Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart.

RATIONALE: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. OBJECTIVES: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms. METHODS AND RESULTS: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFß1 (transforming growth factor ß1), interleukin-1, TNF-α, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. CONCLUSIONS: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.

Mid-term success rate of single stage hybrid ablation of persistent and long-term persistent atrial fibrillation.

INTRODUCTION: Single stage thoracoscopic radiofrequency ablation (RFA) is a treatment method for persistent and long-term persistent atrial fibrillation (AF) offering the possibility for patients otherwise inconsolable by conventional catheter RFA. We present a pilot group of patients after the introduction of the new method at our clinical center. Patients group: A total of 52 patients aged 61.82 ± 9.7 years underwent single stage hybrid ablation (thoracoscopic isolation of pulmonary veins and box lesion followed by catheter verification of the surgical procedure effectivness) for symptomatic persistent and long-term persistent AF with significantly dilated left atrium 57.9 ± 11.0mm in the period September 2016-March 2019. RESULTS: The median duration of the procedure was 232 minutes and the median duration of hospitalization was 10 days. At discharge, 52 patients (100%) had sinus rhythm. 48 of 52 patients (92.3%) had a 6-month follow-up. 41 of 48 (85.4%) and 38 of 44 (86.4%) of patients were AF free at 3-month and 6-month follow-up, respectively. Acute complications were: one left atrial perforation resolved successfully by suture and one transient ischaemic attack without permanent sequelae. Late complications involved one massive pulmonary embolization and an atrioesophageal fistula. There was no periprocedural myocardial infarction or stroke with permanent sequelae. CONCLUSION: Hybrid thoracoscopic-catheter ablation performed during one procedure is an effective and relatively safe mini-invasive method of treatment for long-term persistent atrial fibrillation.

The mechanical regulation of RNA binding protein hnRNPC in the failing heart.

Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by reexpressing fetal contractile proteins via transcriptional and posttranscriptional processes, such as alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is up-regulated and relocates to the sarcomeric Z-disc upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates with the translation machinery. Alterations in hnRNPC expression, phosphorylation, and localization can be mechanically determined and affect the AS of mRNAs involved in mechanotransduction and cardiovascular diseases, including Hippo pathway effector Yes-associated protein 1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by affecting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNA homeostatic mechanoregulation in pathological conditions.

Monitoring of allograft vasculopathy by intravascular ultrasound one month and one year after heart transplantation: A single center study.

AIMS: The aim of this trial was to use intravascular ultrasound (IVUS) to determine whether cardiac allograft vasculopathy (CAV) starts progressing during the first year after heart transplantation (HTx). METHODS: We retrospectively analyzed 51 patients (11 women) who received heart transplants in our center between January 2010 and September 2013 and underwent coronary angiography as well as IVUS examination one month and one year after HTx. Patients with proven calcification and fibrotic plates in the IVUS examination one month after HTx constituted a group with defined donor-transmitted atherosclerosis (DTA). In patients without DTA, measurements of maximal intimal thickening (MIT) were made in two predetermined locations. RESULTS: Eight of the 51 patients had DTA, while 43 did not. These were divided based on maximal intimal thickness (MIT) into a group with MIT < 0.5 mm (27) and MIT ≥ 0.5 mm (16). No patient with MIT < 0.5 mm developed allograft vasculopathy within one year after HTx. CAV developed in three patients (P = 0.045) out of the 16 patients with MIT ≥ 0.5. In patients with DTA, a statistically significant deterioration in percent area stenosis (PAS) occurred in both artery sections (P = 0.01). CONCLUSION: Our trial showed that CAV progresses during the first year after HTx significantly more frequently in patients with DTA and MIT ≥ 0.5 mm. It is essential in these patients to implement an IVUS control examination one year after transplantation. The results can lead to a change in treatment strategy to prevent further progress of the disease.

Embolus entrapped in patent foramen ovale: impending paradoxical embolism.

An impending paradoxical embolism is a rare finding, with fewer than 200 cases being documented so far. A 68-year-old woman, who presented with 3 weeks of increasing exertional dyspnea and exercise intolerance, underwent transesophageal echocardiography with a finding of an embolus in both right and left atria. At an emergent cardiac surgery, a worm-shaped, 5-cm-long thrombus was found in the right atrium, it was protruding to left atrium through the foramen ovale. The thrombus was removed intact, and the foramen ovale was closed. By our experience, an emergent cardiac surgery should always be considered as a treatment option for impending paradoxical embolism.