bims-hafaim 2022-06-19 papers

Issue of 2022‒06‒19
six papers selected by
Kyle McCommis
Saint Louis University

Oxid Med Cell Longev. 2022 ;2022 4253651

Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver.

Yanjie Guo, Xiaoxie Liu, Tao Li, Juanhua Zhao, Yanni Yang, Yanni Yao, Lan Wang, Beibei Yang, Gui Ren, Yanzhen Tan, Shan Jiang.

As heart failure develops, the heart utilizes ketone bodies at increased rates, indicating an adaptive stress response. Thus, increasing ketone body availability exerts protective effects against heart failure. However, although it is the widely used approach for increasing ketone body availability, the ketogenic diet shows limited cardioprotective effects against heart failure. This study was aimed at examining the effects of the ketogenic diet on heart failure and the underlying mechanisms. Pressure overload-induced heart failure was established by transverse aortic constriction (TAC) in mice. Continuous ketogenic diet feeding for 8 weeks failed to protect the heart against heart failure. It showed no significant effects on cardiac systolic function and fibrosis but aggravated cardiac diastolic function in TAC mice. Specifically, it induced systemic lipid metabolic disorder and hepatic dysfunction in TAC mice. It decreased the content of 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), a key enzyme in ketogenesis, and impaired the capacity of hepatic ketogenesis in TAC mice. It preserved the capacity of hepatic ketogenesis and exerted cardioprotective effects against heart failure, increasing cardiac function and decreasing cardiac fibrosis, in liver-specific HMGCL-overexpressed TAC mice. Importantly, we found that alternate-day ketogenic diet feeding did not impair the capacity of hepatic ketogenesis and exerted potent cardioprotective effects against heart failure. These results suggested that alternate-day but not continuous ketogenic diet protects against heart failure through preservation of ketogenesis in the liver.

DOI: https://doi.org/10.1155/2022/4253651

Heart Fail Rev. 2022 Jun 16.

Effects of SGLT2 inhibitors on cardiac structure and function.

Giuseppina Novo, Tommaso Guarino, Daniela Di Lisi, Paolo Biagioli, Erberto Carluccio.

SGLT2 inhibitors reduce cardiovascular death or hospitalization for heart failure, regardless of the presence or absence of diabetes in patients at high cardiovascular risk and in those with heart failure and reduced ejection fraction (HFrEF). In patients with HF and preserved EF, empagliflozin also showed favorable effects mainly related to the reduction of hospitalization for heart failure. These favorable effects are beyond the reduction of glycemic levels and mainly related to beneficial hemodynamic and anti-inflammatory effects of these drugs and improved cardiac energy metabolism. In this review, we aimed to evaluate the effects of SGLT2 inhibitor on cardiac remodeling and function, which is still incompletely clear.

Keywords: Cardiac remodeling; Diastolic function; Ejection fraction; Heart failure; Left ventricle; SGLT2 inhibitors; Systolic function

DOI: https://doi.org/10.1007/s10741-022-10256-4

Circ Res. 2022 Jun 14. 101161CIRCRESAHA121319817

Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure.

Zhen Li, Huijing Xia, Thomas E Sharp, Kyle B LaPenna, John W Elrod, Kevin M Casin, Ken Liu, John W Calvert, Vinh Q Chau, Fadi N Salloum, Shi Xu, Ming Xian, Noriyuki Nagahara, Traci T Goodchild, David J Lefer.

BACKGROUND: Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure.METHODS: Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency.
RESULTS: Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction.
CONCLUSIONS: Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.

Keywords: branched chain amino acid; cell death; heart failure; hydrogen sulfide; mitochondrial respiration

DOI: https://doi.org/10.1161/CIRCRESAHA.121.319817

Front Pharmacol. 2022 ;13 887991

Epigenetic Reader Bromodomain Containing Protein 2 Facilitates Pathological Cardiac Hypertrophy via Regulating the Expression of Citrate Cycle Genes.

Zhirong Lin, Zhenzhen Li, Zhen Guo, Yanjun Cao, Jingyan Li, Peiqing Liu, Zhuoming Li.

The bromodomain and extra-terminal domain proteins (BETs) family serve as epigenetic "readers", which recognize the acetylated histones and recruit transcriptional regulator complexes to chromatin, eventually regulating gene transcription. Accumulating evidences demonstrate that pan BET inhibitors (BETi) confer protection against pathological cardiac hypertrophy, a precursor progress for developing heart failure. However, the roles of BET family members, except BRD4, remain unknown in pathological cardiac hypertrophy. The present study identified BRD2 as a novel regulator in cardiac hypertrophy, with a distinct mechanism from BRD4. BRD2 expression was elevated in cardiac hypertrophy induced by β-adrenergic agonist isoprenaline (ISO) in vivo and in vitro. Overexpression of BRD2 upregulated the expression of hypertrophic biomarkers and increased cell surface area, whereas BRD2 knockdown restrained ISO-induced cardiomyocyte hypertrophy. In vivo, rats received intramyocardial injection of adeno-associated virus (AAV) encoding siBRD2 significantly reversed ISO-induced pathological cardiac hypertrophy, cardiac fibrosis, and cardiac function dysregulation. The bioinformatic analysis of whole-genome sequence data demonstrated that a majority of metabolic genes, in particular those involved in TCA cycle, were under regulation by BRD2. Real-time PCR results confirmed that the expressions of TCA cycle genes were upregulated by BRD2, but were downregulated by BRD2 silencing in ISO-treated cardiomyocytes. Results of mitochondrial oxygen consumption rate (OCR) and ATP production measurement demonstrated that BRD2 augmented cardiac metabolism during cardiac hypertrophy. In conclusion, the present study revealed that BRD2 could facilitate cardiac hypertrophy through upregulating TCA cycle genes. Strategies targeting inhibition of BRD2 might suggest therapeutic potential for pathological cardiac hypertrophy and heart failure.

Keywords: bromodomain and extra-terminal domain (BET) family; bromodomain containing protein 2 (BRD2); cardiac hypertrophy; cardiac metabolism; citrate cycle (TCA cycle)

DOI: https://doi.org/10.3389/fphar.2022.887991

Cardiovasc Diabetol. 2022 Jun 17. 21(1): 109

Effects of glycemic traits on left ventricular structure and function: a mendelian randomization study.

Sizhi Ai, Xiaoyu Wang, Shanshan Wang, Yilin Zhao, Shuxun Guo, Guohua Li, Zhigang Chen, Fei Lin, Sheng Guo, Yan Li, Jihui Zhang, Guoan Zhao.

BACKGROUND: Adverse ventricular structure and function is a key pathogenic mechanism of heart failure. Observational studies have shown that both insulin resistance (IR) and glycemic level are associated with adverse ventricular structure and function. However, whether IR and glycemic level are causally associated with cardiac structure and function remains unclear.METHODS: Genetic variants for IR, fasting insulin, HbA1c, and fasting glucose were selected based on published genome-wide association studies, which included 188,577, 108,557, 123,665, and 133,010 individuals of European ancestry, respectively. Outcome datasets for left ventricular (LV) parameters were obtained from UK Biobank Cardiovascular Magnetic Resonance sub-study (n = 16,923). Mendelian randomization (MR) analyses with the inverse-variance weighted (IVW) method were used for the primary analyses, while weighted median, MR-Egger, and MR-PRESSO were used for sensitivity analyses. Multivariable MR analyses were also conducted to examine the independent effects of glycemic traits on LV parameters.
RESULTS: In the primary IVW MR analyses, per 1-standard deviation (SD) higher IR was significantly associated with lower LV end-diastolic volume (β = - 0.31 ml, 95% confidence interval [CI] - 0.48 to - 0.14 ml; P = 4.20 × 10-4), lower LV end-systolic volume (β = - 0.34 ml, 95% CI - 0.51 to - 0.16 ml; P = 1.43 × 10-4), and higher LV mass to end-diastolic volume ratio (β = 0.50 g/ml, 95% CI 0.32 to 0.67 g/ml; P = 6.24 × 10-8) after Bonferroni adjustment. However, no associations of HbA1c and fasting glucose were observed with any LV parameters. Results from sensitivity analyses were consistent with the main findings, but with a slightly attenuated estimate. Multivariable MR analyses provided further evidence for an independent effect of IR on the adverse changes in LV parameters after controlling for HbA1c.
CONCLUSIONS: Our study suggests that genetic liability to IR rather than those of glycemic levels are associated with adverse changes in LV structure and function, which may strengthen our understanding of IR as a risk factor for heart failure by providing evidence of direct impact on cardiac morphology.

Keywords: Glycemic traits; Insulin resistance; Left ventricular structure and function; Mendelian randomization

DOI: https://doi.org/10.1186/s12933-022-01540-6

Curr Vasc Pharmacol. 2022 Jun 10.

Intermittent Fasting as Possible Treatment for Heart Failure.

Salvador Garza-González, Bianca Nieblas, María M Solbes-Gochicoa, Julio Altamirano, Noemí García.

Western-style diet often leads to food overconsumption, which triggers the development of comorbidities such as obesity, insulin resistance, hypercholesterolemia, hypertriglyceridemia, type 2 diabetes, and heart failure (HF). Several studies suggested that intermittent fasting (IF) protects against the development of those morbidities. This study presents evidence of the beneficial effects of IF on HF. Based on the current evidence, we discuss the potential molecular mechanisms by which IF works and where liver ketone bodies (KBs) play important roles. There is evidence that IF promotes a metabolic switch in highly metabolic organs, such as the heart, which increases the use of KBs during fasting. However, besides their role as energy substrates, KBs participate in the signaling pathways that control the expression of genes involved in oxidative stress protection and metabolism. Several molecular factors, such as adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor, fibroblast growth factor 21 (FGF21), sirtuins, and nuclear factor erythroid 2-related factor 2 (Nrf2) are involved. Furthermore, IF appears to maintain circadian rhythms, essential in highly metabolically active organs. Finally, we highlight the important research topics that need to be pursued to improve current knowledge and strengthen the potential of IF as a preventive and therapeutic approach to HF.

Keywords: caloric restriction; cardiovascular diseases; insulin resistance; intermittent fasting; ketosis; metabolic syndrome; obesity; oxidative stress

DOI: https://doi.org/10.2174/1570161120666220610151915