Human Adult and Pediatric Multimodal Transcriptomic Atlas of Progression from Pressure-Loaded to Failing Right Ventricle [adult RV single-nucleus RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE345646 | GEO | 2026/09/04
REPOSITORIES: GEO
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Project description:Bulk RNA-sequencing of right ventricular free-wall tissue from 142 human hearts spanning non-failing (NF, n=29), compensated/pressure-loaded right ventricle (pRV, n=78) and right ventricular failure (RVF, n=35). Part of an integrated atlas that also includes single-nucleus RNA-seq and Xenium spatial profiling of the same cohort.
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Project description:Right ventricular dysfunction (RVD) independently predicts worse outcomes in both heart failure (HF) and pulmonary hypertension (PH), irrespective of their etiologies. Yet no evidence-based therapies exist for RVD and progression towards RV failure (RVF) can occur in spite of optimal medical treatment of HF or PH. This disparity reflects our insufficient understanding of the molecular pathophysiology of RVF. To identify molecular mechanisms that may uniquely underlie RVF, we investigated the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using weighted gene co-expression network and module-phenotype analyses, we identified a 279-member gene module that correlated significantly and specifically with RVF. Within this module, WIPI1 served as a genetic hub, HSPB6, SNAP47, and MAP4 as drivers, and PRDX5 as a repressor of RVF. We subsequently confirmed the ventricular specificity and temporal relationship of Wipi1, Hspb6, and Map4 transcript expression changes in murine models of pressure overload induced RV failure versus LV failure and subsequently uncovered differential dysregulation of autophagy in the failing RV versus the failing LV, namely a shift towards excessive non-canonical, Beclin1-independent, Wipi1/LC3II-mediated autophagy in RVF. In vitro siRNA silencing of Wipi1 partially protected isolated neonatal rat ventricular cardiac myocytes against aldosterone-induced failing phenotype. Moreover, silencing Wipi1 blunted mitochondrial superoxide production and limited non-canonical autophagy in this in vitro RVF model. Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and autophagy in cardiac myocytes. Inhibition of Wipi1 may hold promise as a therapeutic target for RVF.
2018-10-05 | GSE120852 | GEO
Project description:Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are yet unknown. Research is hampered by the lack of a good RVF model. Our aim was to study the pathophysiology of RVF in a rat model of chronic pressure load. Wistar rats (n=19) were subjected to pulmonary artery banding (PAB, 1.1mm) or sham surgery (CON). All PAB rats developed RVF (reduced cardiac output, RV stroke volume, TAPSE, increased end diastolic pressure, all p<0.05 vs. CON) but clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination ensued in a subset (5/12) of rats (RVF+) after a period of 52±5 days. Rats with RVF+ had significantly worse RV function and pericardial effusion and liver congestion compared to RVF rats without symptoms (all p<0.05), despite similar pressure load (p=NS RVF vs. RVF+). Chronic pulmonary artery banding invariably leads to RV failure in rats, and a subset transitions to advanced clinical RVF. RVF is characterized by enhanced contractility, progressive diastolic dysfunction and derangement of energy metabolism, thus improving diastolic function and targeting RV metabolism may be the keys to treating RVF. Total RNA optainded ( Heart) of 7 Controls ,5 RVF+ and 4 RVF samples where used for this array study
2014-12-08 | E-GEOD-46863 | biostudies-arrayexpress
Project description:Single-nucleus RNA-sequencing of right ventricular tissue from mice subjected to pulmonary artery banding (PAB), graded by echocardiography into sham, moderate and severe RV dysfunction.
2026-09-04 | GSE345854 | GEO
Project description:Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are yet unknown. Research is hampered by the lack of a good RVF model. Our aim was to study the pathophysiology of RVF in a rat model of chronic pressure load. Wistar rats (n=19) were subjected to pulmonary artery banding (PAB, 1.1mm) or sham surgery (CON). All PAB rats developed RVF (reduced cardiac output, RV stroke volume, TAPSE, increased end diastolic pressure, all p<0.05 vs. CON) but clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination ensued in a subset (5/12) of rats (RVF+) after a period of 52±5 days. Rats with RVF+ had significantly worse RV function and pericardial effusion and liver congestion compared to RVF rats without symptoms (all p<0.05), despite similar pressure load (p=NS RVF vs. RVF+). Chronic pulmonary artery banding invariably leads to RV failure in rats, and a subset transitions to advanced clinical RVF. RVF is characterized by enhanced contractility, progressive diastolic dysfunction and derangement of energy metabolism, thus improving diastolic function and targeting RV metabolism may be the keys to treating RVF.
2014-12-08 | GSE46863 | GEO
Project description:Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibrofatty replacement predominantly involved in right ventricle and clinically by ventricular arrhythmias.In this study, we set out to characterize the cardiac novel long-noncoding RNAs using deep RNA sequencing data from human heart tissues. Particularly, we identified AC specific novel lncRNAs that contribute to AC pathophysiology by comparing the lncRNAs transcripts of nine AC explanted hearts (RV), five non-diseased donor hearts (RV), four non-AC failing hearts (dilated cardiomyopathy, RV). To dissect the roles of novel lncRNAs in ARVC from LV, we also include six non-diseased donor hearts (LV) and six ARVC explanted hearts (LV) in the analysis. In the identified novel AC lncRNAs, a large part of them are derived from enhancer regions and acting as cis- elements to potentially regulate lipogenesis or lipid metabolism related genes. Finally, we validated several of these AC specific novel lncRNAs and their potential targets in independent patient samples. Collectively, we identified high-confidence AC specific novel lncRNAs from human samples and suggest their potential roles as cis- elements in AC pathology. Further study of these novel AC lncRNAs could provide new opportunities for diagnosis and therapeutic intervention.
2020-11-20 | GSE107156 | GEO
Project description:Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved RV-targeted treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified changes in multiple metabolic pathways in the RV of PAB pigs, and pathway alterations that were conserved between species. However, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs. When compared to humans, the pig PAB molecular signature was more similar to patients with RVF than rodents. These data suggest there are divergent molecular responses of RVF across species, and pigs more accurately recapitulate the metabolic molecular signature of human RVF.
2023-03-01 | GSE224428 | GEO
Project description:Background: Right ventricular (RV) and left ventricular (LV) myocardium differ in their response to pressure-overload hypertrophy (POH). In this report we use microarray and proteomic analyses to identify pathways modulated by LV-, and RV-POH in the immature heart. Methods: Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta (LV-POH; n=6). RV-POH was achieved by banding the pulmonary artery (n=6). Sham–control animals (SC; n=6 each) were sham-manipulated. Following 4 (LV-POH) and 6 weeks (RV-POH) recovery, the hearts were removed and matched sample RNA and proteins were isolated for microarray and proteomic analysis. Results: There was no difference in body weight in RV-, LV-POH vs. SC but there was a significant increase vs. SC in RV (3.2±0.8g vs. 1.2±0.3g; P<0.01) and LV weight (7.08±0.6g vs. 4.02±0.2g; P<0.01). Fractional area change (RV-POH) and shortening fraction (LV-POH) decreased significantly (23±6 vs. 47±6 and 21±4 vs.44±2, respectively, P<0.01). Microarray analysis demonstrated that LV-POH enriched pathways for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium and protein kinase-A signalling. RV-POH enriched pathways for cardiac oxidative phosphorylation. Proteomic analysis revealed 19 proteins were uniquely expressed in LV-POH vs. SC. Functional annotation clustering analysis indicated significant enrichment for the mitochondrion, cellular macromolecular complex assembly and oxidative phosphorylation. RV-POH had 15 uniquely expressed proteins vs. SC. Functional annotation clustering analysis indicated significant enrichment in structural constituents of muscle, cardiac muscle tissue development and calcium handling. Conclusion: Our results identify unique transcript and protein expression profiles in LV, RV-POH and provide new insight into the biological basis of ventricular specific hypertrophy. 3 different conditions: PAB-RV vs. Sham-control RV, PAB-RV [test] vs. PAB-LV [control], AOB-LV vs. Sham-control LV.
2011-06-24 | E-GEOD-30194 | biostudies-arrayexpress
Project description:Abstract: Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included tfam (−0.45-fold), suggesting impaired mitochondrial biogenesis, Cyp2e1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (Dhrs7c) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (Galnt13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (Postn; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (Ltbp2), thrombospondin4 (Thbs4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, Annexin A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.
2018-09-11 | GSE119754 | GEO