bims-hafaim 2021-05-23 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–05–23
thirteen papers selected by
Kyle McCommis, Saint Louis University

AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis.
FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo.
Sodium-Glucose CoTransporter-2 Inhibitor Empagliflozin Ameliorates Sunitinib-Induced Cardiac Dysfunction via Regulation of AMPK-mTOR Signaling Pathway-Mediated Autophagy.
Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells.
Hsp90 inhibitor attenuates the development of pathophysiological cardiac fibrosis in mouse hypertrophy via suppression of the calcineurin-NFAT and c-Raf-Erk pathways.
Constitutive Protein Kinase G Activation Exacerbates Stress-induced Cardiomyopathy.
Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism.
Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition.
Yes-Associated Protein is Involved in Myocardial Fibrosis in Rats with Diabetic Cardiomyopathy.
Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.
Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis.
Narrative review of metabolomics in cardiovascular disease.
Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

Sci Rep. 2021 May 18. 11(1): 10553

AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis.

Jamie Francisco, Yu Zhang, Yasuki Nakada, Jae Im Jeong, Chun-Yang Huang, Andreas Ivessa, Shinichi Oka, Gopal J Babu, Dominic P Del Re.

Fibrosis is a hallmark of heart disease independent of etiology and is thought to contribute to impaired cardiac dysfunction and development of heart failure. However, the underlying mechanisms that regulate the differentiation of fibroblasts to myofibroblasts and fibrotic responses remain incompletely defined. As a result, effective treatments to mitigate excessive fibrosis are lacking. We recently demonstrated that the Hippo pathway effector Yes-associated protein (YAP) is an important mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Yet, whether YAP activation in cardiac fibroblasts is sufficient to drive fibrosis, and how fibroblast YAP affects myocardial inflammation, a significant component of adverse cardiac remodeling, are largely unknown. In this study, we leveraged adeno-associated virus (AAV) to target cardiac fibroblasts and demonstrate that chronic YAP expression upregulated indices of fibrosis and inflammation in the absence of additional stress. YAP occupied the Ccl2 gene and promoted Ccl2 expression, which was associated with increased macrophage infiltration, pro-inflammatory cytokine expression, collagen deposition, and cardiac dysfunction in mice with cardiac fibroblast-targeted YAP overexpression. These results are consistent with other recent reports and extend our understanding of YAP function in modulating fibrotic and inflammatory responses in the heart.

DOI: https://doi.org/10.1038/s41598-021-89989-5
JACC Basic Transl Sci. 2021 Apr;6(4): 365-380

FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo.

Christian Kuhn, Maja Menke, Frauke Senger, Claudia Mack, Franziska Dierck, Susanne Hille, Inga Schmidt, Gabriele Brunke, Pia Bünger, Nesrin Schmiedel, Rainer Will, Samuel Sossalla, Derk Frank, Thomas Eschenhagen, Lucie Carrier, Renate Lüllmann-Rauch, Ashraf Yusuf Rangrez, Norbert Frey.

  Autophagy is a cellular degradation process that has been implicated in diverse disease processes. The authors provide evidence that FYCO1, a component of the autophagic machinery, is essential for adaptation to cardiac stress. Although the absence of FYCO1 does not affect basal autophagy in isolated cardiomyocytes, it abolishes induction of autophagy after glucose deprivation. Likewise, Fyco1-deficient mice subjected to starvation or pressure overload are unable to respond with induction of autophagy and develop impaired cardiac function. FYCO1 overexpression leads to induction of autophagy in isolated cardiomyocytes and transgenic mouse hearts, thereby rescuing cardiac dysfunction in response to biomechanical stress.

Keywords:  BFA, bafilomycin A1; CSA, cell surface area; FYCO1; GFP, green fluorescent protein; KO, knockout; MHC, myosin heavy chain; NRCM, neonatal rat cardiomyocytes; RFP, red fluorescent protein; TAC, transverse aortic constriction; TG, transgenic; WT, wild-type; autophagy; heart failure; mRNA, messenger ribonucleic acid; microRNA, micro–ribonucleic acid

DOI:  https://doi.org/10.1016/j.jacbts.2021.01.001
Front Pharmacol. 2021 ;12 664181

Sodium-Glucose CoTransporter-2 Inhibitor Empagliflozin Ameliorates Sunitinib-Induced Cardiac Dysfunction via Regulation of AMPK-mTOR Signaling Pathway-Mediated Autophagy.

Changzhen Ren, Kaiqiang Sun, Yanda Zhang, Yangxi Hu, Bowen Hu, Jian Zhao, Zhiqing He, Ru Ding, Weizhong Wang, Chun Liang.

  Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to decrease the adverse cardiac events and risks of cardiovascular mortality among patients with or without diabetes, which has made these drugs promising treatment options for patients with chronic heart failure. Cardiac dysfunction is a common and severe side effect induced by cancer chemotherapies, which seriously affects the prognosis and life quality of tumor patients. However, it is not clear whether SGLT2 inhibitors have cardiovascular benefits in patients with cancer chemotherapy-related cardiac dysfunction. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role against sunitinib (SNT)-induced cardiac dysfunction in a mouse model. Methods: Male C57BL/6J mice were randomized into control (control, n = 8), empagliflozin (EMPA, n = 8), sunitinib (SNT, n = 12), or sunitinib and empagliflozin coadministration (SNT + EMPA, n = 12) groups. EMPA, SNT, or SNT-combined EMPA was given via oral gavage for consecutive 28 days. Cardiovascular functions and pathological changes were examined, and the underlying mechanisms of EMPA's effects were investigated in H9c2 cardiomyocytes. Results: Mice in the SNT group exhibited dramatically elevated blood pressure (systolic blood pressure [SBP] 134.30 ± 6.455 mmHg vs. 114.85 ± 6.30 mmHg) and impaired left ventricular function (left ventricular ejection fraction [LVEF] 50.24 ± 3.06% vs. 84.92 ± 2.02%), as compared with those of the control group. However, EMPA could ameliorate SNT-induced cardiotoxicity, both in terms of SBP (117.51 ± 5.28 mmHg vs. 134.30 ± 6.455 mmHg) and LVEF (76.18 ± 5.16% vs. 50.24 ± 3.06 %). In H9c2 cardiomyocytes, SNT-induced cardiomyocyte death and cell viability loss as well as dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling-mediated autophagy were restored by EMPA. However, these favorable effects mediated by EMPA were blocked by the inhibition of AMPK or autophagy. Conclusion: EMPA could ameliorate SNT-induced cardiac dysfunction via regulating cardiomyocyte autophagy, which was mediated by the AMPK-mTOR signaling pathway. These findings supported that SGLT2 inhibitor therapy could be a potential cardioprotective approach for cardiovascular complications among patients receiving SNT. However, these favorable effects still need to be validated in clinical trials.

Keywords:  autophagy; cardiotoxicity; empagliflozin; heart failure; sunitinib

DOI:  https://doi.org/10.3389/fphar.2021.664181
Cell Biosci. 2021 May 17. 11(1): 89

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells.

M Tajes, C Díez-López, C Enjuanes, P Moliner, J L Ferreiro, A Garay, S Jiménez-Marrero, S Yun, S G Sosa, L Alcoberro, J González-Costello, E García-Romero, L Yañez-Bisbe, B Benito, J Comín-Colet.

   BACKGROUND: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells.
METHODS: HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production.
RESULTS: Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells.
CONCLUSIONS: HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.

Keywords:  Cardiac cell; Heart failure; Iron deficiency; Mitochondria function; Neurohormonal activation

DOI:  https://doi.org/10.1186/s13578-021-00605-5
J Cardiovasc Pharmacol. 2021 Mar 12.

Hsp90 inhibitor attenuates the development of pathophysiological cardiac fibrosis in mouse hypertrophy via suppression of the calcineurin-NFAT and c-Raf-Erk pathways.

Tetsuro Marunouchi, Miyuki Nakashima, Saika Ebitani, Sakiko Umezu, Kasane Karasawa, Emi Yano, Kouichi Tanonaka, Kouichi Tanonka.

ABSTRACT: In the previous study, we showed that an Hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), attenuates hypertrophic remodeling of cardiomyocytes during the development of heart failure. In this present study, we investigated the effects of 17-AAG on cardiac fibrosis during the development of heart failure. We used pressure-loaded cardiac hypertrophic mice prepared by constriction of the transverse aorta (TAC), which induces significant cardiac fibrosis without scar tissue. From the 6th week after the TAC operation, vehicle or 17-AAG was administered intraperitoneally twice a week. Eight weeks after the operation, the vehicle-treated animals showed chronic heart failure. On the other hand, cardiac deterioration of the 17-AAG-treated animals was attenuated. In 17-AAG-treated animals, when the degree of fibrosis was observed by histological staining, their volume of fibrosis was found to be reduced. The content of calcineurin, an Hsp90 client protein, and the level of dephosphorylated NFATc2, a transcription factor in the cardiac fibroblasts, in the TAC mice was reduced by treatment with 17-AAG. Furthermore, c-Raf and Erk signaling, indicators for cell proliferation and collagen synthesis, was also attenuated. In in vitro experiments, the proliferation and collagen synthesis of the cultured cardiac fibroblasts were attenuated by the presence of 17-AAG. When cardiac fibroblasts were incubated with angiotensin II, calcineurin-NFATc2 and c-Raf-Erk signaling in the cells were activated. These activations were attenuated by 17-AAG. Our findings suggest that suppression of the calcineurin-NFAT and c-Raf-Erk pathways may partially contribute to the attenuation of myocardial fibrosis caused by treatment with 17-AAG. Therefore, our data imply that the Hsp90 inhibitor may have potential for novel therapeutic strategy for the treatment of heart failure.

DOI: https://doi.org/10.1097/FJC.0000000000001017
Br J Pharmacol. 2021 May 17.

Constitutive Protein Kinase G Activation Exacerbates Stress-induced Cardiomyopathy.

Gerburg K Schwaerzer, Darren E Casteel, Federico Cividini, Hema Kalyanaraman, Shunhui Zhuang, Yusu Gu, Nancy D Dalton, Kirk L Peterson, Wolfgang H Dillmann, Gerry R Boss, Renate B Pilz.

   BACKGROUND AND PURPOSE: Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodeling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed, and the effects of long-term PKG activation in the heart are unknown.
EXPERIMENTAL APPROACH: We characterized the cardiac phenotype of mice carrying a heterozygous knock-in mutation of PKG1 (Prkg1R177Q/+ ), which causes constitutive, cGMP-independent activation of the kinase. We examined isolated cardiac myocytes and intact mice, the latter after stress induced by surgical transaortic constriction or angiotensin II (Ang II) infusion.
KEY RESULTS: Cardiac myocytes from Prkg1R177Q/+ mice showed altered phosphorylation of sarcomeric proteins and reduced contractility in response to electrical stimulation, compared to cells from wild type mice. Under basal conditions, young PKG1R177Q/+ mice exhibited no obvious cardiac abnormalities, but aging animals developed mild increases in cardiac fibrosis. In response to Ang II infusion or fixed pressure overload induced by transaortic constriction, young PKGR177Q/+ mice exhibited excessive hypertrophic remodeling with increased fibrosis and myocyte apoptosis, leading to increased left ventricular dilation and dysfunction compared to wild type litter mates.
CONCLUSION AND IMPLICATIONS: Long-term PKG1 activation in mice may be harmful to the heart, especially in the presence of pressure overload and neurohumoral stress.

Keywords:  cGMP-dependent protein kinase; cardiac hypertrophy; fibrosis; phosphorylation of sarcomeric proteins; stress-induced dilated cardiomyopathy

DOI:  https://doi.org/10.1111/bph.15530
Cardiovasc Toxicol. 2021 May 21.

Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism.

Yang Liu, Shuang Li, Zhanqun Gao, Shuangjia Li, Qingyun Tan, Yanmei Li, Dongwei Wang, Qingdong Wang.

  Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme for tryptophan metabolism, involved in immune cell differentiation/maturation and cancer biology. IDO1 is also expressed in cardiomyocytes, but its roles in the cardiovascular system are not fully understood. Here, we reported the functions of IDO1 during cardiac hypertrophy. Quantitative real-time PCR and Western blot experiments demonstrated the upregulation of IDO1 mRNA and protein levels in human and hypertrophic mouse hearts, as well as in angiotensin II (Ang II)-induced hypertrophic rat cardiomyocytes. IDO1 activity and metabolite product kynurenine were upregulated in rodent hypertrophic hearts and cardiomyocytes. Inhibition of IDO1 activity with PF-06840003 reduced Ang II-induced cardiac hypertrophy and rescued cardiac function in mice. siRNA-mediated knockdown of Ido1 repressed Ang II-induced growth in cardiomyocyte size and overexpression of hypertrophy-associated genes atrial natriuretic peptide (Anp or Nppa), brain natriuretic peptide (Bnp or Nppb), β-myosin heavy chain (β-Mhc or Myh7). By contrast, adenovirus-mediated rat Ido1 overexpression in cardiomyocytes promoted hypertrophic growth induced by Ang II. Mechanism analysis showed that IDO1 overexpression was associated with PI3K-AKT-mTOR signaling to activate the ribosomal protein S6 kinase 1 (S6K1), which promoted protein synthesis in Ang II-induced hypertrophy of rat cardiomyocytes. Finally, we provided evidence that inhibition of PI3K with pictilisib, AKT with perifosine, or mTOR with rapamycin, blocked the effects of IDO1 on protein synthesis and cardiomyocyte hypertrophy in Ang II-treated cells. Collectively, our findings identify that IDO1 promotes cardiomyocyte hypertrophy partially via PI3K-AKT-mTOR-S6K1 signaling.

Keywords:  AKT; Cardiac hypertrophy; IDO1; MTOR; Protein synthesis; S6K1

DOI:  https://doi.org/10.1007/s12012-021-09657-y
Evid Based Complement Alternat Med. 2021 ;2021 5577875

Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition.

Wenwu Bai, Min Ren, Wen Cheng, Xiaoting Lu, Deshan Liu, Bo Wang.

Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson's trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-β1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and β-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-β1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-β1/Smad pathways in failing hearts.

DOI: https://doi.org/10.1155/2021/5577875
Diabetes Metab Syndr Obes. 2021 ;14 2133-2143

Yes-Associated Protein is Involved in Myocardial Fibrosis in Rats with Diabetic Cardiomyopathy.

Maomao Hu, Han Wang, Shengnan Li, Feng Yan, Changning Fu, Lei Li, Yalin Yu, Jie Xiong, Bo Dong.

   Introduction: Recent studies have shown that YAP is closely related to the pathological process of cardiovascular diseases. But the role of YAP in cardiac injury of diabetic cardiomyopathy (DCM) is still unclear.
Methods: Diabetic cardiomyopathy rat model was established and divided into control group, DCM group, LV-SC-shRNA group and LV-YAP-shRNA group. LV-SC-shRNA group and LV-YAP-shRNA group were injected with lentivirus expressing SC-shRNA and YAP-shRNA via tail vein, respectively. Primary rat cardiac fibroblasts (CFs) were stimulated with high concentration of glucose and treated with recombinant lentivirus expressing either SC-shRNA or YAP-shRNA to observe the expression of CTGF and fibronectin, so as to observe the effect of inhibiting YAP on the pathogenesis of DCM.
Results: Compared with control group, high glucose markedly increased YAP mRNA and protein expression in DCM and CFs. Inhibition of YAP decreased myocardial fibrosis and improved cardiac function in the DCM model and decreased the expression of CTGF and fibronectin in CFs. The result suggested that YAP plays a key role in the pathological progression of DCM, and the underlying mechanisms may be associated with TEAD and CTGF.
Discussion: We found that the expression of YAP was increased both in vivo and in vitro, suggesting that YAP is closely related to DCM, and YAP knockdown can reduce myocardial fibrosis in rat model of DCM by reducing the expression of PAI-1, collagen I, collagen III, CTGF and profilin, as well as the expression of CTGF and fibronectin in CFs. This study revealed that YAP plays an important role in the pathological process of diabetic cardiomyopathy, and down-regulation of YAP expression may provide a new therapeutic target for DCM.

Keywords:  diabetic cardiomyopathy; myocardial fibrosis; yes-associated protein

DOI:  https://doi.org/10.2147/DMSO.S302466
Nat Commun. 2021 05 19. 12(1): 2942

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.

Thomas G Martin, Valerie D Myers, Praveen Dubey, Shubham Dubey, Edith Perez, Christine S Moravec, Monte S Willis, Arthur M Feldman, Jonathan A Kirk.

The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

DOI: https://doi.org/10.1038/s41467-021-23272-z
Front Cardiovasc Med. 2021 ;8 645122

Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis.

Marwa Tantawy, Lakshmi Manasa Chekka, Yimei Huang, Timothy J Garrett, Sonal Singh, Chintan P Shah, Robert F Cornell, Rachid C Baz, Michael G Fradley, Nida Waheed, David L DeRemer, Lihui Yuan, Taimour Langaee, Keith March, Carl J Pepine, Jan S Moreb, Yan Gong.

  Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.

Keywords:  Cardio-oncology; carfilzomib; metabolomcis; proteasome inhibitors; proteomic

DOI:  https://doi.org/10.3389/fcvm.2021.645122
J Thorac Dis. 2021 Apr;13(4): 2532-2550

Narrative review of metabolomics in cardiovascular disease.

Julian Müller, Thomas Bertsch, Justus Volke, Alexander Schmid, Rebecca Klingbeil, Yulian Metodiev, Bican Karaca, Seung-Hyun Kim, Simon Lindner, Tobias Schupp, Maximilian Kittel, Gernot Poschet, Ibrahim Akin, Michael Behnes.

  Cardiovascular diseases are accompanied by disorders in the cardiac metabolism. Furthermore, comorbidities often associated with cardiovascular disease can alter systemic and myocardial metabolism contributing to worsening of cardiac performance and health status. Biomarkers such as natriuretic peptides or troponins already support diagnosis, prognosis and treatment of patients with cardiovascular diseases and are represented in international guidelines. However, as cardiovascular diseases affect various pathophysiological pathways, a single biomarker approach cannot be regarded as ideal to reveal optimal clinical application. Emerging metabolomics technology allows the measurement of hundreds of metabolites in biological fluids or biopsies and thus to characterize each patient by its own metabolic fingerprint, improving our understanding of complex diseases, significantly altering the management of cardiovascular diseases and possibly personalizing medicine. This review outlines current knowledge, perspectives as well as limitations of metabolomics for diagnosis, prognosis and treatment of cardiovascular diseases such as heart failure, atherosclerosis, ischemic and non-ischemic cardiomyopathy. Furthermore, an ongoing research project tackling current inconsistencies as well as clinical applications of metabolomics will be discussed. Taken together, the application of metabolomics will enable us to gain more insights into pathophysiological interactions of metabolites and disease states as well as improving therapies of patients with cardiovascular diseases in the future.

Keywords:  Metabolomics; atherosclerosis; heart failure; ischemic heart disease

DOI:  https://doi.org/10.21037/jtd-21-22
Circ Heart Fail. 2021 May;14(5): e008100

Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

HEART-FID Trial Investigators

   BACKGROUND: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited.
METHODS: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance.
CONCLUSIONS: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Keywords:  heart failure; hospitalizations; iron; outcomes; prognosis; survival

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.120.008100