (hazard ratio 0.88, 95% CI 0.62 to 1.27, p = 0.51). Propensity score analysis confirmed the neutral effect of onsite cardiac surgery on long-term survival (hazard ratio 0.99, 95% CI 0.66 to 1.50, p = 0.97). In conclusion, patients who underwent unprotected LM PCI at NSCs presented with greater acuity of illness. Despite this, the availability of onsite cardiac surgical support was not associated with in-hospital, 30-day, or long-term outcomes underscoring the safety of LM PCI in NSCs.

SummaryChemical synapses between axons and dendrites mediate much of the brain’s intercellular communication. Here we describe a new kind of synapse – the axo-ciliary synapse - between axons and primary cilia. By employing enhanced focused ion beam – scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between the serotonergic axons arising from the brainstem, and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, 5-hydroxytryptamine receptor 6 (HTR6), whose mutation is associated with learning and memory defects. Using a newly developed cilia-targeted serotonin sensor, we show that optogenetic stimulation of serotonergic axons results in serotonin release onto cilia. Ciliary HTR6 stimulation activates a non-canonical Gαq/11-RhoA pathway. Ablation of this pathway results in nuclear actin and chromatin accessibility changes in CA1 pyramidal neurons. Axo-ciliary synapses serve as a distinct mechanism for neuromodulators to program neuron transcription through privileged access to the nuclear compartment.

Aims The use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II-receptor blockers (ARBs) post-myocardial infarction (MI) is supported by evidence based on trials performed in the thrombolysis era. This was prior to primary percutaneous coronary intervention (PCI) being routine practice, and with little direct evidence for the use of these medications in patients with preserved left ventricular (LV) function. This study sought to determine whether there is an association between ACEi/ARB use after PCI for acute coronary syndrome (ACS) and long-term all-cause mortality, with a particular focus on patients with preserved LV function. Methods This multicentre, observational study evaluated prospectively collected data of 21,388 patients (> 18 years old) that underwent PCI for NSTEMI and STEMI between 2005 and 2018, and were alive at 30 day follow-up. Results In total, 83.8% of patients were using ACEi/ARBs. Kaplan–Meier analysis demonstrated ACEi/ARB use was associated with a significantly lower mortality in the entire cohort (15.0 vs. 22.7%; p p Conclusion ACEi/ARB therapy post-PCI is associated with significantly lower long-term mortality in patients with reduced and preserved LV function. These findings provide contemporary evidence for using these agents in the current era of routine primary PCI, including those with preserved EF. Graphical abstract

Background: Glycoprotein IIb/IIIa inhibitors (GPIs) are a treatment option in the management of acute coronary syndromes (ACSs). Evidence supporting the use of GPIs predates trials establishing the benefits of P2Y12 inhibitors, routine early invasive therapy, and thrombectomy devices in patients with ACS. Objective: The aim of this study was to determine trends in GPI use and their associated outcomes in contemporary practice. Methods: We assessed GPI use in patients with ACS undergoing percutaneous coronary intervention (PCI) from the Melbourne Interventional Group registry (2005-2013). The primary endpoint was the 30-day incidence of major adverse cardiovascular events (MACE). The safety endpoint was in-hospital major bleeding. Results: GPIs were used in 40.5% of 12 357 patients with ACS undergoing PCI. GPI use decreased over the study period ( P for trend

Repeat hospitalizations for recurrent acute coronary syndrome (ACS) or unplanned revascularization after acute myocardial infarction (MI) are common, costly and potentially preventable. We aim to describe 10-year trends and identify independent risk factors of these repeat hospitalizations.We analyzed data from 9615 patients from the Melbourne Interventional Group registry (2005-2014) who underwent percutaneous coronary intervention (PCI) for their index MI and survived to discharge. Patients with ≥1 hospitalization for recurrent ACS events and/or unplanned revascularization in the year after discharge were included in the recurrent coronary hospitalization group. We assessed yearly trends of recurrent coronary events and identified independent predictors using multivariate analysis.Recurrent coronary hospitalization occurred in 1175 (12.2%) patients. There was a significant decrease in the rate of recurrent ACS hospitalization (15.3%-7.6%, P for trend.001) and unplanned revascularization (4.2%-2.1%, P for trend = .01), but not in all-cause re-hospitalizations (P for trend = .28). On multivariate analysis, female gender, diabetes mellitus, previous coronary bypass surgery, previous PCI, reduced ejection fraction, heart failure, multi-vessel coronary disease and obstructive sleep apnea were independent predictors of recurrent coronary hospitalizations (all P .05).Recurrent hospitalization for ACS or unplanned revascularization has decreased significantly over the past decade. Risk factors for such events are numerous and largely non-modifiable, however they identify a cohort of patients in whom non-culprit vessel PCI in multi-vessel disease, optimization of left ventricular dysfunction and diabetes management may improve outcomes.

Background High systolic blood pressure (SBP) increases cardiac afterload, whereas low diastolic blood pressure (DBP) may lead to impaired coronary perfusion. Thus, wide pulse pressure (high systolic, low diastolic [HSLD]) may contribute to myocardial ischemia and also be a predictor of adverse cardiovascular events. Objectives The purpose of this study was to determine the relationship between pre-procedural blood pressure and long-term outcome following percutaneous coronary intervention (PCI). Methods The study included 10,876 consecutive patients between August 2009 and December 2016 from the Melbourne Interventional Group registry undergoing PCI with pre-procedural blood pressure recorded. Patients with ST-segment elevation myocardial infarction, cardiogenic shock, and out-of-hospital cardiac arrest were excluded. Patients were divided into 4 groups according to SBP (high ≥120 mm Hg, low 70 mm Hg, low ≤70 mm Hg). Results Mean pulse pressure was 60 ± 21 mm Hg. Patients with HSLD were older and more frequently women, with higher rates of hypercholesterolemia, renal impairment, diabetes, and multivessel and left main disease (all p ≤ 0.0001). There was no difference in 30-day major adverse cardiac events, but at 12 months the HSLD group had a greater incidence of myocardial infarction (p = 0.018) and stroke (p = 0.013). Long-term mortality was highest for HSLD (7.9%) and lowest for low systolic, high diastolic (narrow pulse pressure) at 2.1% (p = 0.0002). Cox regression analysis demonstrated significantly lower long-term mortality in the low systolic, high diastolic cohort (hazard ratio: 0.50; 99% confidence interval: 0.25 to 0.98; p = 0.04). Conclusions Pulse pressure at the time of index PCI is associated with long-term outcomes following PCI. A wide pulse pressure may serve as a surrogate marker for risk following PCI and represents a potential target for future therapies.

OBJECTIVES To evaluate the clinical characteristics and outcomes of patients with peripheral vascular disease (PVD) undergoing percutaneous coronary intervention (PCI) in a contemporary setting, and to determine whether use of drug-eluting stents (DESs) improves outcomes. BACKGROUND PVD was an independent risk factor for adverse outcomes following PCI in the bare-metal stent (BMS) era. It is not known whether outcomes in these patients have improved with advances in interventional techniques and stent technology, as they have for the general population. METHODS Eighteen thousand three hundred and eighty patients undergoing PCI from an Australian registry between 2005 and 2013 were studied. Clinical and procedural data, 30-day and 12-month outcomes were compared in those with and without a reported history of PVD. Outcomes were also compared between patients with PVD who received DES and those who received BMS. Long-term mortality was compared using Australian National Death Index (NDI) linkage. RESULTS Patients with PVD (n = 1,251, 6.8%) were older and had more prevalent diabetes, hypertension, cerebrovascular disease, heart failure, renal impairment, ostial lesions, left main, and multi-vessel disease (p

BACKGROUND Diabetes mellitus (DM) is a predictor of restenosis and late stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting-stents (DES). Real-world data on rates of early ST is lacking. We compared clinical outcomes of patients with and without DM from the Victorian cardiac outcomes registry. METHODS Consecutive patients undergoing PCI with DES were analyzed with primary outcome being ST at 30-days. Secondary outcomes including major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS Of 43,209 patients included, 9730 (22.5%) had DM. At 30 days, DM was independently associated with higher rates of early ST (0.7% vs. 0.5%) OR 1.41 (95% confidence interval; 1.05-1.87, p = 0.02), MACE (4.1% vs. 3.5%, p = 0.004) and mortality (1.9% vs. 1.5%, p = 0.01). Increased risk was not simply due to treatment. Patients with DM requiring insulin were equally affected in regard to MACE (4.7% vs. 3.9%, p = 0.069) and mortality (1.9%, vs. 1.8%, p = 0.746). On National Death Index linkage, patients with DM had increased all-cause mortality over five-year follow-up (OR 1.69 CI 1.55-1.83, p = < 0.001). CONCLUSION In this large real-world-registry, DM was an independent predictor of early ST, MACE and mortality at 30 days. These data suggest additional therapeutic strategies are required to reduce the risk of early complications in patients with DM undergoing PCI with DES.

There is paucity of data examining long-term outcomes of premature coronary artery disease (CAD). We aimed to investigate the short- and long-term clinical outcomes of patients with premature CAD treated by percutaneous coronary intervention (PCI) compared to older cohorts. We analyzed data from 27,869 patients who underwent PCI from 2005-2017 enrolled in a multicenter PCI registry. Patients were divided into three age groups: young group (≤ 45 years), middle-age group (46-65 years) and older group (>65 years). There were higher rates of current smokers in the young (n = 1,711) compared to the middle-age (n = 12,830) and older groups (n = 13,328) (54.2% vs 34.6% vs 11%) and the young presented more frequently with acute coronary syndrome (ACS) (78% vs 66% vs 62%), all p

Elucidating the formation of molecular complexes in living cells is key for understanding cellular homeostasis, but has not been amenable to quantitative microscopy. Here we established a platform for real-time quantification of molecular interactions to monitor the formation of complexes that results in a differential diffusion from their components. We have applied this to one of the most dynamic processes: the regulation of mRNA translation. We observe that diffusion of initiation factors (IFs) changes markedly upon their association with mRNA. Quantifying their binding dynamics revealed the sequence of IFs assembly and disassembly in cell lines and the clustering of translation in neurons. This methodology revealed translation regulation at unprecedented spatial and temporal resolution and can be applied to the formation of any endogenous complex that results in a measurable shift in diffusion.

Understanding cellular architecture is essential for understanding biology. Electron microscopy (EM) uniquely visualizes cellular structures with nanometer resolution. However, traditional methods, such as thin-section EM or EM tomography, have limitations inasmuch as they only visualize a single slice or a relatively small volume of the cell, respectively. Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) demonstrated the ability to image cellular samples at 4-nm isotropic voxels with rather limited imageable volume. Here, we present 3D EM images of whole cells and tissues with two orders of magnitude increases in imageable volume at 4-nm voxels. Such data with a combined fine resolution scale and large sample size do not currently exist, and are enabled by the advances in higher precision and stability of FIB milling, together with enhanced signal detection and faster SEM scanning. More importantly, we have generated a volume EM atlas encompassing ten diverse datasets of whole cells and tissues, from cancer cells to immune cells, and from mouse pancreatic islets to Drosophila neural tissues. These open-access data (via OpenOrganelle) represent a foundation to nucleate a new field of high-resolution whole-cell volume EM and subsequent analyses, and invite biologists to explore this new paradigm and pose fundamentally new questions.

Background Left ventricular dysfunction and ischaemic heart disease are common amongst women, however, women tend to present later and are less likely to receive guideline-directed medical therapy compared to their male counterparts. Purpose To investigate if a sex discrepancy exists for optimal medical therapy (OMT) and long-term mortality in a cohort of patients with known ischaemic heart disease (IHD) and left ventricular dysfunction. Methods We analysed prospectively collected data from a multicentre registry database collected between 2005–2018 on pharmacotherapy 30-days post percutaneous coronary intervention (PCI) in 13,015 patients with left ventricular ejection fraction (LVEF) Results Mean age was 65±12 years; women represented 20.2% (2,634) of the cohort. Women were on average 5 years older, had higher average BMI, higher rates of hypertension, diabetes, renal dysfunction, prior stroke and rheumatoid arthritis. Men were more likely to have sleep apnoea, be current/ex-smokers and to have had prior myocardial infarction, PCI and bypass surgery. Overall, 72.3% (9,411) of patients were on OMT, which was similar between sexes (72.7% in women vs. 72.2% in men, p=0.58). Rates of BB therapy were similar between sexes (85.2% vs. 84.5%, p=0.38), while women were less likely to be on an ACEi/ARB (80.4% vs. 82.4%, p=0.02) and more likely to be on a MRA (12.1% vs. 10.0%, p=0.003). Amongst those with LVEF ≤35% (n=1,652), BB (88.7% vs. 87.3%, p=0.46), ACEi/ARB (83.3% vs. 82.1%, p=0.59) and MRA use (32.5% vs. 33.3%, p=0.78) was comparable. Aspirin use was similar between sexes (95.3% vs. 95.9%, p=0.12), while women were less likely to be on statin therapy (93.5% vs. 95.3%, p Conclusion From this large multicentre registry, we found similar rates of guideline-directed pharmacotherapy for left ventricular dysfunction between sexes, however women were less likely to be on appropriate IHD secondary prevention. The increased unadjusted long-term mortality amongst women is likely due to differing baseline risk, given that adjusted mortality was similar between sexes. Kaplan-Meier Survival Analysis Funding Acknowledgement Type of funding source: None

Background Recent evidence from animal studies suggests that elastin degradation accelerates atherosclerosis and increases risk of plaque rupture and subsequent myocardial infarction and stroke. Desmosine is an elastin-specific degradation product. We analysed the prognostic value of plasma desmosine (pDES) in a cohort of patients with coronary artery disease (CAD). Methods Patients with CAD (n=400) undergoing elective coronary angiography were prospectively recruited over 3 years and had bloods drawn for analysis of pDES using a validated stable isotope dilution liquid chromatography-tandem mass spectrometry method. Patients were followed up for 12 months for major adverse cardiovascular events (MACE: composite of death, myocardial infarction, target vessel repeat revascularisation, target lesion revascularisation, and heart failure hospital admission). The upper limit of normal for pDES is 0.35 ng/mL. The predictive value of pDES for MACE was analysed with Cox-proportional hazards ratio (HR) model and Kaplan-Meier survival analysis. Results During follow-up, there were 36 MACE events. Median pDES level across the entire cohort was 0.3 ng/mL (IQR 0.23–0.41 ng/mL). Patients with a pDES level >0.35 ng/mL were more likely to be male and older with a mean age of 69.7±10.3 years, have a history of prior stroke or transient ischaemic attack (TIA) and COPD. In univariable analysis, a pDES level of >0.35 ng/mL was associated with an increased risk of MACE (HR 4.76, 95% CI: 2.34–9.68, p0.35 ng/mL was associated with risk of MACE after adjustment for age, sex, COPD status and previous stroke and TIA (HR 3.97; 95% CI: 1.82–8.67, p=0.001) (Figure). Conclusion Increased elastin degradation as measured by elevated pDES levels, predicts outcomes in patients with CAD independent of traditional cardiovascular risk factors and may play a role as a future biomarker in these patients. Kaplan-Meier survival analysis Funding Acknowledgement Type of funding source: None

Background Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is associated with increased risk of cardiovascular events and mortality. Despite this, data regarding long-term outcomes following percutaneous coronary intervention (PCI) are limited. Methods We identified 756 patients with RA from the Melbourne Interventional Group PCI registry (2005–2018) and compared outcomes to the remaining cohort (N=38,579). Cox regression analysis was performed to assess risk of adverse cardiac events including long-term mortality (derived from linkage with the National Death Index [NDI]). Results Patients with RA were older (68.9±10.0 vs. 64.6±12.0 years) and more often female (40% vs. 23%), with higher rates of hypertension (70% vs 67%), previous stroke (9% vs 6%), peripheral vascular disease (9% vs 6%), obstructive sleep apnoea (10% vs 5%), chronic lung disease (22% vs 12%), prior myocardial infarction (32% vs 27%), and impaired renal function (eGFR20mm in 39% vs 35%), and rates of no reflow were higher (5% vs 3%), all p Conclusions Patients with RA undergoing PCI have more comorbidities and longer, more complex coronary lesions. After adjustment, risk of short-term adverse outcomes are similar, while risk of long-term mortality is higher, particularly among patients with acute coronary syndromes. Funding Acknowledgement Type of funding source: None

Aims We sought to investigate if sex disparity exists for secondary prevention pharmacotherapy following acute coronary syndrome (ACS) and impact on long-term clinical outcomes. Methods and results We analysed data on medical management 30-day post-percutaneous coronary intervention (PCI) for ACS in 20 976 patients within the multicentre Melbourne Interventional Group registry (2005–2017). Optimal medical therapy (OMT) was defined as five guideline-recommended medications, near-optimal medical therapy (NMT) as four medications, sub-optimal medical therapy (SMT) as ≤3 medications. Overall, 65% of patients received OMT, 27% NMT and 8% SMT. Mean age was 64 ± 12 years; 24% (4931) were female. Women were older (68 ± 12 vs. 62 ± 12 years) and had more comorbidities. Women were less likely to receive OMT (61% vs. 66%) and more likely to receive SMT (10% vs. 8%) compared to men, P Conclusion Women are less likely to be prescribed optimal secondary prevention medications following PCI for ACS. Lower adjusted long-term mortality amongst women suggests that as well as baseline differences between gender, optimization of secondary prevention medical therapy amongst women can lead to improved outcomes. This highlights the need to focus on minimizing the gap in secondary prevention pharmacotherapy between sexes following ACS.

Background: Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18–85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis. Results: A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group ( P =0.09, log-rank). There was a higher rate of total death (8 versus 1; P =0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; P =0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%). Conclusions: The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au ; Unique identifier: ACTRN12615000861550.

OBJECTIVES: We aimed to assess the outcomes of cardiogenic shock (CS) complicating acute coronary syndromes (ACS). BACKGROUND: CS remains the leading cause of mortality in patients presenting with ACS despite advances in care. METHODS: We studied 13,184 patients undergoing percutaneous coronary intervention (PCI) for all subtypes of ACS enrolled prospectively in a large multicentre Australian registry (Melbourne Interventional Group registry) from 2005 to 2013. All-cause mortality was obtained via linkage to the National Death Index. Patients were divided into those with and those without CS. RESULTS: Compared to the non-CS group (n = 12,548, 95.2%), the CS group (n = 636, 4.8%) had a higher proportion of out-of-hospital cardiac arrest (OHCA) (31.1 vs. 2.2%) and ST-elevation myocardial infarction (STEMI) presentation (89 vs. 34%), both p

AIMS The aim of the study was to evaluate long-term outcomes of transient versus persistent no-reflow. METHODS AND RESULTS A total of 17,547 patients with normal flow post percutaneous coronary intervention (PCI) were compared to 590 patients (3.2%) with transient no-reflow and 144 patients (0.8%) with persistent no-reflow. Long-term all-cause mortality was obtained by linkage with the National Death Index (NDI). No-reflow patients were more likely to have presented with ST-elevation myocardial infarction (STEMI), out-of-hospital cardiac arrest (OHCA) or cardiogenic shock (all p