bims-hafaim 2022-09-25 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022‒09‒25
eleven papers selected by
Kyle McCommis
Saint Louis University

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy.
Independent and combined effects of liraglutide and aerobic interval training on glycemic control and cardiac protection in diabetic cardiomyopathy rats.
"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency".
Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy.
The diagnostic value of peroxisome proliferator-activated receptor-γ coactivator-1α in identifying different chronic heart failure phenotypes.
FGF21-Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity.
Mitochondrial quality control mechanisms as molecular targets in diabetic heart.
Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart.
Optimal Pharmacologic Treatment of Heart Failure With Preserved and Mildly Reduced Ejection Fraction: A Meta-analysis.
Insulin Resistance Is Associated With Heart Failure With Recovered Ejection Fraction in Patients Without Diabetes.
Sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway.

Cells. 2022 Sep 11. pii: 2835. [Epub ahead of print]11(18):

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy.

Teresa Campbell, Jesse Slone, Taosheng Huang.

  Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.

Keywords:  calcium; dilated cardiomyopathy; ferroptosis; hypertrophic cardiomyopathy; iron overload; mitochondrial cardiomyopathy; mitochondrial genome; mtDNA; reactive oxygen species

DOI:  https://doi.org/10.3390/cells11182835
Biochem Biophys Res Commun. 2022 Sep 09. pii: S0006-291X(22)01266-9. [Epub ahead of print]629 112-120

Independent and combined effects of liraglutide and aerobic interval training on glycemic control and cardiac protection in diabetic cardiomyopathy rats.

Huan Cai, Linling Zhou, Jingqin Liu, Zelin Li, Shuchun Chen.

  OBJECTIVE: This study intended to explore the hypoglycemic and cardioprotective effects of 8-week aerobic interval training combined with liraglutide and elucidate the underlying mechanisms.METHOD: Male Wistar rats were randomly divided into 5 groups - normal control group (CON), diabetic cardiomyopathy group (DCM), high-dose liraglutide group (DH), low-dose liraglutide group (DL), and aerobic interval training combined with liraglutide group (DLE). High-fat diet and streptozotocin (STZ) were used to induce the DCM model, and both the liraglutide administration group and combination therapy group allocated to 8 weeks of either liraglutide or liraglutide and exercise intervention. Cardiac functions were analyzed by electrocardiography. Blood biochemical parameters were measured to judge glycemic control conditions. Hematoxylin and eosin (HE) staining and Sirus red staining was used to identify cardiac morphology and collagen accumulation, respectively. Advanced glycation end products (AGEs) were determined by enzymatic methods. The mRNA expression of myocardial remodeling genes (BNP, GSK3β, α-MHC, β-MHC and PPARα) and the protein expression of GLP-1, GLP-1R were analyzed.
RESULTS: DCM rats developed hyperglycemia, impaired cardiac function with accumulation of AGEs and collagen (P < 0.05). The development of hyperglycemia and cardiac dysfunction was significantly attenuated with all interventions, as reduced cardiac fibrosis and improved cardiac function (P < 0.05). Cardiac remodeling genes were normalized after all interventions, these positive modifications were due to increased GLP-1 and GLP-1R expression in DCM heart (P < 0.05). Liraglutide combined with AIT significantly increased the diameters of cardiomyocytes, increased the α-MHC expressionx, reduced PPARαexpression and reduced the fluctuation of blood glucose level, which showed the safety and effective of medicine combined with exercise.
CONCLUSION: Liraglutide combined with AIT intervention normalized blood glucose alleviates myocardial fibrosis and improves cardiac contractile function in DCM rats, supporting the efficacy and safety of the combination therapy.

Keywords:  Aerobic interval training; Cardioprotection; Diabetic cardiomyopathies; Joint intervention; Liraglutide

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.018
J Lipid Res. 2022 Sep 14. pii: S0022-2275(22)00107-9. [Epub ahead of print] 100274

"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency".

Jide Oluwadare, Ainara G Cabodevilla, Ni-Huiping Son, Yunying Hu, Adam E Mullick, Michael Verano, Jose O Alemán, Ravichandran Ramasamy, Ira J Goldberg.

  Lipid accumulation in non-adipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human Neutral Lipid Storage Disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl knockout mice a low- or high-fat diet, we found heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double knockout mice also deficient in either cardiac lipoprotein lipase (LpL) or cluster of differentiation (CD) 36, which is involved in an LpL-independent pathway for fatty acid uptake in the heart. We show neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo fatty acid synthesis. Thus, we conclude pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.

Keywords:  CD36; LpL; dietary fat; fatty acid synthesis; heart failure; lipid accumulation; lipid droplets; lipotoxicity; myocardial lipid uptake; storage diseases

DOI:  https://doi.org/10.1016/j.jlr.2022.100274
Int J Mol Sci. 2022 Sep 09. pii: 10456. [Epub ahead of print]23(18):

Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy.

Martha Lucía Díaz, Karl Burgess, Richard Burchmore, María Adelaida Gómez, Sergio Alejandro Gómez-Ochoa, Luis Eduardo Echeverría, Carlos Morillo, Clara Isabel González.

  Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe clinical form of chronic Chagas disease, representing one of the leading causes of morbidity and mortality in Latin America, and a growing global public health problem. There is currently no approved treatment for CCC; however, omics technologies have enabled significant progress to be made in the search for new therapeutic targets. The metabolic alterations associated with pathogenic mechanisms of CCC and their relationship to cellular and immunopathogenic processes in cardiac tissue remain largely unknown. This exploratory study aimed to evaluate the potential underlying pathogenic mechanisms in the failing myocardium of patients with end-stage heart failure (ESHF) secondary to CCC by applying an untargeted metabolomic profiling approach. Cardiac tissue samples from the left ventricle of patients with ESHF of CCC etiology (n = 7) and healthy donors (n = 7) were analyzed using liquid chromatography-mass spectrometry. Metabolite profiles showed altered branched-chain amino acid and acylcarnitine levels, decreased fatty acid uptake and oxidation, increased activity of the pentose phosphate pathway, dysregulation of the TCA cycle, and alterations in critical cellular antioxidant systems. These findings suggest processes of energy deficit, alterations in substrate availability, and enhanced production of reactive oxygen species in the affected myocardium. This profile potentially contributes to the development and maintenance of a chronic inflammatory state that leads to progression and severity of CCC. Further studies involving larger sample sizes and comparisons with heart failure patients without CCC are needed to validate these results, opening an avenue to investigate new therapeutic approaches for the treatment and prevention of progression of this unique and severe cardiomyopathy.

Keywords:  Chronic Chagas cardiomyopathy; heart failure; metabolites; metabolomics

DOI:  https://doi.org/10.3390/ijms231810456
Front Cardiovasc Med. 2022 ;9 973705

The diagnostic value of peroxisome proliferator-activated receptor-γ coactivator-1α in identifying different chronic heart failure phenotypes.

Shiwen Zhang, Yufei Zhou, Yanfang Ma, Zhan Li, Yinglong Hou.

  Background: Despite advances in diagnosing and treating chronic heart failure (HF), the underlying mechanisms in different HF phenotypes remain unclear. Mitochondrial energy metabolism is crucial in HF etiology. Our study aimed to explore the value of metabolic-associated biomarker peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in identifying different HF phenotypes.Methods: A total of 172 participants were enrolled in the Affiliated Hospital of Xuzhou Medical University and were subsequently divided into four groups based on the European Society of Cardiology HF management guideline: the non-HF control (Control, N = 46), heart failure with reduced ejection fraction (HFrEF, N = 54), heart failure with mildly reduced ejection fraction (HFmrEF, N = 22), and heart failure with preserved ejection fraction (HFpEF, N = 50) groups. Each participant's baseline data were recorded, blood samples were taken, and echocardiography was conducted. The level of PGC1α expression was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The receiver operative characteristics (ROC) curve was further established in the four groups to assess the diagnostic value for overall HF and each HF phenotype with the calculation of the area under the curve (AUC) and 95% confidence interval (CI).
Results: PGC1α expression was significantly increased in HF patients (315.0 ± 69.58 nmol/L) compared to non-HF participants (233.3 ± 32.69 nmol/L). Considering different HF phenotypes, PGC1α expression was considerably higher in the HFmrEF group (401.6 ± 45.1 nmol/L)than in the other two phenotypes (299.5 ± 62.27 nmol/L for HFrEF and 293.5 ± 56.37 nmol/L for HFpEF, respectively).Furthermore, the AUCs of PGC1α in overall HF and each HF phenotype were all over 0.8, showing the ideal diagnostic value. Additionally, we provided the cut-off criteria for clinical use, which needs further validation. There was no significant correlation between PGC1α and N-terminal (NT)-prohormone B-type natriuretic peptide (BNP)/blood glucose, suggesting that PGC1α might exert a unique function in HF yet in a different pattern.
Conclusion: We discovered that PGC1α could be used as a potential biomarker for differentiating HF patients from those without HF and for distinguishing HFmrEF from HFrEF and HFpEF.

Keywords:  diagnostic; heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; peroxisome proliferator-activated receptor-γ coactlvator-1α

DOI:  https://doi.org/10.3389/fcvm.2022.973705
Circulation. 2022 Sep 22. 101161CIRCULATIONAHA122059631

FGF21-Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity.

Leigang Jin, Leiluo Geng, Lei Ying, Lingling Shu, Kevin Ye, Ranyao Yang, Yan Liu, Yao Wang, Yin Cai, Xue Jiang, Qin Wang, Xingqun Yan, Boya Liao, Jie Liu, Fuyu Duan, Gary Sweeney, Connie Wai Hong Woo, Yu Wang, Zhengyuan Xia, Qizhou Lian, Aimin Xu.

  BACKGROUND: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms.METHODS: The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell-derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction.
RESULTS: Treadmill exercise markedly induced cardiac expression of β-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of β-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell-derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM.
CONCLUSIONS: The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM.
REGISTRATION: URL: https://www.
CLINICALTRIALS: gov; Unique identifier: NCT03240978.

Keywords:  FGF21; SIRT3; diabetic cardiomyopathy; exercise; mitochondrial dysfunction

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.059631
Metabolism. 2022 Sep 17. pii: S0026-0495(22)00191-3. [Epub ahead of print] 155313

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.

Xing Chang, Yukun Li, Chen Cai, Feng Wu, Jing He, Yaoyuan Zhang, Jiankai Zhong, Ying Tan, Ruxiu Liu, Hang Zhu, Hao Zhou.

  Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.

Keywords:  Diabetic cardiomyopathy; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial quality control; Mitophagy

DOI:  https://doi.org/10.1016/j.metabol.2022.155313
Mol Cell Biol. 2022 Sep 20. e0016322

Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart.

Christian Riehle, Eric T Weatherford, Nicholas S McCarty, Alec Seei, Bharat P Jaishy, Rajkumar Manivel, Paolo Galuppo, Chantal Allamargot, Tariq Hameed, Ryan L Boudreau, Johann Bauersachs, Robert M Weiss, E Dale Abel.

  Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion. Heart failure was characterized by cardiomyocyte loss and disarray, increased proapoptotic signaling, and increased autophagy. Suppression of autophagy by activating mTOR signaling did not prevent heart failure. Transcriptional profiling revealed reduced serum response factor (SRF) transcriptional activity and decreased mRNA levels of genes encoding sarcomere and gap junction proteins as early as 3 days post-gene deletion, in concert with ultrastructural evidence of sarcomere disruption and intercalated discs within 1 week after gene deletion. These data confirm conserved roles for constitutive insulin and IGF1 signaling in suppressing autophagic and apoptotic signaling in the adult heart. The present study also identifies an unexpected role for insulin and IGF1 signaling in regulating an SRF-mediated transcriptional program, which maintains expression of genes encoding proteins that support sarcomere integrity in the adult heart, reduction of which results in rapid development of heart failure.

Keywords:  cardiac remodeling; cardiac structure; heart failure; insulin signaling

DOI:  https://doi.org/10.1128/mcb.00163-22
JAMA Netw Open. 2022 Sep 01. 5(9): e2231963

Optimal Pharmacologic Treatment of Heart Failure With Preserved and Mildly Reduced Ejection Fraction: A Meta-analysis.

Boyang Xiang, Ruiqi Zhang, Xiaoguang Wu, Xiang Zhou.

Importance: In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).Objective: To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF.
Data Sources: A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021.
Study Selection: Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), β-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF.
Data Extraction and Synthesis: Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model.
Main Outcomes and Measures: The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model.
Results: In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes.
Conclusions and Relevance: The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and β-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.

DOI: https://doi.org/10.1001/jamanetworkopen.2022.31963
J Am Heart Assoc. 2022 Sep 21. e026184

Insulin Resistance Is Associated With Heart Failure With Recovered Ejection Fraction in Patients Without Diabetes.

Chen Die Yang, Wen Qi Pan, Shuo Feng, Jin Wei Quan, Jia Wei Chen, Xin Yi Shu, Muladili Aihemaiti, Feng Hua Ding, Wei Feng Shen, Lin Lu, Rui Yan Zhang, Xiao Qun Wang.

  Background Because of advances in medical treatments, a substantial proportion of patients with heart failure (HF) have experienced recovery of ejection fraction (EF), termed HF with recovered EF (HFrecEF). Insulin resistance (IR) is prevalent in HF and tightly related with prognosis. This study investigates the relationship between IR and the incidence of HFrecEF in patients who are nondiabetic. Methods and Results A total of 262 patients with HF with reduced EF (HFrEF) who were nondiabetic were consecutively enrolled. Patients were classified into HFrecEF (follow-up EF>40% and ≥10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. IR was estimated by an updated homeostasis model assessment for IR (HOMA2-IR). The median HOMA2-IR level was 1.05 (interquartile range [IQR], 0.67-1.63) in our cohort of patients with HF who were nondiabetic. During follow-up, 121 (odds ratio [OR], 46.2% [95% CI 40.2-52.2]) patients developed HFrecEF. Compared with patients with HFrEF, patients with HFrecEF had significantly lower HOMA2-IR levels (0.92 [IQR, 0.61-1.37] versus 1.14 [IQR, 0.75-1.78], P=0.007), especially in nonischemic HF. Log2-transformed HOMA2-IR was inversely correlated to improvements in EF (Pearson's r=-0.25, P<0.001). After multivariable adjustment, a doubling of HOMA2-IR was associated with a 42.8% decreased likelihood of HFrecEF (OR, 0.572 [95% CI, 0.385-0.827]). Conclusions This study reveals that IR is independently associated with compromised development of HFrecEF in patients who are nondiabetic.

Keywords:  HOMA2‐IR; heart failure with recovered ejection fraction; heart failure with reduced ejection fraction; insulin resistance

DOI:  https://doi.org/10.1161/JAHA.122.026184
Front Cardiovasc Med. 2022 ;9 908037

Sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway.

Xiaoping Zhan, Lijun Cheng, Ning Huo, Lin Yu, Changle Liu, Tong Liu, Guangping Li, Huaying Fu.

  Purpose: The mechanism of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) reducing the incidence of atrial fibrillation remains unclear. We hypothesize that sodium-glucose cotransporter-2 inhibitor alleviated atrial remodeling in STZ-induced diabetic rats by targeting TLR4 pathway.Methods: A total of 42 rats were randomly assigned into three groups: control group (CON group); diabetes group (DM group): diabetes mellitus rats were established by 65 mg/kg streptozotocin (STZ) intraperitoneal injection; and diabetes + dapagliflozin group (DM + DAPA group): diabetic rats were given DAPA gavage administration (DAPA 2mg/kg/d for 4 weeks by gavage administration), 14 rats in each group. Epicardial multiple-lead recording and intracardiac electrophysiology studies were performed to investigate the electrical remodeling in the heart and the atrial fibrillation inducibility in each group. Western blot analysis and real-time PCR were used to determine the protein and mRNA expression of toll-like receptor 4 (TLR4), interleukin receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor-kappa B (NF-κB), and type I collagen (collagen I).
Results: Compared with rats in CON group, rats in DM group showed marked myocardial fibrosis, ectopic pacing excitement, reduced conduction velocity, decreased cardiac function. TLR4/IRAK1/TRAF6/NF-κB, collagen I proteins expressions and incidence of atrial fibrillation (27.3%) were increased in DM group. Parts of these changes were reversed by treatment of DAPA. Incidence of atrial fibrillation was decreased in DM + DAPA group (2.8%).
Conclusions: SGLT-2i dapagliflozin may prevent diabetic rats' atrial remodeling and reduce the inducibility of atrial fibrillation partly by targeting TLR4/IRAK1/TRAF6/NF-κB inflammatory pathway.

Keywords:  TLR4; atrial fibrillation; atrial remodeling; dapagliflozin; diabetes mellitus

DOI:  https://doi.org/10.3389/fcvm.2022.908037