Mind The Gap, Aboriginal and Torres Strait Islander Cardiovascular Health: A Narrative Review.

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.

Specificity of Myocardial Perfusion Imaging: Issues With Proposed MBS Item Review.

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.

Differential regulation of two FLNA transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies.

Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG+1 and ATG+82 . A male with CIPO (c.18_19del) exclusively expressed FLNA ATG+82 , implicating the longer protein isoform (ATG+1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG+1 while the third utilizes ATG+82 . Transcripts sponsoring translational initiation at ATG+1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development.

Elevated Soluble Suppressor of Tumorigenicity 2 Predict Hospital Admissions Due to Major Adverse Cardiovascular Events (MACE).

The role of soluble suppression of tumorigenicity (sST2) as a biomarker in predicting clinical outcomes in patients with cardiovascular diseases (CVD) has not been fully elucidated. In this study, we sought to determine the relationship between sST2 levels and any unplanned hospital readmissions due to a major adverse cardiovascular event (MACE) within 1 year of first admission. Patients (n = 250) admitted to the cardiology unit at John Hunter Hospital were recruited. Occurrences of MACE, defined as the composite of total death, myocardial infarction (MI), stroke, readmissions for heart failure (HF), or coronary revascularization, were recorded after 30, 90, 180, and 365 days of first admission. On univariate analysis, patients with atrial fibrillation (AF) and HF had significantly higher sST2 levels vs. those who did not. Increasing levels of sST2 by quartiles were significantly associated with AF, HF, older age, low hemoglobin, low eGFR, and high CRP levels. On multivariate analysis: high sST2 levels and diabetes remained as risk predictors of any MACE occurrence; an sST2 level in the highest quartile (Q4: >28.4 ng/mL) was independently associated with older age, use of beta-blockers, and number of MACE events within a 1 year period. In this patient cohort, elevated sST2 levels are associated with unplanned hospital admission due to MACE within 1 year, independent of the nature of the index cardiovascular admission.

Prevalence and survival associated with pulmonary hypertension after mitral valve replacement: National echocardiography database of Australia study.

The specific prevalence and outcome of pulmonary hypertension after mitral valve replacement (MVR) is not well documented. The aim of the study was to determine the prevalence and prognostic impact of pulmonary hypertension after MVR. In addition, we sought to determine the threshold of mortality risk according to echocardiography derived pulmonary pressures and those echocardiographic characteristics that are associated with increased mortality. Using the National Echocardiography Database of Australia, patients who had undergone MVR were identified with estimated right ventricular systolic pressure (eRVSP) assessed and linked to patient mortality during mean follow up of 1917 days. Classification and regression tree analysis was used to identify the most powerful predictors of mortality. A total of 10,994 patients who had undergone echocardiography following MVR (mean age 65.2 ± 16, 44.8% women) were studied (mean follow-up 1917 days). The prevalence of PH (defined as eRSVP ≥40 mmHg) was 64.1% (7042/10,994). Severe PH (eRVSP ≥60 mmHg) was seen in 42.3% (4671/10,994). Mortality in individuals with PH was greater than amongst individuals without PH (41.1% vs. 26.3%). Age, tricuspid regurgitation and left ventricular dysfunction were also associated with mortality. There is a high prevalence of PH after MVR which confers an adverse prognosis. Improved therapeutic approaches to mitral valve disease and the subsequent development of PH are essential.

Patient characteristics, short-term and long-term outcomes after incident heart failure admissions in a regional Australian setting.

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.

Heart failure outcomes in Aboriginal and Torres Strait Islander peoples in the Hunter New England region of New South Wales.

Background Aboriginal and Torres Strait Islander suffer poor health outcomes, driven predominately by cardiovascular disease. Previous work has focused on remote communities although majority of Aboriginal and Torres Strait Islander patients live in urban New South Wales. We describe the heart failure characteristics and outcomes of the Aboriginal and Torres Strait Islander patients in Hunter New England Health, New South Wales, Australia. Methods A large retrospective, multi-centre cohort study from 2007 till 2016 in a geographically diverse Local Health District. The primary outcomes were all-cause mortality and all-cause readmission. The Aboriginal and Torres Strait Islander cohort was described by demographics, locality, and outcomes relative to the non-Indigenous patients from the same time period. Findings During the study period there were 20,480 index admissions, of which 3.1% identified as Aboriginal and/or Torres Strait Islander. Aboriginal and Torres Strait Islander people admitted were younger by an average of 15 years (81 vs 66 years, p < 0.001), were more likely to live in a non-metropolitan locality (80 vs 61%, p < 0.001). Once adjustments were made for age, there was no significant difference in all-cause mortality. Indigenous status was a strong predictor of readmission on multivariate analysis, hazard ratio of 1.31 (p < 0.001). Interpretation Aboriginal and Torres Strait Islander patients, compared to non-Indigenous patients, who are admitted with heart failure are younger, more commonly live in rural localities and suffer from a higher burden of comorbidities. Once adjustments are made for age and co-morbidities, indigenous status does not portend a worse outcome.

Calcium/Calmodulin-Dependent Protein Kinase II Delta Inhibition and Ventricular Remodeling After Myocardial Infarction: A Randomized Clinical Trial.

Importance: After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling. Objective: To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018. Interventions: Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo. Main Outcomes and Measures: The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed. Results: A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period. Conclusions and Relevance: Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02557217.

Pulmonary Hypertension Due to Left Heart Disease: Diagnosis, Pathophysiology, and Therapy.

Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common type of PH and is defined as mean pulmonary artery systolic pressure of >20 mm Hg and pulmonary capillary wedge pressure >15 mm Hg during right heart catheterization. LHD may lead to elevated left atrial pressure alone, which in the absence of intrinsic pulmonary vascular disease will result in PH without changes in pulmonary vascular resistance. Persistent elevation in left atrial pressure may, however, also be associated with subsequent pulmonary vascular remodeling, vasoconstriction, and an increase in pulmonary vascular resistance. Hence, there are 2 subgroups of PH due to LHD, isolated postcapillary PH and combined post- and precapillary PH, with these groups have differing clinical implications. Differentiation of pulmonary arterial hypertension and PH due to LHD is critical to guide management planning; however, this may be challenging. Older patients, patients with metabolic syndrome, and patients with imaging and clinical features consistent with left ventricular dysfunction are suggestive of LHD etiology rather than pulmonary arterial hypertension. Hemodynamic measures such as diastolic pressure gradient, transpulmonary gradient, and pulmonary vascular resistance may assist to differentiate pre- from postcapillary PH and offer prognostic insights. However, these are influenced by fluid status and heart failure treatment. Pulmonary arterial hypertension therapies have been trialed in the treatment with concerning results reflecting disease heterogeneity, variation in inclusion criteria, and mixed end point criteria. The aim of this review is to provide an updated definition, discuss possible pathophysiology, clinical aspects, and the available treatment options for PH due to LHD.

Heparin Administration, but Not Myocardial Ischemia or Necrosis, Leads to Midkine Elevation.

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.

Ochronosis of the aortic valve.

Ochronosis is the bluish-black discolouration of connective tissue, including heart valves, joints, kidney and the skin. It is due to the deposition of homogentisic acid (HGA) commonly found in alkaptonuria. Ochronosis in the aortic valve is a rare occurrence and there is limited data available on the most appropriate choice of valve prosthesis in these patients. This case involves a 72-year-old male with symptomatic aortic stenosis and on echocardiogram a severe calcific trileaflet aortic stenosis with normal ejection fraction. Intraoperative aortic cannulation was routine and uncomplicated, and bluish-black discolouration of aortic valve was noted. Thorough decalcification was undertaken and a bioprosthetic valve was chosen in accordance with patient's age and preference. There were no complications post-operatively and the patient reported being well. Ochronosis affecting the aortic valve is a rare condition and there is limited data on the recurrence rate as well as the natural history of the disease. This case reports aims to provide data to facilitate further research to better understand the natural history of aortic valve ochronosis and rates of recurrence following bioprosthetic aortic valve replacement (AVR).