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New Frontiers in the Biological Cardiac Rhythm Generator: Preserving Atrioventricular Node Architecture in Decellularized Scaffolds

ABSTRACT: Cardiac implantable electronic devices are the current standard for managing arrhythmias, yet their use remains limited bydevice-related mechanical failures , infection risk, and suboptimal long-term biocompatibility. Developing a biological alternative capable of restoring intrinsic pacemaking function therefore represents an important clinical and technological challenge. In this study, we report the development of a bioengineered cardiac scaffold derived from porcine atrioventricular nodes. A Tergitol-based decellularization protocol was optimized to achieve complete removal of cellular and nuclear components while preserving the three-dimensional architecture and key extracellular matrix constituents. Comprehensive morphological, ultrastructural, proteomic and mechanical analyses confirmed ECM integrity and maintenance of structural organization, including collagen preservation with mild fiber realignment. These results demonstrate that the proposed decellularization strategy yields an ECM scaffold that retains the native features essential for supporting pacemaker tissue architecture. This work lays the groundwork for the creation of next-generation, tissue-derived cardiac scaffolds, with ongoing efforts directed toward ECM-derived hydrogel fabrication, cytocompatibility evaluation, and future integration with cardiomyocytes for biologically inspired pacemaker applications.

INSTRUMENT(S):

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Heart

SUBMITTER: Anna Maria Tolomeo

LAB HEAD: Anna Maria Tolomeo

PROVIDER: PXD073301 | Pride | 2026-02-20

REPOSITORIES: Pride

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			Action	DRS
	2025-03-13_MS_AMT_Heart_AVN_N25_Nativo_01.raw	Raw
	2025-03-13_MS_AMT_Heart_AVN_N25_Nativo_02.raw	Raw
	2025-03-13_MS_AMT_Heart_AVN_N25_Nativo_03.raw	Raw
	2025-03-13_MS_AMT_Heart_AVN_N50_Decell_01.raw	Raw
	2025-03-13_MS_AMT_Heart_AVN_N50_Decell_02.raw	Raw

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Project description:Rationale: Cardiac extracellular matrix (ECM) 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 (i) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (ii) determine the underlying molecular mechanisms. Methods and Results: We first performed decellularization of human and murine ECM (dECM) and then analyzed the pathological changes occurring in dECM during HF by atomic force (AFM), two-photon microscopy, high-resolution 3D image analysis and computational fluid dynamics (CFD) simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts (CFs) based on YAP-TEAD mechanosensing activity and collagen contraction assays. The analysis of HF dECM resulting from ischemic (IHD) or dilated cardiomyopathy (DCM), as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3D topography. As compared to 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 CFs highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFß1, Interleukin-1, TNF-alpha and BDNF signaling pathways. Functional tests performed on HF CFs 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 multi-parametric approach has highlighted repercussions of ECM remodeling on cell homing, CF activation and focal adhesion protein expression via hyper-activated YAP signaling during HF. Key words: Decellularization, extracellular matrix, dilated cardiomyopathy, ischemic heart disease, YAP, dilated cardiomyopathy, mechanobiology.

Project description:Right ventricular free wall (RVFW) pacing results in left ventricular dyssynchrony with early septal shortening followed by late lateral contraction that reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechano-energetics, yet little is known about its molecular consequences. We tested the hypothesis that dyssynchrony selectively alters regional gene expression in mice, employing a novel miniature implantable cardiac pacemaker. Mice were subjected to 1-week overdrive RVFW pacing (720 min-1, baseline HR 520-620 min-1) to induce dyssynchrony (pacemaker: 3V lithium battery, rate programmable, 0.8 grams, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler at implantation and terminal study, and dyssynchrony by echocardiography. Gene expression from left ventricular septal and lateral-wall myocardium were assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to 4 synchronously contracting controls. Of 22,000 genes surveyed, only 18 genes displayed significant (p<0.01) differential expression between septal/lateral walls exceeding 1.5-fold relative to any disparities in synchronous controls. These changes were confirmed by qPCR with excellent correlations. Most (16) of the genes showed greater septal expression. Of particular interest were 7 genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One-week cardiac dyssynchrony triggers regional differential expression differences in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart. Keywords: Murine cardiac dyssynchrony and differential gene expression, Agilent, microarray, pacing

Project description:Right ventricular free wall (RVFW) pacing results in left ventricular dyssynchrony with early septal shortening followed by late lateral contraction that reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechano-energetics, yet little is known about its molecular consequences. We tested the hypothesis that dyssynchrony selectively alters regional gene expression in mice, employing a novel miniature implantable cardiac pacemaker. Mice were subjected to 1-week overdrive RVFW pacing (720 min-1, baseline HR 520-620 min-1) to induce dyssynchrony (pacemaker: 3V lithium battery, rate programmable, 0.8 grams, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler at implantation and terminal study, and dyssynchrony by echocardiography. Gene expression from left ventricular septal and lateral-wall myocardium were assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to 4 synchronously contracting controls. Of 22,000 genes surveyed, only 18 genes displayed significant (p<0.01) differential expression between septal/lateral walls exceeding 1.5-fold relative to any disparities in synchronous controls. These changes were confirmed by qPCR with excellent correlations. Most (16) of the genes showed greater septal expression. Of particular interest were 7 genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One-week cardiac dyssynchrony triggers regional differential expression differences in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart. Experiment Overall Design: Left ventricle segments from the mouse heart - septal and lateral, were isolated from 4 dyssynchronous mice that were kept separate. RNA from the synchronous mice were pooled into a control septal and lateral sample. Functional genomic analysis was conducted on these 10 RNA samples with fluorophore reversal, such that each sample was assayed on two different microarrays. Corresponding septal and lateral samples from the same heart were paired on the same microarray to measure the relative differences in gene expression between the different regions of the heart then differences were compared across multiple mice to find overlapping genes that were affected by the pacememaker implantation.

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New Frontiers in the Biological Cardiac Rhythm Generator: Preserving Atrioventricular Node Architecture in Decellularized Scaffolds

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