bims-hafaim 2025-03-09 papers

Issue of 2025–03–09
six papers selected by
Kyle McCommis, Saint Louis University

Int J Med Sci. 2025 ;22(5): 1223-1236

CD36 knockdown attenuates pressure overload-induced cardiac injury by preventing lipotoxicity and improving myocardial energy metabolism.

Jing Geng, Xiaoliang Zhang, Ying Wang, Dong Guo, Panpan Liu, Siying Pu, Xue Yang, Qi Liang, Pan Chang, Tao Li, Lang Hu, Yanjie Guo.

Introduction: The heart predominantly derives its energy from fatty acid (FA) oxidation. However, the uncoupling of lipid uptake and FA oxidation can result in abnormal cardiac lipid accumulation and lipotoxicity, particularly in the context of heart failure. CD36 is a critical mediator of FA uptake in cardiac tissue. Studies have shown that genetic deletion of CD36 can prevent the onset of cardiac hypertrophy and dysfunction in murine models of obesity and diabetes. Nevertheless, the precise role of CD36 knockdown or knockout in the development and progression of cardiac dysfunction under conditions of pressure overload remains unclear. Objective: This study aims to investigate the feasibility of CD36 partially knockdown in the prevention of cardiac lipotoxicity and functional impairment in pressure overload heart. Methods: Cardiac-specific CD36 totally knockout (CKO) and partially knockdown (CKD) mice were induced by genetics deletion and AAV-9 CD36 shRNA injection, respectively. Both CD36 CKO and CKD mice were subjected to transverse aortic constriction (TAC) operation to induce cardiac pressure overload. Cardiac function was measured by echocardiography. Cardiac lipid accumulation, FA oxidation and metabolic sate were also examined. Results: TAC operation induced significant cardiac dysfunction and pathological cardiac remodeling, accompanied by aberrant intra-myocardial lipid deposition and impaired FAO capacity. CD36 CKO attenuated aberrant lipid accumulation in the failing heart, while aggravated TAC-induced cardiac energy deprivation and oxidative stress. In contrast, CD36 CKD ameliorated TAC-induced lipid accumulation and excessive oxidative stress in the mice heart, accompanied by improved mitochondrial respiration function. Moreover, CD36 CKD induced a robust increase in glycolytic flux into the TCA cycle, which led to preserved ATP generation. As a result, CD36 CKD prevented the development of pressure overload-induced cardiac hypertrophy and dysfunction. Conclusion: In this study, we reported that CD36 CKD, not CD36 CKO, was able to protect against cardiac functional impairment in the pressure-overload heart. Manipulating CD36 was a feasible strategy to achieve an optimal point which maintain cardiac energy supply while avoiding lipotoxicity.

Keywords: FA oxidation; cardiac hypertrophy; lipid uptake; lipotoxicity; oxidative stress

DOI: https://doi.org/10.7150/ijms.107224

J Card Fail. 2025 Mar 03. pii: S1071-9164(25)00101-0. [Epub ahead of print]

Therapeutic Ketosis for Heart Failure: A State-of-the-Art-Review.

Nandan Kodur, Christopher Nguyen, W H Wilson Tang.

Heart failure is characterized by an energy-deprived heart, and in recent years it has been found that the failing heart increases ketone body oxidation to meet its energy demands. Accumulating evidence suggests that this metabolic adaptation is cardioprotective, suggesting that interventions that boost blood ketone levels could aid the failing heart. Indeed, multiple small clinical trials with short-term follow up have demonstrated that supplying the failing heart with exogenous ketone bodies may improve myocardial function across various manifestations of heart failure. As such, therapeutic ketosis, which is a metabolic state in which blood ketone levels are mildly elevated, could have great potential to ameliorate heart failure. Therapeutic ketosis can be achieved endogenously via exercise or dietary practices, exogenously via supplementation with ketone bodies, or pharmacologically via treatment with a sodium-glucose cotransporter-2 inhibitor. Although ketosis-inducing practices cannot be routinely recommended to patients with heart failure at this time due to a lack of robust data regarding the long-term benefits and risks, anecdotal evidence suggests that some patients have begun to adopt ketosis-inducing practices, so it is important for clinicians to be aware of how to optimally manage patients who are in therapeutic ketosis. In this review, we discuss myocardial ketone metabolism in heart failure, the current evidence for therapeutic ketosis in patients with heart failure, a framework to distinguish between therapeutic ketosis and the pathologic state of ketoacidosis, and practical considerations for managing patients adhering to ketosis-inducing practices.

Keywords: heart failure; ketone bodies; ketosis; therapeutic ketosis

DOI: https://doi.org/10.1016/j.cardfail.2025.01.028

Mitochondrion. 2025 Mar 04. pii: S1567-7249(25)00020-0. [Epub ahead of print] 102023

Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling.

Dan Wu, Qingxun Hu, Huimin Li, Yun Yin, Pei Wang, Wang Wang.

Obesity is an independent risk factor for heart failure with preserved ejection fraction (HFpEF). Dynamin related protein 1 (Drp1) is a key regulator of mitochondrial morphology, bioenergetics and quality control. The role of endogenous Drp1 in obesity induced HFpEF remains largely unknown. Here, adult heterozygous Drp1 floxed (Drp1fl/+) mice were bred with αMHC-MerCreMer mice and injected with tamoxifen to induce heterogenous Drp1 knockout (hetCKO) in the heart. Control and hetCKO mice exhibited similar increases in body weight and blood glucose and developed insulin resistance after 18-week high-fat diet (HFD)-fed. HFD had no effect on cardiac contractility but induced diastolic dysfunction, fibrosis, cell death and inflammation in Control and hetCKO mice hearts. Importantly, all these adverse effects were exacerbated in the hearts of hetCKO mice, suggesting aggravated cardiac remodeling and diastolic dysfunction. HFD induced mitochondrial fission was blocked, whereas energy deficiency was exaggerated in hetCKO hearts. These effects were associated with suppressed mitochondrial quality control via mitophagy, and increased apoptosis and oxidative stress. These findings suggest that endogenous Drp1 may play an important role in limiting metabolic stress induced heart dysfunction through regulating mitophagy, oxidative stress, mitochondrial function, apoptosis, and inflammation. Our study provides critical insights into how endogenous Drp1 plays a beneficial role in metabolic stress-induced HFpEF.

Keywords: Dynamin related protein 1; Heart failure with preserved ejection fraction; Lipid overload; Mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.mito.2025.102023

Biomol Biomed. 2025 Feb 24.

The regulatory role of exercise in heart failure and myocardial energy metabolism: A review.

Yuanhao Li, Dongli Gao, Peixia Li, Xulei Duan, Youli Liu, Chengyan Wu, Libo Wang, Xuehui Wang.

Myocardial energy metabolism is crucial for maintaining optimal heart function. The heart, having limited energy storage capacity, is dependent on a continuous energy supply; any disruptions or alterations in energy metabolism pathways can lead to insufficient myocardial energy, potentially triggering heart failure (HF). Exercise, as a safe and economical non-pharmacological intervention, is widely recognized to enhance cardiovascular health and modify myocardial energy metabolism patterns. However, the specific mechanisms by which exercise regulates myocardial metabolism to prevent and treat HF remain unclear. This review aims to detail the characteristics of myocardial metabolism under normal physiological and HF conditions, to further explore the impact of different exercise modalities on myocardial metabolism, and to summarize the molecular mechanisms by which exercise protects the heart by optimizing myocardial energy metabolism. Ultimately, this article aims to provide an in-depth understanding and evidence for the application of exercise interventions in cardiac rehabilitation.

DOI: https://doi.org/10.17305/bb.2025.12072

J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13761

Therapeutic Targeting of Decr1 Ameliorates Cardiomyopathy by Suppressing Mitochondrial Fatty Acid Oxidation in Diabetic Mice.

Qing-Bo Lu, He-Ting Sun, Kuo Zhou, Jia-Bao Su, Xin-Yu Meng, Guo Chen, Ao-Yuan Zhang, An-Jing Xu, Chen-Yang Zhao, Yuan Zhang, Yao Wang, Hong-Bo Qiu, Zhuo-Lin Lv, Zheng-Yang Bao, Jian Zhu, Feng Xiao, Xue-Xue Zhu, Hai-Jian Sun.

BACKGROUND: A significant increase in mitochondrial fatty acid oxidation (FAO) is now increasingly recognized as one of the metabolic alterations in diabetic cardiomyopathy (DCM). However, the molecular mechanisms underlying mitochondrial FAO impairment in DCM remain to be fully elucidated.
METHODS: A type 2 diabetes (T2D) mouse model was established by a combination of high-fat diet (HFD) and streptozotocin (STZ) injection. Neonatal rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (HP) to simulate diabetic cardiac injury. Gain- and loss-of-function approaches and RNA sequencing were utilized to investigate the role and mechanism of 2,4-dienoyl-CoA reductase 1 (Decr1) in DCM.
RESULTS: By integrating the genomic data available in the Gene Expression Omnibus (GEO) with DCM rodents, we found that the transcriptional level of Decr1 was consistently upregulated in DCM (+255% for diabetic heart, p < 0.0001; +281% for diabetic cells, p < 0.0001). Cardiomyocytes-specific knockdown of Decr1 preserved cardiac function (+41% for EF, p < 0.0001; +24% for FS, p = 0.0052), inhibited cardiac hypertrophy (-34%, p < 0.0001), fibrosis (-69%, p < 0.0001), apoptosis (-56%, p < 0.0001) and oxidative damage (-59%, p < 0.0001) in DCM mice, while cardiomyocytes-specific overexpression of Decr1 aggravated DCM (-28% for EF, p = 0.0347; -17% for FS, p = 0.0014). Deletion of Decr1 prevented high glucose/palmitate (HG/HP)-induced hypertrophy (-22%, p = 0.0006), mitochondrial dysfunction and apoptosis (-74%, p < 0.0001) in cultured cardiomyocytes. Furthermore, RNA sequencing and functional analysis showed that Decr1 interacted with and upregulated pyruvate dehydrogenase kinase 4 (PDK4) in injured cardiomyocytes, and overexpression of PDK4 eliminated the benefits of Decr1 downregulation in DCM (-20% for EF, p = 0.0071; -28% for FS, p = 0.0022). Mechanistically, PDK4 acted as a kinase that induced phosphorylation and mitochondrial translocation of HDAC3. In the mitochondria, HDAC3 mediated the deacetylation of dehydrogenase trifunctional multienzyme complex α subunit (HADHA), contributing to excessive mitochondrial FAO and subsequent cardiac injury. From a screening of 256 natural products, we identified Atranorin and Kurarinone as potential inhibitors of Decr1, both demonstrating protective effects against DCM (Atranorin, +21% for EF, p = 0.0134; +24% for FS, p = 0.0006; Kurarinone, +20% for EF, p = 0.0183; +27% for FS, p = 0.0001).
CONCLUSIONS: Our study delineates a molecular mechanism by which Decr1 potentiated higher mitochondrial lipid oxidation and cardiac damage by enhancing HADHA deacetylation through the PDK4/HDAC3 signalling pathway.

Keywords: Decr1; PDK4; cardiomyopathy; diabetes; fatty acid oxidation; oxidative stress

DOI: https://doi.org/10.1002/jcsm.13761

JACC Heart Fail. 2025 Feb 20. pii: S2213-1779(25)00080-0. [Epub ahead of print]

Severe Heart Failure and Treatment With Dapagliflozin Across the Ejection Fraction Spectrum: DAPA-HF and DELIVER.

BACKGROUND: Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk.
OBJECTIVES: The authors aimed to assess the prevalence, CV outcome risk, and treatment response to the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin among patients with severe HF across the spectrum of left ventricular ejection fraction (LVEF) in DAPA-HF and DELIVER.
METHODS: Severe HF was adapted from the ESC (European Society of Cardiology) HFA (Heart Failure Association) definition: NYHA functional class III/IV, evidence of HF with reduced, mildly reduced, or preserved LVEF, HF hospitalization within the previous 12 months, and adverse patient-reported symptom burden (Kansas City Cardiomyopathy Questionnaire-Total Symptoms Score <75). Outcomes and the treatment effect of dapagliflozin were assessed for the primary endpoint of CV death or first worsening HF event by severe HF status.
RESULTS: Among 10,948 patients with available data to define severe HF, 730 (6.7%) fulfilled the severe HF definition (296/4,722 [6.2%] with LVEF ≤40%, 192/2,101 [9.1%] with LVEF 41%-49%, and 232/4,125 [5.6%] with LVEF ≥50%). Over a median follow-up of 22 months, the primary endpoint occurred in 231 patients, at a rate of 20 per 100 patient-years (Q1-Q3: 17-23 per 100 patient-years). Patients with severe HF experienced a higher rate of events than patients without severe HF (adjusted HR: 1.85; 95% CI: 1.60-2.12), regardless of LVEF (Pinteraction = 0.98). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of severe HF status (Pinteraction = 0.48) across the LVEF spectrum (3-way Pinteraction = 0.52). The safety profile of dapagliflozin was also consistent regardless of the severe HF status.
CONCLUSIONS: Severe HF was associated with an excess risk of CV events across the spectrum of LVEF. Treatment with the SGLT2i dapagliflozin appeared to be safe and effective in reducing the risk of CV death or worsening HF in this population. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Keywords: clinical trial; dapagliflozin; severe heart failure

DOI: https://doi.org/10.1016/j.jchf.2024.11.023