bims-hafaim 2024-12-22 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024–12–22
seven papers selected by
Kyle McCommis, Saint Louis University

SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.
Proteomic and metabolomic analyses of the human adult myocardium reveal ventricle-specific regulation in end-stage cardiomyopathies.
Impact of SGLT2 inhibitors on cardiovascular outcomes and metabolic events in Chinese han patients with chronic heart failure.
Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.
Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues.
SGLT2 Inhibition Induces Cardioprotection by Increasing Parasympathetic Activity.
NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway.

J Clin Invest. 2024 Dec 16. pii: e176708. [Epub ahead of print]134(24):

SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.

Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman.

  Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.

Keywords:  Cardiology; Glucose metabolism; Intermediary metabolism; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI176708
Commun Biol. 2024 Dec 19. 7(1): 1666

Proteomic and metabolomic analyses of the human adult myocardium reveal ventricle-specific regulation in end-stage cardiomyopathies.

Benjamin Hunter, Mengbo Li, Benjamin L Parker, Yen Chin Koay, Dylan J Harney, Evangeline Pearson, Jacob Cao, Gavin T Chen, Oneka Guneratne, Gordon K Smyth, Mark Larance, John F O'Sullivan, Sean Lal.

The left and right ventricles of the human heart are functionally and developmentally distinct such that genetic or acquired insults can cause dysfunction in one or both ventricles resulting in heart failure. To better understand ventricle-specific molecular changes influencing heart failure development, we first performed unbiased quantitative mass spectrometry on pre-mortem non-diseased human myocardium to compare the metabolome and proteome between the normal left and right ventricles. Constituents of gluconeogenesis, glycolysis, lipogenesis, lipolysis, fatty acid catabolism, the citrate cycle and oxidative phosphorylation were down-regulated in the left ventricle, while glycogenesis, pyruvate and ketone metabolism were up-regulated. Inter-ventricular significance of these metabolic pathways was then found to be diminished within end-stage dilated cardiomyopathy and ischaemic cardiomyopathy, while heart failure-associated pathways were increased in the left ventricle relative to the right within ischaemic cardiomyopathy, such as fluid sheer-stress, increased glutamine-glutamate ratio, and down-regulation of contractile proteins, indicating a left ventricular pathological bias.

DOI: https://doi.org/10.1038/s42003-024-07306-y
Diabetol Metab Syndr. 2024 Dec 18. 16(1): 299

Impact of SGLT2 inhibitors on cardiovascular outcomes and metabolic events in Chinese han patients with chronic heart failure.

Fei Li, Rewaan Baheti, Mengying Jin, Wei Xiong, Jiawei Duan, Peng Fang, Jing Wan.

   OBJECTIVE: This study aimed to evaluate the real-world impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the efficacy, safety, and metabolic profiles of patients with chronic heart failure (CHF), both with and without type 2 diabetes mellitus (T2DM).
METHODS: A cohort of 1,130 patients with reduced ejection fraction chronic heart failure (HFrEF) was recruited from Zhongnan Hospital of Wuhan University, spanning January 2021 to August 2023. Among these, 154 patients received SGLT2i therapy, while 131 patients were assigned to a non-SGLT2i group, following specified inclusion and exclusion criteria. The association between SGLT2i therapy and the risk of primary and secondary endpoints was analyzed, alongside the effect of guideline-recommended heart failure medications at varying dosages on Major Adverse Cardiovascular Events (MACE).
RESULTS: SGLT2i treatment led to reductions in blood pressure, uric acid, NT-proBNP, and pulmonary artery pressure, while increasing body mass index (BMI) and left ventricular ejection fraction (LVEF) in CHF patients. Multivariate Cox regression analysis revealed that SGLT2i therapy reduced the primary endpoint risk by 40.3% (HR 0.597, 95% CI 0.356-0.973, p = 0.047). Univariate Cox regression indicated that SGLT2i might also reduce the incidence of new diagnoses of atrial fibrillation, non-fatal acute myocardial infarction, and MACE in CHF patients. Moreover, the use of a four-drug combination for heart failure management was associated with a lower risk of MACE compared to monotherapy.
CONCLUSION: SGLT2i therapy not only enhances LVEF but also significantly reduces ambulatory blood pressure, uric acid, fasting blood glucose, pulmonary artery pressure, and NT-proBNP levels in CHF patients. Additionally, SGLT2i improves prognosis by lowering the risk of both primary and secondary endpoints. Compared to monotherapy, a four-drug regimen for CHF substantially reduces the risk of MACE, supporting the effectiveness of comprehensive treatment strategies.

Keywords:  Cardiovascular endpoints; Heart failure; Metabolism; Sodium-glucose cotransporter-2 inhibitors; Therapeutic drugs

DOI:  https://doi.org/10.1186/s13098-024-01553-z
J Clin Med. 2024 Dec 04. pii: 7391. [Epub ahead of print]13(23):

Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.

Urna Kansakar, Crystal Nieves Garcia, Gaetano Santulli, Jessica Gambardella, Pasquale Mone, Stanislovas S Jankauskas, Angela Lombardi.

  Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes.

Keywords:  BHB; SGLT2 inhibitors; cardiovascular disease; diabetes; exogenous ketones; metabolism; supplements

DOI:  https://doi.org/10.3390/jcm13237391
J Clin Invest. 2024 Dec 16. pii: e187097. [Epub ahead of print]134(24):

Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues.

Justin H Berger, Brian N Finck.

Despite the impressive clinical benefits and widespread adoption of sodium glucose cotransporter 2 inhibitors (SGLT2i) to treat all classes of heart failure, their cardiovascular mechanisms of action are poorly understood. Proposed mechanisms range broadly and include enhanced ketogenesis, where the mild ketosis associated with SGLT2i use is presumed to be beneficial. However, in this issue of the JCI, carefully conducted metabolic flux studies by Goedeke et al. comparing the effects of SGLT2i and exogenous ketones suggest differential effects. Thus, the mechanisms of action for SGLT2i are likely pleiotropic, and further work is needed to fully understand their beneficial effects.

DOI: https://doi.org/10.1172/JCI187097
Circ Res. 2024 Dec 17.

SGLT2 Inhibition Induces Cardioprotection by Increasing Parasympathetic Activity.

Maryna V Basalay, Alla Korsak, Zhenhe He, Alexander V Gourine, Sean M Davidson, Derek M Yellon.



Keywords:  glucose; heart failure; sodium-glucose transporter 2; sodium-glucose transporter 2 inhibitors; stroke volume

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324708
Cardiovasc Res. 2024 Dec 06. pii: cvae250. [Epub ahead of print]

NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway.

Anna Zoccarato, Ioannis Smyrnias, Christina M Reumiller, Anne D Hafstad, Mei Chong, Daniel A Richards, Celio X C Santos, Asjad Visnagri, Sharwari Verma, Daniel I Bromage, Min Zhang, Xiaohong Zhang, Greta Sawyer, Richard Thompson, Ajay M Shah.

AIMS: The transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 enhances resistance of mouse hearts to chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. Here, we investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress.
METHODS AND RESULTS: Cardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 redirected glucose metabolism towards the pentose phosphate pathway (PPP), a branch pathway of glycolysis, and mitigated pressure overload-induced cardiomyocyte death and cardiac dysfunction. Activation of NRF2 also protected against myocardial infarction-induced DNA damage in remote myocardium and cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP.
CONCLUSIONS: These results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby generating NADPH and providing nucleotides to prevent stress-induced DNA damage and cardiac dysfunction.

DOI: https://doi.org/10.1093/cvr/cvae250