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Background: Previous studies of mechanical strain anomalies in myocardial infarction (MI) have been largely limited to analysis of one-dimensional (1D) and two-dimensional (2D) strain parameters. Advances in cardiovascular magnetic resonance (CMR) methods now permit a complete three-dimensional (3D) interrogation of myocardial regional strain. The aim of this study was to investigate the incremental value of CMR-based 3D strain and to test the hypothesis that 3D strain is superior to 1D or 2D strain analysis in the assessment of viability using a porcine model of infarction. Methods: Infarction was induced surgically in 20 farm pigs. Cine, late gadolinium enhancement, and CMR tagging images were acquired at 11 days before (baseline), and 11 days (early) and 1 month (late) after induction of infarct. Harmonic phase analysis was performed to measure circumferential, longitudinal, and radial strains in myocardial segments, which were defined based on the transmurality of delayed enhancement. Univariate, bivariate, and multivariate logistic regression models of strain parameters were created and analyzed to compare the overall diagnostic accuracy of 3D strain analysis with 1D and 2D analyses in identifying the infarct and its adjacent regions from healthy myocardium. Results: 3D strain differed significantly in infarct, adjacent, and remote segments (p < 0.05) at early and late post-MI. In univariate, bivariate, and multivariate analyses, circumferential, longitudinal, and radial strains were significant factors (p < 0.001) in differentiation of infarct and adjacent segments from baseline values. In identification of adjacent segments, receiver operating characteristic analysis using the 3D strain multivariate model demonstrated a significant improvement (p < 0.01) in overall diagnostic accuracy in comparison with 2D (circumferential and radial) and 1D (circumferential) models (3D: 96%, 2D: 81%, and 1D: 71%). A similar trend was observed in identification of infarct segments. Conclusions: Cumulative 3D strain information accurately identifies infarcts and their neighboring regions from healthy myocardium. The 3D interrogation of myocardial contractility provides incremental diagnostic accuracy in delineating the dysfunctional and nonviable myocardium in comparison with 1D or 2D quantification of strain. The infarct neighboring regions are the major beneficiaries of the 3D assessment of regional strain. [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes that increase myocyte energy demand and lead to cardiac hypertrophy. However, it is unknown whether a common metabolic trait underlies cardiac phenotype at the early disease stage. To address this question and define cardiac biochemical pathology in early-stage HCM, we studied two HCM mouse models that express pathogenic variants in cardiac troponin T ( Tnt2 ) or myosin heavy chain ( Myh6 ) genes, and have marked differences in cardiac imaging phenotype, mitochondrial function at early disease stage., Methods: We used a combination of echocardiography, transcriptomics, mass spectrometry-based untargeted metabolomics (GC-TOF, HILIC, CSH-QTOF), and computational modeling (CardioNet) to examine cardiac structural and metabolic remodeling at early disease stage (5 weeks of age) in R92W-TnT +/- and R403Q-MyHC +/- mutant mice. Data from mutants was compared with respective littermate controls (WT)., Results: Allele-specific differences in cardiac phenotype, gene expression and metabolites were observed at early disease stage. LV diastolic dysfunction was prominent in TnT mutants. Differentially-expressed genes in TnT mutant hearts were predominantly enriched in the Krebs cycle, respiratory electron transport, and branched-chain amino acid metabolism, whereas MyHC mutants were enriched in mitochondrial biogenesis, calcium homeostasis, and liver-X-receptor signaling. Both mutant hearts demonstrated significant alterations in levels of purine nucleosides, trisaccharides, dicarboxylic acids, acylcarnitines, phosphatidylethanolamines, phosphatidylinositols, ceramides and triglycerides; 40.4 % of lipids and 24.7 % of metabolites were significantly different in TnT mutants, whereas 10.4 % of lipids and 5.8 % of metabolites were significantly different in MyHC mutants. Both mutant hearts had a lower abundance of unsaturated long-chain acyl-carnitines (18:1, 18:2, 20:1), but only TnT mutants showed enrichment of FA18:0 in ceramide and cardiolipin species. CardioNet predicted impaired energy substrate metabolism and greater phospholipid remodeling in TnT mutants than in MyHC mutants., Conclusions: Our systems biology approach revealed marked differences in metabolic remodeling in R92W-TnT and R403Q-MyHC mutant hearts, with TnT mutants showing greater derangements than MyHC mutants, at early disease stage. Changes in cardiolipin composition in TnT mutants could contribute to impairment of energy metabolism and diastolic dysfunction observed in this study, and predispose to energetic stress, ventricular arrhythmias under high workloads such as exercise., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Hypertrophic cardiomyopathy (HCM) is associated with phenotypic variability. To gain insights into transcriptional regulation of cardiac phenotype, single-nucleus linked RNA-/ATAC-seq was performed in 5-week-old control mouse-hearts (WT) and two HCM-models (R92W-TnT, R403Q-MyHC) that exhibit differences in heart size/function and fibrosis; mutant data was compared to WT. Analysis of 23,304 nuclei from mutant hearts, and 17,669 nuclei from WT, revealed similar dysregulation of gene expression, activation of AP-1 TFs (FOS, JUN) and the SWI/SNF complex in both mutant ventricular-myocytes. In contrast, marked differences were observed between mutants, for gene expression/TF enrichment, in fibroblasts, macrophages, endothelial cells. Cellchat predicted activation of pro-hypertrophic IGF-signaling in both mutant ventricular-myocytes, and profibrotic TGFβ-signaling only in mutant-TnT fibroblasts. In summary, our bioinformatics analyses suggest that activation of IGF-signaling, AP-1 TFs and the SWI/SNF chromatin remodeler complex promotes myocyte hypertrophy in early-stage HCM. Selective activation of TGFβ-signaling in mutant-TnT fibroblasts contributes to genotype-specific differences in cardiac fibrosis., Competing Interests: Competing Interests statement The authors declare no competing interests.