bims-hafaim Biomed News
on Heart Failure Metabolism
Issue of 2021‒02‒28
23 papers selected by
Kyle McCommis
Saint Louis University

  1. J Exp Med. 2021 May 03. pii: e20201206. [Epub ahead of print]218(5):
      Meteorin-like/Meteorin-β (Metrnl/Metrnβ) is a secreted protein produced by skeletal muscle and adipose tissue that exerts metabolic actions that improve glucose metabolism. The role of Metrnβ in cardiac disease is completely unknown. Here, we show that Metrnβ-null mice exhibit asymmetrical cardiac hypertrophy, fibrosis, and enhanced signs of cardiac dysfunction in response to isoproterenol-induced cardiac hypertrophy and aging. Conversely, adeno-associated virus-mediated specific overexpression of Metrnβ in the heart prevents the development of cardiac remodeling. Furthermore, Metrnβ inhibits cardiac hypertrophy development in cardiomyocytes in vitro, indicating a direct effect on cardiac cells. Antibody-mediated blockage of Metrnβ in cardiomyocyte cell cultures indicated an autocrine action of Metrnβ on the heart, in addition to an endocrine action. Moreover, Metrnβ is highly produced in the heart, and analysis of circulating Metrnβ concentrations in a large cohort of patients reveals that it is a new biomarker of heart failure with an independent prognostic value.
  2. J Am Coll Cardiol. 2021 Mar 02. pii: S0735-1097(21)00067-X. [Epub ahead of print]77(8): 1073-1088
      BACKGROUND: Mitochondrial dysfunction results in an imbalance between energy supply and demand in a failing heart. An innovative therapy that targets the intracellular bioenergetics directly through mitochondria transfer may be necessary.OBJECTIVES: The purpose of this study was to establish a preclinical proof-of-concept that extracellular vesicle (EV)-mediated transfer of autologous mitochondria and their related energy source enhance cardiac function through restoration of myocardial bioenergetics.
    METHODS: Human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) were employed. iCM-conditioned medium was ultracentrifuged to collect mitochondria-rich EVs (M-EVs). Therapeutic effects of M-EVs were investigated using in vivo murine myocardial infarction (MI) model.
    RESULTS: Electron microscopy revealed healthy-shaped mitochondria inside M-EVs. Confocal microscopy showed that M-EV-derived mitochondria were transferred into the recipient iCMs and fused with their endogenous mitochondrial networks. Treatment with 1.0 × 108/ml M-EVs significantly restored the intracellular adenosine triphosphate production and improved contractile profiles of hypoxia-injured iCMs as early as 3 h after treatment. In contrast, isolated mitochondria that contained 300× more mitochondrial proteins than 1.0 × 108/ml M-EVs showed no effect after 24 h. M-EVs contained mitochondrial biogenesis-related messenger ribonucleic acids, including proliferator-activated receptor γ coactivator-1α, which on transfer activated mitochondrial biogenesis in the recipient iCMs at 24 h after treatment. Finally, intramyocardial injection of 1.0 × 108 M-EVs demonstrated significantly improved post-MI cardiac function through restoration of bioenergetics and mitochondrial biogenesis.
    CONCLUSIONS: M-EVs facilitated immediate transfer of their mitochondrial and nonmitochondrial cargos, contributing to improved intracellular energetics in vitro. Intramyocardial injection of M-EVs enhanced post-MI cardiac function in vivo. This therapy can be developed as a novel, precision therapeutic for mitochondria-related diseases including heart failure.
    Keywords:  bioenergetics; heart failure; human stem cells; mitochondria; myocardial infarction
  3. Eur J Heart Fail. 2021 Feb 25.
      AIMS: The aim of this study was to synthesize the evidence on the effect of HFrEF pharmacotherapy on health-related quality of life (HRQoL).METHODS AND RESULTS: We searched MEDLINE, Embase, CENTRAL, CINAHL, and the WHO International Clinical Trials Registry Platform in June 2020. Randomized placebo-controlled trials evaluating contemporary HFrEF pharmacotherapy and reporting HRQoL as an outcome were included. Two reviewers independently assessed studies for eligibility, extracted data, and assessed risk of bias and GRADE certainty of evidence. The primary outcome was HRQoL at last available follow-up analyzed using a random-effects model. We included 37 studies from 5770 identified articles. Risk of bias was low in 10 trials and high/unclear in 27 trials. High-certainty evidence from meta-analyses demonstrated improved HRQoL over placebo with sodium-glucose cotransporter-2 (SGLT2) inhibitors (standardized mean difference [SMD] 0.16, 95% confidence interval [CI] 0.08-0.23) and intravenous iron (SMD 0.52, 95% CI 0.04-1.00). Furthermore, high-certainty evidence from ≥1 landmark trial further supported improved HRQoL with angiotensin receptor blockers (ARBs) (SMD 0.09, 95% confidence interval [CI] 0.02-0.17), ivabradine (SMD 0.14, 95% CI 0.04-0.23), hydralazine-nitrate (SMD 0.24, 95% CI 0.04-0.44) versus placebo, and for angiotensin receptor-neprilysin inhibitor (ARNI) compared with an angiotensin-converting enzyme (ACE) inhibitor (SMD 0.09, 95% CI 0.02-0.17). Findings were inconclusive for ACE inhibitors, beta-blockers, digoxin, and oral iron based on low-to-moderate-certainty evidence.
    CONCLUSION: ARBs, ARNIs, SGLT2 inhibitors, ivabradine, hydralazine-nitrate, and intravenous iron improved HRQoL in patients with HFrEF. These findings can be incorporated into discussions with patients to enable shared decision-making.
    Keywords:  Guideline-directed medical therapy; Supplementary Appendix; Supplementary Files Legends; Supplementary Table; heart failure; medications; quality of life
  4. Open Vet J. 2021 Jan;10(4): 363-370
      Background: Heart failure syndrome is an aspect of primary or secondary heart disease and is associated with decompensation, formation, and activation of pathological interactions between regulation systems. This results in myocardial energy metabolism alteration. This study was carried out to defy some metabolic aspects of myocardial tissue insulin resistance (IRM) development in canine heart failure.Aim: To investigate the myocardial tissue concentration of adenosine triphosphate (ATP), glucose transporters 1 and 4, pyruvate dehydrogenase (PDH), hexokinase 2, insulin receptor (InsR), and adropin (ADR) protein and to screen metabolic changes and IRM in canine myocardium with heart failure.
    Methods: We studied 28 dogs of different sexes, ages, and breeds. Groups were formed according to primary pathology: apparently healthy dogs (HD, n = 6); dogs with CDVD (CDVDD, n = 8); dogs with DCM (DCMD, n = 6); and dogs with doxorubicin chemotherapy and doxorubicin-induced cardiomyopathy (DoxCMD, n = 8). Animals in the study were diagnosed for primary disease by standard methods and algorithms. Animals were euthanized due to incurable neurological disease, refractory heart failure, or by owners will. The material was obtained immediately after death, fixed in liquid nitrogen, and stored in -80°C refrigerator. Studied proteins concentrations were analyzed in a specialized research laboratory, using ELISA kits, provided by Cloud-Clone Corp.
    Results: ATP, GLUT1, and GLUT4 concentrations in myocardial tissue from the valvular disease group did not differ from the HD group. In CDVD, we found depression of PDH, hexokinase II (HX2), and ADR concentrations in comparison to HD. InsR was significantly lower in the CDVD and DoxCMD groups in comparison to the HD group, but in the DCM group, it was twofold higher than in the HD group. In the DCMD and DoxCMD groups, all parameters were lower than in the HD group. ATP, HX2, ADR, GLUT1, and GLUT4 were higher in the CDVD group, than in the DCM and DoxCM groups. PDH in the CDVD and DoxCM groups did not differ. PDH was depleted in the DCM to CDVD and DoxCM groups. InsR did not differ between the CDVD and DoxCM groups, but was upregulated in the DCM to CDVD and DoxCM groups.
    Conclusion: Development of myocardial tissue IRM is a part of the structural, functional and metabolic remodeling in dogs with heart failure of different etiology. At the late stages, we found significant changes in energy supply availability and production in the myocardium.
    Keywords:  Canine; Cardiomyopathy; Heart failure; Insulin resistance; Myocardial metabolism
  5. Int J Biochem Cell Biol. 2021 Feb 17. pii: S1357-2725(21)00036-4. [Epub ahead of print] 105952
      Cardiac fibrosis and myocyte hypertrophy play contributory roles in the progression of diseases such as heart Failure (HF) through what is collectively termed cardiac remodelling. The phosphoinositide 3- kinase (PI3K), protein kinase B (Akt) and mammalian target for rapamycin (mTOR) signalling pathway (PI3K/Akt- mTOR) pathway is an important pathway in protein synthesis, cell growth, cell proliferation, and lipid metabolism. The sphingolipid, dihydrosphingosine 1 phosphate (dhS1P) has been shown to bind to high density lipids in plasma. Unlike its analog, spingosine 1 phosphate (S1P), the role of dhS1P in cardiac fibrosis is still being deciphered. This study was conducted to investigate the effect of dhS1P on PI3K/Akt signalling in primary cardiac fibroblasts and mycoytes. Our findings demonstrate that inhibiting PI3K reduced collagen synthesis in neonatal cardiac fibroblasts (NCFs), and hypertrophy in neonatal cardiac myocytes (NCMs) induced by dhS1P, in vitro. Reduced activation of the PI3K/Akt- mTOR signalling pathway led to impaired translation of fibrotic proteins such as collagen 1 (Coll1) and transforming growth factor β (TGFβ) and inhibited the transcription and translation of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). PI3K inhibition also affected the S1P receptors and gene expression of enzymes such as the dihydroceramide delta 4 desaturase (DEGS1) and sphingosine kinase 1 (SK1) in the de novo sphingolipid pathway. While in myocytes, PI3K inhibition reduced myocyte hypertrophy induced by dhS1P by reducing skeletal muscle α- actin (αSKA), and reduced protein translation due to increased glycogen synthase kinase 3β (GSK3β) mRNA expression. Our findings show a relationship between the PI3K/Akt- mTOR signalling cascade and exogenous dhS1P induced collagen synthesis and myocyte hypertrophy in primary neonatal cardiac cells.
    Keywords:  Cardiac remodelling; Dihydrosphingosine 1 Phosphate; Fibrosis; Hypertrophy; PI3K; Protein Kinase B/Akt; Sphingolipid; mTOR; ribosomal protein S6
  6. J Cardiovasc Med (Hagerstown). 2021 Apr 01. 22(4): 268-278
      AIMS: Diabetic cardiomyopathy represents the main cause of death among diabetic people. Despite this evidence, the molecular mechanisms triggered by impaired glucose and lipid metabolism inducing heart damage remain unclear. The aim of our study was to investigate the effect of altered metabolism on the early stages of cardiac injury in experimental diabetes.METHODS: For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35 mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot.
    RESULTS: Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia.
    CONCLUSION: Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.
  7. ESC Heart Fail. 2021 Feb 27.
      AIMS: Neprilysin (NEP), a zinc metallopeptidase, degrades a variety of bioactive peptides including natriuretic peptides terminating their biological action on arterial blood pressure and natriuresis. Pharmacological inhibition of NEP reduces mortality in patients with heart failure with reduced ejection fraction. Physiological interventions reducing NEP levels are unknown in humans. Because obesity leads to increased NEP levels and increases the risk for heart failure, we hypothesized that weight loss reduces NEP concentrations in plasma and tissue.METHODS AND RESULTS: We randomized overweight to obese human subjects to a low-fat or low-carbohydrate hypocaloric 6 month weight loss intervention. Soluble NEP was determined in plasma, and NEP mRNA was analysed from subcutaneous adipose tissue before and after diet. Low-fat diet-induced weight loss reduced soluble NEP levels from 0.83 ± 0.18 to 0.72 ± 0.18 μg/L (P = 0.038), while subcutaneous adipose tissue NEP mRNA expression was reduced by both dietary interventions [21% (P = 0.0057) by low-fat diet and 16% (P = 0.048) by low-carbohydrate diet]. We also analysed the polymorphisms of the gene coding for NEP, rs9827586 and rs701109, known to be associated with plasma NEP levels. For both single-nucleotide polymorphisms, minor allele carriers (A/A) had higher baseline plasma NEP levels (rs9827586: β = 0.53 ± 0.23, P < 0.0001; rs701109: β = 0.43 ± 0.22, P = 0.0016), and minor allele carriers of rs9827586 responded to weight loss with a larger NEP reduction (rs9827586: P = 0.0048).
    CONCLUSIONS: Our study identifies weight loss via a hypocaloric low-fat diet as the first physiological intervention in humans to reduce NEP in plasma and adipose tissue. Specific single-nucleotide polymorphisms further contribute to the decrease. Our findings may help to explain the beneficial effect of weight loss on cardiac function in patients with heart failure.
    Keywords:  Heart failure; Hypocaloric low-fat diet; Natriuretic peptides; Neprilysin
  8. J Cell Physiol. 2021 Feb 21.
      Aerobic exercise increases M2 AChR, which thus improves cardiac function in cardiovascular disease (CVD) rats. This study aimed to determine whether aerobic exercise could ameliorate pressure overload-induced heart hypertrophy through M2 AChR, and to elucidate the underlying mechanisms of action. Mice were used to establish the myocardial hypertrophy model by transverse aortic constriction (TAC), and subjected to 2, 4, and 8 weeks of moderate-intensity aerobic exercise and choline intervention (14 mg/kg/day). Our results showed that 4 and 8 weeks of exercise and choline intervention reduced excessive mitochondrial fission and autophagy of myocardial mitochondria, thereby improving the ultrastructure and function of mitochondria after TAC. Moreover, 8-week exercise and choline intervention have enhanced parasympathetic function and promoted the expression of M2 AChR. In addition, 8-week exercise and choline intervention also inhibited the protein expression of myocardial MFN2, PERK/eIF2α/ATF4, and NLRP3/caspase-1/IL-1β signaling pathways, thereby effectively reducing mitochondrial fusion, endoplasmic reticulum stress, and inflammation. Taken together, these data suggest that pressure overload led to cardiac hypertrophy, cardiac dysfunction, and decreased parasympathetic function in cardiac tissues. Aerobic exercise attenuated cardiac dysfunction by modulating the expression of proteins involved in mitochondrial quality control, and induced endoplasmic reticulum stress and inflammation, thereby reducing cardiac hypertrophy and improving cardiac function in impaired heart tissues following TAC, which was likely mediated by M2 AChR activation.
    Keywords:  M2AChR; aerobic exercise; choline; endoplasmic reticulum stress; inflammation; mitochondrial quality control; myocardial hypertrophy
  9. Cell Death Dis. 2021 Feb 26. 12(2): 216
      Mitochondrial dysfunction and impaired Ca2+ handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca2+ release-activated calcium channel protein 1) calcium channel is important for the increase in Ca2+ entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca2+ influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca2+ entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1-Drp1 axis is a novel target for treating DCM.
  10. J Mol Cell Cardiol. 2021 Feb 23. pii: S0022-2828(21)00042-0. [Epub ahead of print]
      High-throughput experiments suggest that almost 20% of human proteins may be S-palmitoylatable, a post-translational modification (PTM) whereby fatty acyl chains, most commonly palmitoyl chain, are linked to cysteine thiol groups that impact on protein trafficking, distribution and function. In human, protein S-palmitoylation is mediated by a group of 23 palmitoylating 'Asp-His-His-Cys' domain-containing (DHHC) enzymes. There is no information on the scope of protein S-palmitoylation, or the pattern of DHHC enzyme expression, in the heart. We used resin-assisted capture to pull down S-palmitoylated proteins from human, dog, and rat hearts, followed by proteomic search to identify proteins in the pulldowns. We identified 454 proteins present in at least 2 species-specific pulldowns. These proteins are operationally called 'cardiac palmitoylome'. Enrichment analysis based on Gene Ontology terms 'cellular component' indicated that cardiac palmitoylome is involved in cell-cell and cell-substrate junctions, plasma membrane microdomain organization, vesicular trafficking, and mitochondrial enzyme organization. Importantly, cardiac palmitoylome is uniquely enriched in proteins participating in the organization and function of t-tubules, costameres and intercalated discs, three microdomains critical for excitation-contraction coupling and intercellular communication of cardiomyocytes. We validated antibodies targeting DHHC enzymes, and detected eleven of them expressed in hearts across species. In conclusion, we provide resources useful for investigators interested in studying protein S-palmitoylation and its regulation by DHHC enzymes in the heart. We also discuss challenges in these efforts, and suggest methods and tools that should be developed to overcome these challenges.
    Keywords:  Cardiac disease; Palmitoylation; Protein palmitoyl transferase; Proteomics
  11. J Bioenerg Biomembr. 2021 Feb 25.
      The C57BL/6 mouse strain have been commonly used for the genetic background animal models and experimental research. There are several major sources of C57BL/6 substrains for the biomedical research community which display genetic and phenotypic differences. Previous studies have suggested that the varies in baseline of cardiovascular phenotypes as well as in response to pressure overload by transverse aortic constriction (TAC). To investigate whether there exist substrain specific differences in response to heart failure post myocardial infarction (MI), consequently the impaired mitochondrial respiration, we performed MI surgery on two commonly used C57BL/6 substrains: C57BL/6J (BL/6J) and C57BL/6NCrl (BL/6N) mice. Subsequently, measurements about cardiac function, histology and mitochondrial respiration capacities were conducted to evaluate the differences. The data showed that C57BL/6J(BL/6J) mice is more resistant to the attack of MI, evidenced by lower mortality, less infarct size and better preserved cardiac function after MI, especially exhibited better mitochondrial respiration capacities, compared with the C57BL/6NCrl(BL/6N) mice.
    Keywords:  C57BL/6 mouse; Heart failure; Mitochondrial respiration; Myocardial infarction; OXPHOS
  12. Eur J Prev Cardiol. 2020 Apr 29. pii: 2047487320920755. [Epub ahead of print]
      AIMS: In heart failure, oxygen uptake and cardiac output measurements at peak and during exercise are important in defining heart failure severity and prognosis. Several cardiopulmonary exercise test-derived parameters have been proposed to estimate stroke volume during exercise, including the oxygen pulse (oxygen uptake/heart rate). Data comparing measured stroke volume and the oxygen pulse or stroke volume estimates from the oxygen pulse at different stages of exercise in a sizeable population of healthy individuals and heart failure patients are lacking.METHODS: We analysed 1007 subjects, including 500 healthy and 507 heart failure patients, who underwent cardiopulmonary exercise testing with stroke volume determination by the inert gas rebreathing technique. Stroke volume measurements were made at rest, submaximal (∼50% of exercise) and peak exercise. At each stage of exercise, stroke volume estimates were obtained considering measured haemoglobin at rest, predicted exercise-induced haemoconcentration and peripheral oxygen extraction according to heart failure severity.
    RESULTS: A strong relationship between oxygen pulse and measured stroke volume was observed in healthy and heart failure subjects at submaximal (R2 = 0.6437 and R2 = 0.6723, respectively), and peak exercise (R2 = 0.6614 and R2 = 0.5662) but not at rest. In healthy and heart failure subjects, agreement between estimated and measured stroke volume was observed at submaximal (-3 ± 37 and -11 ± 72 ml, respectively) and peak exercise (1 ± 31 and 6 ± 29 ml, respectively) but not at rest.
    CONCLUSION: In heart failure patients, stroke volume estimation and oxygen pulse during exercise represent stroke volume, albeit with a relevant individual data dispersion so that both can be used for population studies but cannot be reliably applied to a single subject. Accordingly, whenever needed stroke volume must be measured directly.
    Keywords:  Stroke volume; exercise; heart failure; oxygen pulse
  13. J Am Heart Assoc. 2021 Feb 24. e019463
      Background Recent studies have increasingly shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors may have beneficial cardiovascular and metabolic effects in patients without diabetes mellitus. Hence, we conducted a systematic review and meta-analysis to determine the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. Methods and Results Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on August 30, 2020 for articles published from January 1, 2000 to August 30, 2020, for studies that examined the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. A random-effects pairwise meta-analysis model was used to summarize the studies. A total of 8 randomized-controlled trials were included with a combined cohort of 5233 patients. In patients without diabetes mellitus, those with heart failure treated with SGLT2 inhibitors had a 20% relative risk reduction in cardiovascular deaths and heart failure hospitalizations, compared with those who were not treated (risk ratio, 0.78; P<0.001). We additionally found that treatment with SGLT2 inhibitors improved multiple metabolic indices. Patients on SGLT2 inhibitors had a reduction in body weight of -1.21 kg (P<0.001), body mass index of -0.47 kg/m2 (P<0.001), systolic blood pressure of -1.90 mm Hg (P=0.04), and fasting plasma glucose of -0.38 mmol/L (P=0.05), compared with those without. There were no between-group differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, waist circumference, diastolic blood pressure, glycated hemoglobin, low-density lipoprotein cholesterol levels, and estimated glomerular filtration rates. Across our combined cohort of 5233 patients, hypoglycemia was reported in 22 patients. Conclusions SGLT2 inhibitors improve cardiovascular outcomes in patients without diabetes mellitus with heart failure. In patients without diabetes mellitus, SGLT2 inhibitors showed positive metabolic outcomes in weight and blood pressure control.
    Keywords:  nondiabetics; sodium/glucose cotransporter 2 inhibitors
  14. Heart. 2021 Feb 26. pii: heartjnl-2020-318060. [Epub ahead of print]
      Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor-mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.
    Keywords:  heart failure; heart failure with reduced ejection fraction; pharmacology; systemic review
  15. Cardiovasc Toxicol. 2021 Feb 21.
      Epigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.
    Keywords:  Cardiac hypertrophy; Epigenetics; Histone methylation; PHF19; SIRT2
  16. Diabetes Obes Metab. 2021 Feb 24.
      AIMS: To explore early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure.MATERIALS AND METHODS: Patients with type 2 diabetes on metformin treatment were randomized to double-blind 6-week placebo or dapagliflozin 10 mg daily treatment. Investigations included cardiac function and structure with myocardial resonance imaging (MRI); cardiac oxygen consumption, perfusion and efficiency with [11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [18 F]-FTHA PET, analyzed by ANCOVA as least square means with 95% confidence intervals.
    RESULTS: Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had mean age 64.4 years, BMI 30.2 kg/m2 , and HbA1c 6.7%. Body weight and HbA1c were significantly decreased by dapagliflozin vs placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work -0.095 (-0.145, -0.043) J/g/min, and LV oxygen consumption were significantly reduced -0.30 (-0.49, -0.12) J/g/min by dapagliflozin, but changes were not statistically significant vs changes in placebo group. Change in left atrial maximal volume with dapagliflozin vs placebo was -3.19 (-6.32, -0.07) mL/m2 , p = 0.056. Peak global radial strain decreased with dapagliflozin vs placebo, -3.92 (-7.57, -0.28) %, p = 0.035; peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake was increased by dapagliflozin vs placebo, 0.024 (0.004, 0.044) μmol/g/min, p = 0.018, while cardiac uptake was unchanged.
    CONCLUSIONS: This exploratory study indicates reduced heart work but limited effects on myocardial function, efficiency, and cardiac fatty acid uptake, while hepatic fatty acid uptake increased, after 6 weeks treatment with dapagliflozin.
    CLINICAL TRIAL REGISTRATION: NCT03387683. This article is protected by copyright. All rights reserved.
    Keywords:  SGLT2 inhibitor; dapagliflozin; type 2 diabetes
  17. Eur J Heart Fail. 2021 Feb 22.
      BACKGROUND: Anaemia is common in heart failure and associated with worse outcomes. We examined the effect of dapagliflozin on correction of anaemia in patients with heart failure and reduced ejection fraction (HFrEF) in DAPA-HF. We also analyzed the effect of dapagliflozin on outcomes, according to anaemia status at baseline.METHODS: Anaemia was defined at baseline as a haematocrit <39% in men and <36% in women. Resolution of anaemia was defined as two consecutive haematocrit measurements above these thresholds at any time during follow-up. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death..
    FINDINGS: Of the 4744 patients randomized in DAPA-HF, 4691 had a haematocrit available at baseline, of which 1032 were anaemic (22.0%). The rate of the primary outcome was higher in patients with anaemia (16.1 per 100 person-years) compared with those without (12.9 per 100 person-years). Anaemia was corrected in 62.2% of patients in the dapagliflozin group, compared with 41.1% of patients in the placebo group. The effect of dapagliflozin on the primary outcome was consistent in anaemic compared with non-anaemic patients (HR 0.68 [95%CI 0.52-0.88] versus 0.76 [0.65-0.89]; P-interaction=0.44). Similar findings were observed for cardiovascular death, HF hospitalization, and all-cause mortality. Patients with resolution of anaemia had better outcomes than those in which anaemia persisted.
    CONCLUSION: Patients with anaemia had worse outcomes in DAPA-HF. Dapagliflozin corrected anaemia more often than placebo and improved outcomes, irrespective of anaemia status at baseline.
    Keywords:  Heart failure and reduced ejection fraction; anaemia; clinical trials; sodium-glucose cotransporter 2 inhibitor
  18. J Diabetes Complications. 2021 Feb 05. pii: S1056-8727(21)00048-9. [Epub ahead of print] 107881
      BACKGROUND: Cardiorenal complications are common in patients with dysmetabolism and diabetes. The present study aimed to examine if a nonhuman primate (NHP) model with spontaneously developed metabolic disorder and diabetes develops similar complications to humans, such as proteinuria and cardiac dysfunction at resting condition or diminished cardiac functional reserve following dobutamine stress echocardiography (DSE).METHODS AND RESULTS: A total of 66 dysmetabolic and diabetic cynomolgus (Macaca fascicularis) NHPs were enrolled to select 19 NHPs (MetS) with marked metabolic disorders and diabetes (fasting blood glucose: 178 ± 18 vs. 61 ± 3 mg/dL) accompanied by proteinuria (ACR: 134 ± 34 vs. 1.5 ± 0.4 mg/mmol) compared to 8 normal NHPs (CTRL). Under resting condition, MetS NHPs showed mild left ventricular (LV) diastolic dysfunction (E/A: 1 ± 0.06 vs. 1.5 ± 0.13), but with preserved ejection fraction (EF: 65 ± 2 vs. 71 ± 3%) compared to CTRL. DSE with an intravenous infusion of dobutamine at ascending doses (5, 10, 20, 30 and 40 μg/kg/min, 7 min for each dose) resulted in a dose-dependent increase in cardiac function, however, with a significantly diminished magnitude at the highest dose of dobutamine infusion (40 μg/kg/min) in both diastole (E/A: -12 ± 3 vs. -38 ± 5%) and systole (EF: 25 ± 3 vs. 33 ± 5%) as well as ~42% reduced cardiac output reserve (COR: 63 ± 8 vs. 105 ± 18%, p < 0.02) in the MetS compared to CTRL NHPs.
    CONCLUSION: These data demonstrate that MetS NHPs with cardiorenal complications: proteinuria, LV diastolic dysfunction and preserved LV systolic function under resting conditions displayed compromised cardiac functional reserve under dobutamine stress. Based on these phenotypes, this NHP model of diabetes with cardiorenal complications can be used as a highly translational model mimic human disease for pharmaceutical research.
    Keywords:  Cardiorenal dysfunction; Diabetic complications; Dobutamine tress test; Echocardiography; Metabolic syndrome; Monkey stress
  19. Oxid Med Cell Longev. 2021 ;2021 6679100
      Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3-/- mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson's trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.
  20. Nat Rev Cardiol. 2021 Feb 22.
      Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell's secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.
  21. Am J Physiol Heart Circ Physiol. 2021 Feb 26.
      Wnt/β-catenin signalling plays a key role in pathological cardiac remodelling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may realise a tissue-specific clinical targeting strategy. Drosophila Pygo codes for the core interaction factor of Wnt/β-catenin. Two Pygo homologs, Pygo1 and Pygo2, have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease remains unelucidated. Here, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios and increased cell size. The canonical β-catenin/T-cell transcription factor 4 complex was abundant in Pygo1-overexpressingtransgenic(Pygo1-TG) cardiac tissue,and the downstream genes of Wnt signaling, i.e., Axin2, Ephb3, and C-myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodelling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.
    Keywords:  Pygo1; Wnt/β-catenin signaling; cardiac hypertrophy
  22. Eur J Pharmacol. 2021 Feb 18. pii: S0014-2999(21)00115-1. [Epub ahead of print] 173962
      Reperfusion causes undesirable damage to the ischemic myocardium while restoring the blood flow. In this study, we evaluated the effects of dexpramipexole (DPX) on myocardial injury induced by ischemia/reperfusion (I/R) in-vivo and the hypoxia/reoxygenation (HR) in-vitro and examined the functional mechanisms of DPX. DPX protected cells against H/R-induced mitochondrial dysfunction and prevented H/R damage. Both myocardial infarct size and tissue damage due to I/R was reduced upon DPX treatment. We discovered that DPX enhanced mitophagy in-vivo and in-vitro, which was accompanied by enhanced expression of PINK1 and Parkin. Knock-down of PINK1 and Parkin by specific siRNAs reversed DPX-induced inhibition of myocardial I/R injury. These findings suggest that DPX might protect against myocardial injury via PINK1 and Parkin.
    Keywords:  dexpramipexole; ischemia; mitophagy; myocardial; reperfusion