Sex-based differences in the phenotypic expression and prognosis of idiopathic non-ischaemic cardiomyopathy: a cardiovascular magnetic resonance study.

AIMS: We sought to characterize sex-related differences in cardiovascular magnetic resonance-based cardiovascular phenotypes and prognosis in patients with idiopathic non-ischaemic cardiomyopathy (NICM). METHODS AND RESULTS: Patients with NICM enrolled in the Cardiovascular Imaging Registry of Calgary (CIROC) between 2015 and 2021 were identified. Z-score values for chamber volumes and function were calculated as standard deviation from mean values of 157 sex-matched healthy volunteers, ensuring reported differences were independent of known sex-dependencies. Patients were followed for the composite outcome of all-cause mortality, heart failure admission, or ventricular arrhythmia. A total of 747 patients were studied, 531 (71%) males. By Z-score values, females showed significantly higher left ventricular (LV) ejection fraction (EF; median difference 1 SD) and right ventricular (RV) EF (difference 0.6 SD) with greater LV mass (difference 2.1 SD; P < 0.01 for all) vs. males despite similar chamber volumes. Females had a significantly lower prevalence of mid-wall striae (MWS) fibrosis (22% vs. 34%; P < 0.001). Over a median follow-up of 4.7 years, 173 patients (23%) developed the composite outcome, with equal distribution in males and females. LV EF and MWS were significant independent predictors of the outcome (respective HR [95% CI] 0.97 [0.95-0.99] and 1.6 [1.2-2.3]; P = 0.003 and 0.005). There was no association of sex with the outcome. CONCLUSION: In a large contemporary cohort, NICM was uniquely expressed in females vs. males. Despite similar chamber dilation, females demonstrated greater concentric remodelling, lower reductions in bi-ventricular function, and a lower burden of replacement fibrosis. Overall, their prognosis remained similar to male patients with NICM.

Prognostic Utility of Cardiovascular Magnetic Resonance-Based Phenotyping in Patients With Muscular Dystrophy.

Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively investigated in adult patients with muscular dystrophy. Methods and Results We prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb-girdle muscular dystrophy, and type 1 myotonic dystrophy (median age, 36.0 [interquartile range, 23.0-50.0] years; 51 [34.5%] women) over 7.7 years in addition to an age- and sex-matched healthy control cohort (n=50). Cardiovascular magnetic resonance markers, including 3-dimensional strain and fibrosis, were assessed for their respective association with major adverse cardiac events. Our results showed that markers of contractile performance were reduced across all muscular dystrophy groups. In particular, the dystrophinopathies cohort experienced reduced left ventricular (LV) ejection fraction and high burden of replacement fibrosis. Patients with type 1 myotonic dystrophy showed a 26.8% relative reduction in LV mass with corresponding reduction in chamber volumes. Eighty-two major adverse cardiac events occurred over a median follow-up of 5.2 years. Although LV ejection fraction was significantly associated with major adverse cardiac events (adjusted hazard ratio [aHR], 3.0 [95% CI, 1.4-6.4]) after adjusting for covariates, peak 3-dimensional strain amplitude demonstrated greater predictive value (minimum principal amplitude: aHR, 5.5 [95% CI, 2.5-11.9]; maximum principal amplitude: aHR, 3.3 [95% CI, 1.6-6.8]; circumferential amplitude: aHR, 3.4 [95% CI, 1.6-7.2]; longitudinal amplitude: aHR, 3.4 [95% CI, 1.7-6.9]; and radial strain amplitude: aHR, 3.0 [95% CI, 1.4-6.1]). Minimum principal strain yielded incremental prognostic value beyond LV ejection fraction for association with major adverse cardiac events (change in χ2=13.8; P<0.001). Conclusions Cardiac dysfunction is observed across all muscular dystrophy subtypes; however, the subtypes demonstrate distinct phenotypic profiles. Myocardial deformation analysis highlights unique markers of principal strain that improve risk assessment over other strain markers, LV ejection fraction, and late gadolinium enhancement in this vulnerable patient population.

Normative healthy reference values for global and segmental 3D principal and geometry dependent strain from cine cardiac magnetic resonance imaging.

3-Dimensional (3D) myocardial deformation analysis (3D-MDA) enables novel descriptions of geometry-independent principal strain (PS). Applied to routine 2D cine cardiovascular magnetic resonance (CMR), this provides unique measures of myocardial biomechanics for disease diagnosis and prognostication. However, healthy reference values remain undefined. This study describes age- and sex-stratified reference values from CMR-based 3D-MDA, including 3D PS. One hundred healthy volunteers were prospectively recruited following institutional ethics approval and underwent CMR imaging. 3D-MDA was performed using validated software. Age- and sex-stratified global and segmental strain measures were derived for conventional geometry-dependent [circumferential (CS), longitudinal (LS), and radial (RS)] and geometry-independent [minimum (minPS) and maximum principal (maxPS)] directions of deformation. Layer-specific contraction angle interactions were determined using local minPS vectors. The average age was 43 ± 15 years and 55% were women. Strain measures were higher in women versus men. 3D PS-based assessment of maximum tissue shortening (minPS) and maximum tissue thickening (maxPS) were greater than corresponding geometry-dependent markers of LS and RS, consistent with improved representation of local tissue deformations. Global maxPS amplitude best discriminated both age and sex. Segmental analyses showed greater strain amplitudes in apical segments. Transmural PS contraction angles were higher in females and showed a heterogeneous distribution across segments. In this study we provided age and sex-based reference values for 3D strain from CMR imaging, demonstrating improved capacity for 3D PS to document maximal local tissue deformations and to discriminate age and sex phenotypes. Novel markers of layer-specific strain angles from 3D PS were also described.

Machine learning prediction of atrial fibrillation in cardiovascular patients using cardiac magnetic resonance and electronic health information.

Background: Atrial fibrillation (AF) is a commonly encountered cardiac arrhythmia associated with morbidity and substantial healthcare costs. While patients with cardiovascular disease experience the greatest risk of new-onset AF, no risk model has been developed to predict AF occurrence in this population. We hypothesized that a patient-specific model could be delivered using cardiovascular magnetic resonance (CMR) disease phenotyping, contextual patient health information, and machine learning. Methods: Nine thousand four hundred forty-eight patients referred for CMR imaging were enrolled and followed over a 5-year period. Seven thousand, six hundred thirty-nine had no prior history of AF and were eligible to train and validate machine learning algorithms. Random survival forests (RSFs) were used to predict new-onset AF and compared to Cox proportional-hazard (CPH) models. The best performing features were identified from 115 variables sourced from three data domains: (i) CMR-based disease phenotype, (ii) patient health questionnaire, and (iii) electronic health records. We evaluated discriminative performance of optimized models using C-index and time-dependent AUC (tAUC). Results: A RSF-based model of 20 variables (CIROC-AF-20) delivered an overall C-index of 0.78 for the prediction of new-onset AF with respective tAUCs of 0.80, 0.79, and 0.78 at 1-, 2- and 3-years. This outperformed a novel CPH-based model and historic AF risk scores. At 1-year of follow-up, validation cohort patients classified as high-risk of future AF by CIROC-AF-20 went on to experience a 17.3% incidence of new-onset AF, being 24.7-fold higher risk than low risk patients. Conclusions: Using phenotypic data available at time of CMR imaging we developed and validated the first described risk model for the prediction of new-onset AF in patients with cardiovascular disease. Complementary value was provided by variables from patient-reported measures of health and the electronic health record, illustrating the value of multi-domain phenotypic data for the prediction of AF.

Influence of Sex-Based Differences in Cardiac Phenotype on Atrial Fibrillation Recurrence in Patients Undergoing Pulmonary Vein Isolation.

Background: Pulmonary vein isolation (PVI) is a commonly engaged therapy for symptomatic atrial fibrillation (AF). Prior studies have documented elevated AF recurrence rates among females vs. males. Sex-specific mechanisms underlying this phenomenon are poorly understood. This prospective cohort study aimed to evaluate the sex-based differences in cardiac phenotype and their influence on (AF) recurrence following first-time PVI. Methods: A total of 204 consecutive patients referred for first-time PVI and 101 healthy subjects were prospectively studied by cardiovascular magnetic resonance (CMR) imaging. Multi-chamber volumetric and functional measures were assessed by sex-corrected Z-score analyses vs. healthy subjects. Patients were followed for a median of 2.6 years for the primary outcome of clinical AF recurrence. Multivariable analyses adjusting for age and comorbidities were performed to identify independent predictors of AF recurrence. Results: AF recurrence following first PVI occurred in 41% of males and 59% of females (p = 0.03). Females were older with higher prevalence of hypertension and thyroid disorders. Z-score-based analyses revealed significantly reduced ventricular volumes, greater left atrial (LA) volumes, and reduced LA contractility in females vs. males. Multivariable analysis revealed each of LA minimum and pre-systolic volumes and booster EF Z-scores to be independently associated with AF recurrence, providing respective hazard ratios of 1.10, 1.19, and 0.89 (p = 0.001, 0.03, and 0.01). Conclusion: Among patients referred for first time PVI, females were older and demonstrated significantly poorer LA contractile health vs. males, the latter independently associated with AF recurrence. Assessment of LA contractile health may therefore be of value to identify female patients at elevated risk of AF recurrence. Factors influencing female patient referral for PVI at more advanced stages of atrial disease warrant focused investigation.

Natural History of Myocardial Injury After COVID-19 Vaccine-Associated Myocarditis.

BACKGROUND: Acute myocarditis is a rare complication of mRNA-based COVID-19 vaccination. Little is known about the natural history of this complication. METHODS: Baseline and convalescent (≥ 90 days) cardiac magnetic resonance (CMR) imaging assessments were performed in 20 consecutive patients meeting Updated Lake Louise Criteria for acute myocarditis within 10 days of mRNA-based vaccination. CMR-based changes in left ventricular volumes, mass, ejection fraction (LVEF), markers of tissue inflammation (native T1 and T2 mapping), and fibrosis (late gadolinium enhancement [LGE] and extracellular volume [ECV]) were assessed between baseline and convalescence. Cardiac symptoms and clinical outcomes were captured. RESULTS: Median age was 23.1 years (range 18-39 years), and 17 (85%) were male. Convalescent evaluations were performed at a median (IQR) 3.7 (3.3-6.2) months. The LVEF showed a mean 3% absolute improvement, accompanied by a 7% reduction in LV end-diastolic volume and 5% reduction in LV mass (all P < 0.015). Global LGE burden was reduced by 66% (P < 0.001). Absolute reductions in global T2, native T1, and ECV of 2.1 ms, 58 ms, and 2.9%, repectively, were documented (all P ≤ 0.001). Of 5 patients demonstrating LVEF ≤ 50% at baseline, all recovered to above this threshold in convalescence. A total of 18 (90%) patients showed persistence of abnormal LGE although mean fibrosis burden was < 5% of LV mass in 85% of cases. No patient experienced major clinical outcomes. CONCLUSIONS: COVID-19 mRNA vaccine-associated myocarditis showed rapid improvements in CMR-based markers of edema, contractile function, and global LGE burden beyond 3 months of recovery in this young patient cohort. However, regional fibrosis following edema resolution was commonly observed, justifying need for ongoing surveillance.

Machine Learning Patient-Specific Prediction of Heart Failure Hospitalization Using Cardiac MRI-Based Phenotype and Electronic Health Information.

Background: Heart failure (HF) hospitalization is a dominant contributor of morbidity and healthcare expenditures in patients with systolic HF. Cardiovascular magnetic resonance (CMR) imaging is increasingly employed for the evaluation of HF given capacity to provide highly reproducible phenotypic markers of disease. The combined value of CMR phenotypic markers and patient health information to deliver predictions of future HF events has not been explored. We sought to develop and validate a novel risk model for the patient-specific prediction of time to HF hospitalization using routinely reported CMR variables, patient-reported health status, and electronic health information. Methods: Standardized data capture was performed for 1,775 consecutive patients with chronic systolic HF referred for CMR imaging. Patient demographics, symptoms, Health-related Quality of Life, pharmacy, and routinely reported CMR features were provided to both machine learning (ML) and competing risk Fine-Gray-based models (FGM) for the prediction of time to HF hospitalization. Results: The mean age was 59 years with a mean LVEF of 36 ± 11%. The population was evenly distributed between ischemic (52%) and idiopathic non-ischemic cardiomyopathy (48%). Over a median follow-up of 2.79 years (IQR: 1.59-4.04) 333 patients (19%) experienced HF related hospitalization. Both ML and competing risk FGM based models achieved robust performance for the prediction of time to HF hospitalization. Respective 90-day, 1 and 2-year AUC values were 0.87, 0.83, and 0.80 for the ML model, and 0.89, 0.84, and 0.80 for the competing risk FGM-based model in a holdout validation cohort. Patients classified as high-risk by the ML model experienced a 34-fold higher occurrence of HF hospitalization at 90 days vs. the low-risk group. Conclusion: In this study we demonstrated capacity for routinely reported CMR phenotypic markers and patient health information to be combined for the delivery of patient-specific predictions of time to HF hospitalization. This work supports an evolving migration toward multi-domain data collection for the delivery of personalized risk prediction at time of diagnostic imaging.

Mid-wall striae fibrosis predicts heart failure admission, composite heart failure events, and life-threatening arrhythmias in dilated cardiomyopathy.

Heart failure (HF) admission is a dominant contributor to morbidity and healthcare costs in dilated cardiomyopathy (DCM). Mid-wall striae (MWS) fibrosis by late gadolinium enhancement (LGE) imaging has been associated with elevated arrhythmia risk. However, its capacity to predict HF-specific outcomes is poorly defined. We investigated its role to predict HF admission and relevant secondary outcomes in a large cohort of DCM patients. 719 patients referred for LGE MRI assessment of DCM were enrolled and followed for clinical events. Standardized image analyses and interpretations were conducted inclusive of coding the presence and patterns of fibrosis observed by LGE imaging. The primary clinical outcome was hospital admission for decompensated HF. Secondary heart failure and arrhythmic composite endpoints were also studied. Median age was 57 (IQR 47-65) years and median LVEF 40% (IQR 29-47%). Any fibrosis was observed in 228 patients (32%) with MWS fibrosis pattern present in 178 (25%). At a median follow up of 1044 days, 104 (15%) patients experienced the primary outcome, and 127 (18%) the secondary outcome. MWS was associated with a 2.14-fold risk of the primary outcome, 2.15-fold risk of the secondary HF outcome, and 2.23-fold risk of the secondary arrhythmic outcome. Multivariable analysis adjusting for all relevant covariates, inclusive of LVEF, showed patients with MWS fibrosis to experience a 1.65-fold increased risk (95% CI 1.11-2.47) of HF admission and 1-year event rate of 12% versus 7% without this phenotypic marker. Similar findings were observed for the secondary outcomes. Patients with LVEF > 35% plus MWS fibrosis experienced similar event rates to those with LVEF ≤ 35%. MWS fibrosis is a powerful and independent predictor of clinical outcomes in patients with DCM, identifying patients with LVEF > 35% who experience similar event rates to those with LVEF below this conventionally employed high-risk phenotype threshold.

Improved accuracy and precision with three-parameter simultaneous myocardial T1 and T2 mapping using multiparametric SASHA.

PURPOSE: To develop and validate a three-parameter model for improved precision multiparametric SAturation-recovery single-SHot Acquisition (mSASHA) cardiac T1 and T2 mapping with high accuracy in a single breath-hold. METHODS: The mSASHA acquisition consists of nine images of variable saturation recovery and T2 preparation in 11 heartbeats with T1 and T2 values calculated using a three-parameter model. It was validated in simulations and phantoms at 3 T with comparison to a four-parameter joint T1 -T2 technique. The mSASHA acquisition was compared with MOLLI, SASHA, and T2 -prepared balanced SSFP in 10 volunteers. RESULTS: The mSASHA technique had high accuracy in phantoms compared to spin echo, with -0.2 ± 0.3% T1 error and -2.4 ± 1.3% T2 error. The mSASHA coefficient of variation in phantoms for T1 was similar to MOLLI (0.7 ± 0.2% for both) and T2 -prepared balanced SSFP for T2 (1.3 ± 0.7% vs 1.4 ± 0.3%, adjusted p > .05 for both). In simulations, three-parameter mSASHA had higher precision than four-parameter joint T1 -T2 for both T1 and T2 (46% and 11% reductions in T1 and T2 interquartile range for native myocardium). In vivo myocardial mSASHA T1 was similar to SASHA (1523 ± 18 ms vs 1520 ± 18 ms) with similar coefficient of variation to both MOLLI and SASHA (3.3 ± 0.6% vs 3.1 ± 0.6% and 3.3 ± 0.5% respectively, adjusted p > .05 for all). Myocardial mSASHA T2 was 37.1 ± 1.1 ms with similar precision to T2 -prepared balanced SSFP (6.7 ± 1.7% vs 6.0 ± 1.6%, adjusted p > .05). CONCLUSION: Three-parameter mSASHA provides high-accuracy cardiac T1 and T2 quantification in a single breath-hold with similar precision to MOLLI and T2 -prepared balanced SSFP. Further study is required to both establish normative values and demonstrate clinical utility in patient populations.

Right ventricular insertion site fibrosis in a dilated cardiomyopathy referral population: phenotypic associations and value for the prediction of heart failure admission or death.

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 < 0.01), RV end-systolic volume index (56 ± 26 vs. 45 ± 17 ml/m2, p < 0.01)], lower bi-ventricular function [LVEF 35 ± 12 vs. 39 ± 10% (p < 0.01), RV ejection fraction (RVEF) 43 ± 12 vs. 48 ± 10% (p < 0.01)], and higher extracellular volume (ECV). Patient with solitary RVI site fibrosis experienced a non-significant 1.4-fold risk of the primary outcome, increasing to a significant 2.6-fold risk when accompanied by MWS fibrosis. 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.

Effect of Active Cancer on the Cardiac Phenotype: A Cardiac Magnetic Resonance Imaging-Based Study of Myocardial Tissue Health and Deformation in Patients With Chemotherapy-Naïve Cancer.

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.

Right Ventricular Ejection Fraction for the Prediction of Major Adverse Cardiovascular and Heart Failure-Related Events: A Cardiac MRI Based Study of 7131 Patients With Known or Suspected Cardiovascular Disease.

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<0.001) and 1.5-fold increased risk of the secondary outcome (P<0.001). RVEF was an independent predictor following comprehensive covariate adjustment, inclusive of LV ejection fraction. Patients with an RVEF<40% experienced a 3.1-fold risk of the primary outcome (P<0.001) with a 1-year cumulative event rate of 22% versus 7% above this cutoff. 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.

Neural-Network-Based Diagnosis Using 3-Dimensional Myocardial Architecture and Deformation: Demonstration for the Differentiation of Hypertrophic Cardiomyopathy.

The diagnosis of cardiomyopathy states may benefit from machine-learning (ML) based approaches, particularly to distinguish those states with similar phenotypic characteristics. Three-dimensional myocardial deformation analysis (3D-MDA) has been validated to provide standardized descriptors of myocardial architecture and deformation, and may therefore offer appropriate features for the training of ML-based diagnostic tools. We aimed to assess the feasibility of automated disease diagnosis using a neural network trained using 3D-MDA to discriminate hypertrophic cardiomyopathy (HCM) from its mimic states: cardiac amyloidosis (CA), Anderson-Fabry disease (AFD), and hypertensive cardiomyopathy (HTNcm). 3D-MDA data from 163 patients (mean age 53.1 ± 14.8 years; 68 females) with left ventricular hypertrophy (LVH) of known etiology was provided. Source imaging data was from cardiac magnetic resonance (CMR). Clinical diagnoses were as follows: 85 HCM, 30 HTNcm, 30 AFD, and 18 CA. A fully-connected-layer feed-forward neural was trained to distinguish HCM vs. other mimic states. Diagnostic performance was compared to threshold-based assessments of volumetric and strain-based CMR markers, in addition to baseline clinical patient characteristics. Threshold-based measures provided modest performance, the greatest area under the curve (AUC) being 0.70. Global strain parameters exhibited reduced performance, with AUC under 0.64. A neural network trained exclusively from 3D-MDA data achieved an AUC of 0.94 (sensitivity 0.92, specificity 0.90) when performing the same task. This study demonstrates that ML-based diagnosis of cardiomyopathy states performed exclusively from 3D-MDA is feasible and can distinguish HCM from mimic disease states. These findings suggest strong potential for computer-assisted diagnosis in clinical practice.

Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury.

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.

Prognostic Value of Late Gadolinium Enhancement for the Prediction of Cardiovascular Outcomes in Dilated Cardiomyopathy: An International, Multi-Institutional Study of the MINICOR Group.

BACKGROUND: Dilated cardiomyopathy is associated with increased risk of major cardiovascular events. Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging is a unique tissue-based marker that, in single-center studies, suggests strong prognostic value. We retrospectively studied associations between LGE presence and adverse cardiovascular events in patients with dilated cardiomyopathy in a multicenter setting as part of an emerging global consortium (MINICOR [Multi-Modal International Cardiovascular Outcomes Registry]). METHODS: Consecutive patients with dilated cardiomyopathy referred for cardiac magnetic resonance (2000-2017) at 12 institutions in 4 countries were studied. Using multivariable Cox proportional hazard and semiparametric Fine and Gray models, we evaluated the association between LGE and the composite primary end point of all-cause mortality, heart transplantation, or left ventricular assist device implant and a secondary arrhythmic end point of sudden cardiac death or appropriate implantable cardioverter-defibrillator shock. RESULTS: We studied 1672 patients, mean age 56±14 years (29% female), left ventricular ejection fraction 33±11%, and 25% having New York Heart Association class III to IV; 650 patients (39%) had LGE. During 2.3 years (interquartile range, 1.0-4.3) follow-up, 160 patients experienced the primary end point, and 88 experienced the arrhythmic end point. In multivariable analyses, LGE was associated with 1.5-fold (hazard ratio, 1.45 [95% CI, 1.03-2.04]) risk of the primary end point and 1.8-fold (hazard ratio, 1.82 [95% CI, 1.20-3.06]) risk of the arrhythmic end point. Primary end point risk was increased in patients with multiple LGE patterns, although arrhythmic risk was higher among patients receiving primary prevention implantable cardioverter-defibrillator and widening QRS. CONCLUSIONS: In this large multinational study of patients with dilated cardiomyopathy, the presence of LGE showed strong prognostic value for identification of high-risk patients. Randomized controlled trials evaluating LGE-based care management strategies are warranted.

Hyperventilation-induced heart rate response as a potential marker for cardiovascular disease.

An increase of heart rate to physical or mental stress reflects the ability of the autonomous nervous system and the heart to respond adequately. Hyperventilation is a user-controlled breathing maneuver that has a significant impact on coronary function and hemodynamics. Thus, we aimed to investigate if the heart rate response to hyperventilation (HRRHV) can provide clinically useful information. A pooled analysis of the HRRHV after 60 s of hyperventilation was conducted in 282 participants including healthy controls; patients with heart failure (HF); coronary artery disease (CAD); a combination of both; or patients suspected of CAD but with a normal angiogram. Hyperventilation significantly increased heart rate in all groups, although healthy controls aged 55 years and older (15 ± 9 bpm) had a larger HRRHV than each of the disease groups (HF: 6 ± 6, CAD: 8 ± 8, CAD+/HF+: 6 ± 4, and CAD-/HF-: 8 ± 6 bpm, p < 0.001). No significant differences were found between disease groups. The HRRHV may serve as an easily measurable additional marker of cardiovascular health. Future studies should test its diagnostic potential as a simple, inexpensive pre-screening test to improve patient selection for other diagnostic exams.

Natural History of Myocardial Injury and Chamber Remodeling in Acute Myocarditis.

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.

Cardiovascular risk is associated with a transmural gradient of myocardial oxygenation during adenosine infusion.

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.

3D myocardial deformation analysis from cine MRI as a marker of amyloid protein burden in cardiac amyloidosis: validation versus T1 mapping.

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.

Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery.

BACKGROUND: Infarcted myocardium can remodel after successful reperfusion, resulting in left ventricular dilation and heart failure. Epicardial infarct repair (EIR) using a bioinductive extracellular matrix (ECM) biomaterial is a novel surgical approach to promote endogenous myocardial repair and functional recovery after myocardial infarction. Using a pre-clinical porcine model of coronary ischemia-reperfusion, we assessed the effects of EIR on regional functional recovery, safety, and possible mechanisms of benefit. METHODS: An ECM biomaterial (CorMatrix ECM) was applied to the epicardium after 75 minutes of coronary ischemia in a porcine model. Following ischemia-reperfusion injury, animals were randomly assigned in 2:1 fashion to EIR (n = 8) or sham treatment (n = 4). Serial cardiac magnetic resonance imaging was performed on normal (n = 4) and study animals at baseline (1 week) and 6 weeks after treatment. Myocardial function and tissue characteristics were assessed. RESULTS: Functional myocardial recovery was significantly increased by EIR compared with sham treatment (change in regional myocardial contraction at 6 weeks, 28.6 ± 14.0% vs 4.2 ± 13.5% wall thickening, p < 0.05). Animals receiving EIR had reduced adhesions compared with animals receiving sham treatment (1.44 ± 0.51 vs 3.08 ± 0.89, p < 0.05). Myocardial fibrosis was not increased, and EIR did not cause myocardial constriction, as left ventricular compliance by passive pressure distention at matched volumes was similar between groups (13.9 ± 4.0 mm Hg in EIR group vs 16.0 ± 5.2 mm Hg in sham group, p = 0.61). Animals receiving EIR showed evidence of vasculogenesis in the region of functional recovery. CONCLUSIONS: In addition to the beneficial effects of successful reperfusion, EIR using a bioinductive ECM enhances myocardial repair and functional recovery. Clinical translation of EIR early after myocardial infarction as an adjunct to surgical revascularization may be warranted in the future.