bims-hafaim 2021-10-24 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–10–24
nine papers selected by
Kyle McCommis, Saint Louis University

Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy.
Targeting PPARα in low ambient temperature exposure-induced cardiac dysfunction and remodeling.
Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation.
Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis.
AZD2014, a dual mTOR inhibitor, attenuates cardiac hypertrophy in vitro and in vivo.
PKM2 promotes angiotensin-II-induced cardiac remodelling by activating TGF-β/Smad2/3 and Jak2/Stat3 pathways through oxidative stress.
Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression.
Dapagliflozin Versus Sacubitril-Valsartan to Improve Outcomes of Patients with Reduced Ejection Fraction and Diabetes Mellitus.
Mitochondrial Telomerase Reverse Transcriptase Protects from Myocardial Ischemia/reperfusion Injury by Improving Complex I Composition and Function.

Circulation. 2021 Oct 21.

Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy.

Sara Ranjbarvaziri, Kristina B Kooiker, Mathew Ellenberger, Giovanni Fajardo, Mingming Zhao, Alison Schroer Vander Roest, Rahel A Woldeyes, Tiffany T Koyano, Robyn Fong, Ning Ma, Lei Tian, Gavin M Traber, Frandics Chan, John Perrino, Sushma Reddy, Wah Chiu, Joseph C Wu, Joseph Y Woo, Kathleen M Ruppel, James A Spudich, Michael P Snyder, Kévin Contrepois, Daniel Bernstein.

Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites [ATP, ADP, and phosphocreatine (PCr)] and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.053575
Mil Med Res. 2021 Oct 19. 8(1): 53

Targeting PPARα in low ambient temperature exposure-induced cardiac dysfunction and remodeling.

Xi-Yao Chen, Yang Jiao, Fu-Yang Zhang.

  The present study demonstrates that the down-regulation of peroxisome proliferator-activated receptor-α (PPARα) results in chronic low ambient temperature (LT) exposure-induced cardiac dysfunction and remodeling, emphasizing the therapeutic potential of PPARα activation strategies (e.g. fenofibrate treatment) in LT-associated cardiac injury.

Keywords:  Cardiac dysfunction; Fatty acid metabolism; Low ambient temperature; Peroxisome proliferator-activated receptor-α; Remodeling

DOI:  https://doi.org/10.1186/s40779-021-00347-y
Front Cardiovasc Med. 2021 ;8 701745

Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation.

Zhi-Teng Chen, Qing-Yuan Gao, Mao-Xiong Wu, Meng Wang, Run-Lu Sun, Yuan Jiang, Qi Guo, Da-Chuan Guo, Chi-Yu Liu, Si-Xu Chen, Xiao Liu, Jing-Feng Wang, Hai-Feng Zhang, Yang-Xin Chen.

  Objective: To explore the role of glycolysis in cardiac fibroblast (CF) activation and cardiac fibrosis after myocardial infarction (MI). Method: In vivo: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was injected into the abdominal cavity of the MI or sham mice every day. On the 28th day, cardiac function was measured by ultrasonic cardiography, and the hearts were harvested. Masson staining and immunofluorescence (IF) were used to evaluate the fibrosis area, and western blot was used to identify the glycolytic level. In vitro, we isolated the CF from the sham, MI and MI with 2-DG treatment mice, and we also activated normal CF with transforming growth factor-β1 (TGF-β1) and block glycolysis with 2-DG. We then detected the glycolytic proteins, fibrotic proteins, and the concentrations of lactate and glucose in the culture medium. At last, we further detected the fibrotic and glycolytic markers in human fibrotic and non-fibrotic heart tissues with masson staining, IF and western blot. Result: More collagen and glycolytic protein expressions were observed in the MI mice hearts. The mortality increased when mice were treated with 2-DG (100 mg/kg/d) after the MI surgery (Log-rank test, P < 0.05). When the dosage of 2-DG declined to 50 mg/kg/d, and the treatment was started on the 4th day after MI, no statistical difference of mortality between the two groups was observed (Log-rank test, P = 0.98). The collagen volume fraction was smaller and the fluorescence signal of α-smooth muscle actin (α-SMA) was weaker in mice treated with 2-DG than PBS. In vitro, 2-DG could significantly inhibit the increased expression of both the glycolytic and fibrotic proteins in the activated CF. Conclusion: Cardiac fibrosis is along with the enhancement of CF activation and glycolysis. Glycolysis inhibition can alleviate cardiac fibroblast activation and cardiac fibrosis after myocardial infarction.

Keywords:  cardiac fibrosis; fibroblast activation; glycolysis; heart failure; myocardial infarction

DOI:  https://doi.org/10.3389/fcvm.2021.701745
J Clin Pharmacol. 2021 Oct 17.

Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis.

Hongtao Yu, Sanchita Basu, Weifeng Tang, Robert C Penland, Peter J Greasley, Jan Oscarsson, David W Boulton, K Melissa Hallow.

  Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce the risk of worsening heart failure (HF) in subjects with HF and a reduced ejection fraction (HFrEF) in multiple clinical trials. The DAPACARD clinical trial was conducted to examine the effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes mellitus (T2DM) subjects. As a complement to the clinical study, a mechanistic mathematical model of cardiorenal physiology was used to quantify the influence of established natriuretic/diuretic effects of SGLT2i on cardiac function (myocardial efficiency and global longitudinal strain). Virtual participants reflecting the participant-level characteristics in the DAPACARD trial were produced by varying model parameters over physiologically plausible ranges. A second virtual population was generated by inducing a state of HFrEF in the DAPACARD T2DM virtual participants (DAPACARD-HFrEF virtual participants) for comparison. Cardiac responses to placebo and SGLT2i were simulated over 42 days. Cardiac hemodynamic improvements were predicted in DAPACARD-HFrEF virtual participants but not in DAPACARD virtual participants. In particular, the natriuresis/diuresis induced by SGLT2i improved the global longitudinal strain and myocardial efficiency in DAPACARD-HFrEF virtual participants within the first 14 days (change from baseline: global longitudinal strain: -0.95% and myocardial efficiency: 0.34%), whereas the global longitudinal strain and myocardial efficiency in DAPACARD virtual participants were slightly worse (change from baseline: global longitudinal strain: 0.35% and myocardial efficiency: -0.01%). The results of the DAPACARD virtual participants modeling were in line with the clinical data but do not preclude additional effects from other mechanisms of SGLT2i. This article is protected by copyright. All rights reserved.

Keywords:  HFrEF; SGLT2i; cardiorenal modeling; dapagliflozin; global longitudinal strain; myocardial efficiency

DOI:  https://doi.org/10.1002/jcph.1987
J Biol Eng. 2021 Oct 21. 15(1): 24

AZD2014, a dual mTOR inhibitor, attenuates cardiac hypertrophy in vitro and in vivo.

Byung-Hyun Cha, Minjin Jung, Angela S Kim, Victoria C Lepak, Brett A Colson, David A Bull, Youngwook Won.

  Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway.

Keywords:  AZD2014; Cardiac hypertrophy; Cardiomyocyte; mTOR inhibitor

DOI:  https://doi.org/10.1186/s13036-021-00276-3
J Cell Mol Med. 2021 Oct 23.

PKM2 promotes angiotensin-II-induced cardiac remodelling by activating TGF-β/Smad2/3 and Jak2/Stat3 pathways through oxidative stress.

Xiyu Zhang, Cuiting Zheng, Zhenqiang Gao, Lingling Wang, Chen Chen, Yuanyuan Zheng, Yan Meng.

  Hypertensive cardiac remodelling is a common cause of heart failure. However, the molecular mechanisms regulating cardiac remodelling remain unclear. Pyruvate kinase isozyme type M2 (PKM2) is a key regulator of the processes of glycolysis and oxidative phosphorylation, but the roles in cardiac remodelling remain unknown. In the present study, we found that PKM2 was enhanced in angiotensin II (Ang II)-treated cardiac fibroblasts and hypertensive mouse hearts. Suppression of PKM2 by shikonin alleviated cardiomyocyte hypertrophy and fibrosis in Ang-II-induced cardiac remodelling in vivo. Furthermore, inhibition of PKM2 markedly attenuated the function of cardiac fibroblasts including proliferation, migration and collagen synthesis in vitro. Mechanistically, suppression of PKM2 inhibited cardiac remodelling by suppressing TGF-β/Smad2/3, Jak2/Stat3 signalling pathways and oxidative stress. Together, this study suggests that PKM2 is an aggravator in Ang-II-mediated cardiac remodelling. The negative modulation of PKM2 may provide a promising therapeutic approach for hypertensive cardiac remodelling.

Keywords:  Ang II; PKM2; cardiac remodelling; oxidative stress; shikonin

DOI:  https://doi.org/10.1111/jcmm.17007
Cardiovasc Diabetol. 2021 Oct 18. 20(1): 210

Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression.

Maria Ida Maiorino, Miriam Longo, Lorenzo Scappaticcio, Giuseppe Bellastella, Paolo Chiodini, Katherine Esposito, Dario Giugliano.

   BACKGROUND: Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs.
METHODS: An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression.
RESULTS: The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = - 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = - 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death.
CONCLUSIONS: The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

Keywords:  Cardiorenal outcomes; Cardiovascular outcome trials; DPP-4i; GLP-1RA; Glycemic control; MACE; Meta-regression; SGLT-2i; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12933-021-01401-8
Am J Cardiovasc Drugs. 2021 Oct 21.

Dapagliflozin Versus Sacubitril-Valsartan to Improve Outcomes of Patients with Reduced Ejection Fraction and Diabetes Mellitus.

Ariel Hammerman, Joseph Azuri, Enis Aboalhasan, Ronen Arbel.

BACKGROUND: Comorbid heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (DM) is associated with a very high risk of HF events. Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), and dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, improve HF outcomes in these patients, but their comparative value for money in this patient population has not yet been determined.
OBJECTIVE: We aimed to compare the cost needed to treat (CNT) to avoid an HF event with each drug.
METHODS: CNT was estimated by multiplying the annualized number needed to treat (NNT) to prevent one HF event by the annual cost of each therapy. HF events were defined as the first event of hospitalization for HF or cardiovascular mortality. Drug efficacy data were extracted from published secondary analyses of patients with DM in the DAPA-HF and PARADIGM-HF trials. Drug costs were estimated as 75% of the 2021 US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed on parameters that may have affected the CNT.
RESULTS: The annualized NNT was 24 (95% confidence interval [CI] 16-54) for dapagliflozin and 57 (95% CI 31-433) for the ARNI. At an annual cost of $US4523 and 5099, respectively, the CNT was $US108,563 (95% CI 72,375-244,267) for dapagliflozin and $US290,671 (95% CI 158,084-2,208,079) for the ARNI.
CONCLUSIONS: Dapagliflozin seems to offer greater value for money than the ARNI for patients with HFrEF and DM. Our results provide support for contemporary guidelines advocating the use of dapagliflozin in these patients.

DOI: https://doi.org/10.1007/s40256-021-00506-5
Circulation. 2021 Oct 21.

Mitochondrial Telomerase Reverse Transcriptase Protects from Myocardial Ischemia/reperfusion Injury by Improving Complex I Composition and Function.

Niloofar Ale-Agha, Philipp Jakobs, Christine Goy, Mark Zurek, Julia Rosen, Nadine Dyballa-Rukes, Sabine Metzger, Jan Greulich, Florian von Ameln, Olaf Eckermann, Klaus Unfried, Fedor Brack, Maria Grandoch, Matthias Thielmann, Markus Kamler, Nilgün Gedik, Petra Kleinbongard, Andre Heinen, Gerd Heusch, Axel Gödecke, Joachim Altschmied, Judith Haendeler.

Background: The catalytic subunit of telomerase, Telomerase Reverse Transcriptase (TERT) has protective functions in the cardiovascular system. TERT is not only present in the nucleus, but also in mitochondria. However, it is unclear whether nuclear or mitochondrial TERT is responsible for the observed protection and appropriate tools are missing to dissect this. Methods: We generated new mouse models containing TERT exclusively in the mitochondria (mitoTERT mice) or the nucleus (nucTERT mice) to finally distinguish between the functions of nuclear and mitochondrial TERT. Outcome after ischemia/reperfusion, mitochondrial respiration in the heart as well as cellular functions of cardiomyocytes, fibroblasts, and endothelial cells were determined. Results: All mice were phenotypically normal. While respiration was reduced in cardiac mitochondria from TERT-deficient and nucTERT mice, it was increased in mitoTERT animals. The latter also had smaller infarcts than wildtype mice, whereas nucTERT animals had larger infarcts. The decrease in ejection fraction after one, two and four weeks of reperfusion was attenuated in mitoTERT mice. Scar size was also reduced and vascularization increased. Mitochondrial TERT protected a cardiomyocyte cell line from apoptosis. Myofibroblast differentiation, which depends on complex I activity, was abrogated in TERT-deficient and nucTERT cardiac fibroblasts and completely restored in mitoTERT cells. In endothelial cells, mitochondrial TERT enhanced migratory capacity and activation of endothelial NO synthase. Mechanistically, mitochondrial TERT improved the ratio between complex I matrix arm and membrane subunits explaining the enhanced complex I activity. In human right atrial appendages, TERT was localized in mitochondria and there increased by remote ischemic preconditioning. The Telomerase activator, TA-65 evoked a similar effect in endothelial cells, thereby increasing their migratory capacity, and enhanced myofibroblast differentiation. Conclusions: Mitochondrial, but not nuclear TERT, is critical for mitochondrial respiration and during ischemia/reperfusion injury. Mitochondrial TERT improves complex I subunit composition. TERT is present in human heart mitochondria, and remote ischemic preconditioning increases its level in those organelles. TA-65 has comparable effects ex vivo and improves migratory capacity of endothelial cells and myofibroblast differentiation. We conclude that mitochondrial TERT is responsible for cardioprotection and its increase could serve as a therapeutic strategy.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.051923