Kenneth Mangion

Effect of Care Guided by Cardiovascular Magnetic Resonance, Myocardial Perfusion Scintigraphy, or NICE Guidelines on Subsequent Unnecessary Angiography Rates: The CE-MARC 2 Randomized Clinical Trial

IMPORTANCE Among patients with suspected coronary heart disease (CHD), rates of invasive angiography are considered too high. OBJECTIVE To test the hypothesis that among patients with suspected CHD, cardiovascular magnetic resonance (CMR)-guided care is superior to National Institute for Health and Care Excellence (NICE) guidelines-directed care and myocardial perfusion scintigraphy (MPS)-guided care in reducing unnecessary angiography. DESIGN, SETTING, AND PARTICIPANTS Multicenter, 3-parallel group, randomized clinical trial using a pragmatic comparative effectiveness design. From 6 UK hospitals, 1202 symptomatic patients with suspected CHD and a CHD pretest likelihood of 10% to 90% were recruited. First randomization was November 23, 2012; last 12-month follow-up was March 12, 2016. INTERVENTIONS Patients were randomly assigned (240:481:481) to management according to UK NICE guidelines or to guided care based on the results of CMR or MPS testing. MAIN OUTCOMES AND MEASURES The primary end point was protocol-defined unnecessary coronary angiography (normal fractional flow reserve >0.8 or quantitative coronary angiography [QCA] showing no percentage diameter stenosis ≥70% in 1 view or ≥50% in 2 orthogonal views in all coronary vessels ≥2.5 mm diameter) within 12 months. Secondary end points included positive angiography, major adverse cardiovascular events (MACEs), and procedural complications. RESULTS Among 1202 symptomatic patients (mean age, 56.3 years [SD, 9.0]; women, 564 [46.9%] ; mean CHD pretest likelihood, 49.5% [SD, 23.8%]), number of patients with invasive coronary angiography after 12 months was 102 in the NICE guidelines group (42.5% [95% CI, 36.2%-49.0%])], 85 in the CMR group (17.7% [95% CI, 14.4%-21.4%]); and 78 in the MPS group (16.2% [95% CI, 13.0%-19.8%]). Study-defined unnecessary angiography occurred in 69 (28.8%) in the NICE guidelines group, 36 (7.5%) in the CMR group, and 34 (7.1%) in the MPS group; adjusted odds ratio of unnecessary angiography: CMR group vs NICE guidelines group, 0.21 (95% CI, 0.12-0.34, P < .001); CMR group vs the MPS group, 1.27 (95% CI, 0.79-2.03, P = .32). Positive angiography proportions were 12.1% (95% CI, 8.2%-16.9%; 29/240 patients) for the NICE guidelines group, 9.8% (95% CI, 7.3%-12.8%; 47/481 patients) for the CMR group, and 8.7% (95% CI, 6.4%-11.6%; 42/481 patients) for the MPS group. A MACE was reported at a minimum of 12 months in 1.7% of patients in the NICE guidelines group, 2.5% in the CMR group, and 2.5% in the MPS group (adjusted hazard ratios: CMR group vs NICE guidelines group, 1.37 [95% CI, 0.52-3.57]; CMR group vs MPS group, 0.95 [95% CI, 0.46-1.95]). CONCLUSIONS AND RELEVANCE In patients with suspected angina, investigation by CMR resulted in a lower probability of unnecessary angiography within 12 months than NICE guideline-directed care, with no statistically significant difference between CMR and MPS strategies. There were no statistically significant differences in MACE rates. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT01664858.

Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping

Noninvasive quantification of myocardial fibrosis in end-stage renal disease is challenging. Gadolinium contrast agents previously used for cardiac magnetic resonance imaging (MRI) are contraindicated because of an association with nephrogenic systemic fibrosis. In other populations, increased myocardial native T1 times on cardiac MRI have been shown to be a surrogate marker of myocardial fibrosis. We applied this method to 33 incident hemodialysis patients and 28 age- and sex-matched healthy volunteers who underwent MRI at 3.0T. Native T1 relaxation times and feature tracking–derived global longitudinal strain as potential markers of fibrosis were compared and associated with cardiac biomarkers. Left ventricular mass indices were higher in the hemodialysis than the control group. Global, Septal and midseptal T1 times were all significantly higher in the hemodialysis group (global T1 hemodialysis 1171 ± 27 ms vs. 1154 ± 32 ms; septal T1 hemodialysis 1184 ± 29 ms vs. 1163 ± 30 ms; and midseptal T1 hemodialysis 1184 ± 34 ms vs. 1161 ± 29 ms). In the hemodialysis group, T1 times correlated with left ventricular mass indices. Septal T1 times correlated with troponin and electrocardiogram-corrected QT interval. The peak global longitudinal strain was significantly reduced in the hemodialysis group (hemodialysis -17.7±5.3% vs. -21.8±6.2%). For hemodialysis patients, the peak global longitudinal strain significantly correlated with left ventricular mass indices (R = 0.426), and a trend was seen for correlation with galectin-3, a biomarker of cardiac fibrosis. Thus, cardiac tissue properties of hemodialysis patients consistent with myocardial fibrosis can be determined noninvasively and associated with multiple structural and functional abnormalities.

A Novel Method for Estimating Myocardial Strain: Assessment of Deformation Tracking Against Reference Magnetic Resonance Methods in Healthy Volunteers

We developed a novel method for tracking myocardial deformation using cardiac magnetic resonance (CMR) cine imaging. We hypothesised that circumferential strain using deformation-tracking has comparable diagnostic performance to a validated method (Displacement Encoding with Stimulated Echoes- DENSE) and potentially diagnostically superior to an established cine-strain method (feature-tracking). 81 healthy adults (44.6 ± 17.7 years old, 47% male), without any history of cardiovascular disease, underwent CMR at 1.5 T including cine, DENSE, and late gadolinium enhancement in subjects >45 years. Acquisitions were divided into 6 segments, and global and segmental peak circumferential strain were derived and analysed by age and sex. Peak circumferential strain differed between the 3 groups (DENSE: −19.4 ± 4.8%; deformation-tracking: −16.8 ± 2.4%; feature-tracking: −28.7 ± 4.8%) (ANOVA with Tukey post-hoc, F-value 279.93, p < 0.01). DENSE and deformation-tracking had better reproducibility than feature-tracking. Intra-class correlation co-efficient was >0.90. Larger magnitudes of strain were detected in women using deformation-tracking and DENSE, but not feature-tracking. Compared with a reference method (DENSE), deformation-tracking using cine imaging has similar diagnostic performance for circumferential strain assessment in healthy individuals. Deformation-tracking could potentially obviate the need for bespoke strain sequences, reducing scanning time and is more reproducible than feature-tracking.

New perspectives on the role of cardiac magnetic resonance imaging to evaluate myocardial salvage and myocardial hemorrhage after acute reperfused ST-elevation myocardial infarction

ABSTRACT Cardiac magnetic resonance (CMR) imaging enables the assessment of left ventricular function and pathology. In addition to established contrast-enhanced methods for the assessment of infarct size and microvascular obstruction, other infarct pathologies, such as myocardial edema and myocardial hemorrhage, can be identified using innovative CMR techniques. The initial extent of myocardial edema revealed by T2-weighted CMR has to be stable for edema to be taken as a retrospective marker of the area-at-risk, which is used to calculate myocardial salvage. The timing of edema assessment is important and should be focused within 2 – 7 days post-reperfusion. Some recent investigations have called into question the diagnostic validity of edema imaging after acute STEMI. Considering the results of these studies, as well as results from our own laboratory, we conclude that the time-course of edema post-STEMI is unimodal, not bimodal. Myocardial hemorrhage is the final consequence of severe vascular injury and a progressive and prognostically important complication early post-MI. Myocardial hemorrhage is a therapeutic target to limit reperfusion injury and infarct size post-STEMI.

Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial

Background In patients with suspected angina pectoris, CT coronary angiography (CTCA) clarifies the diagnosis, directs appropriate investigations and therapies, and reduces clinical events. The effect on patient symptoms is currently unknown. Methods In a prospective open-label parallel group multicentre randomised controlled trial, 4146 patients with suspected angina due to coronary heart disease were randomised 1:1 to receive standard care or standard care plus CTCA. Symptoms and quality of life were assessed over 6 months using the Seattle Angina Questionnaire and Short Form 12. Results Baseline scores indicated mild physical limitation (74±0.4), moderate angina stability (44±0.4), modest angina frequency (68±0.4), excellent treatment satisfaction (92±0.2) and moderate impairment of quality of life (55±0.3). Compared with standard care alone, CTCA was associated with less marked improvements in physical limitation (difference −1.74 (95% CIs, −3.34 to −0.14), p=0.0329), angina frequency (difference −1.55 (−2.85 to −0.25), p=0.0198) and quality of life (difference −3.48 (−4.95 to −2.01), p<0.0001) at 6 months. For patients undergoing CTCA, improvements in symptoms were greatest in those diagnosed with normal coronary arteries or who had their preventative therapy discontinued, and least in those with moderate non-obstructive disease or had a new prescription of preventative therapy (p<0.001 for all). Conclusions While improving diagnosis, treatment and outcome, CTCA is associated with a small attenuation of the improvements in symptoms and quality of life due to the detection of moderate non-obstructive coronary artery disease. Trial registration number: NCT01149590.

Myocardial strain in healthy adults across a broad age range as revealed by cardiac magnetic resonance imaging at 1.5 and 3.0T: Associations of myocardial strain with myocardial region, age, and sex

To assess myocardial strain using cine displacement encoding with stimulated echoes (DENSE) using 1.5T and 3.0T MRI in healthy adults.

Advances in magnetic resonance imaging of the myocardial area at risk and salvage

Cardiac magnetic resonance (CMR) imaging in survivors of acute ST-segment–elevation myocardial infarction (STEMI) provides accurate and precise measurements of left ventricular dimensions, and infarct pathologies are uniquely characterized. Acute coronary artery occlusion initiates a wavefront phenomenon of ischemia1 commencing from the endocardial layer and propagating radially toward the epicardium, and typically, myocardial infarction will supervene unless coronary reperfusion is achieved in a timely manner. The myocardial area at risk is the jeopardized perfusion territory of the culprit artery. See Article by Nordlund et al Ischemia results in an increase in myocardial water content manifesting as myocardial edema, and the local changes in T1 and T2 relaxation times (milliseconds) can be revealed by CMR.2 Myocardial salvage is calculated by subtracting the infarct size on contrast-enhanced CMR from the myocardial area at risk, revealed by T1- or T2-weighted CMR, and predicts the likelihood of functional recovery.2 On the contrary, edema imaging has limitations because the area at risk diminishes in size from ≈5 days post reperfusion,3,4 and T2 relaxation times within the ischemic zone vary as infarct pathologies evolve.5,6 Several CMR methods are now available for imaging myocardial edema7; the most established of which is the T2-weighted short tau inversion recovery (T2-STIR) black blood technique. This method has the advantage of being generically available across all major vendors. However, image quality may be limited when using T2-STIR CMR because of low contrast-to-noise ratio between normal and abnormal myocardium and a propensity for subendocardial bright rim …

Changes and classification in myocardial contractile function in the left ventricle following acute myocardial infarction

In this research, we hypothesized that novel biomechanical parameters are discriminative in patients following acute ST-segment elevation myocardial infarction (STEMI). To identify these biomechanical biomarkers and bring computational biomechanics ‘closer to the clinic’, we applied state-of-the-art multiphysics cardiac modelling combined with advanced machine learning and multivariate statistical inference to a clinical database of myocardial infarction. We obtained data from 11 STEMI patients (ClinicalTrials.gov NCT01717573) and 27 healthy volunteers, and developed personalized mathematical models for the left ventricle (LV) using an immersed boundary method. Subject-specific constitutive parameters were achieved by matching to clinical measurements. We have shown, for the first time, that compared with healthy controls, patients with STEMI exhibited increased LV wall active tension when normalized by systolic blood pressure, which suggests an increased demand on the contractile reserve of remote functional myocardium. The statistical analysis reveals that the required patient-specific contractility, normalized active tension and the systolic myofilament kinematics have the strongest explanatory power for identifying the myocardial function changes post-MI. We further observed a strong correlation between two biomarkers and the changes in LV ejection fraction at six months from baseline (the required contractility (r = − 0.79, p < 0.01) and the systolic myofilament kinematics (r = 0.70, p = 0.02)). The clinical and prognostic significance of these biomechanical parameters merits further scrutinization.

Diagnostic accuracy of 3.0-T magnetic resonance T1 and T2 mapping and T2-weighted dark-blood imaging for the infarct-related coronary artery in Non-ST-segment elevation myocardial infarction

Background Patients with recent non–ST‐segment elevation myocardial infarction commonly have heterogeneous characteristics that may be challenging to assess clinically. Methods and Results We prospectively studied the diagnostic accuracy of 2 novel (T1, T2 mapping) and 1 established (T2‐weighted short tau inversion recovery [T2W‐STIR]) magnetic resonance imaging methods for imaging the ischemic area at risk and myocardial salvage in 73 patients with non–ST‐segment elevation myocardial infarction (mean age 57±10 years, 78% male) at 3.0‐T magnetic resonance imaging within 6.5±3.5 days of invasive management. The infarct‐related territory was identified independently using a combination of angiographic, ECG, and clinical findings. The presence and extent of infarction was assessed with late gadolinium enhancement imaging (gadobutrol, 0.1 mmol/kg). The extent of acutely injured myocardium was independently assessed with native T1, T2, and T2W‐STIR methods. The mean infarct size was 5.9±8.0% of left ventricular mass. The infarct zone T1 and T2 times were 1323±68 and 57±5 ms, respectively. The diagnostic accuracies of T1 and T2 mapping for identification of the infarct‐related artery were similar (P=0.125), and both were superior to T2W‐STIR (P<0.001). The extent of myocardial injury (percentage of left ventricular volume) estimated with T1 (15.8±10.6%) and T2 maps (16.0±11.8%) was similar (P=0.838) and moderately well correlated (r=0.82, P<0.001). Mean extent of acute injury estimated with T2W‐STIR (7.8±11.6%) was lower than that estimated with T1 (P<0.001) or T2 maps (P<0.001). Conclusions In patients with non–ST‐segment elevation myocardial infarction, T1 and T2 magnetic resonance imaging mapping have higher diagnostic performance than T2W‐STIR for identifying the infarct‐related artery. Compared with conventional STIR, T1 and T2 maps have superior value to inform diagnosis and revascularization planning in non–ST‐segment elevation myocardial infarction. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02073422.

Advances in computational modelling for personalised medicine after myocardial infarction

Myocardial infarction (MI) is a leading cause of premature morbidity and mortality worldwide. Determining which patients will experience heart failure and sudden cardiac death after an acute MI is notoriously difficult for clinicians. The extent of heart damage after an acute MI is informed by cardiac imaging, typically using echocardiography or sometimes, cardiac magnetic resonance (CMR). These scans provide complex data sets that are only partially exploited by clinicians in daily practice, implying potential for improved risk assessment. Computational modelling of left ventricular (LV) function can bridge the gap towards personalised medicine using cardiac imaging in patients with post-MI. Several novel biomechanical parameters have theoretical prognostic value and may be useful to reflect the biomechanical effects of novel preventive therapy for adverse remodelling post-MI. These parameters include myocardial contractility (regional and global), stiffness and stress. Further, the parameters can be delineated spatially to correspond with infarct pathology and the remote zone. While these parameters hold promise, there are challenges for translating MI modelling into clinical practice, including model uncertainty, validation and verification, as well as time-efficient processing. More research is needed to (1) simplify imaging with CMR in patients with post-MI, while preserving diagnostic accuracy and patient tolerance (2) to assess and validate novel biomechanical parameters against established prognostic biomarkers, such as LV ejection fraction and infarct size. Accessible software packages with minimal user interaction are also needed. Translating benefits to patients will be achieved through a multidisciplinary approach including clinicians, mathematicians, statisticians and industry partners.