bims-hafaim 2023-06-04 papers

Issue of 2023–06–04
six papers selected by
Kyle McCommis, Saint Louis University

Metabolism. 2023 May 31. pii: S0026-0495(23)00212-3. [Epub ahead of print] 155608

Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction.

Salva R Yurista, Robert A Eder, Aidan Welsh, William Jiang, Shi Chen, Anna N Foster, Adam Mauskapf, W H Wilson Tang, William J Hucker, Jaume Coll-Font, Anthony Rosenzweig, Christopher T Nguyen.

BACKGROUND: Myocardial infarction (MI) is a major risk factor for the development of heart failure with reduce ejection fraction (HFrEF). While previous studies have focused on HFrEF, the cardiovascular effects of ketone bodies in acute MI are unclear. We examined the effects of oral ketone supplementation as a potential treatment strategy in a swine acute MI model.
METHODS: Farm pigs underwent percutaneous balloon occlusion of the LAD for 80 min followed by 72 h reperfusion period. Oral ketone ester or vehicle was administered during reperfusion and continued during the follow-up period.
RESULTS: Oral KE supplementation induced ketonemia 2-3 mmol/l within 30 min after ingestion. KE increased ketone (βHB) extraction in healthy hearts without affecting glucose and fatty acid (FA) consumption. During reperfusion, the MI hearts consumed less FA with no change in glucose consumption, whereas hearts from MI-KE-fed animals consumed more βHB and FA, as well as improved myocardial ATP production. A significant elevation of infarct T2 values indicative of inflammation was found only in untreated MI group compared to sham. Concordantly, cardiac expression of inflammatory markers, oxidative stress, and apoptosis were reduced by KE. RNA-seq analysis identified differentially expressed genes related to mitochondrial energy metabolism and inflammation.
CONCLUSIONS: Oral KE supplementation induced ketosis and enhanced myocardial βHB extraction in both healthy and infarcted hearts. Acute oral supplementation with KE favorably altered cardiac substrate uptake and utilization, improved cardiac ATP levels, and reduced cardiac inflammation following MI.

Keywords: Inflammation; Ischemia reperfusion injury; Ketone; Ketone ester; Metabolism; Myocardial infarction

DOI: https://doi.org/10.1016/j.metabol.2023.155608

Exp Mol Med. 2023 Jun 01.

Comparison of the effects of empagliflozin and sotagliflozin on a zebrafish model of diabetic heart failure with reduced ejection fraction.

Inho Kim, Hyun-Jai Cho, Soo Lim, Seung Hyeok Seok, Hae-Young Lee.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) and dual SGLT1/2 inhibitor sotagliflozin (SOTA) are emerging as heart failure (HF) medications in addition to having glucose-lowering effects in diabetes mellitus (DM). However, the precise mechanism underlying this cardioprotective effect has not yet been elucidated. Here, we evaluated the effects of EMPA and SOTA in a zebrafish model of DM combined with HF with reduced ejection fraction (DM-HFrEF). To compare the effects of the two drugs, survival, locomotion, and myocardial contractile function were evaluated. The structural binding and modulating effects of the two medications on sodium-hydrogen exchanger 1 (NHE1) were evaluated in silico and in vitro. DM-HFrEF zebrafish showed impaired cardiac contractility and decreased locomotion and survival, all of which were improved by 0.2-5 μM EMPA or SOTA treatment. However, the 25 μM SOTA treatment group had worse survival rates and less locomotion preservation than the EMPA treatment group at the same concentration, and pericardial edema and an uninflated swim bladder were observed. SOTA, EMPA and cariporide (CARI) showed similar structural binding affinities to NHE1 in a molecular docking analysis and drug response affinity target stability assay. In addition, EMPA, SOTA, and CARI effectively reduced intracellular Na+ and Ca2+ changes through the inhibition of NHE1 activity. These findings suggest that both EMPA and SOTA exert cardioprotective effects in the DM-HFrEF zebrafish model by inhibiting NHE1 activity. In addition, despite the similar cardioprotective effects of the two drugs, SOTA may be less effective than EMPA at high concentrations.

DOI: https://doi.org/10.1038/s12276-023-01002-3

J Nutr Biochem. 2023 May 26. pii: S0955-2863(23)00103-1. [Epub ahead of print] 109370

Gut-derived short-chain fatty acids bridge cardiac and systemic metabolism and immunity in heart failure.

Anzhu Wang, Zhendong Li, Zhuo Sun, Dawu Zhang, Xiaochang Ma.

Heart failure (HF) represents a group of complex clinical syndromes with high morbidity and mortality and has a significant global health burden. Inflammation and metabolic disorders are closely related to the development of HF, which are complex and depend on the severity and type of HF and common metabolic comorbidities such as obesity and diabetes. An increasing body of evidence indicates the importance of short-chain fatty acids (SCFAs) in regulating cardiac function. In addition, SCFAs represent a unique class of metabolites and play a distinct role in shaping systemic immunity and metabolism. In this review, we reveal the role of SCFAs as a link between metabolism and immunity, which regulate cardiac and systemic immune and metabolic systems by acting as energy substrates, inhibiting the expression of histone deacetylase (HDAC) regulated genes and activating G protein-coupled receptors (GPCRs) signaling. Ultimately cardiac efficiency is improved, cardiac inflammation alleviated and cardiac function in failing hearts enhanced. In conclusion, SCFAs represent a new therapeutic approach for HF.

Keywords: dietary fiber; gut microbiota; heart failure; immunity; metabolism; short-chain fatty acids

DOI: https://doi.org/10.1016/j.jnutbio.2023.109370

Eur Heart J. 2023 Jun 01. pii: ehad273. [Epub ahead of print]

Sodium-glucose cotransporter 2 inhibitors vs. sitagliptin in heart failure and type 2 diabetes: an observational cohort study.

Edouard L Fu, Elisabetta Patorno, Brendan M Everett, Muthiah Vaduganathan, Scott D Solomon, Raisa Levin, Sebastian Schneeweiss, Rishi J Desai.

AIMS: The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differences between agents within the SGLT2i class or for reduced and preserved ejection fraction.
METHODS AND RESULTS: Using Medicare claims data (April 2013 to December 2019), 16 253 SGLT2i initiators vs. 43 352 initiators of sitagliptin aged ≥65 years with type 2 diabetes and HF were included. The primary outcome was a composite of all-cause mortality, hospitalization for HF or urgent visit requiring intravenous diuretics; secondary outcomes included its individual components. Propensity score fine stratification weighted Cox regression was used to adjust for 100 pre-exposure characteristics. Mean age was 74 years; 49.8% were women. Initiation of SGLT2i vs. sitagliptin was associated with a lower risk of the primary composite outcome [adjusted hazard ratio (HR) 0.72; 95% confidence interval 0.67-0.77]. The adjusted HRs were 0.70 (0.63-0.78) for all-cause mortality, 0.64 (0.58-0.70) for hospitalization for HF, and 0.77 (0.69-0.86) for urgent visit requiring intravenous diuretics. Similar associations with the primary composite outcome were observed for all three agents within the SGLT2i class, for reduced and preserved ejection fraction, and subgroups based on demographics, comorbidities, and other HF treatments. Bias-calibrated HRs for the primary endpoint using negative and positive control outcomes ranged between 0.81 and 0.89, suggesting that the observed benefit could not be fully explained by residual confounding.
CONCLUSION: In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HF and type 2 diabetes compared with sitagliptin, with no evidence of heterogeneity across the SGLT2i class or across ejection fraction.

Keywords: Cardiovascular diseases; Cohort studies; Heart failure; Sodium–glucose cotransporter 2 inhibitors; Type 2 diabetes mellitus

DOI: https://doi.org/10.1093/eurheartj/ehad273

Nat Cell Biol. 2023 Jun 01.

Lipid droplet-associated lncRNA LIPTER preserves cardiac lipid metabolism.

Lei Han, Dayang Huang, Shiyong Wu, Sheng Liu, Cheng Wang, Yi Sheng, Xiongbin Lu, Hal E Broxmeyer, Jun Wan, Lei Yang.

Lipid droplets (LDs) are cellular organelles critical for lipid homeostasis, with intramyocyte LD accumulation implicated in metabolic disorder-associated heart diseases. Here we identify a human long non-coding RNA, Lipid-Droplet Transporter (LIPTER), essential for LD transport in human cardiomyocytes. LIPTER binds phosphatidic acid and phosphatidylinositol 4-phosphate on LD surface membranes and the MYH10 protein, connecting LDs to the MYH10-ACTIN cytoskeleton and facilitating LD transport. LIPTER and MYH10 deficiencies impair LD trafficking, mitochondrial function and survival of human induced pluripotent stem cell-derived cardiomyocytes. Conditional Myh10 deletion in mouse cardiomyocytes leads to LD accumulation, reduced fatty acid oxidation and compromised cardiac function. We identify NKX2.5 as the primary regulator of cardiomyocyte-specific LIPTER transcription. Notably, LIPTER transgenic expression mitigates cardiac lipotoxicity, preserves cardiac function and alleviates cardiomyopathies in high-fat-diet-fed and Leprdb/db mice. Our findings unveil a molecular connector role of LIPTER in intramyocyte LD transport, crucial for lipid metabolism of the human heart, and hold significant clinical implications for treating metabolic syndrome-associated heart diseases.

DOI: https://doi.org/10.1038/s41556-023-01162-4

Front Cardiovasc Med. 2023 ;10 1143658

Scientific evidence of sodium-glucose cotransporter-2 inhibitors for heart failure with preserved ejection fraction: an umbrella review of systematic reviews and meta-analyses.

Runmin Li, Guohua Dai, Hui Guan, Wulin Gao, Lili Ren, Xingmeng Wang, Huiwen Qu.

Background: It remains controversial whether sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are effective in treating heart failure with preserved ejection fraction (HFpEF).
Purpose: The objective of this umbrella review is to provide a summary of the available evidence regarding the efficacy and safety of SGLT-2is for the treatment of HFpEF.
Methods: We extracted pertinent systematic reviews and meta-analyses (SRs/MAs) from PubMed, EMBASE, and the Cochrane Library that were published between the inception of the database and December 31, 2022. Two independent investigators assessed the methodological quality, risk of bias, report quality, and evidence quality of the included SRs/MAs in randomized controlled trials (RCTs). We further evaluated the overlap of the included RCTs by calculating the corrected covered area (CCA) and assessed the reliability of the effect size by performing excess significance tests. Additionally, the effect sizes of the outcomes were repooled to obtain objective and updated conclusions. Egger's test and sensitivity analysis were used to clarify the stability and reliability of the updated conclusion.
Results: This umbrella review included 15 SRs/MAs, and their methodological quality, risk of bias, report quality, and evidence quality were unsatisfactory. The total CCA for 15 SRs/MAs was 23.53%, indicating a very high level of overlap. The excess significance tests did not reveal any significant results. Our updated MA demonstrated that the incidence of the composite of hospitalization for heart failure (HHF) or cardiovascular death (CVD), first HHF, total HHF, and adverse events as well as the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and 6 min-walk distance (6MWD) were all substantially improved in the SGLT-2i intervention group compared to the control group. However, there was limited evidence that SGLT-2is could improve CVD, all-cause death, plasma B-type natriuretic peptide (BNP) level, or plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level. Egger's test and sensitivity analysis proved that the conclusion was stable and reliable.
Conclusions: SGLT-2 is a potential treatment for HFpEF with favourable safety. Given the dubious methodological quality, reporting quality, evidence quality, and high risk of bias for certain included SRs/MAs, this conclusion must be drawn with caution.
Systematic Review Registration: https://inplasy.com/, doi: 10.37766/inplasy2022.12.0083, identifier INPLASY2022120083.

Keywords: evidence quality assessment; heart failure with preserved ejection fraction; meta-analysis; overview; sodium-glucose cotransporter-2 inhibitor; systematic review; umbrella review

DOI: https://doi.org/10.3389/fcvm.2023.1143658