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.

The effect of changes to MOLLI scheme on T1 mapping and extra cellular volume calculation in healthy volunteers with 3 tesla cardiovascular magnetic resonance imaging.

BACKGROUND: Diffuse myocardial fibrosis may be quantified with magnetic resonance (MR) by calculating extracellular volume (ECV) fraction from native and post-contrast T1 values. The ideal modified look-locker inversion recovery (MOLLI) sequence for deriving T1 values has not been determined. This study aims to establish if systematic differences exist between suggested MOLLI schemes. METHODS: Twelve phantom gels were studied with inversion recovery spin echo MR at 3.0 tesla to determine reference T1. Gels were then scanned with six MOLLI sequences (3s)3b(3s)5b; 4b(3s)3b(3s)2b; 5b(3s)3b with flip angles of both 35° and 50° at a range of heart rates (HRs). In 10 healthy volunteers MOLLI studies were performed on two separate occasions. Mid ventricular native and post contrast T1 was measured and ECV (%) calculated. RESULTS: In phantoms, the co-efficient of variability at simulated HR [40-100] with a flip angle of 35° ranged from 6.77 to 9.55, and at 50° from 7.71 to 11.10. T1 was under-estimated by all MOLLI acquisitions. Error was greatest with longer T1, and increased as HR increased. The 10 volunteers had normal MR studies. Native T1 time was similar for all acquisitions but highest with the 5b(3s)3b 35° scheme (1,189.1±33.46 ms). Interstudy reproducibility was similar for all MOLLIs. CONCLUSIONS: The 5b(3s)3b MOLLI scheme agreed best with reference T1, without statistical difference between the six schemes. The shorter breath-hold time of 5b(3s)3b scheme may be preferable in clinical studies and warrants further investigation.

Splenic Switch-off: A Tool to Assess Stress Adequacy in Adenosine Perfusion Cardiac MR Imaging.

PURPOSE: To investigate the pharmacology and potential clinical utility of splenic switch-off to identify understress in adenosine perfusion cardiac magnetic resonance (MR) imaging. MATERIALS AND METHODS: Splenic switch-off was assessed in perfusion cardiac MR examinations from 100 patients (mean age, 62 years [age range, 18-87 years]) by using three stress agents (adenosine, dobutamine, and regadenoson) in three different institutions, with appropriate ethical permissions. In addition, 100 negative adenosine images from the Clinical Evaluation of MR Imaging in Coronary Heart Disease (CE-MARC) trial (35 false and 65 true negative; mean age, 59 years [age range, 40-73 years]) were assessed to ascertain the clinical utility of the sign to detect likely pharmacologic understress. Differences in splenic perfusion were compared by using Wilcoxon signed rank or Wilcoxon rank sum tests, and true-negative and false-negative findings in CE-MARC groups were compared by using the Fisher exact test. RESULTS: The spleen was visible in 99% (198 of 200) of examinations and interobserver agreement in the visual grading of splenic switch-off was excellent (κ = 0.92). Visually, splenic switch-off occurred in 90% of adenosine studies, but never in dobutamine or regadenoson studies. Semiquantitative assessments supported these observations: peak signal intensity was 78% less with adenosine than at rest (P < .001), but unchanged with regadenoson (4% reduction; P = .08). Calculated peak splenic divided by myocardial signal intensity (peak splenic/myocardial signal intensity) differed between stress agents (adenosine median, 0.34; dobutamine median, 1.34; regadenoson median, 1.13; P < .001). Failed splenic switch-off was significantly more common in CE-MARC patients with false-negative findings than with true-negative findings (34% vs 9%, P < .005). CONCLUSION: Failed splenic switch-off with adenosine is a new, simple observation that identifies understressed patients who are at risk for false-negative findings on perfusion MR images. These data suggest that almost 10% of all patients may be understressed, and that repeat examination of individuals with failed splenic switch-off may significantly improve test sensitivity.

Imaging Tuberous Sclerosis: The Incremental Benefit of Three-Dimensional and Speckle Tracking Echocardiography.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome and multisystem disorder with autosomal dominant inheritance and variable penetrance. Cardiac rhabdomyomas have been reported in 50-64% of patients with TSC and transthoracic echocardiography is established as the primary imaging modality for their detection. The precise functional assessment of the left ventricle in these patients requires clarification. We report a case of a 19-year-old male with known TSC who was referred for outpatient transthoracic echocardiography (TTE) to investigate for the presence of cardiac rhabdomyomas. TTE demonstrated multiple rhabdomyomas with a normal ejection fraction but altered global and regional deformation on speckle tracking. The regional longitudinal strain was notably reduced in the anterior septum (-11%) and inferior septum (-15%). The global circumferential strain (GCS) was significantly reduced at -15.6%. The distribution of regional circumferential strain reduction for the mid-ventricular segment correlated with the location of cardiac rhabdomyomas.

Single bolus versus split dose gadolinium administration in extra-cellular volume calculation at 3 Tesla.

BACKGROUND: Diffuse myocardial fibrosis may be quantified with cardiovascular magnetic resonance (CMR) by calculating extra-cellular volume (ECV) from native and post-contrast T1 values. Accurate ECV calculation is dependent upon the contrast agent having reached equilibrium within tissue compartments. Previous studies have used infusion or single bolus injections of contrast to calculate ECV. In clinical practice however, split dose contrast injection is commonly used as part of stress/rest perfusion studies. In this study we sought to assess the effects of split dose versus single bolus contrast administration on ECV calculation. METHODS: Ten healthy volunteers and five patients ( 4 ischaemic heart disease, 1 hypertrophic cardiomyopathy) were studied on a 3.0 Tesla (Philips Achieva TX) MR system and underwent two (patients) or three (volunteers) separate CMR studies over a mean of 12 and 30 days respectively. Volunteers underwent one single bolus contrast study (Gadovist 0.15mmol/kg). In two further studies, contrast was given in two boluses (0.075mmol/kg per bolus) as part of a clinical adenosine stress/rest perfusion protocol, boluses were separated by 12 minutes. Patients underwent one bolus and one stress perfusion study only. T1 maps were acquired pre contrast and 15 minutes following the single bolus or second contrast injection. RESULTS: ECV agreed between bolus and split dose contrast administration (coefficient of variability 5.04%, bias 0.009, 95% CI -3.754 to 3.772, r2 = 0.973, p = 0.001)). Inter-study agreement with split dose administration was good (coefficient of variability, 5.67%, bias -0.018, 95% CI -4.045 to 4.009, r2 = 0.766, p > 0.001). CONCLUSION: ECV quantification using split dose contrast administration is reproducible and agrees well with previously validated methods in healthy volunteers, as well as abnormal and remote myocardium in patients. This suggests that clinical perfusion CMR studies may incorporate assessment of tissue composition by ECV based on T1 mapping.

Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease.

BACKGROUND: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. TRIAL DESIGN: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance-guided care, single-photon emission computed tomography-guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines-based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. CONCLUSIONS: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation.

Established and emerging cardiovascular magnetic resonance techniques for the assessment of stable coronary heart disease and acute coronary syndromes.

Coronary heart disease (CHD) is a leading cause of death and disability worldwide. International guidelines recommend cardiovascular magnetic resonance (CMR) as an investigative option in those presenting with chest pain to inform diagnosis, risk stratify and determine the need for revascularization. CMR offers a unique method to assess global and regional cardiac function, myocardial perfusion, myocardial viability, tissue characterisation and proximal coronary anatomy all within a single study. This results in high diagnostic accuracy for the detection of significant coronary stenoses and an established role in the management of both stable CHD and acute coronary syndromes (ACS). The growing evidence base for the prognostic value of CMR, emerging advances in acquisition techniques, improvements in hardware and the completion of current major multi-centre clinical CMR trials will further raise its prominence in international guidelines and routine cardiological practice. This article will focus on the rapidly evolving role of the multi-parametric CMR examination in the assessment of patients with stable and unstable CHD.

The distribution and prognosis of anomalous coronary arteries identified by cardiovascular magnetic resonance: 15 year experience from two tertiary centres.

BACKGROUND: Aberrant coronary arteries represent a diverse group of congenital disorders. Post-mortem studies reveal a high risk of exercise-related sudden cardiac death in those with an anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS) with an inter-arterial course. There is little documentation of lifetime history and long-term follow-up of patients with coronary artery anomalies. METHODS: Patients with anomalous coronary arteries undergoing cardiovascular magnetic resonance over a 15-year period were identified and classified by anatomy and course. Medical records were reviewed for major adverse cardiovascular events (MACE). Revascularisation or myocardial infarction counted only if occurring in the distribution of the anomalous artery. RESULTS: Consecutive patients with coronary artery anomalies were retrospectively identified (n = 172). Median follow-up time was 4.3 years (IQR 2.5-7.8, maximum 15.6). 116 patients had ACAOS of which 64 (55%) had an inter-arterial course (IAC) and 52 (45%) did not. During follow up 110 ACAOS patients were alive, 5 died and 1 lost to follow-up.ACAOS patients experienced 58 MACE events (5 cardiovascular deaths, 5 PCI, 24 CABG and 24 had myocardial infarction). 47 MACE events occurred in ACAOS with IAC and 11 in those without (p < 0.0001), the statistical difference driven by surgical revascularisation and myocardial infarction. CONCLUSIONS: In life, patients with an anomalous coronary artery originating from the opposite sinus of Valsalva taking an IAC have higher rates of both myocardial infarction and surgical revascularisation during long-term follow up, compared to those without IAC.

A case of bronchial aspiration: the importance of early diagnosis and clinical suspicion.

We present a case of foreign body aspiration, the diagnosis of which was delayed until two months after the event. This case highlights the importance of a detailed clinical history in establishing the diagnosis of aspiration and how this was complicated by direct visualization via bronchoscopy which suggested a possible diagnosis of bronchial carcinoma. Subsequent histological analysis confirmed a diagnosis of Brazil nut aspiration, which ultimately required surgical extraction through a rigid endoscope.