bims-hafaim Biomed News
on Heart Failure Metabolism
Issue of 2021‒04‒11
sixteen papers selected by
Kyle McCommis
Saint Louis University

  1. Cell Rep. 2021 Apr 06. pii: S2211-1247(21)00249-7. [Epub ahead of print]35(1): 108935
      Type 2 diabetes (T2D) increases the risk for diabetic cardiomyopathy and is characterized by diastolic dysfunction. Myocardial forkhead box O1 (FoxO1) activity is enhanced in T2D and upregulates pyruvate dehydrogenase (PDH) kinase 4 expression, which inhibits PDH activity, the rate-limiting enzyme of glucose oxidation. Because low glucose oxidation promotes cardiac inefficiency, we hypothesize that FoxO1 inhibition mitigates diabetic cardiomyopathy by stimulating PDH activity. Tissue Doppler echocardiography demonstrates improved diastolic function, whereas myocardial PDH activity is increased in cardiac-specific FoxO1-deficient mice subjected to experimental T2D. Pharmacological inhibition of FoxO1 with AS1842856 increases glucose oxidation rates in isolated hearts from diabetic C57BL/6J mice while improving diastolic function. However, AS1842856 treatment fails to improve diastolic function in diabetic mice with a cardiac-specific FoxO1 or PDH deficiency. Our work defines a fundamental mechanism by which FoxO1 inhibition improves diastolic dysfunction, suggesting that it may be an approach to alleviate diabetic cardiomyopathy.
    Keywords:  FoxO1; diabetic cardiomyopathy; diastolic dysfunction; glucose oxidation; pyruvate dehydrogenase; type 2 diabetes
  2. Circulation. 2021 Apr 09.
      Background: Patients with heart failure and reduced ejection fraction (HFrEF) will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (i.e. first and repeat) hospitalizations for heart failure in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods: The total number of HF hospitalizations and cardiovascular deaths was examined using the proportional rates approach of Lei-Wei-Ying-Yang (LWYY) and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable LWYY model. Results: Of 2371 participants randomized to placebo, 318 experienced 469 hospitalizations for heart failure among; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher NT-proBNP and NYHA class. In the LWYY model the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or CV death was 0.75 (95%CI 0.65-0.88), p=0.0002. In the joint frailty model, rate ratio for total HF hospitalizations was 0.71 (95% CI 0.61-0.82), p<0.0001 while for cardiovascular death the hazard ratio was 0.81(95%CI 0.67-0.98), p=00282. Conclusions: Dapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HFrEF. Clinical Trial Registration: URL: Unique Identifier: NCT03036124.
    Keywords:  SGLT2 inhibitor; dapagliflozin; recurrent hospitalization
  3. J Mol Cell Cardiol. 2021 Apr 03. pii: S0022-2828(21)00069-9. [Epub ahead of print]
      Pathological hypertrophy generally progresses to heart failure. Exploring effective and promising therapeutic targets might lead to progress in preventing its detrimental outcomes. Our current knowledge about lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) is mainly limited to regulate inflammation. However, the role of LITAF in other settings are not that relevant to inflammation, such as cardiac remodeling and heart failure, remains largely unknown. In the present study, we found that the expression of LITAF decreased in hypertrophic hearts and cardiomyocytes. Meanwhile, LITAF protected cultured neonatal rat cardiomyocytes against phenylephrine-induced hypertrophy. Moreover, using LITAF knockout mice, we demonstrated that LITAF deficiency exacerbated cardiac hypertrophy and fibrosis compared with wild-type mice. Mechanistically, LITAF directly binds to the N-terminal of ASK1, thus disrupting the dimerization of ASK1 and blocking ASK1 activation, ultimately inhibiting ASK1-JNK/p38 signaling over-activation and protecting against cardiac hypertrophy. Furthermore, AAV9-mediated LITAF overexpression attenuated cardiac hypertrophy in vivo. Conclusions: Our findings uncover the novel role of LITAF as a negative regulator of cardiac remodeling. Targeting the interaction between LITAF and ASK1 could be a promising therapeutic strategy for pathological cardiac remodeling.
    Keywords:  ASK1; Cardiac hypertrophy; Cardiac remodeling; LITAF
  4. Front Med (Lausanne). 2021 ;8 648259
      Background: The gut microbiome has been linked to the onset of cardiometabolic diseases, in part facilitated through gut microbiota-dependent metabolites such as trimethylamine-N-oxide. However, molecular pathways associated to heart failure mediated by microbial metabolites remain largely elusive. Mitochondria play a pivotal role in cellular energy metabolism and mitochondrial dysfunction has been associated to heart failure pathogenesis. Aim of the current study was to evaluate the impact of gut-derived metabolites on mitochondrial function in cardiomyocytes via an in vitro screening approach. Methods: Based on a systematic Medline research, 25 microbial metabolites were identified and screened for their metabolic impact with a focus on mitochondrial respiration in HL-1 cardiomyocytes. Oxygen consumption rate in response to different modulators of the respiratory chain were measured by a live-cell metabolic assay platform. For one of the identified metabolites, indole-3-propionic acid, studies on specific mitochondrial complexes, cytochrome c, fatty acid oxidation, mitochondrial membrane potential, and reactive oxygen species production were performed. Mitochondrial function in response to this metabolite was further tested in human hepatic and endothelial cells. Additionally, the effect of indole-3-propionic acid on cardiac function was studied in isolated perfused hearts of C57BL/6J mice. Results: Among the metabolites examined, microbial tryptophan derivative indole-3-propionic acid could be identified as a modulator of mitochondrial function in cardiomyocytes. While acute treatment induced enhancement of maximal mitochondrial respiration (+21.5 ± 7.8%, p < 0.05), chronic exposure led to mitochondrial dysfunction (-18.9 ± 9.1%; p < 0.001) in cardiomyocytes. The latter effect of indole-3-propionic acids could also be observed in human hepatic and endothelial cells. In isolated perfused mouse hearts, indole-3-propionic acid was dose-dependently able to improve cardiac contractility from +26.8 ± 11.6% (p < 0.05) at 1 μM up to +93.6 ± 14.4% (p < 0.001) at 100 μM. Our mechanistic studies on indole-3-propionic acids suggest potential involvement of fatty acid oxidation in HL-1 cardiomyocytes. Conclusion: Our data indicate a direct impact of microbial metabolites on cardiac physiology. Gut-derived metabolite indole-3-propionic acid was identified as mitochondrial modulator in cardiomyocytes and altered cardiac function in an ex vivo mouse model.
    Keywords:  cardiomyocyte physiology; gut microbiota; heart failure; microbial metabolites; mitochondrial dysfunction
  5. Oxid Med Cell Longev. 2021 ;2021 6699054
      Background: Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial.Methods and Results: Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene.
    Conclusion: Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.
  6. Front Cardiovasc Med. 2021 ;8 592362
      Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and in vitro assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3'-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients.
    Keywords:  cardiac contractility; heart failure; knockout mice; miR-132/212 family; myocardial infarction
  7. Circulation. 2021 Apr 09.
      Background: Sodium/glucose co-transporter 2 (SGLT2) inhibitors exert robust cardioprotective effects against heart failure in diabetes patients and there is intense interest to identify the underlying molecular mechanisms that afford this protection. As the induction of the late component of the cardiac sodium channel current (late-INa) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-INa. Methods: Electrophysiological, in silico molecular docking, molecular, calcium imaging and whole heart perfusion techniques were employed to address this question. Results: The SGLT2 inhibitor empagliflozin reduced late-INa in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the LQT3 mutations R1623Q or ∆KPQ. Empagliflozin, dapagliflozin and canagliflozin are all potent and selective inhibitors of H2O2-induced late-INa (IC50s = 0.79, 0.58 and 1.26 µM respectively) with little effect on peak-INa. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-INa activator veratridine in a similar manner to tetrodotoxin, ranolazine and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a 3D homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anaesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 inflammasome and improved functional recovery after ischemia. Conclusions: Our results provide evidence that late-INa may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
    Keywords:  Cardiac sodium channel; SGLT2 inhibitors; empagliflozin
  8. J Am Coll Cardiol. 2021 Apr 13. pii: S0735-1097(21)00379-X. [Epub ahead of print]77(14): 1731-1743
      BACKGROUND: The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.OBJECTIVES: This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.
    METHODS: Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.
    RESULTS: AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.
    CONCLUSIONS: The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.
    Keywords:  ARNI; RAS; angiotensin; angiotensin receptor neprilysin inhibition; heart failure; renin; renin-angiotensin system
  9. Circulation. 2021 Apr 06.
      Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an inter-dependent network of signaling cascades. However, how these pathways interact remains unclear, and specifically few direct targets responsible for the pro-hypertrophic role of NFAT have been described. Methods: By engineering a cardiomyocyte-specific ETS2 (a member of E26 transformationspecific sequence (ETS)-domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Results: ETS2 is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation in both mouse (n = 3) and human heart samples (n = 8-19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n = 6-11). Furthermore, silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n = 8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP and Rcan1.4 (n = 4). Additionally, we report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least two hypertrophy-stimulated genes, Rcan1.4 and miR-223 (n = 4-6). Suppression of miR-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n = 6), revealing miR-223 as a novel pro-hypertrophic target of the calcineurin-NFAT and Erk1/2-ETS2 pathways. Conclusions: In aggregate, our findings point to a critical role for ETS2 in calcineurin-NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.
    Keywords:  ETS2; MAPK/Erk pathway; calcineurin-NFAT pathway; miR-223
  10. Circ Res. 2021 Apr 07.
      Rationale: Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts, called myofibroblasts. There are currently no therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure. Objective: We undertook a high-throughput screen to identify small molecule inhibitors of myofibroblast activation that might limit the progression of heart failure. We evaluated the therapeutic efficacy of the polyether ionophore salinomycin in patient derived cardiac fibroblasts and pre-clinical mouse models of ischemic and non-ischemic heart failure. Methods and Results: Here, we demonstrate that salinomycin displays potent anti-fibrotic activity in cardiac fibroblasts obtained from heart failure patients. In pre-clinical studies, salinomycin prevents cardiac fibrosis and functional decline in mouse models of ischemic and non-ischemic heart disease. Remarkably, interventional treatment with salinomycin attenuates pre-established pathological cardiac remodeling secondary to hypertension, and limits scar expansion when administered after a severe myocardial infarction. Mechanistically, salinomycin inhibits cardiac fibroblast activation by preventing p38/MAPK and Rho signaling. Salinomycin also promotes cardiomyocyte survival and improves coronary vessel density, suggesting that cardioprotection conferred by salinomycin occurs via the integration of multiple mechanisms in multiple relevant cardiac cell types. Conclusions: These data establish salinomycin as an anti-fibrotic agent that targets multiple cardioprotection pathways, thereby holding promise for the treatment of heart failure patients.
    Keywords:  fibroblast; heart; salinomycin
  11. Front Pharmacol. 2021 ;12 634365
      Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms. Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy. Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor. Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.
    Keywords:  SPRY1; autophagy; diabetic cardiomyopathy; microRNA-21; vildagliptin
  12. Mol Cell Proteomics. 2021 Mar 31. pii: S1535-9476(21)00045-1. [Epub ahead of print] 100072
      Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and cardiac function regulators. Natriuretic peptide receptor A (NPRA) binds to an ANP or BNP ligand and induces transmembrane signal transduction by elevating the intracellular cyclic guanosine monophosphate (cGMP) levels. However, the metabolic phenotype and related mechanisms induced by NPRA deletion remain ambiguous. Here, we constructed myocardial-specific NPRA deletion mice and detected the heart functional and morphological characteristics by histological analysis and explored the altered metabolic pattern and the expression patterns of proteins by liquid chromatography-mass spectrometry (LC-MS)-based omics technology, 20 replicates of two groups for metabolomics and 10 for proteomics. NPRA deficiency unexpectedly did not result in significant cardiac remodelling or dysfunction. However, compared with the matched littermates, NPRA-deficient mice had significant metabolic differences. Metabolomic results showed that the metabolite levels varied in cardiac tissues and plasma. In total, 33 metabolites were identified in cardiac tissues and 54 were identified in plasma. Compared to control mice, NPRA-deficient mice had 20 upregulated and 6 downregulated metabolites in cardiac tissues and 25 upregulated and 23 downregulated metabolites in plasma. Together, NPRA deficiency resulted in increased nucleotide biosynthesis and histidine metabolism only in heart tissues and decreased creatine metabolism only in plasma. Further proteomic analysis identified 136 differentially abundant proteins in cardiac tissues, including 54 proteins with higer anundance and 82 proteins with lower abundance. Among them, Cytochrome c oxidase subunit 7c and 7b (Cox7c, Cox7b), ATP synthase, H+ transporting, mitochondrial Fo complex subunit F2 (ATP5J2), Ubiquinol-cytochrome c reductase, complex III subunit X (Uqcr10) and Myosin Heavy Chain 7 (Myh7) were mainly involved in related metabolic pathways. These results revealed the essential role of NPRA in metabolic profiles and may elucidate new underlying pathophysiological mechanisms of NPRA in cardiovascular diseases.
    Keywords:  Metabolism; Myocardium; NPRA; Natriuretic peptides; Proteome
  13. Eur J Intern Med. 2021 Apr 03. pii: S0953-6205(21)00084-4. [Epub ahead of print]
      BACKGROUND: To investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus.METHODS: Electronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM).
    RESULTS: A total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72-0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62-0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76-0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77-0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86-0.93).
    CONCLUSIONS: Compared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF.
    Keywords:  Cardiovascular outcomes; Heart failure; Meta-analysis; Sodium-glucose cotransporter-2 inhibitors; Type 2 diabetes mellitus
  14. Clin Investig Arterioscler. 2021 Apr 02. pii: S0214-9168(21)00051-6. [Epub ahead of print]
      Beyond glucemic control there are other important goals when it comes to providing integral care to patients with diabetes mellitus. A bibliographic review was made in order to identify the role played by new antidiabetic drugs in cardiovascular prevention and heart failure. The use of SLGT2i and GLP1a leads to a significant decrease in cardiovascular events, with no difference between the two, except when it comes to hospitalizations for heart failure, where the superiority of the last ones (especially dapaglifozin and empaglifozin) is evident. The current evidence regarding the effect of dpp-4i is diverse, although an increased risk of hospitalizations for heart failure is observed with the use of some drugs of this class (saxagliptin).
    Keywords:  Agonistas del receptor del péptido similar al glucagón tipo 1; Diabetes mellitus tipo 2; Dipeptidylpeptidase-4 inhibitor; Glucagon-like peptide-1 receptor agonists; Heart failure; Inhibidores de la peptidil dipeptidasa 4; Inhibidores del cotransportador sodio/glucosa tipo 2; Insuficiencia cardiaca; Isquemia miocárdica; Myocardial ischemia; Sodium-glucose co-transporter 2 inhibitor; Type 2 diabetes mellitus
  15. Nucleic Acids Res. 2021 Apr 09. pii: gkab228. [Epub ahead of print]
      Deficient maturations of mitochondrial transcripts are linked to clinical abnormalities but their pathophysiology remains elusive. Previous investigations showed that pathogenic variants in MTO1 for the biosynthesis of τm5U of tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR) were associated with hypertrophic cardiomyopathy (HCM). Using mto1 knock-out(KO) zebrafish generated by CRISPR/Cas9 system, we demonstrated the pleiotropic effects of Mto1 deficiency on mitochondrial RNA maturations. The perturbed structure and stability of tRNAs caused by mto1 deletion were evidenced by conformation changes and sensitivity to S1-mediated digestion of tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). Notably, mto1KO zebrafish exhibited the global decreases in the aminoacylation of mitochondrial tRNAs with the taurine modification. Strikingly, ablated mto1 mediated the expression of MTPAP and caused the altered polyadenylation of cox1, cox3, and nd1 mRNAs. Immunoprecipitation assay indicated the interaction of MTO1 with MTPAP related to mRNA polyadenylation. These alterations impaired mitochondrial translation and reduced activities of oxidative phosphorylation complexes. These mitochondria dysfunctions caused heart development defects and hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the mto1KO zebrafish recapitulated the clinical phenotypes in HCM patients carrying the MTO1 mutation(s). Our findings highlighted the critical role of MTO1 in mitochondrial transcript maturation and their pathological consequences in hypertrophic cardiomyopathy.
  16. Diabetes Obes Metab. 2021 Apr;23 Suppl 2 19-27
      AIMS: To examine heart failure (HF) and chronic kidney disease (CKD) risks reduction associated with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared to other glucose-lowering drugs (oGLD) in the early stage of type 2 diabetes patients without established cardiovascular or renal diseases (CVRD-free T2D).MATERIALS AND METHODS: We performed an observational cohort study using a Japanese hospital claims registry, Medical Data Vision. CVRD-free T2D patients were identified between 1 April 2014 and 30 September 2018. SGLT-2i and oGLD new users (and dipeptidyl peptidase 4 inhibitors [DPP-4i] separately) were subjected to 1:1 propensity-score matching analysis. Hazard ratios (HRs) of cardiorenal disease (HF and/or CKD), HF, CKD, stroke, myocardial infarction (MI), and all-cause mortality, were estimated using unadjusted Cox regression.
    RESULTS: A total of 108 362 CVRD-free patients including 54 181 SGLT-2i and 54 181 oGLD users were matched. Baseline characteristics were well balanced (mean age 59.1 years, 63% male, and follow-up 1.50 years [162 970 patient-years]). Compared to oGLD group, SGLT-2i group had lower risk of cardiorenal disease, HF, CKD, stroke, and all-cause mortality with HRs (95% confidence intervals) 0.55 (0.49-0.61), 0.73 (0.61-0.87), 0.45 (0.39-0.52), 0.69 (0.59-0.81), and 0.52 (0.46-0.58), respectively, while no difference in MI. These were consistent in 1:1 propensity-score matching analysis between SGLT-2i and DPP-4i users (n = 17 232 in each group).
    CONCLUSIONS: In Japanese CVRD-free T2D patients, SGLT-2i initiation was associated with lower risk of cardiorenal diseases, stroke, and all-cause mortality compared to oGLD, suggesting preventive effect of SGLT-2i treatment in the early stage of T2D patients without CVRD manifestation.
    Keywords:  SGLT2 inhibitor; cohort study; diabetes complications; diabetic nephropathy; heart failure; pharmaco-epidemiology