Association of Adverse Clinical Outcomes With Peri-Infarct Ischemia Detected by Stress Cardiac Magnetic Imaging.

BACKGROUND: Early invasive revascularization guided by moderate to severe ischemia did not improve outcomes over medical therapy alone, underlying the need to identify high-risk patients for a more effective invasive referral. CMR could determine the myocardial extent and matching locations of ischemia and infarction. OBJECTIVES: This study sought to investigate if CMR peri-infarct ischemia is associated with adverse events incremental to known risk markers. METHODS: Consecutive patients were included in an expanded cohort of the multicenter SPINS (Stress CMR Perfusion Imaging in the United States) study. Peri-infarct ischemia was defined by the presence of any ischemic segment neighboring an infarcted segment by late gadolinium enhancement imaging. Primary outcome events included acute myocardial infarction and cardiovascular death, whereas secondary events included any primary events, hospitalization for unstable angina, heart failure hospitalization, and late coronary artery bypass surgery. RESULTS: Among 3,915 patients (age: 61.0 ± 12.9 years; 54.7% male), ischemia, infarct, and peri-infarct ischemia were present in 752 (19.2%), 1,123 (28.8%), and 382 (9.8%) patients, respectively. At 5.3 years (Q1-Q3: 3.9-7.2 years) of median follow-up, primary and secondary events occurred in 406 (10.4%) and 745 (19.0%) patients, respectively. Peri-infarct ischemia was the strongest multivariable predictor for primary and secondary events (HRadjusted: 1.72 [95% CI: 1.23-2.41] and 1.71 [95% CI: 1.32-2.20], respectively; both P < 0.001), adjusted for clinical risk factors, left ventricular function, ischemia extent, and infarct size. The presence of peri-infarct ischemia portended to a >6-fold increased annualized primary event rate compared to those with no infarct and ischemia (6.5% vs 0.9%). CONCLUSIONS: Peri-infarct ischemia is a novel and robust prognostic marker of adverse cardiovascular events.

The Future of Cardiac Magnetic Resonance Clinical Trials.

Over the past 2 decades, cardiac magnetic resonance (CMR) has become an essential component of cardiovascular clinical care and contributed to imaging-guided diagnosis and management of coronary artery disease, cardiomyopathy, congenital heart disease, cardio-oncology, valvular, and vascular disease, amongst others. The widespread availability, safety, and capability of CMR to provide corresponding anatomical, physiological, and functional data in 1 imaging session can improve the design and conduct of clinical trials through both a reduction of sample size and provision of important mechanistic data that may augment clinical trial findings. Moreover, prospective imaging-guided strategies using CMR can enhance safety, efficacy, and cost-effectiveness of cardiovascular pathways in clinical practice around the world. As the future of large-scale clinical trial design evolves to integrate personalized medicine, cost-effectiveness, and mechanistic insights of novel therapies, the integration of CMR will continue to play a critical role. In this document, the attributes, limitations, and challenges of CMR's integration into the future design and conduct of clinical trials will also be covered, and recommendations for trialists will be explored. Several prominent examples of clinical trials that test the efficacy of CMR-imaging guided pathways will also be discussed.

Prognostic Value of Stress CMR Perfusion Imaging in Patients With Reduced Left Ventricular Function.

OBJECTIVES: The aim of this study was to investigate the prognostic value of stress cardiac magnetic resonance imaging (CMR) in patients with reduced left ventricular (LV) systolic function. BACKGROUND: Patients with ischemic cardiomyopathy are at risk from both myocardial ischemia and heart failure. Invasive testing is often used as the first-line investigation, and there is limited evidence as to whether stress testing can effectively provide risk stratification. METHODS: In this substudy of a multicenter registry from 13 U.S. centers, patients with reduced LV ejection fraction (<50%), referred for stress CMR for suspected myocardial ischemia, were included. The primary outcome was cardiovascular death or nonfatal myocardial infarction. The secondary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, hospitalization for unstable angina or congestive heart failure, and unplanned late coronary artery bypass graft surgery. RESULTS: Among 582 patients (mean age 62 ± 12 years, 34% women), 40% had a history of congestive heart failure, and the median LV ejection fraction was 39% (interquartile range: 28% to 45%). At median follow-up of 5.0 years, 97 patients had experienced the primary outcome, and 182 patients had experienced the secondary outcome. Patients with no CMR evidence of ischemia or late gadolinium enhancement (LGE) experienced an annual primary outcome event rate of 1.1%. The presence of ischemia, LGE, or both was associated with higher event rates. In a multivariate model adjusted for clinical covariates, ischemia and LGE were independent predictors of the primary (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.68 to 4.14; p < 0.001; and HR: 1.86; 95% CI: 1.05 to 3.29; p = 0.03) and secondary (HR: 2.14; 95% CI: 1.55 to 2.95; p < 0.001; and HR 1.70; 95% CI: 1.16 to 2.49; p = 0.007) outcomes. The addition of ischemia and LGE led to improved model discrimination for the primary outcome (change in C statistic from 0.715 to 0.765; p = 0.02). The presence and extent of ischemia were associated with higher rates of use of downstream coronary angiography, revascularization, and cost of care spent on ischemia testing. CONCLUSIONS: Stress CMR was effective in risk-stratifying patients with reduced LV ejection fractions. (Stress CMR Perfusion Imaging in the United States [SPINS] Study; NCT03192891).

Reduced radiation dose with model based iterative reconstruction coronary artery calcium scoring.

Assessing coronary artery calcium (CAC) is a valuable tool for individualizing cardiac risk assessment. In CAC scanning, this technical report assesses the use of a true model-based iterative reconstruction algorithm using forward projected model-based iterative reconstruction ("FIRST") and assess whether FIRST allows for reduced radiation dose CAC scanning on 320-detector row computed tomography (320-CT). Here, 100 consecutive patients prospectively underwent reduced and standard dose scans. For the patients (59 ± 9 years, 61% male) stratified by Agatston categories 0, 1-10, 11-100, 101-400,> 400, agreement between reduced dose with FIRST versus standard dose with FBP was excellent at 81% (95% CI: 73-88%) with kappa 0.74 (95% CI: 0.64-0.85). Median radiation exposure was 75% lower for reduced (0.35 mSv) versus standard dose (1.37 mSv) scans. In conclusion, agreement was excellent for reduced dose with FIRST and standard dose with FBP in 320-detector row CT CAC imaging in well-established categories of cardiovascular risk. These methods make it possible to reduce radiation exposure by 75%.

Subtraction CT angiography improves evaluation of significant coronary artery disease in patients with severe calcifications or stents-the C-Sub 320 multicenter trial.

OBJECTIVES: Diagnostic accuracy of conventional coronary CT angiography (CCTAconv) may be compromised by blooming artifacts from calcifications or stents. Blooming artifacts may be reduced by subtraction coronary CT angiography (CCTAsub) in which non-contrast and contrast CT data sets are subtracted digitally. We tested whether CCTAsub in patients with severe coronary calcification or stents reduces the number of false-positive stenosis evaluations compared with CCTAconv. METHODS: In this study, 180 symptomatic patients scheduled for invasive coronary angiography (ICA) were prospectively enrolled and CT scanned (2013-2016) at three international centers. CCTAconv, and CCTAsub data sets were reconstructed. Target segments were defined as motion-free coronary segments with a suspected stenosis (> 50% of lumen) potentially due to blooming of either calcium or stents. Target segments were evaluated with respect to misregistration artifacts from the CCTAsub reconstruction process, in which case evaluation was omitted. CCTAsub and CCTAconv were compared with ICA. Primary outcome measure was the frequency of false positives by CCTAconv versus CCTAsub to identify > 50% coronary stenosis by ICA on a per-segment level. RESULTS: After exclusion of 76 patients, 104 (14% females) with mean age 67 years and median Agatston score 852 were included. There were 136 target segments with misregistration and 121 target segments without. Accuracy calculations in target segments without misregistration showed a reduction of the false positives from 72% [95% confidence interval (CI): 63-80%] in CCTAconv to 33% (CI:25-42%) in CCTAsub, at the expense of 7% (CI:3-14%) false negatives in CCTAsub. CONCLUSIONS: In severely calcified coronary arteries or stents, CCTAsub reduces the false-positive rate in well-aligned, calcified or stent segments suspected of significant stenosis on CCTAconv. Nevertheless, misregistration artifacts are frequent in CCTAsub. KEY POINTS: • A high calcium-score reduces the diagnostic accuracy in patients scanned with cardiac CT. • These patients would normally need an invasive angiogram for diagnosis. • In this prospective, multicenter study, subtraction CT, when evaluable, reduces false-positive stenosis evaluations. • Subtraction coronary CT angiography may, when evaluable, reduce excessive downstream testing.

Fully quantitative pixel-wise analysis of cardiovascular magnetic resonance perfusion improves discrimination of dark rim artifact from perfusion defects associated with epicardial coronary stenosis.

BACKGROUND: Dark rim artifacts in first-pass cardiovascular magnetic resonance (CMR) perfusion images can mimic perfusion defects and affect diagnostic accuracy for coronary artery disease (CAD). We evaluated whether quantitative myocardial blood flow (MBF) can differentiate dark rim artifacts from true perfusion defects in CMR perfusion. METHODS: Regadenoson perfusion CMR was performed at 1.5 T in 76 patients. Significant CAD was defined by quantitative invasive coronary angiography (QCA) ≥ 50% diameter stenosis. Non-significant CAD (NonCAD) was defined as stenosis by QCA < 50% diameter stenosis or computed tomographic coronary angiography (CTA) < 30% in all major epicardial arteries. Dark rim artifacts had study specific and guideline-based definitions for comparison purposes. MBF was quantified at the pixel-level and sector-level. RESULTS: In a NonCAD subgroup with dark rim artifacts, stress MBF was lower in the subendocardial than midmyocardial and epicardial layers (2.17 ± 0.61 vs. 3.06 ± 0.75 vs. 3.24 ± 0.80 mL/min/g, both p < 0.001) and was also 30% lower than in remote regions (2.17 ± 0.61 vs. 2.83 ± 0.67 mL/min/g, p < 0.001). However, subendocardial stress MBF in dark rim artifacts was 37-56% higher than in true perfusion defects (2.17 ± 0.61 vs. 0.95 ± 0.43 mL/min/g, p < 0.001). Absolute stress MBF differentiated CAD from NonCAD with an accuracy ranging from 86 to 89% (all p < 0.001) using pixel-level analyses. Similar results were seen at a sector level. CONCLUSION: Quantitative stress MBF is lower in dark rim artifacts than remote myocardium but significantly higher than in true perfusion defects. If confirmed in larger series, this approach may aid the interpretation of clinical stress perfusion exams. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00027170 ; first posted 11/28/2001; updated 11/27/2017.

Feasibility of low radiation dose retrospectively-gated cardiac CT for functional analysis in adult congenital heart disease.

BACKGROUND: The use of cardiac computed tomography (CT) in the evaluation of adult congenital heart disease patients is limited due to concerns of high radiation doses. The purpose of this study was to prospectively assess whether low radiation dose cardiac CT is feasible to evaluate ventricular systolic function in adults with congenital heart disease. METHODS: The study group included 30 consecutive patients with significant congenital heart disease who underwent a total of 35 ECG-gated cardiac CT scans utilizing a 320-detector row CT scanner. Each study included a non-contrast scan and subsequent contrast-enhanced retrospectively-gated acquisition. Effective radiation dose was estimated by multiplying the dose length product by a k-factor of 0.014mSv/mGycm. RESULTS: The mean age of the patients was 34.4±8.9years, 60% were men, and mean body mass index was 24.2±4.3kg/m2. A majority of patients (n=28, 93.3%) had contraindications to cardiac MRI. A tube potential of 80kV was used in 27 (77.1%) of the contrast-enhanced scans. The mean signal-to-noise and contrast-to-noise ratios were 11.5±3.9 and 10.3±3.7, respectively. The median radiation dose for non-contrast and contrast-enhanced images were 0.1mSv (0.07-0.2mSv) and 0.94mSv (0.5-2.1mSv), respectively. All 35 CT scans were successfully analyzed for ventricular systolic function. CONCLUSIONS: A low radiation contrast-enhanced, retrospectively-gated cardiac CT with a median radiation dose of less than 1mSv was successful in evaluating ventricular systolic function in 30 consecutive adult congenital heart disease patients who underwent a total of 35 scans.

Prospective evaluation of the influence of iterative reconstruction on the reproducibility of coronary calcium quantification in reduced radiation dose 320 detector row CT.

BACKGROUND: Coronary artery calcium (CAC) predicts coronary heart disease events and is important for individualized cardiac risk assessment. This report assesses the interscan variability of CT for coronary calcium quantification using image acquisition with standard and reduced radiation dose protocols and whether the use of reduced radiation dose acquisition with iterative reconstruction (IR; "reduced-dose/IR ") allows for similar image quality and reproducibility when compared to standard radiation dose acquisition with filtered back projection (FBP; "standard-dose/FBP") on 320-detector row computed tomography (320-CT). METHODS: 200 consecutive patients (60 ± 9 years, 59% male) prospectively underwent two standard- and two reduced-dose acquisitions (800 total scans, 1600 reconstructions) using 320 slice CT and 120 kV tube voltage. Automated tube current modulation was used and for reduced-dose scans, prescribed tube current was lowered by 70%. Image noise and Agatston scores were determined and compared. RESULTS: Regarding stratification by Agatston score categories (0, 1-10, 11-100, 101-400, >400), reduced-dose/IR versus standard-dose/FBP had excellent agreement at 89% (95% CI: 86-92%) with kappa 0.86 (95% CI: 0.81-0.90). Standard-dose/FBP rescan agreement was 93% (95% CI: 89-96%) with kappa = 0.91 (95% CI: 0.86-0.95) while reduced-dose/IR rescan agreement was similar at 91% (95% CI: 87-94%) with kappa 0.88 (95% CI: 0.83-0.93). Image noise was significantly higher but clinically acceptable for reduced-dose/IR (18 Hounsfield Unit [HU] mean) compared to standard-dose/FBP (16 HU; p < 0.0001). Median radiation exposure was 74% lower for reduced- (0.37 mSv) versus standard-dose (1.4 mSv) acquisitions. CONCLUSION: Rescan agreement was excellent for reduced-dose image acquisition with iterative reconstruction and standard-dose acquisition with filtered back projection for the quantification of coronary calcium by CT. These methods make it possible to reduce radiation exposure by 74%. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01621594. UNIQUE IDENTIFIER: NCT01621594.

Regadenoson and adenosine are equivalent vasodilators and are superior than dipyridamole- a study of first pass quantitative perfusion cardiovascular magnetic resonance.

BACKGROUND: Regadenoson, dipyridamole and adenosine are commonly used vasodilators in myocardial perfusion imaging for the detection of obstructive coronary artery disease. There are few comparative studies of the vasodilator properties of regadenoson, adenosine and dipyridamole in humans. The specific aim of this study was to determine the relative potency of these three vasodilators by quantifying stress and rest myocardial perfusion in humans using cardiovascular magnetic resonance (CMR). METHODS: Fifteen healthy normal volunteers, with Framingham score less than 1% underwent vasodilator stress testing with regadenoson (400 µg bolus), dipyridamole (0.56 mg/kg) and adenosine (140 µg /kg/min) on separate days. Rest perfusion imaging was performed initially. Twenty minutes later, stress imaging was performed at peak vasodilation, i.e. 70 seconds after regadenoson, 4 minutes after dipyridamole infusion and between 3-4 minutes of the adenosine infusion. Myocardial blood flow (MBF) in ml/min/g and myocardial perfusion reserve (MPR) were quantified using a fully quantitative model constrained deconvolution. RESULTS: Regadenoson produced higher stress MBF than dipyridamole and adenosine (3.58 ± 0.58 vs. 2.81 ± 0.67 vs. 2.78 ± 0.61 ml/min/g, p = 0.0009 and p = 0.0008 respectively). Regadenoson had a much higher heart rate response than adenosine and dipyridamole respectively (95 ± 11 vs. 76 ± 13 vs. 86 ± 12 beats/ minute) When stress MBF was adjusted for heart rate, there were no differences between regadenoson and adenosine (37.8 ± 6 vs. 36.6 ± 4 µl/sec/g, p = NS), but differences between regadenoson and dipyridamole persisted (37.8 ± 6 vs. 32.6 ± 5 µl/sec/g, p = 0.03). The unadjusted MPR was higher with regadenoson (3.11 ± 0.63) when compared with adenosine (2.7 ± 0.61, p = 0.02) and when compared with dipyridamole (2.61 ± 0.57, p = 0.04). Similar to stress MBF, these differences in MPR between regadenoson and adenosine were abolished when adjusted for heart rate (2.04 ± 0.34 vs. 2.12 ± 0.27, p = NS), but persisted between regadenoson and dipyridamole (2.04 ± 0.34 vs. 1.77 ± 0.33, p = 0.07) and between adenosine and dipyridamole (2.12 ± 0.27 vs. 1.77 ± 0.33, p = 0.01). CONCLUSIONS: Based on fully quantitative perfusion using CMR, regadenoson and adenosine have similar vasodilator efficacy and are superior to dipyridamole.

Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia.

CONTEXT: The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described. OBJECTIVE: The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients. DESIGN, SETTING, AND PARTICIPANTS: A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed. MAIN OUTCOME MEASURES: The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls. RESULTS: TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings. CONCLUSIONS: Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.

Submillisievert median radiation dose for coronary angiography with a second-generation 320-detector row CT scanner in 107 consecutive patients.

PURPOSE: To (a) use a new second-generation wide-volume 320-detector row computed tomographic (CT) scanner to explore optimization of radiation exposure in coronary CT angiography in an unselected and consecutive cohort of patients referred for clinical purposes and (b) compare estimated radiation exposure and image quality with that from a cohort of similar patients who underwent imaging with a previous first-generation CT system. MATERIALS AND METHODS: The study was approved by the institutional review board, and all subjects provided written consent. Coronary CT angiography was performed in 107 consecutive patients with a new second-generation 320-detector row unit. Estimated radiation exposure and image quality were compared with those from 100 consecutive patients who underwent imaging with a previous first-generation scanner. Effective radiation dose was estimated by multiplying the dose-length product by an effective dose conversion factor of 0.014 mSv/mGy ⋅ cm and reported with size-specific dose estimates (SSDEs). Image quality was evaluated by two independent readers. RESULTS: The mean age of the 107 patients was 55.4 years ± 12.0 (standard deviation); 57 patients (53.3%) were men. The median body mass index was 27.3 kg/m(2) (range, 18.1-47.2 kg/m(2)); however, 71 patients (66.4%) were overweight, obese, or morbidly obese. A tube potential of 100 kV was used in 97 patients (90.6%), single-volume acquisition was used in 104 (97.2%), and prospective electrocardiographic gating was used in 106 (99.1%). The mean heart rate was 57.1 beats per minute ± 11.2 (range, 34-96 beats per minute), which enabled single-heartbeat scans in 100 patients (93.4%). The median radiation dose was 0.93 mSv (interquartile range [IQR], 0.58-1.74 mSv) with the second-generation unit and 2.67 mSv (IQR, 1.68-4.00 mSv) with the first-generation unit (P < .0001). The median SSDE was 6.0 mGy (IQR, 4.1-10.0 mGy) with the second-generation unit and 13.2 mGy (IQR, 10.2-18.6 mGy) with the first-generation unit (P < .0001). Overall, the radiation dose was less than 0.5 mSv for 23 of the 107 CT angiography examinations (21.5%), less than 1 mSv for 58 (54.2%), and less than 4 mSv for 103 (96.3%). All studies were of diagnostic quality, with most having excellent image quality. Three of four image quality indexes were significantly better with the second-generation unit compared with the first-generation unit. CONCLUSION: The combination of a gantry rotation time of 275 msec, wide volume coverage, iterative reconstruction, automated exposure control, and larger x-ray power generator of the second-generation CT scanner provides excellent image quality over a wide range of body sizes and heart rates at low radiation doses. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122621/-/DC1.

Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience.

BACKGROUND: Diffuse myocardial fibrosis, and to a lesser extent global myocardial edema, are important processes in heart disease which are difficult to assess or quantify with cardiovascular magnetic resonance (CMR) using conventional late gadolinium enhancement (LGE) or T1-mapping. Measurement of the myocardial extracellular volume fraction (ECV) circumvents factors that confound T1-weighted images or T1-maps. We hypothesized that quantitative assessment of myocardial ECV would be clinically useful for detecting both focal and diffuse myocardial abnormalities in a variety of common and uncommon heart diseases. METHODS: A total of 156 subjects were imaged including 62 with normal findings, 33 patients with chronic myocardial infarction (MI), 33 with hypertrophic cardiomyopathy (HCM), 15 with non-ischemic dilated cardiomyopathy (DCM), 7 with acute myocarditis, 4 with cardiac amyloidosis, and 2 with systemic capillary leak syndrome (SCLS). Motion corrected ECV maps were generated automatically from T1-maps acquired pre- and post-contrast calibrated by blood hematocrit. Abnormally-elevated ECV was defined as >2SD from the mean ECV in individuals with normal findings. In HCM the size of regions of LGE was quantified as the region >2 SD from remote. RESULTS: Mean ECV of 62 normal individuals was 25.4 ± 2.5% (m ± SD), normal range 20.4%-30.4%. Mean ECV within the core of chronic myocardial infarctions (without MVO) (N=33) measured 68.5 ± 8.6% (p<0.001 vs normal). In HCM, the extent of abnormally elevated ECV correlated to the extent of LGE (r=0.72, p<0.001) but had a systematically greater extent by ECV (mean difference 19 ± 7% of slice). Abnormally elevated ECV was identified in 4 of 16 patients with non-ischemic DCM (38.1 ± 1.9% (p<0.001 vs normal) and LGE in the same slice appeared "normal" in 2 of these 4 patients. Mean ECV values in other disease entities ranged 32-60% for cardiac amyloidosis (N=4), 40-41% for systemic capillary leak syndrome (N=2), and 39-56% within abnormal regions affected by myocarditis (N=7). CONCLUSIONS: ECV mapping appears promising to complement LGE imaging in cases of more homogenously diffuse disease. The ability to display ECV maps in units that are physiologically intuitive and may be interpreted on an absolute scale offers the potential for detection of diffuse disease and measurement of the extent and severity of abnormal regions.