bims-hafaim 2025-08-17 papers

JACC Basic Transl Sci. 2025 Aug 11. pii: S2452-302X(25)00310-9. [Epub ahead of print]10(9): 101357

Cracking the Code of a Preclinical Rodent Model of HFpEF: The Mitochondrial Link.

Keywords: HFpEF; cardiac remodeling; heart failure; metabolism; mitochondria

DOI: https://doi.org/10.1016/j.jacbts.2025.101357

Diabetol Metab Syndr. 2025 Aug 14. 17(1): 334

Deep phenotyping of a modified diabetic cardiomyopathy mouse model which reflects clinical disease progression.

Narainrit Karuna, Lauren Kerrigan, Kevin Edgar, Oisin Cappa, David Simpson, Claire Tonry, David J Grieve, Chris J Watson.

Diabetic cardiomyopathy (DbCM) is a progressive disease and common complication of metabolic diabetes. It is characterised by onset of cardiac structural and functional impairments and can lead to direct development of clinical heart failure (HF) or predispose to hypertensive/ischaemic stress. DbCM is a complex disease which involves several metabolic and pathogenic factors. We characterised an established high-fat diet/streptozotocin (HFD/STZ)-induced DbCM model incorporating typical features of human disease to determine its suitability for preclinical evaluation of novel therapeutics prior to advancement to human trials. Male C57BL/6J mice were randomised to HFD and single-dose STZ (100 mg/kg) or control diet (CD) and vehicle. HFD/STZ mice developed type 2 diabetes mellitus (T2DM), reflected by high fasting blood glucose and HbA1c levels, reduced β-cell function, and increased insulin resistance without systolic blood pressure alteration. Furthermore, HFD/STZ mice displayed progressive diastolic dysfunction, evidenced by decreased MV E/A ratio, together with elevated chronic left ventricular (LV) filling pressure parameters, measured by left atrial (LA) area and LA volume, compared to controls, in parallel with LV hypertrophy and fibrosis. Monocyte trafficking into diabetic hearts was identified by single-nuclei RNA sequencing analysis, which revealed an interferon-α response in DbCM mice, whilst plasma proteomics confirmed the involvement of inflammatory processes with elevated plasma C-reactive protein in DbCM progression. Taken together, our HFD/STZ-induced DbCM model exhibits a unique DbCM pre-clinical phenotype reflecting a "triple-hit" of human DbCM features comprising (1) T2DM with insulin resistance, (2) progressive diastolic dysfunction and LV remodelling, and (3) metabolic inflammation. This improved HFD/STZ-induced DbCM model supports clinically relevant research on DbCM progression from early stages to cardiac dysfunction and remodelling as the basis for translational investigation.

Keywords: Cardiac fibrosis; Diabetic cardiomyopathy; Diastolic dysfunction; Heart failure; Metabolic syndrome

DOI: https://doi.org/10.1186/s13098-025-01913-3

J Card Fail. 2025 Aug 09. pii: S1071-9164(25)00333-1. [Epub ahead of print]

Should exogenous ketone body supplementation be considered in patients hospitalized for acute heart failure? Rationale and design of the KETO-AHF trial.

BACKGROUND: Acute heart failure (AHF) is associated with high mortality and contemporary medical treatments provide limited benefits in survival. Emerging evidence suggests that exogenous ketone bodies may have beneficial cardiovascular effects in patients with heart failure. The KETO-AHF trial is designed to assess the clinical benefits of initiating ketone supplementation with 1,3-butanediol compared with placebo in patients hospitalized for AHF with reduced ejection fraction.
METHODS: KETO-AHF is a multicenter, randomized, double-blind, placebo-controlled trial investigating the effects of 1,3-butanediol (33 g three times daily) in patients hospitalized for AHF. Patients with symptoms and signs of AHF requiring intravenous loop diuretics and/or vasoactive treatment, elevated natriuretic peptides, and a left ventricular ejection fraction ≤35%, whether de novo or known heart failure, will be enrolled within five days of hospital admission. Participants will be randomized 1:1 to receive either 1,3-butanediol or placebo for a 30-day treatment period. The study aims to enroll 125 patients in each group. The primary endpoint is a hierarchical composite of all-cause mortality, heart failure rehospitalization, six-minute walk test improvement, and reduction in NT-proBNP levels at 30 days.
CONCLUSION: The KETO-AHF trial will provide insights into the effects of supplementation with the ketone body 1,3-butanediol in patients hospitalized for AHF.

Keywords: 1,3-butanediol; Acute heart failure; ketone bodies; metabolism

DOI: https://doi.org/10.1016/j.cardfail.2025.07.013

bioRxiv. 2025 Jul 18. pii: 2025.07.15.664959. [Epub ahead of print]

NAD⁺ Replenishment Mitigates Cardiomyocyte Senescence and Corrects Heart Failure with Preserved Ejection Fraction in Aged Mice.

Qingxia Huang, Yongjie Wang, Karina Farias, Xinliu Zeng, Qiuying Chen, Huiyong Cheng, Steven S Gross, Jacob Geri, Anthony A Sauve, Yue Yang.

Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure affecting individuals over 65. In this study, we investigated the role of NAD⁺ metabolism in cardiomyocyte senescence and cardiac function. Aged mice exhibited reduced cardiac NAD⁺ levels, impaired NAD⁺ biosynthesis and mobilization, and increased consumption, leading to suppressed SIRT1/6 activity and accumulation of senescent cardiomyocytes. This was accompanied by diastolic dysfunction consistent with HFpEF. In senescent AC16 cardiomyocytes, NAD⁺ depletion promoted senescence, which was reversed by the NAD⁺ precursors nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). In aged mice, two months of NR or NRH treatment improved diastolic function and reduced cardiomyocyte senescence. While NR primarily activated SIRT1 to suppress cell cycle arrest markers, NRH more robustly activated both SIRT1 and SIRT6, enhancing DNA damage repair. Acetylated H2AX, a SIRT6 substrate elevated in aged hearts and senescent cells, was selectively deacetylated by NRH. These findings identify NAD⁺ availability as a critical regulator of cardiac senescence and support NAD⁺ precursors, particularly NRH, as promising senescence-reducing therapies for treating aging-associated HFpEF.

DOI: https://doi.org/10.1101/2025.07.15.664959

Biomed Pharmacother. 2025 Aug 11. pii: S0753-3322(25)00633-X. [Epub ahead of print]191 118439

Soluble guanylate cyclase stimulation improves cardiac function and mitochondrial activity in a rat model of early-stage heart failure with preserved ejection fraction.

Targeting cardiac mitochondrial dysfunction and cardiac metabolic reprogramming is critical for improving chronic heart failure (HF) treatment. While the soluble guanylate cyclase stimulator vericiguat has shown promise in treating HF with reduced ejection fraction (HFrEF), its effects on HF with preserved ejection fraction (HFpEF), particularly on myocardial bioenergetics, remain undefined. This study aimed to clarify the effects of vericiguat on cardiac function and metabolism in a preclinical model of early-stage HF. Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to receive standard care (n = 10) or vericiguat (3 mg/kg/d p.o.) (n = 10) treatment for 4 weeks. ZSF1 lean rats (n = 10) served as controls. Vericiguat improved diastolic function, reduced cardiac hypertrophy and fibrosis and enhanced cardiac mitochondrial basal respiration, upregulating the levels of several mitochondrial electron transport chain proteins from complexes I, II, III and V, along with the ADP/ATP translocase 1 mRNA levels, and partially reversing mitochondrial cristae diffuse dissolution observed in obese control rat hearts. Vericiguat treatment increased cardiac levels of phosphoproteins involved in the pentose phosphate pathway (PPP) (6-phosphogluconolactonase and 6-phosphogluconate dehydrogenase) and in the Krebs cycle (malate dehydrogenase and aspartate aminotransferase), while normalizing the mRNA levels of the master regulator of calcium uptake by the mitochondria (MICU1). Furthermore, vericiguat restored the cardiac levels of key metabolites of the PPP such as 6-phosphogluconate, D-ribose 5-phosphate, and arginine, that were diminished in the obese control group. In conclusion, vericiguat elicits beneficial functional and metabolic responses at cardiac level in an animal model of early-stage HFpEF.

Keywords: Diastolic dysfunction; Heart failure with preserved ejection fraction; Mitochondria; Proteome; Soluble guanylate cyclase stimulator; ZSF1

DOI: https://doi.org/10.1016/j.biopha.2025.118439