bims-hafaim 2025-05-18 papers

Issue of 2025–05–18
five papers selected by
Kyle McCommis, Saint Louis University

Cardiovasc Diabetol. 2025 May 14. 24(1): 208

The effects of SGLT2i on cardiac metabolism in patients with HFpEF: Fact or fiction?

Francesca Cinti, Renzo Laborante, Luigi Cappannoli, Cassandra Morciano, Shawn Gugliandolo, Alfredo Pontecorvi, Francesco Burzotta, Maria Donniacuo, Donato Cappetta, Giuseppe Patti, Andrea Giaccari, Domenico D'Amario.

The rising prevalence of Type 2 diabetes (T2D) has been closely associated with an increased incidence of cardiovascular diseases, particularly heart failure with preserved ejection fraction (HFpEF). Cardiometabolic disturbances in T2D, such as insulin resistance, hyperglycemia, and dyslipidemia, contribute to both microvascular and macrovascular complications, thereby intensifying the risk of heart failure. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as glucose-lowering agents for T2D, have demonstrated promising cardiovascular benefits in patients with heart failure, including those with preserved ejection fraction (HFpEF), regardless of T2D status. These benefits include reduced heart failure hospitalization rates and improvements in various metabolic parameters. This review aims to critically examine the effects of SGLT2i on cardiac metabolism in HFpEF, evaluating whether the observed benefits can truly be attributed to their impact on myocardial energy regulation or whether they represent other, potentially confounding, mechanisms. We will focus on the key metabolic processes possibly modulated by SGLT2i, including myocardial glucose utilization, fatty acid oxidation, and mitochondrial function, and explore their effects on heart failure pathophysiology. Additionally, we will address the role of SGLT2i in other pathogenetic factors involved in HFpEF, such as sodium and fluid balance, inflammation, and fibrosis, and question the extent to which these mechanisms contribute to the observed clinical benefits. By synthesizing the current evidence, this review will provide an in-depth analysis of the mechanisms through which SGLT2i may influence cardiac metabolism in HFpEF, assessing whether their effects are supported by robust scientific data or remain speculative. We will also discuss the potential for personalized treatment strategies, based on individual patient characteristics, to optimize the therapeutic benefits of SGLT2i in managing both T2D and cardiovascular risk. This review seeks to clarify the true clinical utility of SGLT2i in the management of cardiometabolic diseases and HFpEF, offering insights into their role in improving long-term cardiovascular outcomes.

Keywords: Coronary reserve; Diabetes; Heart failure; Inflammation; Metabolism; Microvascular dysfunction; Precision medicine; SGLT2i

DOI: https://doi.org/10.1186/s12933-025-02767-9

Biochem Pharmacol. 2025 May 08. pii: S0006-2952(25)00224-2. [Epub ahead of print]238 116962

Fatty acid synthase inhibition offers protection against pressure-induced cardiac hypertrophy.

Pragya Bharati, Prabha Burman, Satyapriya Mahapatra, Smita Prajapati, Nilesh Khandelwal, Baisakhi Moharana, Anil Nilkanth Gaikwad, Kumaravelu Jagavelu, Kashif Hanif.

Disturbed cardiac metabolism is an important aspect of the pathology of Cardiac hypertrophy (CH) which precede Heart failure (HF). Studies have shown a higher rate of De novo lipogenesis in HF and its inhibition has been protective. However, its role in CH still needs further clarification. For in vitro studies, Phenylephrine (PE) was used to induce CH in adult human ventricular cardiomyocytes (AC16). For in vivo studies, 2 kidney 1 clip (2K1C) and Transverse aortic constriction (TAC) models of rat were used. Fatty acid synthase (FAS), key enzyme of lipogenesis was inhibited using FAS si RNA (30 nM) and C75 (2 mg/kg, i.p. once a week for 8 weeks) in vitro and in vivo respectively. Echocardiography and histochemical staining were used to observe cardiac remodeling. Western blotting, Seahorse analysis, fluorescence microscopy and FACS were performed to detect metabolic alterations, mitochondrial dysfunction, protein synthesis and hypertrophy. We observed increased expression and activity of FAS in PE-exposed AC16 and 2K1C and TAC models of rats. Inhibition of FAS decreased hypertrophy, protein synthesis by malonylation of mTOR, apoptosis, glycolysis, and oxidative stress and restored oxidative phosphorylation in AC16 cells. In rats, FAS inhibition prevented cardiac remodelling in 2K1C and TAC models. It also increased ATP, restored mitochondrial ROS and membrane potential in the TAC model of rats. Our results demonstrated that FAS activity was modulated during CH, and inhibiting it prevented cardiac remodelling and mitochondrial dysfunctions. The findings, therefore, suggest that inhibiting FAS may be a new therapeutic approach to treating CH patients.

Keywords: De novo lipogenesis; Mitochondrial dysfunction; Myocardial metabolism; Oxidative stress; Pressure overload; Protein synthesis

DOI: https://doi.org/10.1016/j.bcp.2025.116962

Circ Res. 2025 May 13.

FoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes.

BACKGROUND: The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localization of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and the type 2 diabetic heart. Posttranslational S-acylation controls protein trafficking, and in this study, we hypothesized that increased CD36 S-acylation may underpin the preferential sarcolemmal localization of CD36, driving metabolic and contractile dysfunction in diabetes.
METHODS AND RESULTS: Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localization, FA oxidation rates, and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, db/db mice, diabetic pigs, and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 using siRNA or lentiviral shRNA decreased CD36 S-acylation. We identified that zDHHC4 expression is under the regulation of the transcription factor FoxO (forkhead box O) 1, as FoxO1 binds to the promotor of zDHHC4 and induces its transcription, as assessed using chromatin immunoprecipitation-seq, chromatin immunoprecipitation-quantitative PCR, luciferase assays, and siRNA silencing. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac zDHHC4 expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates, and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the deacylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content, and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts.
CONCLUSIONS: Activation of the FoxO1-zDHHC4-CD36 S-acylation axis in diabetes drives metabolic and contractile dysfunction in type 2 diabetic heart.

Keywords: cardiovascular diseases; diabetic cardiomyopathies; heart failure; insulin resistance; myocardial infarction

DOI: https://doi.org/10.1161/CIRCRESAHA.124.325918

Front Cardiovasc Med. 2025 ;12 1543153

Efficacy and safety of SGLT2 inhibitors in acute heart failure: a systematic review and meta-analysis of randomized controlled trials.

Ali Ibrahim Rahil, Tirth Bhavsar, Romman Fatima, Aparajitha Rajkumar, Joy Kumar, Hanif Al Majidan, Namrata Gajjala, Wodwentzky Lefranc, Fnu Deeksha, Harshitha Lingegowda, Muhammad Ehsan, Wajeeh Ur Rehman, Hasan Ahmad, Raheel Ahmed.

Background: Acute heart failure (AHF) is a serious medical condition with considerable morbidity and mortality ranging from 20%-30% within the first month following hospital admission. We aimed to evaluate the efficacy and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors administered within the first five days of hospitalization for AHF.
Methods: We utilized various electronic resources such as MEDLINE, Embase, and the Cochrane Library to retrieve relevant randomized controlled trials (RCTs). The meta-analysis was performed using Revman, where the risk ratio (RR) and mean difference (MD) with a 95% confidence interval (CI) were used for dichotomous and continuous variablesrespectively.
Results: A total of seven trials were included in this review. SGLT2 inhibitors were associated with decreased all-cause mortality (RR = 0.61, 95% CI = 0.40, 0.95; P = 0.03), worsening of HF (RR = 0.59, 95%CI = 0.36, 0.97;P = 0.04), and GFR (MD: 1.05, 95% CI = 0.68, 1.43; P < 0.00001) compared with the control group. There were no significant differences between the two groups regarding readmission for HF, cardiovascular mortality, AKI, hypoglycemia, hypotension, and diuretic efficiency. SGLT2 inhibitors were associated with improved KCCQ-CSS scores (MD: -3.82, 95% CI = -7.51, -0.13; P = 0.04).
Conclusion: SGLT2 inhibitors demonstrate overall clinical benefits and a favorable safety profile in acute heart failure, although their impact on readmission rates is limited. Further research is needed to refine patient selection and optimize treatment strategies.
Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024571563, PROSPERO (CRD42024571563).

Keywords: SGLT2 inhibitors; acute heart failure; de-novo heart failure; meta-analysis; systematic review

DOI: https://doi.org/10.3389/fcvm.2025.1543153

Nat Commun. 2025 May 14. 16(1): 4471

Effectiveness of tirzepatide in patients with HFpEF using a target trial emulation retrospective cohort study.

Yu-Min Lin, Kuang-Ming Liao, Tsung Yu, Jheng-Yan Wu, Chih-Cheng Lai.

Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown promise in improving metabolic and cardiovascular profiles in patients with obesity. However, its potential benefits in patients with heart failure with preserved ejection fraction (HFpEF) remain unclear. We conducted a real-world, retrospective cohort study using the TriNetX global database. A total of 14,154 patients with HFpEF were included after 1:1 propensity score matching. Tirzepatide use was associated with significantly lower risks of the primary composite outcome of heart failure exacerbation and all-cause mortality (HR 0.52), as well as reductions in major adverse cardiovascular events (HR 0.64) and major adverse kidney events (HR 0.44). Subgroup analyses demonstrated consistent benefits across different strata. Sensitivity analyses using alternative exposure definitions confirmed the robustness of the findings. These results support the potential clinical utility of tirzepatide in HFpEF management and warrant further investigation in randomized controlled trials.

DOI: https://doi.org/10.1038/s41467-025-59616-2