Professor Andrew Boyle

Background: Recurrent ST-elevation myocardial infarctions (STEMIs) are associated with poorer prognosis. A diminished haematopoietic response has been proposed as the mechanism responsible for this, but has yet to be validated in human studies. We therefore aim to map out the leukocyte response, and its subtypes, following the first and second STEMI to identify if the inflammatory response is dampened after recurrent myocardial infarctions. Methods: Retrospective cohort study of patients presenting with recurrent STEMI undergoing percutaneous coronary intervention. Full blood counts were taken within 24 h of each admission, and daily thereafter. The primary outcome was whether there were any qualitative or quantitative difference in leukocyte cell response (and its subtypes) between first and second STEMI. Results: Thirty-one patients (mean age 59 years [SD 14.9], 26 males [83.9%]) with an average of 3.1 years between infarcts were included in the study. Overall, between first and second STEMI, similar mean leukocyte response (and its subtypes) was observed from admission to day three post PCI. Similarly, the peak leukocyte response (and its subtypes) was similar between the two STEMIs, even after adjusting for infarct size. Conclusions: In recurrent STEMIs, there is no long-term memory effect on the cellular inflammatory response leading to diminished peripherally circulating leucocytes, and its subtypes.

Australia's First Nations Peoples, Aboriginal and Torres Strait Islanders, have reduced life expectancy compared to the wider community. Cardiovascular diseases, mainly driven by ischaemic heart disease, are the leading contributors to this disparity. Despite over a third of First Nations Peoples living in New South Wales, the bulk of the peer-reviewed literature is from Central Australia and Far North Queensland. Regardless of the site of publication, First Nations Peoples are significantly younger at disease onset and have higher rates of comorbidities, in turn driving adverse health events. On top of this, very few First Nations Peoples specific cardiovascular interventions or programs have been shown to improve outcomes. The traditional biomedical model of care is less efficacious and non-traditional models of communication such as clinical yarning may benefit both clinicians and patients. The key purpose of this review is to highlight the deficiencies of our knowledge of cardiovascular burden of disease for First Nations Peoples; and to serve as a catalyst for more dedicated research. We need to have relationships with communities and concentrate on community improvement and partnerships. By involving First Nations Peoples researchers in collaboration with local communities in all levels of health care design and intervention will improve outcomes.

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1 -/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3¿6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Coronary artery calcification is prevalent in coronary heart disease with its progression being predictive of future adverse cardiac events. Its presence is considered to be a marker of interventional procedural complexity. Several adjunctive percutaneous coronary intervention tools, such as modifying balloons, atherectomy devices and intravascular lithotripsy, now exist to successfully treat calcified lesions. In this state-of-the-art review, a step-wise progression of strategies is described to modify coronary plaque, from well-recognised techniques to techniques that should only be considered when standard manoeuvres have proven unsuccessful. Technology has advanced greatly over the past few decades and we discuss how future technologies might shape percutaneous intervention.

Background Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) is now the standard of care, but whether the demonstrated benefits of RM translate into improvements in heart failure (HF) management is controversial. This systematic review addresses the role of RM in patients with HF with a CIED. Methods and results A systematic search of the literature for randomised clinical trials in patients with HF and a CIED assessing efficacy/effectiveness of RM was performed using MEDLINE, PubMed and Embase. Meta-analysis was performed on the effects of RM of CIEDs in patients with HF on mortality and readmissions. Effects on implantable cardiac defibrillator (ICD) therapy, healthcare costs and clinic presentations were also assessed. 607 articles were identified and refined to 10 studies with a total of 6579 patients. Implementation of RM was not uniform with substantial variation in methodology across the studies. There was no reduction in mortality or hospital readmission rates, while ICD therapy findings were inconsistent. There was a reduction in patient-associated healthcare costs and reduction in healthcare presentations. Conclusion RM for patients with CIEDs and HF was not uniformly performed. As currently implemented, RM does not provide a benefit on overall mortality or the key metric of HF readmission. It does provide a reduction in healthcare costs and healthcare presentations. PROSPERO REGISTRATION NUMBER CRD42019129270.

Aims This study aims to (1) define the characteristics of patients with a first admission for heart failure (HF), stratified by type (reduced (HFrEF) vs preserved (HFpEF) ejection fraction) in a regional Australian setting; (2) compare the outcomes in terms of mortality and rehospitalisation and (3) assess adherence to the treatment guidelines. Methods We identified all index hospitalisations with HF to John Hunter Hospital and Tamworth Rural Referral Hospital in the Hunter New England Local Health District over a 12 months. We used the recent Australian HF guidelines to classify HFrEF and HFpEF and assess adherence to guideline-directed therapy. The primary outcome of the study was to compare short-term (1 year) and long-term all-cause mortality and the composite of all-cause hospitalisation or all-cause mortality of patients with HFrEF and HFpEF. Results There were 664 patients who had an index HF admission to John Hunter and Tamworth hospitals in 2014. The median age was 80 years, 47% were female and 22 (3%) were Aboriginal. In terms of HF type, 29% had HFrEF, 37% had HFpEF, while the remainder (34%) did not have an echocardiogram within 1 year of admission and could not be classified. The median follow-up was 3.3 years. HFrEF patients were predominantly male (64%) and in 48% the aetiology was ischaemic heart disease. The 1-year all-cause mortality was 23% in HFpEF subgroup and 29% in HFrEF subgroup (p=0.15). Five-year mortality was 61% in HFpEF and HFrEF patients. Of the HFrEF patients, only 61% were on renin-angiotensin-aldosterone blockers, 74% were on ß-blockers and 39% were on aldosterone antagonist. Conclusion HF patients are elderly and about evenly split between HFrEF and HFpEF. In this regional cohort, both HF types are associated with similar 1-year and 5-year mortality following incident HF hospitalisation. Echocardiography and guideline-directed therapies were underused.

Background: There is an established association between fast-food consumption and metabolic diseases. Some studies also suggest that calorie-dense food promotes a proinflammatory response, which is itself linked with myocardial infarction (MI). Whether increased fast-food availability is a risk factor for MI remains unknown. Aim: To investigate the role of fast-food outlet density (FFD) as a novel environmental risk factor for MI in the Hunter region, New South Wales (NSW). Methods: We conducted a retrospective cohort study using a database of all MI events between 1996 and 2013, extracted from the Hunter Cardiac and Stroke Outcomes unit. FFD was calculated for each local government area (LGA) of the Hunter region, allowing for a comparative analysis. Stratification by fast-food outlet data and LGA resulted in a total of 3070 cases. Weighted linear regression was used to investigate the role of FFD on incidence of MI in regional and rural Australia. Results: FFD was positively correlated with rates of MI, remaining consistent in both single and multivariate predictor models adjusting for age, obesity, hyperlipidaemia, hypertension, smoking status, diabetes and socioeconomic status (P < 0.001). An increase of one fast-food outlet corresponded with four additional cases of MI per 100 000 people per year (4.07, 95% confidence interval, 3.86¿4.28). Conclusions: FFD was positively associated with incidence of MI in both rural and metropolitan areas of NSW. This relationship remained consistent after multivariate adjustment for standard cardiovascular risk factors, highlighting the importance of an individual's food environment as a potential contributor towards their health.

Objective To assess the changes in cardiac hospitalisations, acute coronary syndromes (ACS) and out-of-hospital cardiac arrest (OOHCA) during COVID-19 isolation compared with prior time periods in an area of low COVID-19 disease incidence. Methods Review of all cardiology admissions, non-ST segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI) requiring urgent catheter laboratory activation and OOHCA. The 10-week period of government-imposed social isolation (23 March-31 May 2020) was compared with the same period in 2018, 2019 and a 10-week period prior to social isolation (6 January-15 March 2020). Incidence rate ratios were calculated. Symptom to balloon time was also compared for those requiring catheterisation laboratory activation for STEMI. Results The incidence of COVID-19 in the health district was 0.14 per 100 000 per day during the isolation period. There was a significant reduction in cardiology hospitalisations, NSTEMI and STEMI presentations without changes in OOHCA or symptom to balloon time for STEMI. Conclusions We observed a significant decline in cardiology presentations during social isolation without widespread COVID-19 disease. This provides further evidence for the important influence of social and behavioural factors on coronary event rates.

Introduction: Different endpoint criteria, different durations of follow-up and the completeness of follow-up can dramatically affect the perceived benefits of atrial fibrillation (AF) ablation. Methods: We defined three endpoints for recurrence of AF post ablation in a cohort of 200 patients with symptomatic AF, refractory to antiarrhythmic drugs (AADs). A ¿Strict Endpoint¿ where patients were considered to have a recurrence with any symptomatic or documented recurrence for =30 seconds with no blanking period, and off their AADs, a ¿Liberal Endpoint¿ where only documented recurrences after the blanking period, either on or off AADs were counted, and a ¿Patient-defined Outcome endpoint¿ which was the same as the Liberal endpoint but allowed for up to two recurrences and one repeat ablation or DCCV during follow-up. We also surveyed 50 patients on the waiting list for an AF ablation and asked them key questions regarding what they would consider to be a successful result for them. Results: Freedom from recurrence of atrial tachyarrhythmias (AT) at 5 years was 62% for the Strict Endpoint, 73% for the Liberal Endpoint, and 80% for the Patient-defined Outcome endpoint (p<0.001). Of the 50 patients surveyed awaiting AF ablation, 70% said they would still consider the procedure a success if it required one repeat ablation or one DCCV (p=0.004), and 76% would be accepting of one or two recurrences during follow-up (p<0.001). Conclusion: In this study, the majority of patients still considered AF ablation a successful treatment if they had up to two recurrences of AF, one repeat procedure or one DCCV. Furthermore, a ¿Patient-defined¿ definition of success lead to significantly different results in this AF ablation cohort when compared to conventionally used/guideline directed measures of success.

Background: Diagnosis of critical coronary artery disease, including after acute coronary syndrome presentation (ACS), represents an important indication for early coronary artery bypass graft (CABG) surgery. The study aims to investigate the influence of time from diagnosis to CABG on outcomes and document barriers to early revascularisation. Methods: All patients 18 years and older with an acute presentation due to ACS or critical coronary artery disease who were considered to require urgent inpatient cardiac surgery between January 2016¿February 2019 were included in the study. The primary endpoints were 30-day all-cause mortality or readmission, 1-year all-cause mortality, all-cause readmission. The secondary endpoint was the rate of complications while waiting for surgery. The time duration between diagnostic coronary angiography and surgery was considered as the time interval. Results: Of 266 eligible patients, 251 underwent surgical revascularisation with 15 (6%) not undergoing surgery due to preoperative complications (n=12) or due to perceived prohibitively high surgical risk (n=3). The majority (85%) were male (mean age 67 years), 37% of patients had diabetes and 71% had hypertension. Non-ST elevation myocardial infarction was documented in 51% of the patients. The median time between diagnosis and inpatient CABG was 7 days (IQR 5¿11). Thirty-five per cent (35%) of patients experienced complications while awaiting surgery. Of the 266 patients, 140 patients (53% - cohort 1) underwent surgery within 7 days. The cohort 1 rate of complications was lower than in cohort 2 (surgery after 7 days) (24 vs 47%, p<0.001). Moreover, 1-year mortality was less in cohort 1 (2 vs 8%, p=0.029). Conclusion: In patients requiring urgent inpatient CABG, delay for more than 7 days is associated with a higher rate of in-hospital complications and worse 30 day and 12-month outcomes.

Despite the latest advances in cardiovascular biology and medicine, myocardial infarction (MI) remains one of the major causes of deaths worldwide. While reperfusion of the myocardium is critical to limit the ischemic damage typical of a MI event, it causes detrimental morphological and functional changes known as ¿reperfusion injury.¿ This complex scenario is poorly represented in currently available models of ischemia/reperfusion injury, leading to a poor translation of findings from the bench to the bedside. However, more recent bioengineered in vitro models of the human heart represent more clinically relevant tools to prevent and treat MI in patients. These include 3D cultures of cardiac cells, the use of patient-derived stem cells, and 3D bioprinting technology. This review aims at highlighting the major features typical of a heart attack while comparing current in vitro, ex vivo, and in vivo models. This information has the potential to further guide in developing novel advanced in vitro cardiac models of ischemia/reperfusion injury. It may pave the way for the generation of advanced pathophysiological cardiac models with the potential to develop personalized therapies.

Background: Trans-radial access is increasingly common for cardiac catheterisation. Benefits include reduced bleeding complications, length of hospital stay and costs. Aims: To determine the feasibility of implementing a nurse-led ultrasound programme to measure radial artery diameter before and after cardiac catheterisation; to determine radial artery occlusion (RAO) rates, risk factors for RAO and predictors of radial artery (RA) diameter. Method: A prospective observational cohort study design for 100 consecutive patients undergoing cardiac catheterisation, using RA access. Pre- and post-procedural RA diameter were measured using ultrasound, by specialist nurses trained to do so. Logistic regression analyses were performed to determine risk factors for RAO and predictors of RA diameter with results reported as odds ratios (OR) and 95% confidence intervals (CI). Results: There were no adverse events, supporting the feasibility of nurse led ultrasound programmes. A 4% (n = 4) rate of occlusion was observed. Haemostasis device application time of greater than 190 min was a predictor of RAO (OR 3.12, 95% CI 0.31¿31). Male gender and height were predictors for a RA diameter of >2.2 mm. Conclusions: Nurses can lead the assessment of RA occlusion using ultrasound to enhance planning and care, including monitoring compression times to reduce RAO.

Background: While cardiac catheterisation is typically well tolerated, discomfort and anxiety are commonplace. Sedation using anxiolytic and analgesic medications has the potential to ameliorate such symptoms, however, is variably employed, with lack of standardised regimens and limited evidence. Methods: We performed a review of the role of sedation for cardiac catheterisation, including current practices and summarising available evidence relevant to diagnostic and interventional coronary procedures in the cardiac catheterisation laboratory. Results: Use of sedation and the medication regimens employed are highly variable. Available relevant studies are limited in number and mostly small. Sedation appears to modestly reduce anxiety and pain in most studies. The incidence of radial spasm and the consequent need to alter access site is reduced with procedural sedation. The majority of existing evidence applies to benzodiazepines and opioid use, which appear acceptably efficacious and safe when used with appropriate training and staffing; noting opioid medications reduce the absorption of loading doses of oral anti-platelet drugs. Conclusions: In conclusion, benzodiazepines and opioids result a modest reduction in pain, improved patient tolerability and reduced risk of radial artery spasm. The decision on whether to use sedation, and which agent(s) and dose, should be individualised based on patient factors, including need for oral antiplatelet therapy administration. Appropriate staffing and monitoring is essential.

Background: Stroke remains an important complication of diagnostic cardiac catheterisation and percutaneous coronary intervention and is associated with high rates of in-hospital mortality. Aims: To evaluate the incidence of stroke over a 10-year period and assess the long-term influence of stroke following cardiac catheterisation and PCI on functional outcomes, based on modified Rankin score and mortality. Methods: The study was performed using a case¿control design in a single tertiary referral centre. Patients were identified by correlating those patients undergoing cardiac catheterisation between October 2006 and December 2016 with patients who underwent neuroimaging within 7 days to identify possible cases of suspected stroke or transient ischaemic attack. Results: A total of 21 510 patients underwent cardiac catheterisation during the study period. Sixty (0.28%) patients experienced stroke or transient ischaemic attack. Compared to control patients, those who did experience cerebral ischaemic events were older (70.5 vs 64 years; P < 0.001), with higher rates of atrial fibrillation, hypertension and diabetes mellitus. Stroke complicating cardiac catheterisation was associated with an increased risk of readmission, with a significantly higher hazard of readmission for stroke noted. Despite minimal functional impairment based on modified Rankin score, stroke was associated with a significant risk of early and cumulative mortality. Stroke incidence remained stable over the study period despite changes in procedural practice. Conclusions: The incidence and functional severity of stroke remains low despite evolving procedural practice with a stable incidence over time despite changes in procedural practice; however, post-procedural stroke confirms an increased mortality hazard.

Midkine (MK) is a heparin-binding growth factor, whose role as a biomarker of coronary artery disease, myocardial ischaemia and necrosis has not been well measured. This study quantified serial MK levels in patients undergoing coronary angiography (CA) and identified factors associated with MK. In this single-centre, parallel cohort study, forty patients undergoing CA had arterial samples collected prior, 10 and 20¿min after heparin administration. Four groups were examined: 1¿stable coronary artery disease (CAD) without percutaneous coronary intervention (PCI); 2¿stable CAD for elective PCI; 3¿non-ST elevation myocardial infarction (NSTEMI) with or without PCI; 4¿ST elevation myocardial infarction (STEMI) with primary PCI. Groups 1, 2 and 4 were heparin naïve, allowing assessment of the effects of myocardial necrosis between baseline levels; group 3 had received low-molecular-weight heparin. MK levels were analysed by ELISA. Median MK at baseline did not differ between groups, demonstrating that myocardial ischaemia or necrosis does not affect MK levels. Heparin administration had an immediate effect on median MK at 10¿min, showing an average 500-fold increase that is dose-dependent (R2 = 0.35, p = 0.001). Median MK levels remained elevated at 20¿min following heparin administration. Multivariate analysis showed that the estimated glomerular filtration rate (eGFR) was the only predictor of elevated baseline MK (p = 0.02). Baseline MK did not correlate with high-sensitivity troponin-I (HsTnI) taken just before CA (p = 0.97), or peak HsTnI during admission (p = 0.74). MK is not a reliable marker of myocardial ischaemia or necrosis. MK increased significantly in all patients following heparin administration in a dose-dependent manner.

Background: The most frequent complications from percutaneous electrophysiology procedures relate to vascular access. We sought to perform the first randomised controlled trial for femoral venous haemostasis utilising a simple and novel purse string suture (PSS) technique. Methods: We randomised 200 consecutive patients who were referred for electrophysiology procedures at two different hospitals to either 10 minutes of manual pressure or a PSS over the femoral vein and determined the incidence of vascular access site complications. Results: The mean age was 61.8 ± 12.1 years and 138 (69%) were male. Bleeding requiring addition pressure or a FemStop (Abbott Laboratories, Abbott Park, IL, USA) for complete haemostasis occurred in 17/99 (17%) patients in the PSS arm and 19/101 (19%) patients in the manual pressure arm (p = 0.72). There were no cases of haematoma prolonging hospital stay, arterio-venous fistula, pseudoaneurysm or retroperitoneal bleeding. The mean duration to achieve haemostasis was 45 seconds in the PSS arm and 10 minutes 44 seconds in the manual pressure arm (p < 0.001). Pain/discomfort associated with haemostasis occurred in 15/99 (15%) patients in the PSS arm and in 29/101 (29%) patients receiving manual pressure (p = 0.03). Conclusions: In this randomised trial we demonstrate that an easy to perform PSS is as effective at achieving haemostasis as 10 minutes of manual pressure for catheter ablation procedures. The PSS is considerably faster to perform and is more comfortable for patients than manual pressure.

Myocardial perfusion scanning (MPS) is commonly used to assess patients with an intermediate to high risk of coronary artery disease. Concerns have been raised about the accuracy of this test. There is little recent data regarding the specificity of the MPS in the context of current medical therapy. The primary objective of this study is to determine the specificity of MPS in diagnosing obstructive coronary artery disease. A total of 184 patients fulfilled study criteria. The overall specificity of MPS for obstructive coronary artery disease was 54%.The only demographic variable that influenced specificity was gender: males with a specificity of 66% and females with a specificity of 29% (p-value = 0.001). These results suggest that the real world specificity of MPS is lower than previously indicated, particularly in the female population. The limitations proposed by the Cardiac Services Committee Report are therefore unlikely to improve patient outcomes.

Introduction: There is conflicting information regarding the contemporary incidence of first acute myocardial infarction (AMI) in Australia. We sought to document the regional variations in first AMI incidence in a large health district. Methods: We identified all patients presenting with first AMI in the Hunter region of New South Wales from 2004 to 2013. We calculated age and gender adjusted incidence of AMI and evaluated differences between patients from regional and metropolitan areas. We assessed 30-day and 12-month outcomes, including mortality, through linkage with the NSW Registry of Births Deaths and Marriages. Results: The incidence of first AMI in regional areas was persistently higher throughout the study compared to metropolitan areas (IRR 1.244; 95% CI 1.14¿1.35; p = 0.001). There were no significant differences between regional and metropolitan areas in 30-day and 12-month outcomes following presentation with first AMI. Conclusions: The study demonstrates persistently higher rates in regional compared to metropolitan areas, supporting the need for implementation of targeted intervention and prevention strategies.

Background: Delay in treatment and/or failure to provide reperfusion in ST-segment elevation myocardial infarction (STEMI) impacts on morbidity and mortality. This occurs more often outside metropolitan areas yet the reasons for this are unclear. This study aimed to describe factors associated with missed diagnosis of acute myocardial infarction (MAMI) in a rural and regional setting. Methods: Using a retrospective cohort design, patients who presented with STEMI and failed to receive reperfusion therapy within four hours were identified as MAMI. Univariate analyses were undertaken to identify differences in clinical characteristics between the treated STEMI group and the MAMI group. Mortality, 30-day readmission rates and length of hospital stay are reported. Results: Of 100 patients identified as MAMI (70 male, 30 female), 24 died in hospital. Demographics and time from symptom onset were similar in the treated STEMI and MAMI groups. Of the MAMI patients who died, rural hospitals recorded the highest inpatient mortality (69.6% p = 0.008). MAMI patients compared to treated STEMI patients had higher 30 day readmission (31.6% vs 3.3%, p = 0.001) and longer length of stay (5.5 vs 4.3 days p = 0.029). Inaccurate identification of STEMI on electrocardiogram (72%) and diagnostic uncertainty (65%) were associated with MAMI. The Glasgow algorithm to identify STEMI was utilised on 57% of occasions, with 93% accuracy. Conclusion: Mortality following MAMI is high particularly in smaller rural hospitals. MAMI results in increased length of stay and readmission rate. Electrocardiogram interpretation and diagnostic accuracy require improvement to determine if this improves patient outcomes.

Introduction The prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart. Methods Young adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-ß1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells. Results ECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role. Conclusions ECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro. Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis.

A growing body of evidence has demonstrated that pulmonary arterial capacitance (PAC) is the strongest hemodynamic predictor of clinical outcomes across a wide spectrum of cardiovascular disease, including pulmonary hypertension and heart failure. We hypothesized that a ratio of right ventricular stroke volume (RVOT VTI) to the associated peak arterial systolic pressure (PASP) could function as a reliable non-invasive surrogate for PAC. We performed a prospective study of patients undergoing simultaneous transthoracic echocardiography and right heart catheterization (RHC) for various clinical indications. Measurements of the RVOT VTI/PASP ratio from echocardiographic measurements were compared against PAC calculated from RHC measurements. Correlation coefficients and Bland¿Altman analysis compared the RVOT VTI/PASP ratio with PAC. Forty-five subjects were enrolled, 38% were female and mean age was 54¿years (SD 13¿years). The reason for referral to RHC was most commonly post-heart transplant surveillance (40%), followed by heart failure (22%), and pulmonary hypertension (18%). Pre-capillary pulmonary hypertension was present in 18%, isolated post-capillary pulmonary hypertension was present in 13%, and combined pre-and post-capillary pulmonary hypertension was present in 29%. The RVOT VTI/PASP ratio was obtainable in the majority of patients (78%), and Pearson's correlation demonstrated moderately-strong association between PAC and the RVOT VTI/PASP ratio, r = 0.75 (P < 0.001). Bland¿Altman analysis demonstrated good agreement between measurements without suggestion of systematic bias and a mean difference in standardized units of - 0.133. In a diverse population of patients and hemodynamic profiles, we validated that the ratio of RVOT VTI/PASP to be a reliably-obtained non-invasive marker associated with PAC.

Objectives: Improvements in the management of complex congenital heart disease, including those with single ventricle physiology, have resulted in increased survival. As this population ages, the recognition of cognitive impairment is increasingly important. At present, little is known about the potential mechanisms of cognitive dysfunction. In this cross-sectional study, we aimed to characterize the nature of abnormalities in cerebral blood flow and the relationship to cognitive deficits in adults with single ventricular physiology. Patients: Ten adults with single ventricular physiology (age 18-40¿years) and 12 age- and gender-matched controls underwent transcranial Doppler ultrasound and accompanying cognitive assessment. Outcome Measures: Patients underwent neuropsychological testing that assessed differing cognitive domains, with subjective cognitive decline determined from a 24-question survey. Transcranial Doppler ultrasound was used to assess baseline cerebral blood flow as well as change in cerebral blood flow velocities from baseline and during cognitive testing. Age, ethnicity, individual, and parental education levels were considered in the multivariate analyses. Results: On assessment of cognitive function, the patient group performed more poorly across each of the measured domains. The control group had a significantly greater increase in cerebral blood flow in response to cognitive stimuli compared to the patient cohort; these differences in response to cognitive stimuli were seen to a similar extent across each of the measured cognitive domains. Conclusion: Adults with Fontan physiology are underperforming in assessments of executive function with associated abnormalities in cerebral perfusion potentially contributing to cognitive deficits.

Background: Heart failure (HF) is a common, costly condition with an increasing burden on Australian health care system resources. Knowledge of the burden of HF on patients and on the health system is important for resource allocation. This study is the first systematic review to estimate the mortality and readmission rates after hospitalisation for HF in the Australian population. Methods: We searched for studies of HF hospitalisation in Australia published between January 1990 and May 2016, using a systematic search of PubMed, Medline, Scopus, Web of Science, EMBASE and Cochrane Library databases. Studies reporting 30-day and/or 1-year outcomes for mortality or readmission following hospitalisation were eligible and included in this study. Results: Out of 2889 articles matching the initial search criteria, a total of 13 studies representing 67,255 patients were included in the final analysis. The pooled mean age of heart failure patients was 76.3 years and 51% were male (n = 34,271). The pooled estimated 30-day and 1-year all-cause mortality were 8% and 25% respectively. The pooled estimated 30-day and 1-year all-cause readmission rates were 20% and 56% respectively. There is a high prevalence of comorbidities in heart failure patients. There were limited data on readmission and mortality in rural patients and Indigenous people. Conclusions: Heart failure hospitalisations in Australia are followed by substantial readmission and mortality rates.

Left ventricular end-diastolic pressure (LVEDP) is an easily obtained, physiologically integrative measure of total LV function. LVEDP may be a useful prognostic measure in patients with acute myocardial infarction and utilised to guide medical therapy and assess risk for post myocardial infarction heart failure. To assess the utility of LVEDP as a prognostic measure in patients presenting with acute myocardial infarction. We performed an unrestricted search of electronic databases (1946 to March 2017) using a predefined search strategy. Publications were included if patients had an acute coronary syndrome and LVEDP was measured by cardiac catheterisation and included outcome data specifying major adverse cardiac events. Two reviewers performed independent study selection, data abstraction and quality assessment by using the Cochrane tool for randomised trials and the ROBINS-I tool for non-randomised studies. Our search identified 8637 patients in seven studies. In patients with elevated LVEDP and STEMI, there was a significantly increased risk of 30-day death (three studies, 5372 participants; RR 1.9; 95% CI 1.4¿2.7; p < 0.001; I2 = 35.3%) and heart failure (two studies, 2574 participants; RR 2.9; 95% CI 1.9¿4.5; p = < 0.001; I2 = 0.0%). There was no significant increase in risk of 30¿day reinfarction (RR 1.25; 95% CI 0.77¿2.1; p = 0.37; I2 = 41.3%). Elevated LVEDP measured during cardiac catheterisation for acute myocardial infarction appears to be a predictor of heart failure and mortality.

Background: Left atrium (LA) function can be assessed by volumetric measurements, conventional and tissue Doppler, and more recently, deformation imaging using two-dimensional speckle tracking echocardiography (2DSTE). 2DSTE allows for measurement of volume and deformation and can quantify the contribution of the reservoir, conduit, and contraction phase. A common cause for LA dysfunction in very preterm infants is volume overload with a patent ductus arteriosus (PDA). The aim of this study was to explore the feasibility and reliability of LA 2DSTE in preterm infants, and describe LA function with and without PDA volume load. Methods: We prospectively recruited preterm infants <30¿weeks of gestation referred for assessment of a possible PDA. A cardiac ultrasound was performed at day 3 and in week 4 of life and analyzed using conventional techniques and 2DSTE. Results: Forty-eight infants (32 with PDA) were included. LA 2DSTE analysis was feasible in 96% of measurements with good reliability of strain and volume parameters. Strain rate was less reliable. Poorer LA contraction and reservoir function was associated with larger LA volume index, higher inflow over the mitral valve at early diastole, higher EA ratio, and higher Ee¿ ratio. Poorer conduit function was associated with higher Ee¿ ratio. A larger PDA diameter was found to be an independent contributor to deteriorating LA contraction and reservoir function. Conclusion: LA 2DSTE analysis is feasible in preterm infants and provides detailed information on atrium mechanics. Further studies are needed to explore the clinical value of these new parameters in this population.

Background Survival into adult life in patients with aortic coarctation is typical following surgical and catheter-based techniques to relieve obstruction. Late sequelae are recognised, including stroke, hypertension, and intracerebral aneurysm formation, with the underlying mechanisms being unclear. We hypothesised that patients with a history of aortic coarctation may have abnormalities of cerebral blood flow compared with controls. Methods Patients with a history of aortic coarctation underwent assessment of cerebral vascular function. Vascular responsiveness of intracranial vessels to hypercapnia and degree of cerebral artery stiffness using Doppler-derived pulsatility indices were used. Response to photic stimuli was used to assess neurovascular coupling, which reflects endothelial function in response to neuronal activation. Patient results were compared with age- and sex-matched controls. Results A total of 13 adult patients (males=10; 77%) along with 13 controls underwent evaluation. The mean age was 36.1±3.7 years in the patient group. Patients with a background of aortic coarctation were noted to have increased pulse pressure on blood pressure assessment at baseline with increased intracranial artery stiffness compared with controls. Patients with a history of aortic coarctation had less reactive cerebral vasculature to hypercapnic stimuli and impaired neurovascular coupling compared with controls. Results Adult patients with aortic coarctation had increased intracranial artery stiffness compared with controls, in addition to cerebral vasculature showing less responsiveness to hypercapnic and photic stimuli. Further studies are required to assess the aetiology and consequences of these documented abnormalities in cerebral blood flow in terms of stroke risk, cerebral aneurysm formation, and cognitive dysfunction.

Background: Sustained volume load due to a patent ductus arteriosus (PDA) leads to cardiac remodeling. Remodeling changes can become pathological and are associated with cardiovascular disease progression. Data on remodeling changes in preterm infants is not available. Methods: Clinical and echocardiography data were collected in preterm infants <30 weeks gestation on postnatal day 3 and then every 7¿14 days until closure of the ductus arteriosus. Images were analyzed using conventional techniques and speckle tracking. Remodeling changes of infants with prolonged (>14 days) exposure to a PDA were compared to control infants without a PDA. Results: Thirty out of 189 infants had prolonged exposure to a PDA. The left heart remodeled to a larger and more spherical shape and thus significantly increased in volume. Most changes occurred in the first 4 weeks, plateaued, and then returned to control values. Systolic function and estimates of filling pressure increased and effective arterial elastance reduced with a PDA, however contractility was unchanged. Wall thickness increased after 4 weeks of increased volume exposure. Conclusion: The preterm PDA induces early and significant remodeling of the left heart. A compensated cardiac physiology was seen with preserved systolic function, suggesting adaptive rather than pathological remodeling changes with prolonged exposure to a PDA.

Background: Trends in the incidence of acute myocardial infarction (AMI) provide important information for healthcare providers and can allow for accurate planning of future health needs and targeted interventions in areas with an excess burden of cardiovascular disease. Aim: To investigate the regional variations in AMI incidence in the Hunter region. Methods: Incident cases of AMI identified between 1996 and 2013 from the Hunter New England Health Cardiac and Stroke Outcomes Unit were prospectively collected for this study. We calculated crude and age-adjusted incidence of AMI over an 18-year period and explored differences in remoteness, age, sex and indigenous status. Results: During 1996¿2013, a total of 15 480 cases of AMI were identified. There was a significantly higher incidence of AMI in patients from regional areas compared to patients from metropolitan areas. More importantly, while rates of AMI declined by 28% in metropolitan patients, they increased by 8% in regional patients. Males had higher rates of AMI throughout the study period than females, however there was trend over time towards a reduction in AMI incidence in males that was not seen in females. The age-adjusted incidence of AMI for indigenous patients increased by 48% from 2007 to 2013, compared to a 23% decrease in non-indigenous patients. Conclusion: Between 1996 and 2013 in the Hunter region, the adjusted incidence of AMI increased for regional patients compared to metropolitan patients with a trend towards a higher adjusted incidence of AMI in the indigenous population.

Objective: Long standing pulmonary regurgitation results in deleterious effects on right heart size and function with late consequences of right heart volume overload including ventricular dilatation, propensity to arrhythmia and right heart failure. As sleep disordered breathing may predispose to elevations in pulmonary vascular resistance and associated negative effects on right ventricular function, we sought to assess this in patients with underlying congenital heart disease. Design: We performed a pilot study to evaluate the incidence of sleep-disordered breathing in a patient population with a history of long standing pulmonary valve incompetence in patients with congenital heart disease using overnight oximetry. Patients. Patients with a background of tetralogy of Fallot repair or residual pulmonary incompetence following previous pulmonary valve intervention for congenital pulmonary stenosis were included. Results: Twenty-two patients underwent overnight oximetry. The mean age of the cohort was 34.3 ± 15.2 years with no patients observed to have severe underlying pulmonary hypertension. Abnormal overnight oximetry was seen in 13/22 patients (59.1%) with 2/22 (9.1%) patients considered to have severe abnormalities. Conclusions: An important proportion of patients with a background of pulmonary incompetence complicating congenital heart disease are prone to the development of sleep-disordered breathing as assessed by overnight oximetry. Further study into the prevalence and mechanisms of sleep-disordered breathing in a larger cohort are warranted.

Background Transient bradycardia episodes are common in preterm infants and often secondary to apnea. Decreased ventilation with resultant hypoxemia is believed to be the predominant mechanism. Sudden bradycardias without apnea are also reported, possibly due to vagal stimulation. Point of care ultrasound is used to diagnose and follow cardiovascular complications in preterm infants. Inadvertently, the operator would sometimes capture bradycardia events. This study reports on left ventricular function during such events. Methods We retrospectively reviewed our cardiac ultrasound database for bradycardia events. Apical four or three chamber images before, during and after a bradycardia event were analysed with speckle tracking software which provides systolic and diastolic parameters of myocardial motion, deformation and volume. Results Over a 2¿year period, 15 bradycardia events were noted in 14 patients with a median gestational age of 26¿weeks (range 23 to 29). Heart rate decreased by an average of 43% (171/min to 98/min). Myocardial velocity and longitudinal strain rate during the atrial component of diastole were reduced during bradycardia. Longitudinal strain during systole was increased and radial deformation was unchanged. Ventricular volumes and ejection fraction did not change. Most parameters returned to baseline values after the event. Longitudinal systolic strain rate remained lower and stroke volume was 12% higher compared to baseline. Conclusion Parameters of systolic contractility and stroke volume were maintained and parameters of atrial contractility were reduced during mild to moderate bradycardia in preterm infants. Bradycardia reduces total cardiac output with a compensatory increase detected following the event.

Objective: The system of care in the Hunter New England Local Health District for patients with ST-segment elevation myocardial infarction (STEMI) foresees pre-hospital thrombolysis (PHT) administered by paramedics to patients more than 60 minutes from the cardiac catheterisation laboratory (CCL), and primary percutaneous coronary intervention (PCI) at the CCL for others. We assessed the safety and effectiveness of the pre-hospital diagnosis strategy, which allocates patients to PHT or primary PCI according to travel time to the CCL. Design, setting and participants: Prospective, non-randomised, consecutive, single-centre case series of STEMI patients diagnosed on the basis of a pre-hospital electrocardiogram (ECG), from August 2008 to August 2013. All patients were treated at the tertiary referral hospital (John Hunter Hospital, Newcastle). Main outcome measures: The primary efficacy endpoint was all-cause mortality at 12 months; the primary safety endpoint was bleeding. Results: STEMI was diagnosed in 484 patients on the basis of pre-hospital ECG; 150 were administered PHT and 334 underwent primary PCI. The median time from first medical contact (FMC) to PHT was 35 minutes (IQR, 28¿43 min) and to balloon inflation 130 minutes (IQR, 100¿150 min). In the PHT group, 37 patients (27%) needed rescue PCI (median time, 4 h; IQR, 3¿5 h). The 12-month all-cause mortality rate was 7.0% (PHT, 6.7%; PCI, 7.2%). The incidence of major bleeding (TIMI criteria) in the PHT group was 1.3%; no patients in the primary PCI group experienced major bleeding. Conclusion: PHT can be delivered safely by paramedical staff in regional and rural Australia with good clinical outcomes.

Cardiac resident stem cells (CRSCs) hold much promise to treat heart disease but this remains a controversial field. Here, we describe a novel population of CRSCs, which are positive for W8B2 antigen and were obtained from adult human atrial appendages. W8B2+ CRSCs exhibit a spindle-shaped morphology, are clonogenic and capable of self-renewal. W8B2+ CRSCs show high expression of mesenchymal but not hematopoietic nor endothelial markers. W8B2+ CRSCs expressed GATA4, HAND2, and TBX5, but not C-KIT, SCA-1, NKX2.5, PDGFRa, ISL1, or WT1. W8B2+ CRSCs can differentiate into cardiovascular lineages and secrete a range of cytokines implicated in angiogenesis, chemotaxis, inflammation, extracellular matrix remodeling, cell growth, and survival. In vitro, conditioned medium collected from W8B2+ CRSCs displayed prosurvival, proangiogenic, and promigratory effects on endothelial cells, superior to that of other adult stem cells tested, and additionally promoted survival and proliferation of neonatal rat cardiomyocytes. Intramyocardial transplantation of human W8B2+ CRSCs into immunocompromised rats 1 week after myocardial infarction markedly improved cardiac function (~40% improvement in ejection fraction) and reduced fibrotic scar tissue 4 weeks after infarction. Hearts treated with W8B2+ CRSCs showed less adverse remodeling of the left ventricle, a greater number of proliferating cardiomyocytes (Ki67+cTnT+ cells) in the remote region, higher myocardial vascular density, and greater infiltration of CD163+ cells (a marker for M2 macrophages) into the border zone and scar regions. In summary, W8B2+ CRSCs are distinct from currently known CRSCs found in human hearts, and as such may be an ideal cell source to repair myocardial damage after infarction.

Cardiovascular disease is the leading cause of death in Western countries. A major limitation of current treatments is the inability to efficiently repair or replace dead myocardium. Recently, stem cell-based therapies have been explored as an avenue to circumvent current therapeutic limitations. Overall, these therapies seem to result in small improvements in the contractile function of the heart. The exact mechanism(s) of action that underlie these improvements remain unknown, and it is believed that paracrine effects play a significant role. Previously, we had reported that an extract derived from bone marrow cells, in the absence of any live cell, contained cardioprotective soluble factors. In this study, we identify IL-15 as a putative cardioprotectant within the bone marrow cells paracrine profile. Using an in vitro culture system, we assessed the ability of IL-15 to protect cardiomyocytes under hypoxic conditions. For the first time, we have identified IL-15 receptors on the surface of cardiomyocytes and delineated the signaling system by which hypoxic cardiomyocytes may be protected from cellular death and rescued from oxidative stress with IL-15 treatment. Copyright © 2013 by Lippincott Williams & Wilkins.

BACKGROUND: Severe tortuosity of the right subclavian artery (RSCA) encountered during transradial cardiac catheterization can lead to longer procedures, increased fluoroscopy time, inability to engage the coronary artery ostia, and potentially procedural failure. Increasing age is strongly correlated with subclavian tortuosity; however, the magnitude and direction of age-related changes in aortic and subclavian artery anatomy have not been defined. METHODS: Chest computed tomography (CT) angiograms of 14 patients (6 age <45 years and 8 age =75 years) were evaluated for RSCA tortuosity. Measurements were taken along the midline of the vessel and compared to the straight distance traveled (index of tortuosity = straight distance/midline length). One normal and one tortuous subclavian were selected for three-dimensional printing and various catheters were benchtop tested on both models. RESULTS: The older group had longer (11.95 cm vs 9.6 cm; P<.01) and more tortuous subclavian arteries (lower index of tortuosity, 0.65 vs 0.76; P<.01) with more posterior unfolding (distance to most posterior aspect, 3.74 ± 0.77 cm vs 1.76 ± 0.58 cm; P<.001). Engagement of the coronary arteries of the normal model was significantly easier, with successful engagement of one or both coronaries with every catheter (n=7). Only 2 of 7 catheters (Radial Brachial and Extra Backup 3.0) were able to engage the coronary arteries in the tortuous model. CONCLUSION: Age is associated with elongation, tortuosity, and posterior unfolding of the RSCA. Three-dimensional printing of normal and tortuous arteries is feasible and shows potential to test differences between catheters.

As radial artery pseudoaneurysm (PA) is a rare complication of transradial catheterization, data on their management are sparse. Here, we report the case of a 77-year-old woman who underwent right transradial diagnostic cardiac catheterization, and subsequently developed a symptomatic PA. She underwent initial treatment with 20 minutes of mechanical compression with a Hemoband (Hemoband Corporation) with initial success. Three weeks later, she developed recurrence of her PA, and was treated with 24 hours of mechanical compression, wearing the Hemoband as an outpatient, with sustained resolution of the PA confirmed by ultrasound 1 month later, and no neurologic or further vascular complications. In addition to demonstrating that an initial PA as well as its recurrence can be treated with prolonged mechanical compression, we review the literature regarding radial artery PAs and their treatment.

The arterial switch operation for correction of transposition of the great arteries can be complicated by late stenosis or occlusion of the coronary arteries that are re-implanted to the new aorta. We report the case of a young boy who underwent this operation as a neonate and was found to have an occluded anomalous left anterior descending artery (LAD) before age 3. Subsequent bypass surgery was complicated by anastomotic stricture and kinking of the left internal mammary artery graft to the LAD. At age 7, the LAD territory showed reversible ischemia on nuclear perfusion testing and he was referred for percutaneous coronary intervention. A combined approach with pediatric and adult interventional cardiologists resulted in successful retrograde PCI to recanalize the chronic total occlusion of the LAD. Important features of this technique in pediatric patients are discussed. © 2013 Elsevier Inc.