bims-hafaim 2025-11-09 papers

Issue of 2025–11–09
five papers selected by
Kyle McCommis, Saint Louis University

Front Pharmacol. 2025 ;16 1636810

Empagliflozin's cardioenergetic protective effects through PPARα pathway modulation in heart failure.

Hua Wei, Menghua Yin, Junshun Chang, Bo Feng, Qin Zhou, Xirong Li, Ping Wu, Xiaoshan Guo, Siyuan Chen, Bao Li, Sijin Li.

Background: Heart failure (HF) pathology is complex and seriously life-threatening. SGLT2 inhibitors, as one of the new quadruple drugs for HF treatment, have a complex mechanism for improving HF. Energy metabolism is one of the important aspects of HF pathology, and the PPARα signaling pathway plays an important role in energy metabolism. Therefore, this study aims to observe changes in the PPARα signal transduction pathway in chronic HF by 18F-FDG MicroPET/CT imaging. Based on the myocardial metabolic imaging of 18F-FDG MicroPET/CT, this study aims to verify the mechanism of SGLT2 inhibitor treatment in rats with HF through the PPARα signal transduction pathway of energy metabolism and provide an imaging diagnostic basis.
Results: In 18F-FDG PET/CT myocardial metabolic imaging, pretreatment myocardial glucose metabolism rate (MRGlu) levels in the HC group of HF rats were significantly higher than that in the other three groups. Post-treatment, MRGlu and glucose uptake decreased markedly in the empagliflozin (EMPG) group, while no significant changes were observed in the fenofibrate (FF) group. Compared with normal healthy rats, HF model rats showed a significant increase in MRGlu, and the expression of the lipid metabolism pathway proteins (PPARα, RXRα, CPT1α, and CD36) and the energy metabolism pathway proteins (AMPKα and sirt1) were significantly inhibited, while the expression of the glycolytic pathway protein (GLUT4) was enhanced. After 4 weeks of drug treatment in HF model rats, EMPG showed the same lipid metabolism pathway proteins (PPARα, RXRα, and CPT1α) and energy metabolism pathway proteins (AMPKα and sirt1) as FF, but only EMPG showed a significant decrease in MRGlu, inhibition of glycolytic pathway protein (GLUT 4) expression, and decreased cardiac fibrosis in HF rats.
Conclusion: This study led to the following conclusions. 1) Rats with HF showed a significant increase in MRGlu compared with healthy rats. 2) Empagliflozin can improve the energy supply efficiency of the heart in rats with chronic HF by inhibiting glucose metabolism and promoting lipid metabolism, thereby ameliorating energy metabolism in chronic HF. 3) 18F-FDG MicroPET/CT can observe the energy metabolism changes of HF, and the MRGlu can provide quantitative data for the changes of HF energy metabolism.

Keywords: 18F-FDG PET/CT imaging; PPARα signaling pathway; empagliflozin; heart failure; myocardial metabolism

DOI: https://doi.org/10.3389/fphar.2025.1636810

J Cell Mol Med. 2025 Nov;29(21): e70924

Sphingosine-1-Phosphate Lyase Inhibition Increases Glycolysis in Adult Cardiomyocytes and Restores Glycolytic Flux in Diabetic Cardiomyopathy.

Jens Vogt, Melissa Kim Nowak, Marcel Benkhoff, Hao Hu, Philipp Wollnitzke, Lisa Dannenberg, Amin Polzin, Bodo Levkau.

Sphingosine-1-phosphate (S1P) is a bioactive lipid that affects cardiac contractility and calcium homeostasis and exerts potent cardioprotective properties in myocardial infarction, heart failure, preconditioning. Whether and how it may affect energy metabolism in the heart is still unknown. Here, we examined S1P effects on glycolysis of adult cardiomyocytes (ACM) using Seahorse technology and observed that intracellular S1P rather than extracellular S1P potently potentiates basal glycolysis and increases glycolytic capacity. Accordingly, ACM from mice administered a S1P lyase inhibitor to prevent S1P degradation featured 3-fold higher S1P levels and a 30%-40% increase in basal glycolysis and glycolytic capacity, whereas acute S1P stimulation had no effect. Cardiomyocyte-specific GLUT4-deficient ACM were resistant to this increase, whereas ACM from S1P lyase-inhibited mice featured a 3-fold higher glucose uptake, suggesting that higher glycolysis may be a function of increased glucose influx through GLUT4. Comparing glycolysis in ACM from normal chow-fed mice with ACM from pre-diabetic mice following long-term feeding of a high caloric diet revealed a rapid and progressive loss of glycolytic potential without yet affecting cardiac function despite a beginning hypertrophy on echocardiography. Most importantly, both could be reconstituted to normal by S1P lyase inhibition. As the levels of bioactive lipids such as S1P are altered in obesity and diabetes, understanding their effects on metabolism may help reveal novel aspects of lipid biology in metabolic diseases of the heart.

Keywords: cardiomyocyte; diabetic cardiomyopathy; glycolysis; hypertrophy; metabolism; sphingosine‐1‐phosphate

DOI: https://doi.org/10.1111/jcmm.70924

Ann Med Surg (Lond). 2025 Nov;87(11): 7436-7445

Therapeutic efficacy and safety profile of SGLT-2 inhibitor dapagliflozin in heart failure with reduced and preserved ejection fraction: a systematic review and meta-analysis.

Mohammed Muthanna Al-Ezzi, Saud Muthanna Shakir-Al-Ezzi, Safa Muthanna Shakir Al-Ezzi, Pugazhendi Inban, Yarub Alalousi, Shakir Muthanna Shakir Al-Ezzi, Harshada Santosh Keluskar, Jobby John, Omniat Amir Hussin.

Background: Heart failure (HF) stands as one of the world's major causes of morbidity and mortality, yet there is insufficient therapeutic choice, particularly for patients with heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). Patients treated with SGLT2 inhibitors experience cardiovascular benefits as an additional effect beyond its glucose control capabilities. In this meta-analysis, the effectiveness and safety of SGLT2 inhibitors are assessed for patients with heart failure with reduced ejection fraction (HFrEF), HFpEF, and HFmrEF. Of particular interest is their effect on cardiovascular mortality, heart failure hospitalizations, and symptom burden.
Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Research performed on the Cochrane Library, PubMed, and Embase electronic databases retrieved randomized controlled trials (RCTs) and cohort studies that evaluated SGLT2 inhibitors treatment for patients with reduced (HFrEF), preserved (HFpEF), and mid-range (HFmrEF) ejection fraction levels. The study analyzed cardiovascular mortality together with heart failure hospitalizations and symptom improvement as well as renal function decline among heart failure patients. The analysis incorporated Hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model to pool the data. The assessment of heterogeneity used Cochran's Q test alongside the I2 statistic, and publication bias was evaluated through funnel plots and Egger's regression test.
Results: The examined research included eight studies that utilized clinical trials combined with real-world data for analysis. Both patients with HFrEF (HR: 0.74, 95% CI: 0.65-0.85, P < 0.001) and HFpEF (HR: 0.82, 95% CI: 0.73-0.92, P = 0.0008) experienced significant decreases in cardiovascular death and HF progression through SGLT2 inhibitors treatment. Benefits in HFmrEF patients were similar to those in HFpEF, mainly based on subgroup analyses in the DELIVER trial. Patients treated with SGLT2 inhibitors experienced a 24% reduction in hospital admissions compared to a control group with rates confirmed through an analysis of HR: 0.76 (95% CI: 0.63-0.93, P = 0.01). Patients taking SGLT2 inhibitors showed a 39% decrease in kidney failure risk according to analysis (HR: 0.61, 95% CI: 0.51-0.72, P < 0.001). The treatment showed positive effects on symptoms through early NT-proBNP reduction and improved self-reported patient outcomes. The assessment of heterogeneity showed moderate levels through I2 = 52.7% while detecting no meaningful publication bias.
Conclusion: With their ability to improve symptoms and lower cardiovascular mortality, hospitalizations, and renal decline, SGLT2 inhibitors offer substantial clinical benefits for all three types of heart failure: HFrEF, HFmrEF, and HFpEF. These results lend credence to their incorporation into medical therapy for heart failure that is guided by guidelines, irrespective of diabetes or ejection fraction.

DOI: https://doi.org/10.1097/MS9.0000000000003744

Front Cardiovasc Med. 2025 ;12 1616677

Metabolic perturbations in cardiomyopathies: implications for early diagnosis and targeted interventions.

Rula Al-Shahrabi, Ghadeera Al Mansoori, Muna Al-Saffar, Nadia Akawi.

Cardiomyopathy (CM) is a heterogeneous group of diseases characterized by structural and functional changes in the heart, with the exact cause often remaining unknown. CM can arise from both inherited and acquired metabolic disturbances. Alterations in energy production and substrate utilization impair the heart's contractile function and limit its ability to respond to stress. Given the complexity and dynamic nature of CM, as well as the multiple etiologies involved, we reviewed metabolomic studies employing high-throughput platforms to understand how metabolic pathways shift across CM subtypes and how these perturbations may inform clinical translation. Several recurring disruptions emerge across CM with alterations in amino acid metabolism (valine, leucine, methionine, tryptophan, tyrosine); mitochondrial redox imbalance (NAD/NADH shifts, niacinamide, acylcarnitines); and oxidative stress as central hallmarks. Each subtype, however, displays a different emphasis. For instance, hypertrophic CM is characterized by nucleotide remodeling, particularly in cases involving MYBPC3 mutations; dilated CM shows accumulation of Krebs cycle intermediates and trimethylamine-N-oxide; restrictive CM is associated with amino acid stress related to amyloidosis; tachycardia-induced CM involves fatty acid remodeling and elevated uric acid, while Takotsubo CM is linked to ketone utilization and glutamate excitotoxicity. Overall, a single metabolomic profile cannot capture CM. What emerges from this review is that subtype-specific shifts, and the way they interact, provide meaningful insight into disease mechanisms and highlight pathways with diagnostic, prognostic, and therapeutic relevance. This broader perspective shifts the focus beyond narrow comparisons, making the translational relevance of metabolomics in CM more apparent.

Keywords: LC-MS; cardiomyopathy; cardiovascular disease; heart failure; metabolomics

DOI: https://doi.org/10.3389/fcvm.2025.1616677

World J Cardiol. 2025 Oct 26. 17(10): 109731

Sodium-glucose cotransporter 2 inhibitor in heart failure patients and their outcomes: A meta-analysis of randomized controlled trials.

Saketh Parsi, Pallavi D Shirsat, Lakshmi P Mahali, Salim Surani, Rahul Kashyap.

BACKGROUND: The use of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) patients is increasing significantly, regardless of whether they have a history of diabetes. The effects of SGLT2 inhibitor on HF are likely mediated through multiple mechanisms, including suppression of the renin-angiotensin-aldosterone system (RAAS), reduction in oxidative stress leading to enhanced myocardial efficiency, and attenuation of adverse cardiac remodeling by preventing fibrosis. These pathways are fundamental to reducing mortality, improving patients' quality of life, and alleviating the burden on the United States healthcare system by decreasing HF-related hospitalizations.
AIM: To evaluate SGLT2 inhibitor effects on HF, focusing on hospitalization for HF (HHF), cardiovascular (CV) deaths, and all-cause mortality.
METHODS: A comprehensive search was conducted in PubMed for randomized controlled trials (RCTs) evaluating the effects of SGLT2 inhibitor in HF patients compared to placebo, covering the period from January 1, 2014, to January 1, 2025. The primary outcomes assessed were HHF, CV deaths, and all-cause mortality. RevMan Web 5.4.1 was used to assess the risk of bias heterogeneity and to perform the statistical analyses. A random-effects model was employed for all statistical evaluations.
RESULTS: A total of nine RCTs were included in this analysis: DELIVER, DECLARE-TIMI 58, DAPA-HF, EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, SOLOIST-WHF, EMPULSE, and VERTIS-CV. For HHF, eight trials (excluding the SOLOIST-WHF; n = 25906) were pooled, while CV deaths were assessed using data from eight trials (excluding the EMPULSE; n = 26598). Compared to placebo, SGLT2 inhibitor significantly reduced the risk of HHF (relative risk: 0.74; 95%CI: 0.71-0.77; P < 0.00001) and CV death (odds ratio: 0.88; 95%CI: 0.83-0.92; P = 0.0006). All nine trials (n = 27128) were included in the analysis of all-cause mortality. SGLT2 inhibitor were associated with a statistically significant reduction in all-cause mortality compared to placebo (OR: 0.91; 95%CI: 0.84-0.98; P = 0.02).
CONCLUSION: These results suggest that SGLT2 inhibitor significantly reduce the risk of hospitalization for HF, CV deaths, and all-cause mortality.

Keywords: All-cause mortality; Cardiovascular deaths; Heart failure; Hospitalizations for heart failure; Sodium-glucose cotransporter 2 inhibitor

DOI: https://doi.org/10.4330/wjc.v17.i10.109731