ABSTRACT
Three-dimensional (3D) reconstruction by means of electroanatomic mapping (EAM) systems, allows for the understanding of the mechanism of focal or re-entrant arrhythmic circuits, which can be identified by means of dynamic (activation and propagation) and static (voltage) color-coded maps. However, besides this conventional use, EAM may offer helpful anatomical and functional information for tissue characterisation in several clinical settings. Today, data regarding electromechanical myocardial viability, scar detection in ischaemic and nonischaemic cardiomyopathy and arrhythmogenic right ventricle dysplasia (ARVC/D) definition are mostly consolidated, while emerging results are becoming available in contexts such as Brugada syndrome and cardiac resynchronisation therapy (CRT) implant procedures. As part of an invasive procedure, EAM has not yet been widely adopted as a stand-alone tool in the diagnostic path. We aim to review the data in the current literature regarding the use of 3D EAM systems beyond the definition of arrhythmia.
Subject(s)
Cardiovascular Diseases/diagnosis , Electrophysiologic Techniques, Cardiac/methods , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Brugada Syndrome/diagnosis , Cardiac Resynchronization Therapy Devices , Cardiomyopathies/diagnosis , Cicatrix/diagnosis , Humans , Imaging, Three-Dimensional , Myocardium/pathologyABSTRACT
Three-dimensional (3D) reconstruction by means of electroanatomic mapping (EAM) systems, allows for the understanding of the mechanism of focal or re-entrant arrhythmic circuits along with pacing techniques. However, besides this conventional use, EAM may offer helpful anatomical and functional information. Data regarding electromechanical scar detection in ischaemic (and nonischaemic) cardiomyopathy are mostly consolidated, while emerging results are becoming available in contexts such as arrhythmogenic right ventricular dysplasia (ARVC/D) definition and Brugada syndrome. As part of an invasive procedure, EAM has not yet been widely adopted as a stand-alone tool in the diagnostic path. We aim to review the current literature regarding the use of 3D EAM systems for right ventricle (RV) functional characterisation beyond the definition of arrhythmia.
Subject(s)
Arrhythmogenic Right Ventricular Dysplasia , Heart Ventricles , Arrhythmias, Cardiac/diagnostic imaging , Arrhythmogenic Right Ventricular Dysplasia/diagnostic imaging , Heart Ventricles/diagnostic imaging , Humans , Imaging, Three-Dimensional , Predictive Value of Tests , SyndromeABSTRACT
AIMS: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. METHODS AND RESULTS: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT. CONCLUSIONS: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.
Subject(s)
Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/genetics , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/genetics , Transcriptome/genetics , Tumor Suppressor Protein p53/metabolism , Cluster Analysis , Cohort Studies , Collagen/metabolism , Female , Fibrosis , Gene Expression Regulation , Humans , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , Phenotype , Principal Component Analysis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
BACKGROUND: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood. OBJECTIVES: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. METHODS: A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF). RESULTS: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction. CONCLUSIONS: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
Subject(s)
Arrhythmias, Cardiac/genetics , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/genetics , Adult , Arrhythmias, Cardiac/mortality , Cross-Sectional Studies , Female , Genetic Variation , Humans , Male , Middle Aged , Phenotype , Prognosis , Risk Assessment , Risk FactorsABSTRACT
BACKGROUND: Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures. RESULTS: RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets. CONCLUSIONS: Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.
