bims-hafaim 2025-01-05 papers

Issue of 2025–01–05
three papers selected by
Kyle McCommis, Saint Louis University

Sci Rep. 2025 Jan 02. 15(1): 422

Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension.

Justin H Berger, Yuji Shi, Timothy R Matsuura, Kirill Batmanov, Xian Chen, Kelly Tam, Mackenzie Marshall, Richard Kue, Jiten Patel, Renee Taing, Russell Callaway, Joanna Griffin, Attila Kovacs, Dinesh Hirenallur-Shanthappa, Russell Miller, Bei B Zhang, Rachel J Roth Flach, Daniel P Kelly.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel "two-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka "HFpEF") mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions.

Keywords: Cardiovascular disease; Diastolic dysfunction; Heart failure with preserved ejection fraction; Mouse models

DOI: https://doi.org/10.1038/s41598-024-84515-9

J Pharm Biomed Anal. 2024 Dec 17. pii: S0731-7085(24)00683-6. [Epub ahead of print]255 116641

Joint proteomic and metabolomic analysis reveals renal metabolic remodeling of chronic heart failure mice.

Chunliu Wang, Jie Zhou, Pu Jia, Yang Yang, Ruixue Song, Xiaohui Zheng, Hong Zhang, Ye Li.

Pharmacologic intervention in chronic heart failure (HF) with renal insufficiency is one of the clinical challenges due to the fact that the mechanisms of cardio-renal interactions in chronic heart failure (CHF) progressing have not been fully revealed. In this paper, C57BL/6 mice were applied thoracic aortic narrowing surgery to establish pressure overload CHF model. Cardiac function, serum markers, renal pathologic changes and kidney metabolism were analyzed at 4th, 8th, 12th, and 16th week after surgery respectively to evaluate the heart-Kidney pathologic overlap. Kidney proteomic analysis was performed at 16th week after operation. As a result, renal hypofiltration and exacerbation of pathological damage was observed accompanying cardiac function deterioration after 12th week. 66 differentially expressed proteins and 13 differential metabolites were found to be involved in the cardio-renal pathological overlap. Joint proteomic and metabolomic analysis revealed that signal pathways like Phosphatidylinositol signaling system, Glucagon signaling pathway, the Glyoxylate and dicarboxylate metabolism; DEPs of Pten, Mtmr4, PLC and CPT1, differential metabolites like aspartic acid and isocitrate deserve further investigation.

Keywords: Chronic heart failure; Chronic kidney disease; Metabolic remodeling; Metabolomics; Proteomics

DOI: https://doi.org/10.1016/j.jpba.2024.116641

Cardiovasc Ther. 2024 ;2024 2735577

Invasive Hemodynamic Changes Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Abiodun Idowu, Olayinka Adebolu, Casipit Bruce, Bede Nriagu, Endurance Evbayekha, Kevin Bryan Lo, Olayinka Afolabi-Brown, Janani Rangaswami.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to lower incident heart failure (HF) and HF hospitalizations, but the mechanisms of benefit in relation to invasive hemodynamics remain unclear. Using PRISMA guidelines, we systematically reviewed multiple online databases for randomized trials evaluating the effect of SGLT2i on invasive hemodynamics. Rest and peak exercise invasive hemodynamics were measured via right heart catheterization pre- and postintervention. Random effects model meta-analysis at a 95% confidence interval was done using RevMan 5.0. A total of 3 studies with a total of 145 patients were included in the meta-analysis. SGLT2i was significantly associated with a reduction in pulmonary capillary wedge pressure at rest and peak exercise. Similarly, SGLT2i reduced mean pulmonary artery pressure at rest and peak exercise, respectively; however, this was not statistically significant. This hypothesis-generating study offers mechanistic insights into the central hemodynamic effects of SGLT2i underpinning the HF benefits of SGLT2i.

Keywords: invasive hemodynamics; mean pulmonary artery pressure; pulmonary capillary wedge pressure; right heart catheterization; sodium-glucose cotransporter-2 inhibitors

DOI: https://doi.org/10.1155/2024/2735577