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Myocardial fibrosis, seen in ischemic and nonischemic cardiomyopathies, is associated with adverse cardiac outcomes. Noninvasive imaging plays a key role in early identification and quantification of myocardial fibrosis with the use of an expanding array of techniques including cardiac magnetic resonance, computed tomography, and nuclear imaging. This review discusses currently available noninvasive imaging techniques, provides insights into their strengths and limitations, and examines novel developments that will affect the future of noninvasive imaging of myocardial fibrosis., Competing Interests: Funding Support and Author Disclosures Dr. Ge was supported by the Heart & Stroke Foundation/University of Toronto Polo Chair in Cardiology Young Investigator Award. All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A substantial proportion of patients with acute myocardial infarction develop clinical heart failure, which remains a common and major healthcare burden. It has been shown that in patients with chronic coronary artery disease, ischemic episodes lead to a global pattern of cardiomyocyte remodeling and dedifferentiation, hallmarked by myolysis, glycogen accumulation, and alteration of structural proteins. These changes, in conjunction with an impaired global coronary reserve, may eventually become irreversible and result in ischemic cardiomyopathy. Moreover, noninvasive imaging of myocardial scar and hibernation can inform the risk of sudden cardiac death. Therefore, it would be intuitive that imaging of myocardial viability is an essential tool for the proper use of invasive treatment strategies and patient prognostication. However, this notion has been challenged by large-scale clinical trials demonstrating that, in the modern era of improved guideline-directed medical therapies, imaging of myocardial viability failed to deliver effective guidance of coronary bypass surgery to a reduction of adverse cardiac outcomes. In addition, current available imaging technologies in this regard are numerous, and they target diverse surrogates of structural or tissue substrates of myocardial viability. In this document, we examine these issues in the current clinical context, collect current evidence of imaging technology by modality, and inform future directions.

Objectives: The purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[ 18 F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis., Background: Cardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness., Methods: A total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [ 18 F]florbetapir PET/CT to evaluate cardiac amyloid burden., Results: The active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [ 18 F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min -1 , and the lowest cardiac function by global longitudinal strain (GLS), median GLS -11% (IQR: -8% to -13%). The remission-CA group had expanded extracellular volume (ECV) and [ 18 F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min -1 ), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [ 18 F]florbetapir RI in 50%., Conclusions: Evidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [ 18 F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: In patients with nonischemic dilated cardiomyopathy (NIDCM), native T1, partition coefficient (λ Gd ), and extracellular volume fraction (ECV) mapping may offer prognostic values beyond late gadolinium enhancement (LGE), by scaling the range of myocardial changes., Background: In patients with NIDCM, LGE is seen in 30% of patients and it indicates adverse prognosis., Methods: The study mapped 6 anatomical locations using all 4 cardiac magnetic resonance (CMR) tissue-characterizing methods and associated with outcome. The authors performed T1 mapping of the myocardium and the blood pool, before and serially after contrast injection, using a Look-Locker cine gradient-echo technique to obtain T1 and the corresponding reciprocal R1 values. λ Gd values were derived from the slopes of the least-squares regression lines for myocardial versus blood R1, then adjusted to serum hematocrit to yield ECV., Results: Consecutive 240 NIDCM patients (49 ± 16 years of age; 38% women) underwent CMR for cardiac function, LGE, native T1, λ Gd , and ECV. After a median of 3.8 years, 36 (15%) experienced major adverse cardiac events (MACE), including 22 heart failure hospitalizations and 14 deaths. Nonischemic LGE was detected in 34%, whereas ECV was elevated (≥1 location) in 58%. Comparing the 4 methods, mean ECV and λ Gd both demonstrated strong association with MACE (both p < 0.001). In contrast to native T1 and LGE, ECV values from all 6 locations were associated with MACE and death, with the anteroseptum being the most significant (p < 0.0001). The number of abnormal ECV locations correlated linearly with annual MACE rates (p = 0.0003). Mean ECV was the only predictor to enter a prognostic model that contained age, sex, New York Heart Association functional class, and left ventricular ejection fraction. For every 10% increase, mean ECV portended to a 2.8-fold adjusted increase risk to MACE (p < 0.001)., Conclusions: In this study of patients with NIDCM, mapping the myocardial extent of abnormality using ECV offers prognostication toward heart failure outcomes incremental to LGE or native T1 mapping., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to test whether relative apical sparing (RELAPS) of left ventricular (LV) longitudinal strain (LS) in cardiac amyloidosis (CA) is explained by regional differences in markers of amyloid burden ( 18 F-florbetapir uptake by positron emission tomography [PET] and/or extracellular volume fraction [ECV] by cardiac magnetic resonance (CMR)]., Background: Further knowledge of the pathophysiological basis for RELAPS can help understand the adverse outcomes associated with apical LS impairment., Methods: This was a prospective study of 32 subjects (age 62 ± 7 years; 50% males) with light chain CA. All subjects underwent two-dimensional echocardiography for LS estimation and 18 F-florbetapir PET for quantification of LV florbetapir retention index (RI). A subset also underwent CMR (n = 22) for ECV quantification. Extracellular LV mass (LV mass*ECV) and total florbetapir binding (extracellular LV mass*florbetapir RI) were also calculated. All parameters were measured globally and regionally (base, mid, and apex)., Results: There was a significant base-to-apex gradient in LS (-7.4 ± 3.2% vs. -8.6 ± 4.0% vs. -20.8 ± 6.6%; p < 0.0001), maximal LV wall thickness (15.7 ± 1.9 cm vs. 15.4 ± 2.9 cm vs. 10.1 ± 2.4 cm; p < 0.0001), and LV mass (74.8 ± 21.2 g vs. 60.8 ± 17.3 g vs. 23.4 ± 6.2 g; p < 0.0001). In contrast, florbetapir RI (0.089 ± 0.03 μmol/min/g vs. 0.097 ± 0.03 μmol/min/g vs. 0.085 ± 0.03 μmol/min/g; p = 0.45) and ECV (0.53 ± 0.08 vs. 0.49 ± 0.08 vs. 0.49 ± 0.07; p = 0.15) showed no significant base-to-apex gradient in the tissue concentration or proportion of amyloid infiltration, whereas markers of total amyloid load, such as total florbetapir binding (3.4 ± 1.7 μmol/min vs. 2.8 ± 1.5 μmol/min vs. 0.93 ± 0.49 μmol/min; p < 0.0001) and extracellular LV mass (40.0 ± 15.6 g vs. 30.2 ± 10.9 g vs. 11.6 ± 3.9 g; p < 0.0001), did show a marked base-to-apex gradient., Conclusions: Segmental differences in the distribution of the total amyloid mass, rather than the proportion of amyloid deposits, appear to explain the marked regional differences in LS in CA. Although these 2 matrices are clearly related concepts, they should not be used interchangeably., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although the presence of late gadolinium enhancement (LGE) using cardiovascular magnetic resonance imaging (CMR) is a significant discriminator of events in patients with suspected myocarditis, no data are available on the optimal LGE quantification method., Methods: Six hundred seventy consecutive patients (48 ± 16 years, 59% male) with suspected myocarditis were enrolled between 2002 and 2015. We performed LGE quantitation using seven different signal intensity thresholding methods based either on 2, 3, 4, 5, 6, 7 standard deviations (SD) above remote myocardium or full width at half maximum (FWHM). In addition, a LGE visual presence score (LGE-VPS) (LGE present/absent in each segment) was assessed. For each of these methods, the strength of association of LGE results with major adverse cardiac events (MACE) was determined. Inter-and intra-rater variability using intraclass-correlation coefficient (ICC) was performed for all methods., Results: Ninety-eight (15%) patients experienced a MACE at a medium follow-up of 4.7 years. LGE quantification by FWHM, 2- and 3-SD demonstrated univariable association with MACE (hazard ratio [HR] 1.05, 95% confidence interval [CI]:1.02-1.08, p = 0.001; HR 1.02, 95%CI:1.00-1.04; p = 0.001; HR 1.02, 95%CI: 1.00-1.05, p = 0.035, respectively), whereas 4-SD through 7-SD methods did not reach significant association. LGE-VPS also demonstrated association with MACE (HR 1.09, 95%CI: 1.04-1.15, p < 0.001). In the multivariable model, FWHM, 2-SD methods, and LGE-VPS each demonstrated significant association with MACE adjusted to age, sex, BMI and LVEF (adjusted HR of 1.04, 1.02, and 1.07; p = 0.009, p = 0.035; and p = 0.005, respectively). In these, FWHM and LGE-VPS had the highest degrees of inter and intra-rater reproducibility based on their high ICC values., Conclusions: FWHM is the optimal semi-automated quantification method in risk-stratifying patients with suspected myocarditis, demonstrating the strongest association with MACE and the highest technical consistency. Visual LGE scoring is a reliable alternative method and is associated with a comparable association with MACE and reproducibility in these patients., Trial Registration Number: NCT03470571 . Registered 13th March 2018. Retrospectively registered.

Background Cardiac magnetic resonance imaging ( CMR ) provides useful information for characterizing cardiac masses, but there are limited data on whether CMR can accurately distinguish benign from malignant lesions. We aimed to describe the distribution and imaging characteristics of cardiac masses identified by CMR and to determine the diagnostic accuracy of CMR for distinguishing benign from malignant tumors. Methods and Results We examined consecutive patients referred for CMR between May 2008 and August 2013 to identify those with a cardiac mass. In patients for whom there was histological correlation, 2 investigators blinded to all data analyzed the CMR images to categorize the mass as benign or malignant. For benign masses, readers were also asked to specify the most likely diagnosis. Benign masses were defined as benign neoplastic or non-neoplastic. Malignant masses were defined as primary cardiac or metastatic. Of 8069 patients (mean age: 58±16 years; 55% female) undergoing CMR , 145 (1.8%) had a cardiac mass. In most cases (142, 98%), there was a known cardiac mass before the CMR study. Among 145 patients with a cardiac mass, 93 (64%) had a known history of malignancy. Among 53 cases that had histological correlation, 25 (47%) were benign, 26 (49%) were metastatic, and 2 (4%) were malignant primary cardiac masses. Blinded readers correctly diagnosed 89% to 94% of the cases as benign versus malignant, with a 95% agreement rate (κ=0.83). Conclusions Although C MR can be highly effective in distinguishing benign from malignant lesions, pathology remains the gold standard in accurately determining the type of mass.

Background: Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice., Methods and Results: This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms; P<0.05), followed by a reduction in left ventricular ejection fraction (54±6 versus 63±5%; P<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34±0.03 versus 0.27±0.03; P<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (r=0.90; P<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (P<0.001)., Conclusions: Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality., (© 2016 American Heart Association, Inc.)

Background: The noninvasive assessment of altered myocardium in patients with genetic mutations that are associated with hypertrophic cardiomyopathy (HCM) remains challenging. In this pilot study, we evaluated whether a novel echocardiography-based assessment of myocardial microstructure, the signal intensity coefficient (SIC), could detect tissue-level alterations in HCM sarcomere mutation carriers with and without left ventricular hypertrophy., Methods and Results: We studied 3 groups of genotyped individuals: sarcomere mutation carriers with left ventricular hypertrophy (clinical HCM; n=36), mutation carriers with normal left ventricular wall thickness (subclinical HCM; n=28), and healthy controls (n=10). We compared measurements of echocardiographic SIC with validated assessments of cardiac microstructural alteration, including cardiac magnetic resonance measures of interstitial fibrosis (extracellular volume fraction), as well as serum biomarkers (NTproBNP, hs-cTnI, and PICP). In age-, sex-, and familial relation-adjusted analyses, the SIC was quantitatively different across subjects with overt HCM, subclinical HCM, and healthy controls (P<0.001). Compared with controls, the SIC was 61% higher in overt HCM and 47% higher in subclinical HCM (P<0.001 for both). The SIC was significantly correlated with extracellular volume (r=0.72; P<0.01), with left ventricular mass and E' velocity (r=0.45, -0.60, respectively; P<0.01 for both), and with serum NTproBNP levels (r=0.36; P<0.001)., Conclusions: Our findings suggest that the SIC could serve as a noninvasive quantitative tool for assessing altered myocardial tissue characteristics in patients with genetic mutations associated with HCM. Further studies are needed to determine whether the SIC could be used to identify subclinical changes in patients at risk for HCM and to evaluate the effects of interventions., (© 2016 American Heart Association, Inc.)

Background: Strategies for prevention of sudden cardiac death focus on severe left ventricular (LV) dysfunction, although most sudden cardiac death postmyocardial infarction occurs in patients with mild/moderate LV dysfunction. We tested the hypothesis that infarct heterogeneity by cardiac magnetic resonance is associated with mortality beyond LV ejection fraction (LVEF) in patients with coronary artery disease and LV dysfunction. In addition, we examined the association between infarct heterogeneity and mortality in those with LVEF >35%., Methods and Results: We studied 301 patients with coronary artery disease and LV dysfunction referred for cardiac magnetic resonance. We quantified total infarct mass, infarct core mass, and peri-infarct zone (PIZ) normalized for total infarct mass (%PIZ) using signal-intensity criteria of >2 SDs, >3 SDs, and 2- to -3 SDs above remote myocardium, respectively. Mean LVEF was 41 ± 14%. After 3.9 years median follow-up, 66 (22%) patients died (13 sudden cardiac death; 33 with LVEF >35%). In patients with LVEF >35%, below-median %PIZ carried an annual death rate of 2.8% versus 12% in patients with above-median %PIZ (P<0.001). In a multivariable model, %PIZ maintained strong association with mortality adjusted to patient age, LVEF, right ventricular ejection fraction, prolonged QT interval, and total infarct size and resulted in improve risk reclassification 0.492 (95% confidence interval, 0.183-0.817)., Conclusions: Cardiac magnetic resonance infarct heterogeneity has a strong association with mortality independent of LVEF in patients with coronary artery disease and LV dysfunction, particularly in patients with mild or moderate LV dysfunction. Further studies incorporating cardiac magnetic resonance in clinical decision making for defibrillator therapy are warranted., (© 2014 American Heart Association, Inc.)

T(1) mapping of the heart has evolved into a valuable tool to evaluate myocardial tissue properties, with or without contrast injection, including assessment of myocardial edema and free water content, extracellular volume (expansion), and most recently cardiomyocyte hypertrophy. The magnetic resonance imaging pulse sequence techniques developed for these applications have had to address at least 2 important considerations for cardiac applications: measure magnetization-inversion recoveries during cardiac motion with sufficient temporal resolution for the shortest expected T(1) values, and, second, obtain these measurements within a time during which a patient can comfortably suspend breathing. So-called Look-Locker techniques, and variants thereof, which all sample multiple points of a magnetization recovery after each magnetization preparation, have therefore become a mainstay in this field. The rapid pace of advances and new findings based on cardiac T(1) mapping for assessment of diffuse fibrosis or myocardial edema show that these techniques enrich the capabilities of magnetic resonance imaging for myocardial tissue profiling, which is arguably unmatched by other cardiac imaging modalities.

Objectives: This study tested whether myocardial extracellular volume (ECV) is increased in patients with hypertension and atrial fibrillation (AF) undergoing pulmonary vein isolation and whether there is an association between ECV and post-procedural recurrence of AF., Background: Hypertension is associated with myocardial fibrosis, an increase in ECV, and AF. Data linking these findings are limited. T1 measurements pre-contrast and post-contrast in a cardiac magnetic resonance (CMR) study provide a method for quantification of ECV., Methods: Consecutive patients with hypertension and recurrent AF referred for pulmonary vein isolation underwent a contrast CMR study with measurement of ECV and were followed up prospectively for a median of 18 months. The endpoint of interest was late recurrence of AF., Results: Patients had elevated left ventricular (LV) volumes, LV mass, left atrial volumes, and increased ECV (patients with AF, 0.34 ± 0.03; healthy control patients, 0.29 ± 0.03; p < 0.001). There were positive associations between ECV and left atrial volume (r = 0.46, p < 0.01) and LV mass and a negative association between ECV and diastolic function (early mitral annular relaxation [E'], r = -0.55, p < 0.001). In the best overall multivariable model, ECV was the strongest predictor of the primary outcome of recurrent AF (hazard ratio: 1.29; 95% confidence interval: 1.15 to 1.44; p < 0.0001) and the secondary composite outcome of recurrent AF, heart failure admission, and death (hazard ratio: 1.35; 95% confidence interval: 1.21 to 1.51; p < 0.0001). Each 10% increase in ECV was associated with a 29% increased risk of recurrent AF., Conclusions: In patients with AF and hypertension, expansion of ECV is associated with diastolic function and left atrial remodeling and is a strong independent predictor of recurrent AF post-pulmonary vein isolation., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine whether the extent of late gadolinium enhancement (LGE) can provide additive prognostic information in patients with a nonischemic dilated cardiomyopathy (NIDC) with an indication for implantable cardioverter-defibrillator (ICD) therapy for the primary prevention of sudden cardiac death (SCD)., Background: Data suggest that the presence of LGE is a strong discriminator of events in patients with NIDC. Limited data exist on the role of LGE quantification., Methods: The extent of LGE and clinical follow-up were assessed in 162 patients with NIDC prior to ICD insertion for primary prevention of SCD. LGE extent was quantified using both the standard deviation-based (2-SD) method and the full-width half-maximum (FWHM) method., Results: We studied 162 patients with NIDC (65% male; mean age: 55 years; left ventricular ejection fraction [LVEF]: 26 ± 8%) and followed up for major adverse cardiac events (MACE), including cardiovascular death and appropriate ICD therapy, for a mean of 29 ± 18 months. Annual MACE rates were substantially higher in patients with LGE (24%) than in those without LGE (2%). By univariate association, the presence and the extent of LGE demonstrated the strongest associations with MACE (LGE presence, hazard ratio [HR]: 14.5 [95% confidence interval (CI): 6.1 to 32.6; p < 0.001]; LGE extent, HR: 1.15 per 1% increase in volume of LGE [95% CI: 1.12 to 1.18; p < 0.0001]). Multivariate analyses showed that LGE extent was the strongest predictor in the best overall model for MACE, and a 7-fold hazard was observed per 10% LGE extent after adjustments for patient age, sex, and LVEF (adjusted HR: 7.61; p < 0.0001). LGE quantitation by 2-SD and FWHM both demonstrated robust prognostic association, with the highest MACE rate observed in patients with LGE involving >6.1% of LV myocardium., Conclusions: LGE extent may provide further risk stratification in patients with NIDC with a current indication for ICD implantation for the primary prevention of SCD. Strategic guidance on ICD therapy by cardiac magnetic resonance in patients with NIDC warrants further study., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue-level markers within the myocardium that precede organ-level alterations have not been described., Methods and Results: We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m(2), including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m(2)) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size-adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high-sensitivity C-reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum., Conclusions: Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function.

Proper assessment of the physiologic impact of coronary artery stenosis on the LV myocardium can affect patient prognosis and treatment decisions. Cardiac magnetic resonance imaging (CMR) assesses myocardial perfusion by imaging the myocardium during a first-pass transit of an intravenous gadolinium bolus, with spatial and temporal resolution substantially higher than nuclear myocardial perfusion imaging. Coupled with late gadolinium enhancement (LGE) imaging for infarction during the same imaging session, CMR with vasodilating stress perfusion imaging can qualitatively and quantitatively assess the myocardial extent of hypoperfusion from coronary stenosis independent of infarcted myocardium. This approach has been validated experimentally, and multiple clinical trials have established its diagnostic robustness when compared to stress single-photon emission computed tomography. In specialized centers, dobutamine stress CMR has been shown to have incremental diagnostic value above stress echocardiography due to its high imaging quality and ability to image the heart with no restriction of imaging window. This paper reviews the technical aspects, diagnostic utility, prognostic values, challenges to clinical adaptation, and future developments of stress CMR imaging.

Objectives: This study aimed to test the characteristics of the myocardial extracellular volume fraction (ECV) derived from pre- and post-contrast T1 measurements among healthy volunteers., Background: Cardiac magnetic resonance (CMR) T1 measurements of myocardium and blood before and after contrast allow quantification of the ECV, a tissue parameter that has been shown to change in proportion to the connective tissue fraction., Methods: Healthy volunteers underwent standard CMR imaging with administration of gadolinium. T1 measurements were performed with a Look-Locker sequence followed by gradient-echo acquisition. We tested the segmental, interslice, inter-, intra-, and test-retest characteristics of the ECV, as well as the association of the ECV with other variables. Juvenile and aged mice underwent a similar protocol, and cardiac sections were harvested for measurement of fibrosis., Results: In healthy volunteers (N = 32, 56% female; age 21 to 72 years), the ECV averaged 0.28 ± 0.03 (range 0.23 to 0.33). The intraclass coefficients for the intraobserver, interobserver, and test-retest absolute agreements of the ECV were 0.94 (95% confidence interval: 0.84 to 0.98), 0.93 (95% confidence interval: 0.80 to 0.98), and 0.95 (95% confidence interval: 0.52 to 0.99), respectively. In volunteers, the ECV was associated with age (r = 0.74, p < 0.001), maximal left atrial volume index (r = 0.67, p < 0.001), and indexed left ventricular mass. There were no differences in the ECV between segments in a slice or between slices. In mice (N = 12), the myocardial ECV ranged from 0.20 to 0.32 and increased with age (0.22 ± 0.02 vs. 0.30 ± 0.02, juvenile vs. aged mice, p < 0.001). In mice, the ECV correlated with the extent of myocardial fibrosis (r = 0.94, p < 0.001)., Conclusions: In healthy volunteers, the myocardial ECV ranges from 0.23 to 0.33, has acceptable test characteristics, and is associated with age, left atrial volume, and left ventricular mass. In mice, the ECV also increases with age and strongly correlates with the extent of myocardial fibrosis., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV)., Methods and Results: Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH-, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH- mutation carriers (ECV=0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH-, controls, respectively; P≤0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P<0.001) and global E' velocity (r=-0.48; P<0.001). Late gadolinium enhancement was present in >60% of overt patients with HCM but absent from G+/LVH- subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM., Conclusions: Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.

We aimed to determine whether the myocardial extracellular volume (ECV), measured using T1 measurements obtained during cardiac magnetic resonance imaging were increased in patients treated with anthracyclines. We performed cardiac magnetic resonance imaging and echocardiography and measured the ECV in 42 patients treated with anthracyclines. The data from the cardiac magnetic resonance study were compared to those from healthy volunteers. The anthracycline-treated cohort consisted of 21 men and 21 women with a mean age of 55 ± 17 years, who presented a median of 84 months after chemotherapy with a cumulative anthracycline exposure of 282 ± 65 mg/m(2) and a mean left ventricular ejection fraction of 52 ± 12%. The ECV was elevated in the anthracycline-treated patients compared to the age- and gender-matched controls (0.36 ± 0.03 vs 0.28 ± 0.02, p <0.001). A positive association was found between the ECV and left atrial volume (ECV vs indexed left atrial volume, r = 0.65, p <0.001), and negative association was found between the ECV and diastolic function (E' lateral, r = -0.64, p <0.001). In conclusion, the myocardial ECV is elevated in patients with previous anthracycline treatment and is associated with the diastolic function and increased atrial volumes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Regenerative medicine, including cell therapy, is a promising strategy for recovery of the damaged myocardium. C-kit-positive cardiac stem cells (CSCs) have been shown to improve myocardial function after ischemic injury in animal models and in early clinical experience. We used a chronic large animal model of myocardial infarction with substantial reductions in left-ventricular (LV) ejection fraction and adverse remodeling to examine the effect of late autologous CSC intramyocardial injection on long-term cardiac structure and function., Methods and Results: Thoracotomy and ligation of the proximal left anterior descending artery, additional diagonal branches, and atrial biopsy for CSC culture were performed in canines. Baseline cardiac MRI was performed at 6 weeks postinfarct followed by repeat thoracotomy for randomization to intramyocardial injection of CSCs (n=13) or vehicle alone (n=6). At 30 weeks postmyocardial infarction, repeat MRI was performed. Data were analyzed using nonparametric tests (Wilcoxon signed-rank and rank-sum tests). In control animals, LV end-systolic volume and end-diastolic volume increased from 6 to 30 weeks (median and interquartile range, 51.3 mL [43.3-57.4] to 76.1 mL [72.0-82.4]; P=0.03 and 78.5 mL [69.7-86.1] to 99.2 mL [97.1-100.4]; P=0.03). Left-ventricular ejection fraction declined further (35.2% [27.9-38.7] to 26.4% [22.0-31.0]; P=0.12). In the cell-treated animals, this late adverse LV remodeling was attenuated (LV end-systolic volume, 42.6 mL [38.5-50.5] to 56.1 mL [50.3-63.0]; P=0.01 versus control). There was a nonsignificant attenuation in the increase in LV end-diastolic volume (64.8 mL [60.7-71.3] to 83.5 mL [74.7-90.8]; P=0.14 versus control) and LV ejection fraction change over time differed (30.5% [28.4-33.4] to 32.9% [28.6-36.9]; P=0.04 versus control)., Conclusions: Intramyocardial injection of autologous CSCs in a late phase model of chronic infarction resulted in less increase in LV end-systolic volume and preservation of LV ejection fraction.

Objectives: The aim of this study was to perform direct quantification of myocardial extracellular volume fraction (ECF) with T1-weighted cardiac magnetic resonance (CMR) imaging in patients suspected to have infiltrative heart disease., Background: Infiltrative heart disease refers to accumulation of abnormal substances within the myocardium. Qualitative assessment of late gadolinium enhancement (LGE) remains the most commonly used method for CMR evaluation of patients suspected with myocardial infiltration. This technique is widely available and can be performed in a reproducible and standardized manner. However, the degree of extracellular matrix expansion due to myocardial infiltration in the intercellular space has, to date, not been amenable to noninvasive quantification with LGE., Methods: We performed 3-T CMR in 38 patients (mean age 68 ± 15 years) who were referred for assessment of infiltrative heart disease and also in 9 healthy volunteers as control subjects. The T1 quantification by Look-Locker gradient-echo before and after contrast determined segmental myocardial partition coefficients. The ECF was obtained by referencing the tissue partition coefficient for gadolinium to the plasma volume fraction in blood, derived from serum hematocrit. Cine CMR and LGE imaging in matching locations were also performed., Results: Seventeen patients (45%) had cardiac amyloidosis (CA) (biopsy-confirmed or clinically highly probable), 20 (53%) had a non-amyloid cardiomyopathy, and 1 had lysosomal storage disease. Median global ECF was substantially higher in CA patients (0.49) compared with non-amyloid cardiomyopathy patients (0.33, p < 0.0001) and volunteers (0.24, p = 0.0001). The ECF strongly correlated with visually assessed segmental LGE (r = 0.80, p < 0.0001) and LV mass index (r = 0.69, p < 0.0001), reflecting severity of myocardial infiltration. In patients with CA, ECF was highest in segments with LGE, although it remained elevated in segments without qualitative LGE., Conclusions: The CMR ECF quantification identified substantial expansion of the interstitial space in patients with CA compared with volunteers. Further studies using this technique for diagnosis and assessment of the severity of myocardial infiltration are warranted., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality after myocardial infarction (MI) that is not fully explained by the metabolic effects of diabetes. Acute MI is known to trigger a profound innate inflammatory response with influx of mononuclear cells and production of proinflammatory cytokines that are crucial for cardiac repair. We hypothesized that these same pathways might exert "adjuvant effects" and induce pathological responses in autoimmune-prone T1D hosts. Here, we show that experimental MI in nonobese diabetic mice, but not in control C57BL/6 mice, results in a severe post-infarction autoimmune (PIA) syndrome characterized by destructive lymphocytic infiltrates in the myocardium, infarct expansion, sustained cardiac autoantibody production, and T helper type 1 effector cell responses against cardiac (α-)myosin. PIA was prevented by inducing tolerance to α-myosin, demonstrating that immune responses to cardiac myosin are essential for this disease process. Extending these findings to humans, we developed a panel of immunoassays for cardiac autoantibody detection and found autoantibody positivity in 83% post-MI T1D patients. We further identified shared cardiac myosin autoantibody signatures between post-MI T1D patients and nondiabetic patients with myocarditis, which were absent in post-MI type 2 diabetic patients, and confirmed the presence of myocarditis in T1D by cardiac magnetic resonance imaging techniques. These data provide experimental and clinical evidence for a distinct post-MI autoimmune syndrome in T1D. Our findings suggest that PIA may contribute to worsened post-MI outcomes in T1D and highlight a role for antigen-specific immunointervention to selectively block this pathway.

The prevalence of heart failure due to coronary artery disease continues to increase, and it portends a worse prognosis than non-ischemic cardiomyopathy. Revascularization improves prognosis in these high-risk patients who have evidence of viability; therefore, optimal assessment of myocardial viability remains essential. Multiple imaging modalities exist for differentiating viable myocardium from scar in territories with contractile dysfunction. Given the multiple modalities available, choosing the best modality for a specific patient can be a daunting task. In this review, the physiology of myocardial hibernation and stunning will be reviewed. All the current methods available for assessing viability including echocardiography, cardiac magnetic resonance imaging, nuclear imaging with single photon emission tomography and positron emission tomography imaging and cardiac computed tomography will be reviewed. The effectiveness of the various techniques will be compared, and the limitations of the current literature will be discussed.

Background: Recent studies suggested that bone marrow (BM) cell implantation in patients with severe chronic coronary artery disease (CAD) resulted in modest improvement in symptoms and cardiac function. This study sought to investigate the functional changes that occur within the chronic human ischaemic myocardium after direct endomyocardial BM cells implantation by cardiovascular magnetic resonance (CMR)., Methods and Results: We compared the interval changes of left ventricular ejection fraction (LVEF), myocardial perfusion reserve and the extent of myocardial scar by using late gadolinium enhancement CMR in 12 patients with severe CAD. CMR was performed at baseline and at 6 months after catheter-based direct endomyocardial autologous BM cell (n = 12) injection to viable ischaemic myocardium as guided by electromechanical mapping. In patients randomized to receive BM cell injection, there was significant decrease in percentage area of peri-infarct regions (-23.6%, P = 0.04) and increase in global LVEF (+9.0%, P = 0.02), the percentage of regional wall thickening (+13.1%, P= 0.04) and MPR (+0.25%, P = 0.03) over the target area at 6-months compared with baseline., Conclusions: Direct endomyocardial implantation of autologous BM cells significantly improved global LVEF, regional wall thickening and myocardial perfusion reserve, and reduced percentage area of peri-infarct regions in patients with severe CAD.

Objectives: This investigation sought to study the incremental value of gated rubidium (Rb)-82 positron emission tomography (PET) myocardial perfusion imaging (MPI) over clinical variables for predicting survival and future cardiac events., Background: The prognostic value of Rb-82 PET-MPI and left ventricular ejection fraction (LVEF) reserve (stress minus rest LVEF) is not well defined., Methods: 1,432 consecutive patients undergoing gated rest/vasodilator stress rubidium-82 PET were followed up for at least 1 year. Of these, rest and peak stress LVEF and LVEF reserve were available in 985 patients. Cardiac events (CE) including cardiac death or nonfatal myocardial infarction and all-cause death were assessed., Results: Over a mean follow-up of 1.7 +/- 0.7 years, 83 (5.8%) CE and 140 (9.7%) all-cause death were observed. There was an increase in risk for both end points with an increasing percentage of abnormal and ischemic myocardium. With normal, mild, moderate, or severely ischemic scans, the observed annualized rates of CE were 0.7%, 5.5%, 5%, and 11% and of all-cause death were 3.3%, 7.2%, 6.9%, and 12.5%, respectively. In 985 patients with peak stress gated data, the observed annualized rates of CE (2.1% vs. 5.3%, p < 0.001) and all-cause death (4.3% vs. 9.2%, p < 0.001) were higher in patients with an LVEF reserve <0% compared with those with an LVEF reserve >or=0%. On Cox proportional hazards analysis, after consideration of clinical, historical, and rest LVEF information, stress PET results and LVEF reserve yielded incremental prognostic value with respect to both CE and all-cause death., Conclusions: Vasodilator stress Rb-82 PET-MPI provides incremental prognostic value to historical/clinical variables and rest LVEF to predict survival free of CE and all-cause death. An increasing percentage of ischemia on PET-MPI is associated with an increase in the risk of CE and all-cause death. Left ventricular ejection fraction reserve provides significant independent and incremental value to Rb-82 MPI for predicting the risk of future adverse events.

Assessment of viability is pivotal to the prognosis of patients with chronic coronary artery disease (CAD) and left ventricular dysfunction. Patients with viable myocardium have a better prognosis with revascularization; however, patients with nonviable myocardium have worse outcomes with higher perioperative morbidity and mortality subsequent to revascularization. Cardiac magnetic resonance (CMR) imaging not only is the current reference standard technique in measuring cardiac chamber size and function and myocardial mass and volume but also provides spatially registered 2- or 3-dimensional data sets in myocardial perfusion and myocardial contrast enhancement in the same imaging session. Late gadolinium enhancement by CMR is the best current technique in discriminating myocardial scar versus viable myocardium. An extensive body of preclinical evidence has validated the detection and characterization of the morphology of infarcted tissue. In clinical studies, infarct characteristics by CMR has demonstrated a strong clinical utility in the prediction of left ventricular functional recovery and patient prognosis. In this paper, we aim to review the current CMR techniques in characterizing the spectrum of myocardial changes because of CAD, in the prediction of myocardial viability, and the current evidence of CMR's role in patient prognosis. In addition, we will also review the current literature comparing the clinical utility of CMR with other established imaging modalities in the assessment of CAD.

Background: Contrast-enhanced cardiac magnetic resonance imaging (CMR) can determine the extent of myocardial scar from infarction (MI). However, the prognostic significance of unrecognized myocardial scar by CMR in patients without a history of MI is unknown., Methods and Results: One hundred ninety-five patients without a known prior MI underwent CMR for assessment of left ventricular (LV) function and late gadolinium enhancement (LGE). We assessed the prognostic value of LGE and other CMR variables beyond the strongest clinical predictors and built the best overall models for major adverse cardiac events (MACE) and cardiac mortality. During a median follow-up of 16 months, 31 patients (18%) experienced MACE, including 17 deaths. LGE demonstrated the strongest unadjusted associations with MACE and cardiac mortality (hazard ratios of 8.29 and 10.9, respectively; both P<0.0001). Patients in the lowest tertile of LGE-involved myocardium (mean LV mass, 1.4%) experienced a >7-fold increased risk for MACE. By multivariable analyses, LGE was independently associated with MACE beyond the clinical model (P<0.0001) or the clinical model combined with angiographically significant coronary stenosis (P=0.0007), LV ejection fraction (P=0.001), LV end-systolic volume index (P=0.0006), or segmental WMA (P=0.002). LGE remained the strongest predictor selected in the best overall models for MACE and cardiac mortality., Conclusions: Among patients with a clinical suspicion of coronary artery disease but without a history of MI, LGE involving a small amount of myocardium carries a high cardiac risk. In addition, LGE provides incremental prognostic value to MACE and cardiac mortality beyond common clinical, angiographic, and functional predictors.

Purpose: While both first-pass perfusion and late gadolinium enhancement by cardiovascular magnetic resonance (CMR) can assess coronary microvascular status in acute myocardial infarction (AMI), there are only limited data on their respective diagnostic utility. We aim to evaluate: the utility of first-pass perfusion and late gadolinium enhancement imaging in the detection and quantification of microvascular dysfunction after reperfused acute myocardial infarction, using TIMI frame count (TIMI FC) as the reference standard of microvascular assessment; and their relationship with infarct size and ventricular function., Methods: First-pass perfusion and late gadolinium enhancement imaging were performed in 25 consecutive AMI patients (84% men, age 58 +/- 10) within 72 h of successful reperfusion. We assessed the myocardial extent of microvascular dysfunction using the size of the perfusion defect on first-pass perfusion (PD%) and the hypoenhanced core region within late gadolinium enhancement (MDEcore%). PD%, MDEcore%, and TIMI FC were analyzed independently of each other and with blinding to clinical data. We adjusted PD% and MDEcore% to the myocardial mass subtended by the infarct-related artery according to the 16-segment model., Results: Median infarct size involved 13.9% (interquartile range: 8.5 to 22.2%) of the left ventricle and median left ventricular ejection fraction was 52% (interquartile range: 43 to 61%). PD% demonstrated evidence of microvascular dysfunction more frequently (84% vs. 36% of patients, p < 0.002) and involved a larger myocardial extent (23.5 +/- 17.5% vs. 3.5 +/- 7.7%, p < 0.001) compared to MDEcore%. PD% had strong correlations with TIMI FC (Spearman rho = 0.62, p < 0.001) and infarct size (rho = 0.64, p < 0.001), and a moderate correlation with LVEF (rho = -0.39, p = 0.055). MDEcore% also correlated with TIMI FC (rho = 0.54, p = 0.005) and infarct size (rho = 0.52, p < 0.01) but not with LVEF (p = NS)., Conclusions: PD% appeared to provide a stronger noninvasive assessment of the microvascular function than MDEcore% and correlated well with prognostic markers such as left ventricular ejection fraction and infarct size. Future studies should consider quantitative analyses of both first-pass perfusion and late gadolinium enhancement imaging in the evaluation of novel therapies targeted to the microvasculature of the infarct-related artery.

Objective: Effects of ventricular restraint on the left ventricle are well documented, but effects on the right ventricle are not. We hypothesized that restraint affects the right and left ventricles differently. Methods: We studied acute effects of restraint on left and right ventricular mechanics in healthy sheep (n = 14) with our previously described technique of adjustable and measurable restraint. Transmural pressure, myocardial oxygen consumption indices, diastolic compliance, and end-systolic elastance were assessed at 4 restraint levels for both ventricles. We then studied long-term effects of restraint for 4 months in an ovine model of ischemic dilated cardiomyopathy (n = 6). Heart failure was induced by coronary artery ligation, and polypropylene mesh was wrapped around the heart to simulate clinical restraint therapy. All subjects were followed up with serial cardiac magnetic resonance imaging to assess left and right ventricular volumes and function. Results: Restraint decreased left ventricular transmural pressure (P < .03) and myocardial oxygen consumption indices (P < .05) but not left ventricular diastolic compliance (P = .52). Restraint had no effect on right ventricular transmural pressure (P = .82) or myocardial oxygen consumption indices (P = .72) but reduced right ventricular diastolic compliance (P < .01). In long-term studies, restraint led to reverse left ventricular remodeling with decreased left ventricular end-diastolic volume (P < .006) but did not affect right ventricular end-diastolic volume (P = .82). Conclusions: Ventricular restraint affects the left and right ventricles differently. Benefits of restraint for right ventricular function are unclear. The left ventricle can tolerate more restraint than the right ventricle. With current devices, the right ventricle may limit overall therapeutic efficacy. [Copyright &y& Elsevier]

Background: Recent studies suggested that bone marrow (BM) cell implantation in patients with severe chronic coronary artery disease (CAD) resulted in modest improvement in symptoms and cardiac function. This study sought to investigate the functional changes that occur within the chronic human ischaemic myocardium after direct endomyocardial BM cells implantation by cardiovascular magnetic resonance (CMR). Methods and Results: We compared the interval changes of left ventricular ejection fraction (LVEF), myocardial perfusion reserve and the extent of myocardial scar by using late gadolinium enhancement CMR in 12 patients with severe CAD. CMR was performed at baseline and at 6 months after catheter-based direct endomyocardial autologous BM cell (n = 12) injection to viable ischaemic myocardium as guided by electromechanical mapping. In patients randomized to receive BM cell injection, there was significant decrease in percentage area of peri-infarct regions (-23.6%, P = 0.04) and increase in global LVEF (+9.0%, P = 0.02), the percentage of regional wall thickening (+13.1%, P= 0.04) and MPR (+0.25%, P = 0.03) over the target area at 6-months compared with baseline. Conclusions: Direct endomyocardial implantation of autologous BM cells significantly improved global LVEF, regional wall thickening and myocardial perfusion reserve, and reduced percentage area of peri-infarct regions in patients with severe CAD. [ABSTRACT FROM AUTHOR]

An abstract of the article "The incidence and prognostic value of silent myocardial scar by late gadolinium enhancement in patients with atrial fibrillation," by Tomas G. Neilan, Hoshang Farhad, Ravi Shah, Siddique Abbasi, Otavio R. Coelho-Filho, and Ciaran J. McMullan is presented.

An abstract of the article "Myocardial extracellular volume expansion in patients with hypertension," by Tomas G. Neilan and colleagues is presented.