Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723851 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14301930_1.fastq.gz | Fastqsanger.gz | |||
| SRR14301930_2.fastq.gz | Fastqsanger.gz | |||
| SRR14301931_1.fastq.gz | Fastqsanger.gz | |||
| SRR14301931_2.fastq.gz | Fastqsanger.gz | |||
| SRR14301932_1.fastq.gz | Fastqsanger.gz |
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Project description:Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation, cardiac fibrosis and death in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Both pharmacological and genetic inhibition of phytosterol absorption prevented the induction of both pathways. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These phytosterolemia-associated comorbidities provide novel insight into the underlying pathophysiological mechanism that predispose these patients to increased risk of sudden cardiac death.
2021-08-31 | GSE173123 | GEO
Project description:Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.
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Project description:Atrial fibrillation (AF), the most common arrhythmia, is occasionally associated with cardiac developmental defects, but causal relationships are poorly defined. Importantly, functional compensation for developmental defects may mask increased risk of arrhythmia in adults. Here, we deleted 9 amino acids (Δ9) within a highly conserved A-band region of titin, a giant protein that serves as a molecular spring in cardiomyocytes, in both zebrafish and human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that the cardiac morphology of ttnaΔ9/Δ9 homozygous zebrafish embryos is perturbed and accompanied by reduced functional output, but ventricular function recovers within a few days of embryonic development, with most embryos reaching adulthood. Despite normal ventricular function, ttnaΔ9/Δ9 adults exhibit AF and atrial cardiomyopathy, with a striking absence of fibrosis, and these findings are recapitulated in TTNΔ9/Δ9-hiPSC-aCMs. Electrophysiological and proteomics analyses reveal atrial action potential shortening and increased expression and function of the cardiac potassium channel Kv7.1 and the slow delayed rectifier potassium current (IKs). Pharmacological suppression of IKs in both models prevents AF and improves atrial contractility. Collectively, these findings reveal how a small internal deletion in a large structural protein causes developmental abnormalities that functionally recover but increase the risk of adult cardiac disease via ion channel remodeling. The observed rescue with targeted antiarrhythmic therapy may have broader implications for the treatment of patients who harbor disease-causing rare variants in sarcomeric proteins.
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Project description:Acute myocardial infarction (AMI) is one of the leading causes of death. It is particularly important to predict malignant ventricular arrhythmia (MVA) timely and accurately in patients with AMI. This study aimed to explore biomarkers and to reveal possible mechanisms of MVA in AMI for clinical diagnosis. Blood samples from 190 human subjects were collected to reveal the differentially expressed proteins (DEPs) in three comparisons (AMI/control, AMI+MVA/control, and AMI+MVA/AMI) in proteomics with bioinformatics analysis and validated in new cohorts. The diagnostic value of candidate DEPs predicting AMI+MVA was also evaluated by the receiver operating characteristic curve (ROC). A total of 8,365 peptides and 460 proteins from the LC-MS/MS analysis were identified with 90 in AMI/control, 94 in AMI+MVA/control, and 43 in AMI+MVA/AMI identified as DEPs. TGFBI level had notable decreasing trend in AMI+MVA (161.9 ± 19.0 ng/ml) compared with AMI (P<0.0001) or control (P<0.0001). vWF level in AMI+MVA patients was significantly higher than that in AMI patients (P<0.01) and control (P<0.0001). ROC analysis showed that TGFBI and vWF had the strong and potential value of predicting MVA in AMI. By constructing proteomics profile to identify the protein characteristics this study found that decreased TGFBI and increased vWF are the characteristics of proteins in the MVA patients with AMI. These findings provide new insight into the diagnosis and pathogenesis of the development of MVA. Further, decreased TGFBI and increased vWF are potential predicting biomarkers for diagnosis of MVA in AMI patients.
2024-01-26 | PXD041535 | Pride
Project description:Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found find that the stress kinases p38 and p38/are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that upon activation, the increased activity of p38 and p38/ was cooperatively associated increase the with susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38 and p38wphosphorylatee identified ryanodine receptor 2 (RyR2) and disrupt Kv4.3 channel localization, as a new substrate of p38/. Our data indicate that phosphorylation of SAP97 by activated p38/ also disrupts Kv4.3 localization at the plasma membrane, promoting sarcoplasmic reticulum calcium leak, Ito current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes, and enhanced susceptibility to VF. The importance of this finding is evidenced by the fact that bBlocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals. We have identified p38/-driven phosphorylation of RyR2 and SAP97 as a novel trigger of VF. These results indicate that p38 and p38/ are a new potential therapeutic target for sustained VF prevention.
2023-10-18 | PXD045996 | Pride
Project description:Aims: A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and Results: Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3±1.2 Hz in hPLN-R14del vs. 25.7±1.3 Hz in WT, p<0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital PCR and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9±2.3 Hz vs. 21.3±1.5 Hz; p<0.01). Conclusions: This study is the first to show that disruption of hPLN-R14del allele by AAV9- CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease.
2023-03-11 | PXD031612 | Pride
Project description:To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition.A cohort study was conducted using 1999-2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%.In 1.3 million person-years of antidepressant exposure, we identified 4222 SD/VA outcomes for a rate of 3.3/1000 person-years (95%CI, 3.2-3.4). Compared with paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HRs) were 0.80 (0.67-0.95) for bupropion, 1.24 (0.93-1.65) for doxepin, 0.79 (0.55-1.15) for lithium, and 1.26 (1.11-1.42) for mirtazapine. HRs for amitriptyline, citalopram, fluoxetine, nefazodone, nortriptyline, sertraline, trazodone, and venlafaxine were near unity. For antidepressants having nonnull risks (bupropion and mirtazapine), we observed no relationship with antidepressant dose and some relationships with concomitant cytochrome P-450 inhibition.Of antidepressants studied, only mirtazapine had a statistically significantly greater SD/VA risk versus paroxetine. However, baseline differences between these users suggest that this finding may be attributable to residual confounding. Eleven other antidepressants had SD/VA risks no greater than that of paroxetine, thereby providing reassurance regarding the comparative cardiovascular safety of antidepressants.
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Project description:Impaired Right Ventricular Calcium Cycling Is an Early Risk 2 Factor in R14del-Phospholamban Arrhythmias
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Project description:Ischemic cardiomyopathy (ICM) leads to congestive heart failure and can cause sudden cardiac death due to arrhythmia. Existing molecular knowledge base of ICM is rudimentary because of lack of specific attribution to cell type and function. This study was designed to investigate cell-specific molecular remodeling of ion channels, exchangers and pumps, which are signaling molecules (SM) involved in electrical, signaling and mechanical functions of the heart. Atrial and ventricular myocytes were isolated by laser-capture microdissection from left atrium and ventricle of healthy and ICM human hearts. SM and their splice variants altered by ICM in cardiomyocytes were identified by splice microarray and validated by RT-PCR. Molecular profiling of ICM-related changes showed that SM in atrial and ventricular myocytes remodel following their unique programs. ICM affected 63 genes in ventricular myocytes and 12 genes in atrial myocytes. Only few of the identified genes were previously linked to human cardiac disfunctions.
2010-02-18 | GSE17294 | GEO
Project description:Ischemic cardiomyopathy (ICM) leads to congestive heart failure and can cause sudden cardiac death due to arrhythmia. Existing molecular knowledge base of ICM is rudimentary because of lack of specific attribution to cell type and function. This study was designed to investigate cell-specific molecular remodeling of ion channels, exchangers and pumps, which are signaling molecules (SM) involved in electrical, signaling and mechanical functions of the heart. Atrial and ventricular myocytes were isolated by laser-capture microdissection from left atrium and ventricle of healthy and ICM human hearts. SM and their splice variants altered by ICM in cardiomyocytes were identified by splice microarray and validated by RT-PCR. Molecular profiling of ICM-related changes showed that SM in atrial and ventricular myocytes remodel following their unique programs. ICM affected 63 genes in ventricular myocytes and 12 genes in atrial myocytes. Only few of the identified genes were previously linked to human cardiac disfunctions. In our experiments we used 3 healthy hearts rejected from transplantation procedure and explanted ICM hearts from three male patients. Tissue samples were dissected from left ventricle and left atrial appendages. Atrial and ventricular myocytes were laser-capture microdissected from serial 7-8-µm thick cryostat sections. Individual cellular total RNA samples were analyzed on custom-built Human Ion Channel Splice Arrays slides (ExonHit) manufactured on the Ion Channel Splice Array sv1.1 platform representing 287 human SM, including 248 alternatively spliced ones in total 1655 splicing events and supplemented with capabilities to recognize connexins and ryanodine receptors.
2010-05-14 | E-GEOD-17294 | biostudies-arrayexpress