bims-hafaim 2024-11-03 papers

Issue of 2024‒11‒03
five papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2024 Oct 25. pii: 2024.10.25.619450. [Epub ahead of print]

Integrated systems biology identifies disruptions in mitochondrial function and metabolism as key contributors to heart failure with preserved ejection fraction (HFpEF).

Andrew A Gibb, Kyle LaPenna, Ryan B Gaspar, Nadina R Latchman, Yinfei Tan, Carmen Choya-Foces, Jake E Doiron, Zhen Li, Huijing Xia, Michael P Lazaropoulos, Mariell Conwell, Thomas E Sharp, Traci T Goodchild, David J Lefer, John W Elrod.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases, with no effective treatments. The ZSF1-obese rat model recapitulates numerous clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and LV diastolic dysfunction. Here, we utilized a systems-biology approach to define the early metabolic and transcriptional signatures to gain mechanistic insight into the pathways contributing to HFpEF development.Methods: Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14w of age for extensive physiological phenotyping and LV tissue harvesting for unbiased metabolomics, RNA-sequencing, and assessment of mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes contributing to HFpEF pathology, versus hypertension + metabolic syndrome.
Results: ZSF1-obese rats displayed numerous clinical features of HFpEF. Comparison of ZSF1-lean vs WKY (i.e., hypertension-exclusive effects) revealed metabolic remodeling suggestive of increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by the upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and cellular metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of nearly all catabolic pathways contributing to energy production, manifesting in a marked decrease in the energetic state (i.e., reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Mitochondrial function was also impaired as demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling.
Conclusions: Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential target for intervention.

DOI: https://doi.org/10.1101/2024.10.25.619450

Adv Sci (Weinh). 2024 Oct 28. e2407677

Cardiac Urea Cycle Activation by Time-Restricted Feeding Protects Against Pressure Overload-Induced Heart Failure.

Yanzhen Tan, Min Li, Han Li, Yongzheng Guo, Bing Zhang, Guiling Wu, Jia Li, Qian Zhang, Yang Sun, Feng Gao, Wei Yi, Xing Zhang.

Heart failure is a leading cause of mortality worldwide, necessitating the development of novel therapeutic and lifestyle interventions. Recent studies highlight a potential role of time-restricted feeding (TRF) in the prevention and treatment of cardiac diseases. Here, it is found that TRF protected against heart failure at different stages in mice. Metabolomic profiling revealed that TRF upregulated most circulating amino acids, and amino acid supplementation protected against heart failure. In contrast, TRF showed a mild effect on cardiac amino acid profile, but increased cardiac amino acid utilization and activated the cardiac urea cycle through upregulating argininosuccinate lyase (ASL) expression. Cardiac-specific ASL knockout abolished the cardioprotective effects afforded by TRF. Circulating amino acids also protected against heart failure through activation of the urea cycle. Additionally, TRF upregulated cardiac ASL expression through transcription factor Yin Yang 1, and urea cycle-derived NO contributes to TRF-afforded cardioprotection. Furthermore, arteriovenous gradients of circulating metabolites across the human hearts were measured, and found that amino acid utilization and urea cycle activity were impaired in patients with decreased cardiac function. These results suggest that TRF is a promising intervention for heart failure, and highlight the importance of urea cycle in regulation of cardiac function.

Keywords: amino acid utilization; heart failure; time‐restricted feeding; urea cycle

DOI: https://doi.org/10.1002/advs.202407677

Res Sq. 2024 Oct 15. pii: rs.3.rs-4876095. [Epub ahead of print]

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-induced Cardiotoxicity.

Juan A Azcona, Anja S Wacker, Chul-Hee Lee, Edward K Fung, Thomas M Jeitner, Onorina L Manzo, Annarita Di Lorenzo, John W Babich, Alejandro Amor-Coarasa, James M Kelly.

Purpose Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Procedures : Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [ 18 F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations. Results Significantly higher cardiac [ 18 F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 min to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [ 18 F]FPA in tissues other than the heart. Co-administration of [ 18 F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. Conclusions [ 18 F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

DOI: https://doi.org/10.21203/rs.3.rs-4876095/v1

Front Cardiovasc Med. 2024 ;11 1476976

Vericiguat combined with "new quadruple" therapy enhances cardiac function and life quality in patients with heart failure: a single-center prospective study.

Di Zhao, Yanjuan Zhang, Yonghong Yong, Liansheng Wang, Jiabao Liu.

Objective: To investigate the therapeutic effect of Vericiguat combined with "new quadruple" drugs on patients with heart failure (HF).Methods: From December 1, 2022 to February 1, 2024, 103 patients with heart failure were consecutively enrolled from the cardiology clinic or ward of the First Affiliated Hospital of Nanjing Medical University. Before enrollment, the patients' left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD), N-terminal pro-B-type natriuretic peptide (NT-proBNP), liver and kidney function electrolytes, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) and other indicators were measured. Patients diagnosed with reduced ejection fraction (HFrEF) and with heart failure with mildly reduced ejection fraction (HFmrEF) were treated with Vericiguat combined with "ARNI, BB, MRA, SGLT2i" therapy. Patients diagnosed with preserved ejection fraction (HFpEF) were treated with Vericiguat combined with "ARNI, BB, SGLT2i" therapy. The above indicators were rechecked after 1 month of treatment.
Results: For all patients, comparison after treatment: LVEF (38.1 ± 8.5% vs. 43.1 ± 8.5%, P < 0.01), LVEDD (60.5 ± 8.1 vs. 58.2 ± 7.3 mm, P < 0.01), NT-proBNP (4,567.8 ± 5,163.9 vs. 1,895.6 ± 2,702.1 ng/L, P < 0.01), MLHFQ (45.72 ± 11.09 vs. 32.29 ± 9.41, P < 0.01). Further subgroup analysis showed that Vericiguat combined with "ARNI, BB, SGLT2i or MRA" improved the LVEF and reduced NT-proBNP levels in patients with HFrEF, HFmrEF or HFpEF. and improved patients' quality of life scores. The intergroup comparison showed the therapeutic effect of the combination was equivalent in HF caused by myocardial Infarction (MI), dilated cardiomyopathy (DCM) or Valvular Heart Disease (VHD).
Conclusion: Vericiguat combined with the "new quadruple" therapy has a significant therapeutic effect on patients with heart failure caused by MI, DCM or VHD.

Keywords: Vericiguat; dilated cardiomyopathy; heart failure; myocardial infarction; valvular heart disease

DOI: https://doi.org/10.3389/fcvm.2024.1476976

Cardiovasc Diabetol. 2024 Oct 26. 23(1): 380

ALDH2 mediates the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on improving cardiac remodeling.

Han Liu, Bingchen Jiang, Rui Hua, Xuehao Liu, Bao Qiao, Xiangxin Zhang, Xilong Liu, Wenjun Wang, Qiuhuan Yuan, Bailu Wang, Shujian Wei, Yuguo Chen.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are now recommended for patients with heart failure, but the mechanisms that underlie the protective role of SGLT2i in cardiac remodeling remain unclear. Aldehyde dehydrogenase 2 (ALDH2) effectively prevents cardiac remodeling. Here, the key role of ALDH2 in the efficacy of SGLT2i on cardiac remodeling was studied.METHODS: Analysis of multiple transcriptomic datasets and two-sample Mendelian randomization were performed to find out the differentially expressed genes between pathological cardiac hypertrophy models (patients) and controls. A pathological cardiac hypertrophy mouse model was established via transverse aortic constriction (TAC) or isoproterenol (ISO). Cardiomyocyte-specific ALDH2 knockout mice (ALDH2CMKO) and littermate control mice (ALDH2flox/flox) were generated to determine the critical role of ALDH2 in the preventive effects of dapagliflozin (DAPA) on cardiac remodeling. RNA sequencing, gene knockdown or overexpression, bisulfite sequencing PCR, and luciferase reporter assays were performed to explore the underlying molecular mechanisms involved.
RESULTS: Only ALDH2 was differentially expressed when the differentially expressed genes obtained via Mendelian analysis and the differentially expressed genes obtained from the multiple transcriptome datasets were combined. Mendelian analysis revealed that ALDH2 was negatively related to the severity of myocardial hypertrophy in patients. DAPA alleviated cardiac remodeling in mouse hearts subjected to TAC or ISO. ALDH2 expression was reduced, whereas ALDH2 expression was restored by DAPA in hypertrophic hearts. Cardiomyocyte specific ALDH2 knockout abolished the protective role of DAPA in preventing cardiac remodeling. ALDH2 expression and activity were increased in DAPA-treated neonatal rat primary cardiomyocytes (NRCMs), H9C2 cells and AC16 cells. Moreover, DAPA upregulated ALDH2 in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes. Sodium/proton exchanger 1 (NHE1) inhibition contributed to the regulation of ALDH2 by DAPA. DAPA suppressed the production of reactive oxygen species (ROS), downregulated DNA methyltransferase 1 (DNMT1) and subsequently reduced the ALDH2 promoter methylation level. Further studies revealed that DAPA enhanced the binding of nuclear transcription factor Y, subunit A (NFYA) to the promoter region of ALDH2, which was due to the decreased promoter methylation level of ALDH2.
CONCLUSIONS: The upregulation of ALDH2 plays a critical role in the protection of DAPA against cardiac remodeling. DAPA enhances the binding of NFYA to the ALDH2 promoter by reducing the ALDH2 promoter methylation level through NHE1/ROS/DNMT1 pathway.

Keywords: Aldehyde dehydrogenase 2; Cardiac remodeling; Methylation; Sodium-glucose cotransporter-2 inhibitors; Sodium/proton exchanger 1

DOI: https://doi.org/10.1186/s12933-024-02477-8