bims-hafaim 2024-08-04 papers

Issue of 2024‒08‒04
seven papers selected by
Kyle McCommis, Saint Louis University

Rev Cardiovasc Med. 2022 Nov;23(11): 374

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure with a Preserved Ejection Fraction: A Meta-Analysis of Randomized Controlled Trials.

Yake Lou, Qi Yang, Weicong Zhang, Ying Yu, Jing Huang.

Background: Heart failure is prevalent worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in heart failure patients with reduced ejection fraction, whether SGLT2i are effective in heart failure with preserved ejection fraction (HFpEF) remains to be determined.Methods: All relevant citations in the PubMed, Embase and Cochrane databases were identified from inception to September, 2022. The primary outcome was a composite endpoint of cardiovascular death and hospitalization for heart failure (HHF). A subgroup analysis was performed according to diabetes mellitus status and the ejection fraction. Secondary endpoints were cardiovascular death, hospitalization for heart failure and all cause death.
Results: Seven studies involving 11,604 patients were included in the meta-analysis. Compared with placebo, sodium-glucose cotransporter 2 inhibitors reduced the incidence of the primary outcome by 24%, with an odds ratio (OR) and 95% confidence interval (CI) 0.76 [0.69, 0.84]. For secondary outcomes, sodium-glucose cotransporter 2 inhibitors were associated with a lower incidence of hospitalization for heart failure, but not cardiovascular or all-cause death; the OR and 95% CI were 0.73 [0.66, 0.82], 0.92 [0.81, 1.04], 0.96 [0.88, 1.05], respectively.
Conclusions: This study proves the clinical efficacy of SGLT2i for treatment of HFpEF patients with or without diabetes, which was mainly driven by prevention of HHF rather than cardiovascular or all-cause death.

Keywords: canagliflozin; dapagliflozin; empagliflozin; heart failure; preserved ejection fraction; reduced ejection fraction; sodium-glucose cotransporter 2 inhibitors; sotagliflozin

DOI: https://doi.org/10.31083/j.rcm2311374

Front Mol Med. 2024 ;4 1433102

Editorial: Mitochondrial dysfunction affects mechano-energetic coupling in heart failure.

Jan Dudek, Julia Ritterhoff.

Keywords: cardiomyopathy; heart failure; mechano-energetic coupling; metabolism; mitochondria

DOI: https://doi.org/10.3389/fmmed.2024.1433102

bioRxiv. 2024 Jul 27. pii: 2024.07.26.605401. [Epub ahead of print]

SGLT2 inhibitors activate pantothenate kinase in the human heart.

Nicholas Forelli, Deborah Eaton, Jiten Patel, Caitlyn E Bowman, Ryo Kawakami, Ivan A Kuznetsov, Kristina Li, Claire Brady, Kenneth Bedi, Yijun Yang, Kaustubh Koya, Emily Megill, Daniel S Kanter, Louis G Smith, Gregory R Bowman, Nathaniel Snyder, Jonathan Edwards, Kenneth Margulies, Zoltan Arany.

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.

DOI: https://doi.org/10.1101/2024.07.26.605401

Phytomedicine. 2024 Jul 20. pii: S0944-7113(24)00552-X. [Epub ahead of print]133 155894

Cinnamaldehyde activates AMPK/PGC-1α pathway via targeting GRK2 to ameliorate heart failure.

Zhanchi Xu, Minghui Li, Dongxin Lyu, Haiming Xiao, Shanshan Li, Zhuoming Li, Min Li, Junhui Xiao, Heqing Huang.

BACKGROUND: According to recent research, treating heart failure (HF) by inhibiting G protein-coupled receptor kinase 2 (GRK2) to improve myocardial energy metabolism has been identified as a potential approach. Cinnamaldehyde (CIN), a phenylpropyl aldehyde compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. However, whether CIN inhibits GRK2 to ameliorate myocardial energy metabolism in HF is still unclear.PURPOSE: This study examines the effects of CIN on GRK2 and myocardial energy metabolism to elucidate its underlying mechanism to treat HF.
METHODS: The isoproterenol (ISO) induced HF model in vivo and in vitro were constructed using Sprague-Dawley (SD) rats and primary neonatal rat cardiomyocytes (NRCMs). Based on this, the effects of CIN on myocardial energy metabolism and GRK2 were investigated. Additionally, validation experiments were conducted after interfering and over-expressing GRK2 in ISO-induced NRCMs to verify the regulatory effect of CIN on GRK2. Furthermore, binding capacity between GRK2 and CIN was explored by Cellular Thermal Shift Assay (CETSA) and Microscale Thermophoresis (MST).
RESULTS: In vivo and in vitro, CIN significantly improved HF as demonstrated by reversing abnormal changes in myocardial injury markers, inhibiting myocardial hypertrophy and decreasing myocardial fibrosis. Additionally, CIN promoted myocardial fatty acid metabolism to ameliorate myocardial energy metabolism disorder by activating AMPK/PGC-1α signaling pathway. Moreover, CIN reversed the inhibition of myocardial fatty acid metabolism and AMPK/PGC-1α signaling pathway by GRK2 over-expression in ISO-induced NRCMs. Meanwhile, CIN had no better impact on the stimulation of cardiac fatty acid metabolism and the AMPK/PGC-1α signaling pathway in ISO-induced NRCMs when GRK2 was disrupted. Noticeably, CETSA and MST confirmed that CIN binds to GRK2 directly. The binding of CIN and GRK2 promoted the ubiquitination degradation of GRK2 mediated by murine double mimute 2.
CONCLUSION: This study demonstrates that CIN exerts a protective intervention in HF by targeting GRK2 and promoting its ubiquitination degradation to activate AMPK/PGC-1α signaling pathway, ultimately improving myocardial fatty acid metabolism.

Keywords: AMPK/PGC-1α pathway; Cinnamaldehyde; Fatty acid metabolism; GRK2; Heart failure

DOI: https://doi.org/10.1016/j.phymed.2024.155894

J Lipid Res. 2024 Jul 31. pii: S0022-2275(24)00117-2. [Epub ahead of print] 100612

SCD4 deficiency decreases cardiac steatosis and prevents cardiac remodeling in mice fed a high-fat diet.

Marcin Wolosiewicz, Volodymyr V Balatskyi, Monika K Duda, Anna Filip, James M Ntambi, Viktor O Navrulin, Pawel Dobrzyn.

Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes formation of the first double bond in the carbon chain of saturated fatty acids. Four isoforms of SCD have been identified in mice, the most poorly characterized of which is SCD4, which is cardiac-specific. In the present study, we investigated the role of SCD4 in systemic and cardiac metabolism. We used wildtype (WT) and global SCD4 knockout mice that were fed standard laboratory chow or a high-fat diet (HFD). SCD4 deficiency reduced body adiposity and decreased hyperinsulinemia and hypercholesterolemia in HFD-fed mice. The loss of SCD4 preserved heart morphology in the HFD condition. Lipid accumulation decreased in the myocardium in SCD4-deficient mice and in HL-1 cardiomyocytes with knocked out Scd4 expression. This was associated with an increase in the rate of lipolysis and, more specifically, adipose triglyceride lipase (ATGL) activity. Possible mechanisms of ATGL activation by SCD4 deficiency include lower protein levels of the ATGL inhibitor G0S2 and greater activation by protein kinase A under lipid overload conditions. Moreover, we observed higher intracellular Ca2+ levels in HL-1 cells with silenced Scd4 expression. This may explain the activation of protein kinase A in response to higher Ca2+ levels. Additionally, the loss of SCD4 inhibited mitochondrial enlargement, NADH overactivation, and reactive oxygen species overproduction in the heart in HFD-fed mice. In conclusion, SCD4 deficiency activated lipolysis, resulting in a reduction of cardiac steatosis, prevented the induction of left ventricular hypertrophy, and reduced reactive oxygen species levels in the heart in HFD-fed mice.

Keywords: ATGL; heart; lipid droplets; metabolism; mitochondria

DOI: https://doi.org/10.1016/j.jlr.2024.100612

Rev Cardiovasc Med. 2023 Jan;24(1): 1

SGLT2 Inhibition in Heart Failure with Preserved Ejection Fraction - The New Frontier.

Inês Aguiar-Neves, Diogo Santos-Ferreira, Ricardo Fontes-Carvalho.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with high morbidity and increasing socio-economic burden, compounded by the lack of effective treatment options available to treat this disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have previously been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes and patients with heart failure with reduced ejection fraction (HFrEF). Recent major clinical trials with SGLT2 inhibitors, both empagliflozin and dapagliflozin, have now demonstrated improved cardiovascular outcomes in patients with HFpEF and a significant reduction in heart failure hospitalization. Current evidence shows a potential for cardiovascular benefits with SGLT2 inhibition that is consistent across the spectrum of ejection fraction, age, New York Heart Association (NYHA) functional class, natriuretic peptide levels and diabetes status. Although the cardioprotective mechanisms behind SGLT2 inhibition remain unclear, ongoing clinical studies aim to clarify the role of SGLT2 inhibitors on biomarkers of cardiac metabolism, diastolic function and exercise capacity in HFpEF. This article analyzes current clinical evidence from randomized controlled trials and meta-analyses and explores the potential cardioprotective mechanisms of SGLT2 inhibitors, while also looking towards the future of SGLT2 inhibition in HFpEF.

Keywords: HFpEF; SGLT2 inhibitor; diabetes; gliflozin; heart failure

DOI: https://doi.org/10.31083/j.rcm2401001