o-ring-aortic-banding-versus-traditional-transverse-aortic

O-Ring Aortic Banding Versus Traditional Transverse Aortic Constriction for Modeling Pressure Overload-Induced Cardiac Hypertrophy

Aortic banding in mice is one of the most commonly used experimental models for cardiac pressure overload-induced cardiac hypertrophy and the induction of ...

University Hospital Kiel, Partner Site Hamburg/Kiel/Lübeck

Non-cardiac surgery is associated with significant cardiovascular complications. Reported mortality rate ranges from 1.9% to 4% in unselected patients. A postoperative surge in pro-inflammatory cytokines is a well-known feature and putative contributor to these complications. Despite much clinical research, little is known about the biomolecular changes in cardiac tissue following non-cardiac surgery. In order to increase our understanding, we analyzed whole-transcriptional and metabolic profiling data sets from hearts of mice harvested two, four, and six weeks following isolated thoracotomy. Hearts from healthy litter-mates served as controls. Functional network enrichment analyses showed a distinct impact on cardiac transcription two weeks after surgery characterized by a downregulation of mitochondrial pathways in the absence of significant metabolic alterations. Transcriptional changes were not detectable four and six weeks following surgery. Our study shows distinct and reversible transcriptional changes within the first two weeks following isolated thoracotomy. This coincides with a time period, in which most cardiovascular events happen.

Cardiac transcriptional and metabolic changes following thoracotomy.

Autophagy is a cellular degradation process that has been implicated in diverse disease processes. The authors provide evidence that FYCO1, a component of the autophagic machinery, is essential for adaptation to cardiac stress. Although the absence of FYCO1 does not affect basal autophagy in isolated cardiomyocytes, it abolishes induction of autophagy after glucose deprivation. Likewise, -deficient mice subjected to starvation or pressure overload are unable to respond with induction of autophagy and develop impaired cardiac function. FYCO1 overexpression leads to induction of autophagy in isolated cardiomyocytes and transgenic mouse hearts, thereby rescuing cardiac dysfunction in response to biomechanical stress.

FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo.

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure.

Growing evidence suggests an altered gut microbiome in patients with heart failure (HF). However, the exact interrelationship between microbiota, HF, and its consequences on the metabolome are still unknown. We thus aimed here to decipher the association between the severity and progression of HF and the gut microbiome composition and circulating metabolites. Using a mouse model of transverse aortic constriction (TAC), gut bacterial diversity was found to be significantly lower in mice as early as day 7 post-TAC compared to Sham controls ( = 0.03), with a gradual progressive decrease in alpha-diversity on days 7, 14, and 42 ( = 0.014,  = 0.0016,  = 0.0021) compared to day 0, which coincided with compensated hypertrophy, maladaptive hypertrophy, and overtly failing hearts, respectively. Strikingly, segregated analysis based on the severity of the cardiac dysfunction (EF &lt; 40% vs. EF 40-55%) manifested marked differences in the abundance and the grouping of several taxa. Multivariate analysis of plasma metabolites and bacterial diversity produced a strong correlation of metabolic alterations, such as reduced short-chain fatty acids and an increase in primary bile acids, with a differential abundance of distinct bacteria in HF. In conclusion, we showed that HF begets HF, likely via a vicious cycle of an altered microbiome and metabolic products.

Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations.

We recently reported the correlation of gut bacterial diversity with heart failure using a mouse model of heart failure due to pressure overload induced by transverse aortic constriction (TAC). We found that gut the bacterial diversity is significantly altered and is directly correlated to the severity of heart failure (Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations (Spehlmann, 2022). In addition, stool samples that were collected for the gut microbial diversity analysis, we dissected ileum from the mice after 42 days of TAC. The total DNA was extracted to identify the bacterial diversity resided in ileum using 16S rRNA gene amplicon shotgun sequencing and downstream bioinformatics analysis to determine if it is correlated to the heart failure.

Article	Year
Cardiac transcriptional and metabolic changes following thoracotomy. Scientific reports\| PubMed ID: 32541655	2020
FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo. JACC. Basic to translational science\| PubMed ID: 33997522	2021
AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure. Basic research in cardiology\| PubMed ID: 34089101	2021
Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations. Biomedicines\| PubMed ID: 35453559	2022
Dataset of ileum bacterial diversity in mice after heart failure due to pressure overload. Data in brief\| PubMed ID: 35966944	2022

Nesrin Schmiedel

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