bims-hafaim 2023-01-29 papers

Issue of 2023–01–29
six papers selected by
Kyle McCommis, Saint Louis University

Heart Fail Rev. 2023 Jan 28.

Changes of energy metabolism in failing heart and its regulation by SIRT3.

Xiao Wang, Yuting Huang, Kai Zhang, Feng Chen, Tong Nie, Yun Zhao, Feng He, Jingyu Ni.

Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.

Keywords: Fatty acids; Glucose; Heart failure; Ketone body; Mitochondrion; SIRT3

DOI: https://doi.org/10.1007/s10741-023-10295-5

Eur J Pharmacol. 2023 Jan 20. pii: S0014-2999(23)00042-0. [Epub ahead of print]942 175531

Empagliflozin ameliorates cardiac dysfunction in heart failure mice via regulating mitochondrial dynamics.

YiTing Lyu, JunYu Huo, WanYing Jiang, Wen Yang, ShengChan Wang, ShiGeng Zhang, YanDi Cheng, ZhiXin Jiang, QiJun Shan.

Empagliflozin has cardioprotective effects in patients with heart failure (HF). However, the mechanism by which empagliflozin protects against HF remains controversial. Study aimed to evaluate the effect of empagliflozin on myocardial fibrosis and cardiac function in HF mice and its possible mechanism. C57BL/6 mice were induced with HF by ligation of the left anterior descending coronary artery. At 4 weeks postoperation, mice were randomly given normal saline or empagliflozin for 8 weeks. Echocardiography was used to assess cardiac function. Masson's staining, immunohistochemistry and Western blot analysis were used to detect the degree of myocardial fibrosis. Changes in mitochondria were detected by observing mitochondrial morphology, measuring mitochondrial dynamics-related proteins and analysing the levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP) and adenosine diphosphate (ADP). The mitochondrial fission inhibitor, mdivi1, was used to detect the relationship between mitochondrial dysfunction and cardiac dysfunction in HF mice. HF led to myocardial fibrosis and cardiac dysfunction. However, treatment with empagliflozin reduced these effects. Empagliflozin inhibited mitochondrial fission and improved energy metabolic efficiency in HF mice by regulating the expression of mitochondrial dynamics-related proteins. Similarly, mdivi1 attenuated mitochondrial dysfunction and cardiac dysfunction by inhibiting mitochondrial fission in HF mice. Regulation of mitochondrial dynamics, especially inhibition of mitochondrial fission, may be a potential target for reducing cardiac damage in patients with HF. Empagliflozin improved myocardial fibrosis and cardiac dysfunction by modulating mitochondrial dynamics in HF mice. Thus, the cardiac protective effect of empagliflozin may be related to the normalization of mitochondria and the increase in ATP production.

Keywords: Cardiac dysfunction; Empagliflozin; Heart failure; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion

DOI: https://doi.org/10.1016/j.ejphar.2023.175531

JACC Basic Transl Sci. 2022 Nov;7(11): 1161-1179

Inefficient Batteries in Heart Failure: Metabolic Bottlenecks Disrupting the Mitochondrial Ecosystem.

Brian Schwartz, Petro Gjini, Deepa M Gopal, Jessica L Fetterman.

Mitochondrial abnormalities have long been described in the setting of cardiomyopathies and heart failure (HF), yet the mechanisms of mitochondrial dysfunction in cardiac pathophysiology remain poorly understood. Many studies have described HF as an energy-deprived state characterized by a decline in adenosine triphosphate production, largely driven by impaired oxidative phosphorylation. However, impairments in oxidative phosphorylation extend beyond a simple decline in adenosine triphosphate production and, in fact, reflect pervasive metabolic aberrations that cannot be fully appreciated from the isolated, often siloed, interrogation of individual aspects of mitochondrial function. With the application of broader and deeper examinations into mitochondrial and metabolic systems, recent data suggest that HF with preserved ejection fraction is likely metabolically disparate from HF with reduced ejection fraction. In our review, we introduce the concept of the mitochondrial ecosystem, comprising intricate systems of metabolic pathways and dynamic changes in mitochondrial networks and subcellular locations. The mitochondrial ecosystem exists in a delicate balance, and perturbations in one component often have a ripple effect, influencing both upstream and downstream cellular pathways with effects enhanced by mitochondrial genetic variation. Expanding and deepening our vantage of the mitochondrial ecosystem in HF is critical to identifying consistent metabolic perturbations to develop therapeutics aimed at preventing and improving outcomes in HF.

Keywords: ADP, adenosine diphosphate; ANT1, adenine translocator 1; ATP, adenosine triphosphate; CVD, cardiovascular disease; DCM, dilated cardiomyopathy; DRP-1, dynamin-related protein 1; EET, epoxyeicosatrienoic acid; FADH2/FAD, flavin adenine dinucleotide; HETE, hydroxyeicosatetraenoic acid; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HIF1α, hypoxia-inducible factor 1α; LV, left ventricle; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; NADH/NAD+, nicotinamide adenine dinucleotide; OPA1, optic atrophy protein 1; OXPHOS, oxidative phosphorylation; PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; SIRT1-7, sirtuins 1-7; cardiomyopathy; heart failure; iPLA2γ, Ca2+-independent mitochondrial phospholipase; mPTP, mitochondrial permeability transition pore; metabolism; mitochondria; mitochondrial ecosystem; mtDNA, mitochondrial DNA

DOI: https://doi.org/10.1016/j.jacbts.2022.03.017

Curr Probl Cardiol. 2023 Jan 18. pii: S0146-2806(23)00014-2. [Epub ahead of print] 101597

Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure with Mildly Reduced or Preserved Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Mahmoud Ismayl, Muhannad Aboud Abbasi, Abdullah Al-Abcha, Edward El-Am, Scott Lundgren, Andrew M Goldsweig, Nandan S Anavekar.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of heart failure (HF) hospitalizations and cardiovascular mortality among patients with HF and left ventricular ejection fraction (LVEF) ≤40%. There is emerging evidence of the benefits of SGLT2i in HF patients with a higher LVEF (>40%). We aimed to evaluate the benefits of SGLT2i in different subgroups of patients with HF and LVEF >40%.
METHODS: We searched PubMed, EMBASE, clinicaltrials.gov, Cochrane, and Google Scholar for randomized controlled trials (RCTs) comparing outcomes of SGLT2i vs. placebo in patients with HF and LVEF >40%. The hazard ratios (HRs) and 95% confidence intervals (CIs) in each study were used for the meta-analysis. The primary composite outcome (PCO) was HF hospitalization or cardiovascular mortality. Secondary outcomes included HF hospitalization, cardiovascular mortality, and all-cause mortality.
RESULTS: Six RCTs with 15,989 patients were included (median follow-up=27.3 months, 40.8% females). In patients with HF and LVEF >40%, SGLT2i were associated with significantly lower PCO compared to placebo (HR 0.80; 95% CI 0.74-0.86; p<0.001). This was consistent across 10/13 subgroups examined, including LVEF. SGLT2i also reduced HF hospitalization but not cardiovascular or all-cause mortality. Patients <65 years old, from racial minorities, or from Asia receiving SGLT2i did not demonstrate a significant reduction in PCO.
CONCLUSIONS: SGLT2i significantly reduce the combined risk of HF hospitalization or cardiovascular mortality among patients with HF and LVEF >40%. However, younger patients, racial minorities, and patients from Asia did not demonstrate such a reduction. Further research is necessary to identify the reasons for such disparities.

Keywords: Dapagliflozin; Empagliflozin; HFmrEF; HFpEF; SGLT2i; Sotagliflozin

DOI: https://doi.org/10.1016/j.cpcardiol.2023.101597

Herz. 2023 Jan 26.

[Mechano-energetic defects in heart failure].

Christoph Maack.

Heart failure is characterized by defects in excitation-contraction coupling, energetic deficit and oxidative stress. The energy for cardiac contraction and relaxation is provided in mitochondria, whose function is tightly regulated by excitation-contraction coupling in cardiac myocytes. In heart failure with reduced ejection fraction (HFrEF), alterations in the ion balance in cardiac myocytes impair mitochondrial Ca2+ uptake, which is required for activation of the Krebs cycle, causing an energetic deficit and oxidative stress in mitochondria. Recent clinical studies suggest that in heart failure with preserved ejection fraction (HFpEF), in stark contrast to HFrEF, hypercontractility often occurs as an attempt to compensate for a pathological increase in systemic and pulmonary vascular resistance. This hypercontractility increases cardiac energy and oxygen demands at rest and reduces the contractile, diastolic and coronary reserves, preventing an adequate increase in cardiac output during exercise. Moreover, increased contractility causes long-term maladaptive remodeling processes due to oxidative stress and redox-sensitive prohypertrophic signaling pathways. As overweight and diabetes, particularly in the interplay with hemodynamic stress, are important risk factors for the development of HFpEF, interventions targeting metabolism in particular could ameliorate the development and progression of HFpEF.

Keywords: Cardiac myocytes; Excitation-contraction coupling; Hypercontractility; Ionic balance; Metabolic interventions

DOI: https://doi.org/10.1007/s00059-022-05161-3

Front Cardiovasc Med. 2022 ;9 1066822

Proteome-wide analysis of lysine β-hydroxybutyrylation in the myocardium of diabetic rat model with cardiomyopathy.

Weiguang Luo, Mei He, Qizhi Luo, Yi Li.

Lysine ß-hydroxybutyrylation (kbhb), a novel modification of lysine residues with the ß-hydroxybuty group, is associated with ketone metabolism in numerous species. However, its potential role in diabetes, especially in diabetic cardiomyopathy (DCM), remains largely unexplored. In this study, using affinity enrichment and liquid chromatography-mass spectrometry (LC-MS/MS) method, we quantitatively analyze the kbhb residues on heart tissues of a DCM model rat. A total of 3,520 kbhb sites in 1,089 proteins were identified in this study. Further analysis showed that 336 kbhb sites in 143 proteins were differentially expressed between the heart tissues of DCM and wild-type rats. Among them, 284 kbhb sites in 96 proteins were upregulated, while 52 kbhb sites in 47 proteins were downregulated. Bioinformatic analysis of the proteomic results revealed that these kbhb-modified proteins were widely distributed in various components and involved in a wide range of cellular functions and biological processes (BPs). Functional analysis showed that the kbhb-modified proteins were involved in the tricarboxylic acid cycle, oxidative phosphorylation, and propanoate metabolism. Our findings demonstrated how kbhb is related to many metabolic pathways and is mainly involved in energy metabolism. These results provide the first global investigation of the kbhb profile in DCM progression and can be an essential resource to explore DCM's pathogenesis further.

Keywords: diabetic cardiomyopathy; liquid chromatography-mass spectrometry; lysine β-hydroxybutyrylation; post-translational modification; proteomics

DOI: https://doi.org/10.3389/fcvm.2022.1066822