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Aims Electro-anatomical voltage, conduction velocity (CV) mapping, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) have been correlated with atrial cardiomyopathy (ACM). However, the comparability between these modalities remains unclear. This study aims to (i) compare pathological substrate extent and location between current modalities, (ii) establish spatial histograms in a cohort, (iii) develop a new estimated optimized image intensity threshold (EOIIT) for LGE-MRI identifying patients with ACM, (iv) predict rhythm outcome after pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF). Methods and results Thirty-six ablation-naive persistent AF patients underwent LGE-MRI and high-definition electro-anatomical mapping in sinus rhythm. Late gadolinium enhancement areas were classified using the UTAH, image intensity ratio (IIR >1.20), and new EOIIT method for comparison to low-voltage substrate (LVS) and slow conduction areas <0.2 m/s. Receiver operating characteristic analysis was used to determine LGE thresholds optimally matching LVS. Atrial cardiomyopathy was defined as LVS extent ≥5% of the left atrium (LA) surface at <0.5 mV. The degree and distribution of detected pathological substrate (percentage of individual LA surface are) varied significantly (P < 0.001) across the mapping modalities: 10% (interquartile range 0–14%) of the LA displayed LVS <0.5 mV vs. 7% (0–12%) slow conduction areas <0.2 m/s vs. 15% (8–23%) LGE with the UTAH method vs. 13% (2–23%) using IIR >1.20, with most discrepancies on the posterior LA. Optimized image intensity thresholds and each patient's mean blood pool intensity correlated linearly (R 2 = 0.89, P < 0.001). Concordance between LGE-MRI-based and LVS-based ACM diagnosis improved with the novel EOIIT applied at the anterior LA [83% sensitivity, 79% specificity, area under the curve (AUC): 0.89] in comparison to the UTAH method (67% sensitivity, 75% specificity, AUC: 0.81) and IIR >1.20 (75% sensitivity, 62% specificity, AUC: 0.67). Conclusion Discordances in detected pathological substrate exist between LVS, CV, and LGE-MRI in the LA, irrespective of the LGE detection method. The new EOIIT method improves concordance of LGE-MRI-based ACM diagnosis with LVS in ablation-naive AF patients but discrepancy remains particularly on the posterior wall. All methods may enable the prediction of rhythm outcomes after PVI in patients with persistent AF. [ABSTRACT FROM AUTHOR]

Introduction: Phrenic nerve (PN) injury is a rare but severe complication of radiofrequency (RF) pulmonary vein isolation (PVI). The objective of this study was to characterize the typical intracardiac course of the PN with a three‐dimensional electroanatomic mapping system, to quantify the need for modification of the ablation trajectory to avoid delivering an ablation lesion on sites with PN capture, and to identify very circumscribed areas of common PNC on the routine ablation trajectory of a RF‐PVI, allowing fast and effective PN screening for everyday usage. Methods: We enrolled 137 consecutive patients (63 ± 9 years, 64% men) undergoing PVI. A detailed high output (20 mA) pace‐mapping protocol was performed in the right (RA) and left atrium (LA) and adjacent vasculature. Results: The right PN was most commonly captured in the superior vena cava at a lateral (50%) or posterolateral (23%) position before descending along the RA either straight (29%) or with a posterolateral bend (20%). In the LA, beginning deep within the right superior pulmonary vein (RSPV), the right PN is most frequently detectable anterolateral (31%), then descends to the lateral proximal RSPV (23%), and further towards the lateral antral region (15%) onto the medial LA wall (12%). To avoid delivering an ablation lesion on sites with PN capture, modification of ablation trajectory was necessary in 23% of cases, most commonly in the lateral RSPV antrum (81%). No PN injury occurred. Conclusion: PN mapping frequently reveals the close proximity of the PN to the ablation trajectory during PVI, particularly in the lateral RSPV antrum. Routine PN pacing should be considered during RF PVI procedures. [ABSTRACT FROM AUTHOR]

Aims: Presence of arrhythmogenic left atrial (LA) low-voltage substrate (LVS) is associated with reduced arthythmia freedom rates following pulmonary vein isolation (PVI) in persistent atrial fibrillation (AF). We hypothesized that LA-LVS modifies amplified sinus-P-wave (APW) characteristics, enabling identification of patients at risk for arrhythmia recurrences following PVI.Methods and Results: Ninety-five patients with persistent AF underwent high-density (>1200 sites) voltage mapping in sinus rhythm. Left atrial low-voltage substrate (<0.5 and <1.0 mV) was quantified in a 10-segment LA model. Amplified sinus-P-wave-morphology and -duration were evaluated using digitized 12-lead electrocardiograms (40-80 mm/mV, 100-200 mm/s). 12-months arrhythmia freedom following circumferential PVI was assessed in 139 patients with persistent AF. Left atrial low-voltage substrate was most frequently (84%) found at the anteroseptal LA. Characteristic changes of APW were related to the localization and extent of LA-LVS. At an early stage, LA-LVS predominantly located to the LA-anteroseptum and was associated with APW-prolongation (≥150 ms). More extensive LA-LVS involved larger areas of LA-anteroseptum, leading to morphological changes of APW (biphasic positive-negative P-waves in inferior leads). Severe LA-LVS involved the LA-anteroseptum, roof and posterior LA, but spared the inferior LA, lateral LA, and LA appendage. In this advanced stage, widespread LVS at the posterior LA abolished the negative portion of P-wave in the inferior leads. The delayed activation of the lateral LA and LA appendage produced the late positive deflections in the anterolateral leads, resulting in the "late-terminal P"-pattern. Structured analysis of APW-duration and -morphology stratified patients to their individual extent of LA-LVS (Grade 1: mean LA-LVS 4.9 cm2 at <1.0 mV; Grade 2: 28.6 cm2; Grade 3: 42.3 cm2; P < 0.01). The diagnostic value of APW-duration for identification of LA-LVS was significantly superior to standard P-wave-amplification (c-statistic 0.945 vs. 0.647). Arrhythmia freedom following PVI differed significantly between APW-predicted grades of LA-LVS-severity [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.18-4.83; P = 0.015 for Grade 1 vs. Grade 2; HR 1.79, 95% CI 1.00-3.21, P = 0.049 for Grade 2 vs. Grade 3). Arrhythmia freedom 12 months after PVI was 77%, 53%, and 33% in Grades 1, 2 and 3, respectively.Conclusion: Localization and extent of LA-LVS modifies APW-morphology and -duration. Analysis of APW allows accurate prediction of LA-LVS and enables rapid and non-invasive estimation of arrhythmia freedom following PVI. [ABSTRACT FROM AUTHOR]

Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome. [ABSTRACT FROM AUTHOR]

Aims: Myocardial fibrosis critically contributes to cardiac dysfunction in inflammatory dilated cardiomyopathy (iDCM). Activation of transforming growth factor-b (TGF-b) signalling is a key-step in promoting tissue remodelling and fibrosis in iDCM. Downstream mechanisms controlling these processes, remain elusive. Methods and results: Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice with heart-specific antigen and adjuvant. Using heart-inflammatory precursors, as well as mouse and human cardiac fibroblasts, we demonstrated rapid secretion of Wnt proteins and activation of Wnt/b-catenin pathway in response to TGF-b signalling. Inactivation of extracellular Wnt with secreted Frizzled-related protein 2 (sFRP2) or inhibition of Wnt secretion with Wnt-C59 prevented TGF-b-mediated transformation of inflammatory precursors and cardiac fibroblasts into pathogenic myofibroblasts. Inhibition of T-cell factor (TCF)/β-catenin-mediated transcription with ICG-001 or genetic loss of β-catenin also prevented TGF-β-induced myofibroblasts formation. Furthermore, blocking of Smad-independent TGF-β-activated kinase 1 (TAK1) pathway completely abrogated TGF-β-induced Wnt secretion. Activation of Wnt pathway in the absence of TGF-b, however, failed to transform precursors into myofibroblasts. The critical role of Wnt axis for cardiac fibrosis in iDCM is also supported by elevated Wnt-1/Wnt-5a levels in human samples from hearts with myocarditis. Accordingly, and as an in vivo proof of principle, inhibition of Wnt secretion or TCF/β-catenin-mediated transcription abrogated the development of post-inflammatory fibrosis in EAM. Conclusion: We identified TAK1-mediated rapid Wnt protein secretion as a novel downstream key mechanism of TGF-β-mediated myofibroblast differentiation and myocardial fibrosis progression in human and mouse myocarditis. Thus, pharmacological targeting of Wnts might represent a promising therapeutic approach against iDCM in the future. [ABSTRACT FROM AUTHOR]