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Aims Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome. Methods and results A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow‐up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan–Meier analyses compared to those with no remodelling, log‐rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction. Conclusions Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long‐term outcomes whereas change in left ventricular ejection fraction did not.

Background Dilated cardiomyopathy (DCM) is increasingly recognized as a heterogenous disease with distinct phenotypes on late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging. While mid-wall striae (MWS) fibrosis is a widely recognized phenotypic risk marker, other fibrosis patterns are prevalent but poorly defined. Right ventricular (RV) insertion (RVI) site fibrosis is commonly seen, but without objective criteria has been considered a non-specific finding. In this study we developed objective criteria for RVI fibrosis and studied its clinical relevance in a large cohort of patients with DCM. Methods We prospectively enrolled 645 DCM patients referred for LGE-CMR. All underwent standardized imaging protocols and baseline health evaluations. LGE images were blindly scored using objective criteria, inclusive of RVI site and MWS fibrosis. Associations between LGE patterns and CMR-based markers of adverse chamber remodeling were evaluated. Independent associations of LGE fibrosis patterns with the primary composite clinical outcome of heart failure admission or death were determined by multivariable analysis. Results The mean age was 56 ± 14 (28% female) with a mean left ventricular (LV) ejection fraction (LVEF) of 37%. At a median of 1061 days, 129 patients (20%) experienced the primary outcome. Any abnormal LGE was present in 306 patients (47%), inclusive of 274 (42%) meeting criteria for RVI site fibrosis and 167 (26%) for MWS fibrosis. All with MWS fibrosis showed RVI site fibrosis. Solitary RVI site fibrosis was associated with higher bi-ventricular volumes [LV end-systolic volume index (78 ± 39 vs. 66 ± 33 ml/m2, p = 0.01), RV end-diastolic volume index (94 ± 28 vs. 84 ± 22 ml/m2 (p 2, p Conclusions RVI site fibrosis in the absence of MWS fibrosis is associated with bi-ventricular remodelling and intermediate risk of heart failure admission or death. Our study findings suggest RVI site fibrosis to be pre-requisite for the incremental development of MWS fibrosis, a more advanced phenotype associated with greater LV remodeling and risk of clinical events.

In this study we aimed to investigate left atrial (LA) function, measured from routine cine cardiovascular magnetic resonance imaging, to determine its value for the prediction of sudden cardiac death (SCD) or appropriate implantable cardioverter defibrillator (ICD) shock in patients who received primary prevention ICD implantation.We studied 203 patients with ischemic or idiopathic nonischemic dilated cardiomyopathy who underwent cardiovascular magnetic resonance imaging before primary prevention ICD implantation. LA volumes were measured at end-diastole and end-systole from 4- and 2-chamber cine images, and LA emptying function (LAEF) calculated. Patients were followed for the primary composite end point of SCD or appropriate ICD shock.Mean age was 61 ± 12 years with a mean left ventricular ejection fraction of 24 ± 7%. The mean LAEF was 27 ± 15% (range, 0.9%-73%). At a median follow-up of 1639 days, 35 patients (17%) experienced the primary composite outcome. LAEF was strongly associated with the primary outcome (P = 0.001); patients with an LAEF ≤ 30% experienced a cumulative event rate of 26.1% vs 5.7% (hazard ratio, 5.5; P0.001) in patients above this cutoff. This finding was maintained in multivariable analysis (hazard ratio, 4.7; P = 0.002) and was consistently shown in the ischemic and nonischemic dilated cardiomyopathy subgroups.LAEF is a simple, powerful, and independent predictor of SCD in patients being referred for primary prevention ICD implantation.

Aims In patients with coronary artery disease (CAD), a transmural gradient of myocardial perfusion has been repeatedly observed, with the subendocardial layer showing more pronounced perfusion deficits. Oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) allows for monitoring transmural changes of myocardial oxygenation in vivo. We hypothesized that OS-CMR could help identify a transmural oxygenation gradient as a disease marker in patients at risk for CAD. Methods and results We assessed 34 patients with known CAD and 28 subjects with coronary risk factors but no evidence of significant CAD. Results were compared with 11 healthy volunteers. OS-CMR was performed at 1.5 T, applying a T2*-weighted cine steady state free precession sequence at baseline and during infusion of adenosine. A reader blinded to patient data quantified the relative change of myocardial oxygenation in OS-CMR, defined by the change of signal intensity (ΔSI%) between baseline and during adenosine infusion in the entire myocardium, the subepicardial layer, and the subendocardial layer. SI changes were homogenous throughout the myocardium in healthy subjects, whereas both, patients with risk factors only and patients with CAD, had a significantly smaller ΔSI% in the subendocardial layer than in the subendocardial layer. Both patient groups had an overall decreased ΔSI% across all layers when compared with healthy subjects (P < 0.05). Conclusion Even in the absence of overt CAD, cardiovascular risk factors are associated with a transmural gradient of the myocardial oxygenation response to adenosine as assessed by OS-CMR. An inducible transmural oxygenation gradient may serve as a non-invasive marker for cardiovascular risk.

Background The overlap between cancer and cardiovascular care continues to expand, with intersections emerging before, during, and following cancer therapies. To date, emphasis has been placed on how cancer therapeutics influence downstream cardiac health. However, whether active malignancy itself influences chamber volumes, function, or overall myocardial tissue health remains uncertain. We sought to perform a comprehensive cardiovascular magnetic resonance‐based evaluation of cardiac health in patients with chemotherapy‐naïve cancer with comparison with a healthy volunteer population. Methods and Results Three‐hundred and eighty‐one patients with active breast cancer or lymphoma before cardiotoxic chemotherapy exposure were recruited in addition to 102 healthy volunteers. Both cohorts underwent standardized cardiovascular magnetic resonance imaging with quantification of chamber volumes, ejection fraction, and native myocardial T1. Left ventricular mechanics were incrementally assessed using three‐dimensional myocardial deformation analysis, providing global longitudinal, circumferential, radial, and principal peak‐systolic strain amplitude and systolic strain rate. The mean age of patients with cancer was 53.8±13.4 years; 79% being women. Despite similar left ventricular ejection fraction, patients with cancer showed smaller chambers, increased strain amplitude, and systolic strain rate in both conventional and principal directions, and elevated native T1 versus sex‐matched healthy volunteers. Adjusting for age, sex, hypertension, and diabetes mellitus, the presence of cancer remained associated with these cardiovascular magnetic resonance parameters. Conclusions The presence of cancer is independently associated with alterations in cardiac chamber size, function, and objective markers of tissue health. Dedicated research is warranted to elucidate pathophysiologic mechanisms underlying these findings and to explore their relevance to the management of patients with cancer referred for cardiotoxic therapies.

Background: There is increasing evidence that right ventricular ejection fraction (RVEF) may provide incremental value to left ventricular (LV) ejection fraction for the prediction of major adverse cardiovascular events. To date, generalizable utility for RVEF quantification in patients with cardiovascular disease has not been established. Using a large prospective clinical outcomes registry, we investigated the prognostic value of RVEF for the prediction of major adverse cardiovascular events- and heart failure-related outcomes. Methods: Seven thousand one hundred thirty-one consecutive patients with known or suspected cardiovascular disease undergoing cardiovascular magnetic resonance imaging were prospectively enrolled. Multichamber volumetric quantification was performed by standardized operational procedures. Patients were followed for the primary composite outcome of all-cause death, survived cardiac arrest, admission for heart failure, need for transplantation or LV assist device, acute coronary syndrome, need for revascularization, stroke, or transient ischemic attack. A secondary, heart failure focused outcome of heart failure admission, need for transplantation/LV assist device or death was also studied. Results: Mean age was 54±15 years. The mean LV ejection fraction was 55±14% (range 6%–90%) with a mean RVEF of 54±10% (range 9%–87%). At a median follow-up of 908 days, 870 (12%) patients experienced the primary composite outcome and 524 (7%) the secondary outcome. Each 10% drop in RVEF was associated with a 1.3-fold increased risk of the primary outcome ( P P P Conclusions: RVEF is a powerful and independent predictor of major adverse cardiac events with broad generalizability across patients with known or suspected cardiovascular disease. These findings support migration towards biventricular phenotyping for the classification of risk in clinical practice. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04367220.

Background Global longitudinal strain (GLS), most commonly measured at the endocardium, has been shown to be superior to left ventricular (LV) ejection fraction (LVEF) for the identification of systolic dysfunction and prediction of outcomes in heart failure (HF). We hypothesized that strains measured at different myocardial layers (endocardium = ENDO, epicardium = EPI, average = AVE) will have distinct diagnostic and predictive performance for patients with HF. Methods Layer-specific GLS, layer-specific global circumferential strain (GCS) and global radial strain (GRS) were evaluated by cardiovascular magnetic resonance imaging (CMR) feature tracking in the Alberta HEART study. A total of 453 subjects consisted of healthy controls (controls, n = 77), at-risk for HF (at-risk, n = 143), HF with preserved ejection fraction (HFpEF, n = 87), HF with mid-range ejection fraction (HFmrEF, n = 88) and HF with reduced ejection fraction (HFrEF, n = 58). For outcomes analysis, CMR-derived imaging parameters were adjusted with a base model that included age and N-terminal prohormone of b-type natriuretic peptide (NT-proBNP) to test their independent association with 5-year all-cause mortality. Results GLS_EPI distinguished all groups with preserved LVEF (controls − 16.5 ± 2.4% vs. at-risk − 15.5 ± 2.7% vs. HFpEF − 14.1 ± 3.0%, p Conclusion Global strains measured on endocardium, epicardium or averaged across the wall thickness are not equivalent for the identification of systolic dysfunction or outcomes prediction in HF. The endocardium-specific strains were shown to have poorest all-around performance. GLS_AVE and GRS were the only CMR parameters to be significantly associated with 5-year all-cause mortality in multivariable analysis. GLS_EPI and GRS, as well as the difference in endocardial and epicardial strains, were sensitive to systolic dysfunction among HF patients with normal LVEF (> 55%), in whom lower strains were associated with increased concentricity.

Background: Cancer Therapeutics-related Cardiac Dysfunction (CTRCD) is defined by an interval drop in contractile performance to below reference lower limits of normal. This definition assumes healthy reference data appropriately represent referral populations with active cancer. However, the influence of active cancer on cardiac chamber volumes and contractile performance has not been established. Using cardiac magnetic resonance (CMR), we studied chamber volume- and deformation-based markers in ~400 cancer patients with comparison to ~100 healthy controls. Methods: 394 active cancer patients referred for first-time anthracycline-based chemotherapy and 102 healthy volunteers (HV) were recruited. Both underwent identical CMR protocols with quantification of chamber volumes and ejection fraction (EF). Left ventricular (LV) mechanics were also assessed by 3D myocardial deformation analysis (3D-MDA), providing global longitudinal, circumferential, radial and principal peak-systolic strain amplitude and rate. Results: The mean age was 53.8±13 years (78% female), with 64% having breast cancer and 36% lymphoma. Table 1 summarizes CMR findings of cancer patients versus HV, stratified by sex. Chamber volumes were significantly smaller while LV mass was significantly greater versus HV. LV EF and global longitudinal (GLS) were similar. However, cancer patients demonstrated significantly higher radial, circumferential and maximal principal strain amplitude. Peak-systolic strain rates were also consistently elevated. Conclusion: Chemotherapy-naïve cancer patients have smaller chamber volumes, greater LV mass, and higher radial, circumferential, and maximal principal strain versus healthy subjects. LV EF and peak GLS remain similar, and therefore are most appropriate to define CTRCD. However, an altered state of cardiac health is apparent by all other CMR-based markers, reflecting a unique cardiac phenotype of patients with active cancer.

Background Cardiovascular diseases remain the leading cause of morbidity worldwide and impose the highest economic burden among noncommunicable diseases. Much of these costs are related to hospitalizations for adverse cardiovascular events, which may be reduced by targeted management of high-risk patients. Cardiac markers derived from CMR imaging have been shown to be strong independent predictors of prognosis within specific cohorts. However, its capacity to broadly contribute to risk models aimed at predicting incident cardiac hospitalization has not been demonstrated. Purpose Using a large clinical outcomes registry of patients clinically referred for CMR, develop and validate a nomogram for prediction of cardiovascular hospital admission. Methods A total of 7127 consecutive patients were prospectively recruited between 02/2015 and 07/2019. All patients completed standardized health questionnaires and CMR imaging protocols. A nomogram was developed for prediction of cardiovascular hospitalization, inclusive of admission for heart failure, MI, cardiac arrest, heart transplant, LVAD implantation, or stroke. The risk model was derived from 80% (n=5702) of the cohort using Cox modelling that included CMR, medication, laboratory, and patient-reported health variables. Model validation was assessed by discrimination and calibration procedures applied to the remaining 20% of patients (n=1425). A minimum follow-up of six months was mandated. Results The derivation cohort was comprised of 38% females with a median age of 56 (IQR 44–65) years. During a median follow-up of 934 days, 514 (9.0%) events occurred. The validation cohort was similarly comprised of 37% females with a median age of 57 (IQR 44–66) years. During a median follow-up of 970 days, 142 (10.0%) events occurred. Numerous CMR parameters were significantly different between those experiencing versus not experiencing the primary composite outcome, including: LVEF (44% vs 59%, p Conclusion Using data available at time of CMR imaging, we derived and validated a Cox-based nomogram that offers robust prediction of future cardiovascular admissions. This tool may provide value for the identification of patients who may benefit from targeted surveillance and management strategies, and may offer a foundation for improved patient-specific cost modelling. Figure 1 Funding Acknowledgement Type of funding source: None

Background Right ventricular (RV) function remains poorly recognized for its value in predicting cardiovascular events at a population level. Cardiovascular Magnetic Resonance (CMR) imaging is the gold standard for RV assessment. Purpose To define the independent prognostic value of RVEF for the prediction of major adverse cardiovascular events (MACE) as primary outcome in patients with known or suspected cardiovascular disease. Methods Data was obtained from the Cardiovascular Imaging Registry of Calgary (CIROC). Patients underwent standardized CMR imaging protocols and analysis. Clinical events were identified from administrative data. Results 7,131 patients were included. 870 primary outcome events occurred over 2.5 years follow-up. RVEF provided equivalent predictive utility versus LVEF (Table 1). There was an increase in events with worsening severity of RVEF (Figure 1), with a significant “threshold-effect” at an RVEF of 40%. Conclusions RVEF is a strong and independent predictor of MACE at a population level. Figure 1 Funding Acknowledgement Type of funding source: None

Aims Left ventricular hypertrophy (LVH) is the most common form of myocardial remodelling and predicts adverse outcomes in patients with coronary artery disease (CAD). However, sex-specific prevalence and prognostic significance of LVH patterns are poorly understood. We investigated the sex-specific influence of LVH pattern on clinical outcomes in patients undergoing cardiovascular magnetic resonance (CMR) and coronary angiography following adjustment for co-morbidities including CAD burden. Methods and results Patients undergoing CMR and coronary angiography between 2005 and 2013 were included. Volumetric measurements of left ventricular (LV) mass with classification of concentric vs. eccentric remodelling patterns were determined from CMR cine images. Multivariable Cox analysis was performed to assess independent associations with the primary outcome of all-cause mortality. In total, 3754 patients were studied (mean age 59.3 ± 13.1 years), including 1039 (27.7%) women. Women were more likely to have concentric remodelling (8.1% vs. 2.1%, P Conclusion Patterns of LV remodelling differ by sex and LVH and provides prognostic information in both men and women. Our findings support the presence of sex-specific factors influencing LV remodelling.

We sought to examine whether elongation of the mitral valve leaflets in patients with hypertrophic cardiomyopathy (HCM) is synergistic to septal wall thickness (SWT) in the development of left ventricular outflow tract obstruction (LVOTO). HCM is a common genetic cardiac disease characterized by asymmetric septal hypertrophy and predisposition towards LVOTO. It has been reported that elongation of the mitral valve leaflets may be a primary phenotypic feature and contribute to LVOTO. However, the relative contribution of this finding versus SWT has not been studied. 152 patients (76 with HCM and 76 non-diseased age, race and BSA-matched controls) and 18 young, healthy volunteers were studied. SWT and the anterior mitral valve leaflet length (AMVLL) were measured using cine MRI. The combined contribution of these variables (SWT × AMVLL) was described as the Septal Anterior Leaflet Product (SALP). Peak LVOT pressure gradient was determined by Doppler interrogation and defined as “obstructive” if ≥ 30 mmHg. Patients with HCM were confirmed to have increased AMVLL compared with controls and volunteers (p

Background Standardized patient phenotyping using cardiovascular magnetic resonance (CMR) imaging has been shown to be of clinical value for prediction of adverse events in patients with heart failure and reduced ejection fraction (HFrEF). Studies have validated the prognostic capacity of function (LV, RV and LA) and replacement fibrosis burden in patients with ischemic and non-ischemic cardiomyopathy. The translation and validation of routine CMR-based phenotyping into clinical practice has yet to be demonstrated in prospective studies. Purpose This study was designed to explore feasibility and prognostic value of routine CMR-based patient phenotyping in a high-volume clinical referral center for patients with HFrEF. Methods One thousand three hundred and ninety-three consecutive patients with chronic HFrEF were prospectively recruited between January 2015 and June 2018. Chronic HFrEF was defined by LVEF≤50% by CMR, with no recent (within 90 days) acute myocardial infarction or myocarditis diagnosis. Patients with congenital heart disease and those without LGE CMR protocol were excluded. All patients underwent standardized CMR protocols with multi-chamber volumetric analysis and regional myocardial fibrosis coding. Pharmacy, ECG, laboratory and patient reported data was used for statistical modelling. A minimum three-month follow-up was mandated to identify the composite clinical outcome of heart failure hospitalization or death. Results The cohort had a median age of 61 years with 23% being female. The median follow-up was 737 days with 146 patients (10.5%) experiencing the composite outcome. Numerous imaging and non-imaging variables were significantly different between patients with and without the composite outcome, including: median LVEF (32% vs 39%, p Conclusions This study demonstrates the feasibility and prognostic value of automated patient phenotyping that captures patient reported data, imaging, and administrative data for risk prediction modelling in HFrEF. The incremental application of machine learning is being explored. Acknowledgement/Funding J White: Early Investigator Award (Heart and Stroke Foundation of Alberta), Calgary Health Trust

Background: Cardiovascular magnetic resonance (CMR) imaging is commonly used to diagnose acute myocarditis. However, the natural history of CMR-based tissue markers and their association with left ventricular recovery is poorly explored. We prospectively investigated the natural history of CMR-based myocardial injury and chamber remodeling over 12 months in patients with suspected acute myocarditis. Methods: One hundred patients with suspected acute myocarditis were enrolled. All underwent CMR evaluations at baseline and 12 months, inclusive of T2 and late gadolinium enhancement. Blinded quantitative analyses compared left ventricular chamber volumes, function, myocardial edema, and necrosis at each time point using predefined criteria. The predefined primary outcomes were improvement in left ventricular ejection fraction ≥10% and improvement in the indexed left ventricular end diastolic volume ≥10% at 12 months. Results: The mean age was 39.9±14.5 years (82 male) with baseline left ventricular ejection fraction of 57.1±11.2%. A total of 72 patients (72%) showed late gadolinium enhancement at baseline with 57 (57%) having any T2 signal elevation. Left ventricular volumes and EF improved significantly at 12 months. Global late gadolinium enhancement extent dropped from 8.5±9.2% of left ventricular mass to 3.0±5.2% ( P =0.0001) with prevalence of any late gadolinium enhancement dropping to 48%. Reductions in global T2 signal ratio occurred at 12 months (1.85±0.3 to 1.56±0.2; P =0.0001) with prevalence of T2 ratio ≥2.0 dropping to 7%. Neither marker provided associations with the primary outcomes. Conclusions: In clinically suspected acute myocarditis, significant reductions in tissue injury markers occur during the first 12 months of convalescence. Neither the presence nor extent of the investigated CMR-based tissue injury markers were predictive of our pre-defined function or remodeling outcomes at 12 months in this referral population.

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.

Hypertrophic cardiomyopathy (HCM) is characterized by myocardial disarray, hypertrophy, and fibrosis. Reduced global longitudinal strain and presence of late gadolinium enhancement (LGE) by cardiac magnetic resonance imaging (CMR) have been associated with an adverse prognosis. This study evaluated 3D principal and conventional strain characteristics of non-enhanced myocardium in patients with HCM. 3D principal and conventional strain analysis was conducted in 51 HCM patients and 38 healthy controls. Principal strain was reduced within the non-enhanced myocardium of HCM as compared with controls (maximum principal: 51.5 ± 23.7 vs. 75.1 ± 21.4%, P < 0.0001; minimum principal: - 18.4 ± 4.0 vs. - 20.1 ± 2.9%, P < 0.05). Principal strain within the non-enhanced myocardium was incrementally reduced in HCM patients with extensive global LGE ( ≥ 15%) (maximum principal: 41.6 ± 17.5 vs. 56.9 ± 25.9%, P < 0.05; minimum principal: - 16.9 ± 3.9 vs. - 19.1 ± 4.0%, P = 0.1), as was longitudinal ( - 10.5 ± 2.6 vs. - 12.7 ± 2.6%, P < 0.05) and circumferential strain ( - 11.0 ± 2.7 vs. - 14.0 ± 2.9%, P < 0.01). Principal strain within non-enhanced myocardium was significantly correlated with indexed LV mass (P < 0.0001), maximum (P = 0.0008), and mean wall thickness (P < 0.0001), but not LGE (P = 0.0841). In adjusted analysis, all strain measures within non-enhanced myocardium were independently associated with indexed LV mass (maximum principal: P = 0.0003; minimum principal: P = 0.0039; longitudinal: P = 0.0015; circumferential: P = 0.0002; radial: P = 0.0023). 3D principal strain of non-enhanced myocardium was significantly reduced in HCM patients as compared with controls, and was incrementally reduced among patients with more extensive global LGE. Comprehensive strain assessment may be considered in routine CMR assessment of HCM patients.

Quetiapine, an atypical antipsychotic, has been used for the treatment of several neuropsychiatric disorders. However, the underlying mechanism of the broad therapeutic range of quetiapine remains unknown. We previously reported that several aversive conditions affect dorsal/ventral hippocampal neurogenesis differentially. This study was aimed to elucidate the positive effects of chronic treatment with quetiapine on regional differences in hippocampal proliferation and immature neurons and behavioral changes under psychosocial stress using the Resident-Intruder paradigm. Twenty-three male Sprague-Dawley rats were intraperitoneally administered a vehicle or quetiapine (10 mg/kg) once daily for 28 days. Two weeks after starting the injections, animals were exposed to intermittent social defeat (four times over two weeks). The behavioral effects of stress and quetiapine were evaluated by the Novelty-Suppressed Feeding (NSF) test. The stereological quantification of hippocampal neurogenesis was estimated using immunostaining with Ki-67 and doublecortin (DCX). Chronic quetiapine treatment stimulated the Ki-67- and DCX-positive cells in the dorsal hippocampus, but not in the ventral subregion. The stress-induced changes in neurogenesis and hyponeophagic behavior were not reversed by repeated administration of quetiapine. Future study with additional behavioral tests is needed to elucidate the functional significance of the quetiapine-induced increase in dorsal hippocampal neurogenesis.

Cardiac amyloidosis (CA) is a significant contributor to heart failure with preserved ejection fraction and is appreciating expanding therapeutic options. Non-invasive tools aimed at accurate identification and surveillance of therapeutic response are of immediate and expanding need. While native and post-contrast T1 mapping quantify expansion of the extra-cellular compartment from amyloid protein deposition, 3D strain analysis of non-contrast cine images offers unique advantages relevant to high prevalence of renal insufficiency in this population and reduced dependency on field strength, pulse sequence, and vendor implementation. We aimed to evaluate global and segmental associations between 3D strain and T1 mapping in patients with cardiac amyloidosis. Twenty consecutive patients with confirmed CA were recruited and underwent a standardized cardiovascular magnetic resonance imaging protocol at 3 T including using multi-planar cine imaging and T1 mapping using a shortened modified look-locker inversion recovery sequence. T1 mapping was performed pre- and (when permitted by renal function) post-contrast and measured for segmental T1 values. Spatially-matched 3D strain-based measures were similarly calculated. Mean left ventricular ejection fraction was 61 ± 21% (range 30-73%). Mean global native T1 was 1308 ± 96 ms. Post-contrast T1 and partition coefficient were 558 ± 104 ms and 0.85 ± 0.31, respectively. Global myocardial strain values were 8.1 ± 2.9% in the longitudinal direction, - 9.2 ± 3.4% in the circumferential direction, and 41.7 ± 22.8% in the maximum principal direction. Segmental analyses confirmed relative worsening in T1 values and reductions in strain values in the basal myocardial segments with relative sparing of the apical segments. Significant associations between T1 and strain-based measures were observed globally and segmentally, with the strongest associations found both globally and segmentally in the circumferential and minimum principal directions of deformation. This study identifies strong associations between 3D myocardial strain and T1-mapping based markers of regional amyloid protein deposition. These findings support expanded investigation of myocardial strain as a surrogate marker of response to novel therapeutic strategies in patients with cardiac amyloidosis.

Inflammation that occurs following acute myocardial infarction plays a pivotal role in "healing" by facilitating the creation of a supportive scar. (18)F-FDG, which is taken up avidly by macrophages, has been proposed as a marker of cell-based inflammation. However, its reliability as an accurate indicator of inflammation has not been established, particularly in the early post infarction period when regional myocardial perfusion is often severely compromised. METHODS: Nine adult dogs underwent left anterior descending coronary occlusion with or without reperfusion. Animals were imaged between 7 to 21 days post infarction with Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) following: a) bolus injection of Gd-DTPA, b) bolus injection of (18)F-FDG, c) bolus injection of 99Tc-DTPA to simulate the distribution of Gd-DTPA (which represents its partition coefficient in well perfused tissue) and d) the injection of (111)Indium-labeled white blood cells 24 hours earlier. Following sacrifice, myocardial tissue concentrations of (18)F, (111)In and 99Tc were determined in a well counter. Linear regression analysis evaluated the relationships between a) the concentrations of (111)In vs (18)F and b) the dependence of the ratio of (111)In/(18)F to the apparent distribution volume of (99m)Tc-DTPA. RESULTS: In seven of the nine animals (111)In increased as (18)F increased with the other two animals showing weak negative slopes. With respect to the dependence of (111)In/(18)F with partition coefficient four animals showed no dependence and four showed a week positive slope with one animal showing a negative slope. Further, in regions of extensive microvascular obstruction, (18)F significantly underestimated the extent of the presence of (111)In. CONCLUSION: In the early post myocardial infarction period, PET (18)F-FDG imaging following a single bolus administration may underestimate the extent and degree of inflammation within regions of microvascular obstruction.

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder associated with elevated risk of lethal ventricular arrhythmias. While the absence of myocardial fibrosis on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) appears to identify lower risk individuals, approximately two

Objectives The goal of this study was to assess associations between left ventricular (LV) mass, all-cause mortality, and need for revascularization in patients undergoing coronary angiography. Background LV hypertrophy is associated with adverse cardiovascular outcomes in healthy subjects. However, its influence in those with known or suspected coronary artery disease is poorly understood. Methods A total of 3,754 patients (mean age 59.3 ± 13.1 years) undergoing invasive coronary angiography and cardiac magnetic resonance (CMR) (mean interval 1.0 ± 1.5 months) were studied. LV mass and volumes were determined from cine images and indexed to body surface area. Analyses were adjusted for CMR variables, medical comorbidities, and severity of coronary artery disease (Duke Jeopardy Score) and were stratified to LV function. Results At a median of 44.9 months, 315 patients (8.4%) died and 168 patients (4.5%) underwent revascularization. Multivariable analysis showed that each 10 g/m 2 increase in LV mass index was associated with a 6% greater risk of mortality (hazard ratio: 1.06; 95% confidence interval [CI]: 1.01 to 1.11; p = 0.02) and a 10% greater need for revascularization (hazard ratio: 1.10; 95% CI: 1.04 to 1.17; p 35% with respective hazard ratios of 2.93 (95% CI: 1.92 to 4.47) and 2.20 (95% CI: 1.21 to 3.98). Conclusions LV mass index is an independent predictor of all-cause mortality and need for revascularization. This finding establishes relevance for LV mass measurements in clinical decision-making surrounding both the need and timing of revascularization in this population.

Background— Left ventricular ejection fraction remains the primary risk stratification tool used in the selection of patients for implantable cardioverter defibrillator therapy. However, this solitary marker fails to identify a substantial portion of patients experiencing sudden cardiac arrest. In this study, we examined the incremental value of considering right ventricular ejection fraction for the prediction of future arrhythmic events in patients with systolic dysfunction using the gold standard of cardiovascular magnetic resonance. Methods and Results— Three hundred fourteen consecutive patients with ischemic cardiomyopathy or nonischemic dilated cardiomyopathy undergoing cardiovascular magnetic resonance were followed for the primary outcome of sudden cardiac arrest or appropriate implantable cardioverter defibrillator therapy. Blinded quantification of left ventricular and right ventricular (RV) volumes was performed from standard cine imaging. Quantification of fibrosis from late gadolinium enhancement imaging was incrementally performed. RV dysfunction was defined as right ventricular ejection fraction ≤45%. Among all patients (164 ischemic cardiomyopathy, 150 nonischemic dilated cardiomyopathy), the mean left ventricular ejection fraction was 32±12% (range, 6–54%) with mean right ventricular ejection fraction of 48±15% (range, 7–78%). At a median of 773 days, 49 patients (15.6%) experienced the primary outcome (9 sudden cardiac arrest, 40 appropriate implantable cardioverter defibrillator therapies). RV dysfunction was independently predictive of the primary outcome (hazard ratio=2.98; P =0.002). Among those with a left ventricular ejection fraction >35% (N=121; mean left ventricular ejection fraction, 45±6%), RV dysfunction provided an adjusted hazard ratio of 4.2 ( P =0.02). Conclusions— RV dysfunction is a strong, independent predictor of arrhythmic events. Among patients with mild to moderate LV dysfunction, a cohort greatly contributing to global sudden cardiac arrest burden, this marker provides robust discrimination of high- versus low-risk subjects.

Cardiac magnetic resonance (CMR) imaging is commonly used to diagnose acute myocarditis. However, the natural history of CMR-based tissue markers and their association with left ventricular (LV) recovery is poorly explored. We prospectively investigated the natural history of CMR-based myocardial

Background Postconditioning is a potential cardioprotective strategy that has demonstrated conflicting and variable reductions in infarct size in human trials. Objectives To determine whether postconditioning could increase the extent of myocardial salvage in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). Methods One hundred two patients (aged 57 ± 11 years; 88% male) were randomly assigned to a postconditioning or standard protocol. Cardiovascular magnetic resonance imaging was performed 3 days after PPCI to measure the volumetric extent of myocardial necrosis and the area at risk. Results With similar time-to-reperfusion (170 ± 84 minutes in the postconditioning group vs. 150 ± 70 minutes in the standard group, P = 0.22), the myocardial salvage index was not significantly different between the postconditioned group and the control group, averaging 42 ± 22% vs. 33 ± 21%, respectively (P = 0.08). Furthermore, postconditioning was not associated with a smaller infarct size compared to controls (13 ± 7 g/m2 vs. 15 ± 8 g/m2, respectively, P = 0.18). Conclusions Postconditioning does not significantly increase myocardial salvage or reduce infarct size in patients with STEMI undergoing PPCI. However, the possibility of a more modest impact of postconditioning cannot be excluded with our sample size. (J Interven Cardiol 2013;26:482-490)

Background Expert subjective reporting of mid-wall septal fibrosis on late gadolinium enhancement (LGE) images has been shown to predict major cardiovascular outcomes in patients with non-ischemic dilated cardiomyopathy (NIDCM). This study aims to establish objective criteria for non-experts to report clinically relevant septal fibrosis and compare its performance by such readers versus experts for the prediction of cardiovascular events. Methods LGE cardiovascular magnetic resonance (CMR) was performed in 118 consecutive patients with NIDCM (mean age 57 ± 14, 42 % female) and the presence of septal fibrosis scored by expert readers. CMR-naive readers performed signal threshold-based LGE quantification by referencing mean values of remote tissue and applying these to a pre-defined anatomic region to measure septal fibrosis. All patients were followed for the primary composite outcome of cardiac mortality or appropriate implantable cardioverter-defibrillator (ICD) therapy. Results The mean LVEF was 32 ± 12 %. At a median follow-up of 1.9 years, 20 patients (17 %) experienced a primary composite outcome. Expert visual scoring identified 55 patients with septal fibrosis. Non-expert septal fibrosis quantification was highly reproducible and identified mean septal fibrosis burden for three measured thresholds as follows; 5SD: 2.9 ± 3.6 %, 3SD: 6.9 ± 6.3 %, and 2SD: 11.1 ± 7.5 % of the left ventricular (LV) mass, respectively. By ROC analysis, optimal thresholds for prediction of the primary outcome were; 5SD: 2.74 % (HR 8.7, p 5SD threshold) was the strongest independent predictor of the primary outcome (HR 8.7) and provided improved risk reclassification beyond LVEF alone (NRI 0.54, 95 % CI 0.16–0.92, p = 0.005). Conclusions Novice readers were able to achieve superior risk prediction for future cardiovascular events versus experts using objective criteria for septal fibrosis in patients with NIDCM. Patients with a septal fibrosis burden >2.74 % of the LV mass (>5SD threshold) were at a 9-fold higher risk of cardiac death or appropriate ICD therapy versus those not meeting this criteria. As such, this study validates reproducible criteria applicable to all levels of expertise to identify NIDCM patients at high risk of future cardiovascular events.

Background The presence and transmurality of posterolateral scar within the left ventricle by late gadolinium enhancement (LGE) imaging has been shown to portend poor response to cardiac resynchronization therapy due to placement of the LV lead in this region. Unfortunately, the use of gadolinium is contraindicated in patients with significant renal dysfunction due to the risk of nephrogenic systemic fibrosis. Alternative measures of regional myocardial non-viability by 4D strain analysis may be highly useful for CRT evaluation in patients with heart failure and renal dysfunction.

Background Mid-wall striae pattern late gadolinium enhancement (LGE) has been shown to independently predict future outcomes in patients with dilated non-ischemic cardiomyopathy (NICM). Standardized quantification tools are of particular interest for clinical translation of this novel imaging marker. However, signal intensity (SI) based threshold techniques, such as Signal Threshold versus Reference Mean (STRM) and Full Width at Half Maximum (FWHM), have been inconsistently applied and their performance in this population is unknown. The purpose of this study was to compare the accuracy of semi-automated LGE quantification techniques against expert-prescribed threshold assignment in patients with NICM.

Background The burden and location of replacement fibrosis by Late Gadolinium Enhancement (LGE) MRI is a recognized predictor of non-response in patients undergoing cardiac resynchronization therapy (CRT). However, the capacity of the non-scarred tissue to respond favorably is felt to be dependent upon incremental factors. In this study we explored the utility of 4D strain analysis of non-scarred myocardial tissue to predict response to CRT.

In experimental animal models and human autopsy studies, hemorrhagic infarction caused by microvascular injury has been detected after coronary reperfusion. The purpose of this study was to determine whether detection of myocardial edema with T2-weighted MRI is influenced by the presence of microvascular obstruction.Thirty-seven patients underwent black-blood fat-suppressed T2-weighted, rest perfusion, and late gadolinium-enhanced MRI 5.4 +/- 3.1 days after the onset of acute myocardial infarction. On T2-weighted MR images, the signal intensity in relation to that of remote myocardium was determined in the late gadolinium-enhanced and periinfarction areas. Segment-based analysis was performed to determine whether the presence of microvascular obstruction influences the detection of myocardial edema.The averaged signal intensity in the late gadolinium-enhanced area without microvascular obstruction was significantly higher than the signal intensity in remote normal myocardium (relative signal intensity, 1.83 +/- 0.50; p0.001). In contrast, the signal intensity in the microvascular obstruction area on T2-weighted images was not significantly different from the signal intensity in remote myocardium (relative signal intensity, 1.14 +/- 0.26). The percentages of late gadolinium-enhanced segments with high signal intensity on T2-weighted MR images were 95% (73/77) without microvascular obstruction and 30% (22/73) with microvascular obstruction.With T2-weighted MRI, infarction-associated edema can be reliably detected in infarct lesions without microvascular obstruction. Microvascular obstruction, however, does not necessarily exhibit high signal intensity on T2-weighted MRI. Careful attention is required in interpretation of cardiac MR images of patients who have experienced acute myocardial infarction and undergone percutaneous coronary intervention. The findings on T2-weighted MR images can be substantial underestimates of the extent of acute myocardial infarction.

To evaluate the influence of the osmotic pressure of solutions used for reconstituting the ultrasound contrast agent "Levovist" on the degree of video intensity of the enhancement and video intensity decay in contrast echocardiogram, we used 6 solutions with different osmotic pressures in both vitro and in vivo experiments.In the in vitro experiments, Levovist was reconstituted with 6 kinds of solutions with different osmotic pressures (Lactate Ringer's solution, 2.5%, 5%, 7.5%, and 20% glucose and distilled water) and peak video intensities and video intensity decay were measured. In the in vivo experiments, contrast echocardiography was performed in 7 adult volunteers, following the intravenous injections of Levovist, previously reconstituted with one of 2 solutions (5% glucose or distilled water).In vitro, at peak time, Levovist reconstituted with either Lactate Ringer's solution, 2.5% glucose, 5% glucose, or distilled water had good peak video intensities. At 30 s after peak time, Levovist reconstituted with Lactate Ringer's solution had greater enhancement and less decay than the other 5 solutions (P0.001). In vivo, at 180 heart beats after peak time, the video intensity decay with 5% glucose was greater than that with distilled water (150+/-13 dB, 123+/-25 dB, respectively, P0.05).In this study, among various (2.5-20%) glucose solutions, the stability of the microbubbles differed, depending on the degree of osmotic pressure of the respective solutions; 5% glucose was the best. However, overall, the most suitable solution for reconstituting Levovist, was Lactate Ringer's solution. These findings could lead to effective strategies for better contrast echocardiography using Levovist by changing the current solution of choice to Lactate Ringer's solution or 5% glucose.

Purpose Chronic pulmonary arterial thromboembolism (CPATE) often causes right ventricular (RV) pressure overload but the relationship between the degrees of CPATE and RV pressure overload is not clear. To quantify the degrees of CPATE and RV pressure overload, we performed multislice computed tomography (CT) and Tissue Doppler Imaging (TDI) and compared the two modalities. Materials and methods Sixteen consecutive subjects (4 men, 12 women; age 27–72 with proven CPATE underwent CT. The right vascular obstruction index (VOI), the left VOI, and the total VOI (TVOI) were determined using the scoring system of Qanadli. The early systolic myocardial velocity (Sw) and diastole myocardial velocity (Ew) at the tricuspid annulus and the early diastolic tricuspid inflow ( E ) were obtained by TDI in the apical four chamber view; RV systolic pressure (RVSP) was estimated by pressure gradient of tricuspid valve regurgitation. E /Ew was calculated as the parameter of RV diastolic function. Results The right VOI was 23±10%, the left VOI was 18±10%, and TVOI was 41±14%. The means with ranges of Sw, Ew, E /Ew, RVSP, and brain natriuretic peptide (BNP) were 10.7 (range 7.7–14.6) cm/s, 7.7 (range 4.2–10.6) cm/s, 5.0 (range 2.2–8.1), 55 (range 26–90) mm Hg, and 50.3 (range 12.2–165) pg/ml, respectively. The correlation coefficients between Sw, Ew, E /Ew, RVSP, and BNP and either larger of right or left side (LVOI) and TVOI were 0.041, −0.163 (Sw vs. LVOI, TVOI), −0.153, −0.232 (Ew vs. LVOI, TVOI), 0.145, 0.241 ( E /Ew vs. LVOI, TVOI), 0.255, 0.401 (RVSP vs. LVOI, TVOI), and 0.192, 0.170 (BNP vs. LVOI, TVOI), respectively. The correlation coefficient between RVSP and BNP was 0.390. Conclusions TVOI was better correlated with RVSP ( R =0.401) than the other parameters (Sw, Ew, E /Ew, and BNP), and this was similar to the degree that BNP was correlated with RVSP ( R =0.390). TVOI can be a better indicator of RVSP than LVOI. CT VOI may be a useful parameter to assess CPATE morphologically.

Cardiac amyloidosis is generally a progressive disease with a poor prognosis, so early diagnosis and appropriate treatments are important. Although cardiac amyloidosis can be diagnosed definitively by endomyocardial biopsy, non-invasive methods of diagnosis are desired because of a great risk in biopsy. In ECG-gated enhanced multislice computed tomography, not only clear images of the cardiac morphology but also the character of myocardium indicating fibrosis can be identified. We demonstrate two patients with cardiac amyloidosis who showed marked thickening of left ventricular wall with partial fibrotic changes by enhanced multislice computed tomography.

Background CMR can be used to assess the structure and function of athletes’ hearts. However, diastolic function is not routinely measured with CMR. Mitral annular (MA) motion, commonly assessed by tissue Doppler imaging, is an important element of diastole that may help to distinguish physiological remodeling from pathological processes of the heart. CMR has been shown to play a useful role in evaluating MA motion. This study aims to characterize the global left ventricular diastolic function in endurance athletes by 3D volume tracking of the MA, using conventional cine-CMR images. Methods CMR studies of 24 high-level endurance athletes (age 22 ± 3) were retrospectively selected from a database. Routine CMR studies from 39 patients with normal hearts (age 42 ± 16) and 29 hypertrophic cardiomyopathy (HCM) patients (age 52 ± 17) with normal ejection fractions were included for comparison. Using normalized cross-correlation, feature-tracking of the atrioventricular junctions was performed over the cardiac cycle, in routine long-axis 2-, 3-, and 4-chamber cine-CMR views. This resulted in 6 spatial MA points per cardiac phase, which were interpolated with a spline for 3D MA reconstruction. The 3D volume swept out by the MA was then calculated; the net sweep volume at a given cardiac phase was derived from the sum of the incremental volumes starting from end-diastole.

Background An understanding of inflammation following myocardial infarction may be of importance in the development of novel therapeutics to limit the development of heart failure following myocardial injury. However, the quantification of inflammation in this setting continues to be challenging. Hybrid FDG PET/MR may offer a non-invasive in vivo solution through intrinsic registration of these complementary modalities. This study sought to validate its use in a canine model of myocardial infarction (MI).

We report a case of central diabetes insipidus, hypothyroidism, and subsequent hypopituitarism due to lymphocytic hypophysitis masking a germinoma in a 13-year-old pubertal girl. Magnetic resonance revealed an enlarged pituitary gland and a mass lesion in the pituitary stalk and inferior hypothalamus. Open cranial surgery of the anterior pituitary showed active hypophysitis with lymphocytic infiltrates but without necrosis. Despite prednisolone therapy, 1 year later an enlarged, irregular cystic mass lesion had developed; in the pituitary stalk and inferior hypothalamus, a endoscopic biopsy revealed germinoma. Lymphocytic hypophysitis in children may be the first sign of a host reaction to an occult germinoma. The diagnosis of central diabetes insipidus with a thickened pituitary stalk requires long-term follow-up to establish the underlying cause.