Morphogenesis of myocardial trabeculae in the mouse embryo

Formation of trabeculae in the embryonic heart and the remodelling that occurs prior to birth is a conspicuous, but poorly understood, feature of vertebrate cardiogenesis. Mutations disrupting trabecular development in the mouse are frequently embryonic lethal, testifying to the importance of the trabeculae, and aberrant trabecular structure is associated with several human cardiac pathologies. Here, trabecular architecture in the developing mouse embryo has been analysed using high-resolution episcopic microscopy (HREM) and three-dimensional (3D) modelling. This study shows that at all stages from mid-gestation to birth, the ventricular trabeculae comprise a complex meshwork of myocardial strands. Such an arrangement defies conventional methods of measurement, and an approach based upon fractal algorithms has been used to provide an objective measure of trabecular complexity. The extent of trabeculation as it changes along the length of left and right ventricles has been quantified, and the changes that occur from formation of the four-chambered heart until shortly before birth have been mapped. This approach not only measures qualitative features evident from visual inspection of 3D models, but also detects subtle, consistent and regionally localised differences that distinguish each ventricle and its developmental stage. Finally, the combination of HREM imaging and fractal analysis has been applied to analyse changes in embryonic heart structure in a genetic mouse model in which trabeculation is deranged. It is shown that myocardial deletion of the Notch pathway component Mib1 (Mib1(flox/flox); cTnT-cre) results in a complex array of abnormalities affecting trabeculae and other parts of the heart.This work was supported by funding to TJM from the Medical Research Council (U117562103); to JCM by the Higher Education Funding Council for England; to JLdlP and GL by grants SAF2010-17555 and SAF2013-45543-R from the Spanish Ministry of Economy and Competitiveness (MINECO); and to GC by a research fellowship at the University College London Biomedical Research Centre from the UK National Institutes of Health Research Cardiometabolic Programme.S

Using Australia’s National Data Linkage Demonstration Project (NDLDP) to improve cardiac care: Towards a national, whole-of-population linked data resource for evidence-informed health policy

Introduction In Australia, the Commonwealth, State and Territory governments are each responsible for specific aspects of health care. Historically, cross-jurisdictional health data have not been linked routinely, resulting in significant blind spots in our understanding of the interplay between hospital and primary care, a major impediment to evidence-informed health policy. Objectives and Approach In December 2016, the Australian Health Ministers’ Advisory Council approved the NDLDP, to establish the value of national linked data to inform health planning and policy. The Australian Institute of Health and Welfare (AIHW) linked five years of hospital, emergency department, pharmaceutical dispensing, medical services claims and mortality data for Australia’s two most populous states (New South Wales and Victoria). The Victorian Agency for Health Innovation (VAHI) is leading the ‘Delivering better cardiac outcomes: Primary, specialist and hospital care’ project to demonstrate the value of the collection in identifying evidence-practice gaps and driving change in cardiac care. Results The NDLDP combined data for over 10 million individuals with over 7 billion records of health transactions, utilising a new strategy for confidentialising dates to protect patient privacy. The NDLDP is governed by a Steering Committee; the AIHW is the data custodian approving outputs from analyses within a secure host environment. VAHI established a Project Steering Committee to oversee roll-out, governance and capacity building of the approved cardiac project. The VAHI project was instigated by evidence that best-practice pharmacological treatments for cardiac care are underutilised in Australia, but with no quantification of the population-level extent of this gap. The project quantified significant variations and underuse of post-discharge pharmacological care for patients admitted to hospital with key cardiac conditions, including atrial fibrillation and acute myocardial infarction. Conclusion/Implications This collaboration between government, clinical networks and academic researchers demonstrated this novel data linkage can enable evaluation of patient care pathways across both hospital and community-based services. These linked data resources provide essential information to investigate variation in care in Australia and improve care integration in cardiac care and beyond

SMARTphone-based, early cardiac REHABilitation in patients with acute coronary syndromes [SMART-REHAB Trial]: A randomized controlled trial protocol

© 2016 The Author(s). Background: There are well-documented treatment gaps in secondary prevention of coronary heart disease and no clear guidelines to assist early physical activity after acute coronary syndromes (ACS). Smartphone technology may provide an innovative platform to close these gaps. This paper describes the study design of a randomized controlled trial assessing whether a smartphone-based secondary prevention program can facilitate early physical activity and improve cardiovascular health in patients with ACS. Methods: We have developed a multi-faceted, patient-centred smartphone-based secondary prevention program emphasizing early physical activity with a graduated walking program initiated on discharge from ACS admission. The program incorporates; physical activity tracking through the smartphone's accelerometer with interactive feedback and goal setting; a dynamic dashboard to review and optimize cardiovascular risk factors; educational messages delivered twice weekly; a photographic food diary; pharmacotherapy review; and support through a short message service. The primary endpoint of the trial is change in exercise capacity, as measured by the change in six-minute walk test distance at 8-weeks when compared to baseline. Secondary endpoints include improvements in cardiovascular risk factor status, psychological well-being and quality of life, medication adherence, uptake of cardiac rehabilitation and re-hospitalizations. Discussion: This randomized controlled trial will use a smartphone-phone based secondary prevention program to emphasize early physical activity post-ACS. It will provide evidence regarding the feasibility and utility of this innovative platform in closing the treatment gaps in secondary prevention. Trial registration: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on April 4, 2016. The registration number is ACTRN12616000426482

Abnormal septal convexity into the left ventricle occurs in subclinical hypertrophic cardiomyopathy.

BACKGROUND: Sarcomeric gene mutations cause hypertrophic cardiomyopathy (HCM). In gene mutation carriers without left ventricular (LV) hypertrophy (G + LVH-), subclinical imaging biomarkers are recognized as predictors of overt HCM, consisting of anterior mitral valve leaflet elongation, myocardial crypts, hyperdynamic LV ejection fraction, and abnormal apical trabeculation. Reverse curvature of the interventricular septum (into the LV) is characteristic of overt HCM. We aimed to assess LV septal convexity in subclinical HCM. METHODS: Cardiovascular magnetic resonance was performed on 36 G + LVH- individuals (31 ± 14 years, 33 % males) with a pathogenic sarcomere mutation, and 36 sex and age-matched healthy controls (33 ± 12 years, 33 % males). Septal convexity (SCx) was measured in the apical four chamber view perpendicular to a reference line connecting the mid-septal wall at tricuspid valve insertion level and the apical right ventricular insertion point. RESULTS: Septal convexity was increased in G + LVH- compared to controls (maximal distance of endocardium to reference line: 5.0 ± 2.5 mm vs. 1.6 ± 2.4 mm, p ≤ 0.0001). Expected findings occurred in G + LVH- individuals: longer anterior mitral valve leaflet (23.5 ± 3.0 mm vs. 19.9 ± 3.1 mm, p ≤ 0.0001), higher relative wall thickness (0.31 ± 0.05 vs. 0.29 ± 0.04, p ≤ 0.05), higher LV ejection fraction (70.8 ± 4.3 % vs. 68.3 ± 4.4 %, p ≤ 0.05), and smaller LV end-systolic volume index (21.4 ± 4.4 ml/m(2) vs. 23.7 ± 5.8 ml/m(2), p ≤ 0.05). Other morphologic measurements (LV angles, sphericity index, and eccentricity index) were not different between G + LVH- and controls. CONCLUSIONS: Septal convexity is an additional previously undescribed feature of subclinical HCM

Maximal wall thickness measurement in hypertrophic cardiomyopathy

Objectives The aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM). Background Left ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD). Methods A 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death. Results MWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years’ experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range –59% to 117% [SD ±20%] and –61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk). Conclusions Using the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM

Clinical application of cardiac computed tomography: implications for chest pain assessment

Chest pain is a common and potentially life-threatening symptom that represents a global health and economic challenge. The prompt and accurate evaluation of chest pain has considerable implications for patient morbidity and mortality as well as on health care economics, however accurate identification of the aetiology of a patient’s chest pain is associated with many diagnostic challenges and potential pitfalls. Most current diagnostic strategies for chest pain focus on the detection of acute coronary syndromes and are based on the premise that other potential diagnoses can be excluded with careful clinical assessment. Therefore, efforts to improve the efficacy of the evaluation of chest pain patients have incorporated newer diagnostic strategies and modalities, such as new cardiac biomarkers and non-invasive imaging techniques. These approaches are typically used in various combinations as part of diagnostic protocols for patients admitted to chest pain units. If the initial evaluation shows no evidence of acute coronary syndrome or myocardial ischaemia, a confirmatory study is usually performed to exclude obstructive coronary artery disease or ischaemia. Although exercise treadmill testing (often with echocardiography or myocardial perfusion imaging) is widely used as a confirmatory test, coronary computed tomography angiography (CCTA) is becoming increasingly used as an alternative, primarily due to its very high sensitivity and negative predictive value in excluding obstructive coronary artery disease as a cause of chest pain. However, CCTA is a relatively new technique compared to established stress testing techniques, and has not yet demonstrated safe long-term outcomes in the acute chest pain setting. Since the introduction of CCTA imaging approximately 15 years ago there has been a steady improvement in image acquisition time, number of x-ray detectors employed, spatial and temporal resolution as well as a reduction in radiation and contrast dose. This has resulted in improved image quality and diagnostic accuracy for the detection of obstructive coronary artery disease, non-coronary structural heart disease and myocardial ischaemia, all of which are important aspects in determining the aetiology of a patient’s chest pain with the potential to change risk stratification of coronary artery disease. This includes patients with stable chest pain syndromes, as well as patients at low to intermediate risk of an acute coronary syndrome who present to an Emergency Department with acute chest pain. In addition there is growing interest in applications beyond assessment of coronary anatomy, including evaluation of non-coronary cardiac anatomy and extracardiac structures that may identify an alternate cause for the patient’s chest pain, as well as assessment of myocardial perfusion, which simultaneously allows a single examination to identify coronary artery anatomy, coronary artery stenosis and the functional significance of coronary artery stenoses. Whether recent CCTA advances translate into more accurate diagnosis of the cause of patients’ chest pain is yet to be fully determined. Similarly, it is not yet known whether the use of this technology will result in acceptable long-term safety outcomes in the chest pain population presenting to the Emergency Department. A more in depth exploration of the potential role of novel CCTA techniques in these areas is essential to establish the place and appropriateness of this technology in contemporary cardiac practice. This thesis, which explores the clinical application of CCTA and other novel imaging techniques in the contemporary assessment of chest pain, has the following specific aims: 1. To provide an in-depth review of the current evidence regarding the clinical utility of CCTA in the assessment of stable and acute chest pain syndromes, considering the latest advances in CCTA techniques and their potential clinical application to improve patient care in a cost-effective manner (chapter 2). 2. To provide a comprehensive overview of the role of multidetector computed tomography in the assessment of structural heart disease, including the detection of alternate causes of chest pain beyond coronary artery disease, the evaluation of myocardial perfusion and the assessment of emerging peri-procedural clinical applications (chapter 3). 3. To evaluate the long-term safety outcomes and hospital readmission rates of patients presenting to the Emergency Department with possible acute coronary syndrome after investigation with a novel CCTA-guided algorithm (chapter 4). 4. To establish the prevalence and anatomic characteristics of coronary arteries arising from an anomalous location detected by CCTA and determine the impact of high-risk anatomic characteristics on patient management and medium-term safety outcomes (chapter 5). 5. To determine the diagnostic accuracy of combined 320-detector CCTA and adenosine stress computed tomography perfusion imaging in detecting perfusion abnormalities caused by obstructive coronary artery disease in symptomatic patients; and to investigate whether 320-detector computed tomography perfusion imaging, when added to resting CCTA, provides incremental diagnostic accuracy to CCTA alone in detecting myocardial ischaemia (chapter 6). 6. To investigate whether patients undergoing treadmill stress echocardiography with an abnormal left ventricular contractile response to exercise without obstructive coronary artery disease or other established causes have resting left ventricular long-axis dysfunction, and to determine independent associations with this abnormal response (chapter 7)

Beyond the Coronary Arteries: Evolving Applications of Multi-detector Cardiac Computed Tomography in the Assessment of Non-coronary Structures

Beyond the assessment of coronary artery anatomy, multi-detector computed tomography (MDCT) can be used to provide detailed structural evaluation of multiple non-coronary structures. The purpose of this review is to provide a clinical update on the evolving niche applications of MDCT in the assessment of non-coronary structures, including the assessment of the left ventricle for perfusion and scar, the evaluation of the right ventricle, pericardium and coronary anomalies. Additionally, an overview of the roles of MDCT in the assessment of congenital heart disease and intra-cardiac masses will be reviewed