Qiang Tong Lab

The study of the molecular mechanism of caloric restriction may lead to pharmaceutical treatments that may mimic caloric restriction’s beneficial effects. Sir2 gene, which encodes a NAD+-dependent protein deacetylase, was reported to mediate the effect of caloric restriction in yeast. We have demonstrated that the expressions of two of the seven mammalian Sir2 homologues, SIRT2 and SIRT3, are up-regulated in response to dietary restriction, cold exposure and oxidative stress. We have illustrated the molecular mechanism of SIRT2’s action in oxidative stress resistance and the inhibition of adipocyte formation. We have also shown how SIRT3 activates adaptive thermogenesis program in brown adipose tissue and how SIRT3 regulates glucose disposal and fat oxidation in skeletal muscle. To understand the underlying molecular mechanisms, we have identified several substrate proteins for SIRT2 and SIRT3. Research is under way to investigate the actions of sirtuins in gain or loss-of-function animal models.

We are studying the development of adipose tissue and its changes during obesity. By investigating how mature adipocytes are derived from multi-potent precursor cells, we can gain insight into obesity prevention. In addition, by studying how factors produced by adipocytes and adipose tissue influence whole body metabolism, we may learn how obesity causes insulin resistance and subsequent type-2 diabetes. We have revealed that the expression of the PU.1 transcription factor is increased by obesity in visceral but not subcutaneous adipose tissues. We further found that in adipocytes, PU.1 up-regulates the generation of free radicals and pro-inflammatory cytokines to suppress insulin signaling. We are currently exploring the possibility to ameliorate obesity-associated metabolic dysfunction by targeting the PU.1 pathway.

Xi-rui Ge, Jue Wang, Yu-fang Che, Qiang Tong, Shu LZ, Zhang TM, and Lo JM (1988)  Monoclonal antibodies distinguishing human small cell lung cancer from non-small cell lung cancer.  Acta Biologiae Experimentalis Sinica, 21(2): 251-255.

Qiang Tong and Xi-rui Ge (1991) The effect of neuropeptides substance K and substance P on murine spenocytes and thymocytes. Chinese Journal of Immunology, 7(5): 263-267.

Sissy M. Jhiang, Linda Fithian, Patria Smanik, Jeffrey Mcgill, Qiang Tong and Ernest L. Mazzaferri (1993)  Cloning of the human taurine transporter and characterization of taurine uptake in thyroid cells.  FEBS Letters, 318: 139-144.

4Shunhua Xing, Qiang Tong, Toshimitsu Suzuki and Sissy M Jhiang (1994) Alternative splicing of the RET proto-oncogene at intron 4. Biochemical and Biophysical Research Communications, 205: 1526-1532.

Qiang Tong, Yishuan li, Patricia A Sminik, Linda Fithian, Shunhua Xing, Ernest L Mazzaferri and Sissy M Jhiang (1995)  Characterization of promoter region and oligomerization domain of H4(D10S170), a gene frequently rearranged with the ret proto-oncogene.  Oncogene, 10: 1781-1787.

Sissy M Jhiang, John E Sagartz, Qiang Tong, Jan Parker-Thornburg, Charles C. Capen, Je-Yoel Cho, Shunhua Xing and Catherine Ledent (1996) Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology, 137: 375-378. 

G. H. Jossart, B. O'Brien, J.-F. Cheng, Qiang Tong, S.M. Jhiang, Q. Duh, O.H. Clark and H.-U.G. Weier (1996)  A novel multicolor hybridization scheme applied to localization of transcribed sequence (D10S170/H4) and deletion mapping in the thyroid cancer cell line TPC-1. Cytogenetics and Cell Genetics, 75: 254-257.

John E. Sagartz, Sissy M. Jhiang, Qiang Tong, and Charles C. Capen (1997) Thyroid stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene.  Laboratory Investigation, 76: 307-318.

Qiang Tong, Shunhua Xing and Sissy M. Jhiang (1997) Leucine zipper mediated dimerization is essential for the hyperphosphorylation and oncogenic activity of PTC1 oncoprotein. J Biol Chem. 272: 9043-9047.

Qiang Tong, Kwon-Yul Ryu and Sissy M. Jhiang (1997) Characterization of the promoter of rat Na+/I- symporter gene.  Biochemical and Biophysical Research Communications, 239:34-41.

Shunhua Xing, Tara L. Furminger, Qiang Tong and Sissy M. Jhiang (1998)  Signal transduction pathways activated by RET in PC12 cells.  The Journal of Biological Chemistry, 273: 4909-4914.

K.-Y. Ryu, Qiang Tong and S.M. Jhiang (1998) Promoter characterization of the human Na+/I- symporter.  J. Clin. Endo. Metab. 83: 3247-51.

S.M. Jhiang, J.Y. Cho, T.L. Furminger, J.E. Sagartz, Qiang Tong, C.C. Capen, E.L.Mazzaferri, (1998)  Thyroid carcinomas in RET/PTC transgenic mice. Recent Results in Cancer Research. 154:265-70.  

Qiang Tong, Gökhan Dalgin, Haiyan Xu, Chao-Nan Ting, Jeffrey M. Leiden and Gökhan S. Hotamisligil (2000)  Function of GATA Transcription Factors in Preadipocyte-Adipocyte Transition.  Science, 290: 134-138.

Tong Q, Hotamisligil GS. Molecular mechanisms of adipocyte differentiation. Rev Endocr Metab Disord. 2001 Oct;2(4):349-55. Review. PubMed PMID: 11725721.

James M. Way, Cem Z. Görgün, Qiang Tong, K. Teoman Uysal, Kathleen K. Brown, W. Wallace Harrington, William R. Oliver, Jr., Timothy M. Willson, Steven A. Kliewer, and Gökhan S. Hotamisligil (2001)  Adipose Tissue Resistin Expression Is Severely Suppressed in Obesity and Stimulated by Peroxisome Proliferator-activated Receptor Agonists. J Biol Chem. 276: 25651-25653.

Qiang Tong, Jean-Louis Sankalé, Colleen M. Hadigan, Guo Tan, Eric S. Rosenberg, Phyllis J. Kanki, Steven K. Grinspoon and Gökhan S. Hotamisligil  (2003) Regulation of Adiponectin In HIV-Infected Patients: Relationship to Body Composition and Metabolic Indices, J Clin Endocrinol Metab, 88(4):1559-64.

Qiang Tong, Judy Tsai, Gökhan S. Hotamisligil (2003) GATA transcription factors and fat cell formation. Drug News Perspect. 16(9):585-8.

Qiang Tong, Judy Tsai, Guo Tan, Gökhan Dalgin, and Gökhan S. Hotamisligil (2005) Interaction between GATA and the C/EBP Family of Transcription Factors is Critical in GATA-Mediated Suppression of Adipocyte Differentiation, Mol. Cell Biol, 25(2):706-715.

Tong Shi, Fei Wang, Emily Stieren, and Qiang Tong (2005) SIRT3, A Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function And Thermogenesis In Brown Adipocytes, J Biol Chem,  280(14):13560-13567.

Judy Tsai, Qiang Tong, Guo Tan, Aaron N. Chang, Stuart H. Orkin, Gökhan S. Hotamisligil (2005) The Transcription Factor GATA2 Regulates Differentiation of Brown Adipocytes, EMBO reports, 6(9):879-884.

Jean-Louis G. Sankalé, Qiang Tong, Colleen M. Hadigan, Guo Tan, Steven K. Grinspoon, Phyllis J. Kanki, Gökhan S. Hotamisligil (2006) Regulation of Adiponectin in Adipocytes Upon Exposure to HIV-1. HIV Medicine. 74:268-274.

Qiang Tong and Gökhan S. Hotamisligil (2007) Cell fate in the mammary gland. Nature 15; 445(7129):724-6. 

Fei Wang, Margaret Nguyen, F. Xiao-Feng Qin, and Qiang Tong (2007) SIRT2 Deacetylates FOXO3a in Response to Oxidative Stress and Caloric Restriction. Aging Cell, 6:505-14.

Fei Wang and Qiang Tong (2008) Transcription Factor PU.1 Is Expressed in White Adipose and Inhibits Adipocyte Differentiation. Am J Physiol-Cell Physiol, 295:C213-20.

Fei Wang and Qiang Tong (2009) SIRT2 Suppresses Adipocyte Differentiation by Deacetylating Foxo1 and Enhancing Foxo1’s Repressive Interaction with PPARγ. Mol. Biol. Cell, 20:801-8.

Julia Skokowa, Dan Lan, Basant Kumar Thakur, Fei Wang, Kshama Gupta, Gunnar Cario, Annette Muller Brechlin, Axel Schambach, Lars Hinrichsen, Gustav Meyer, Matthias Gaestel, Martin Stanulla, Qiang Tong and Karl Welte (2009) NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent pathway. Nature Med, 15:151-8.

Dina Bellizzi, Giuseppina Covello, Fausta Di Cianni, Qiang Tong, Giovanna de Benedictis (2009) Identification of GATA2 and AP-1 activator elements within the enhancer VNTR occurring in intron 5 of the human SIRT3 gene, Mol Cells, 28:87-92.

Orsolya M. Palacios, Juan J. Carmona, Shaday Michan, Ke Yun Chen, Yasuko Manabe, Jack Lee Ward III, Laurie J. Goodyear, and Qiang Tong (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α, in skeletal muscle, Aging, 1:771-783.

Huseyin Cimen, Min-Joon Han, Yongjie Yang, Qiang Tong, Hasan Koc and Emine C. Koc (2010) Regulation of Succinate Dehydrogenase Activity by SIRT3 in Mammalian Mitochondria. Biochemistry, 49:304-311. PMCID: PMC2826167

Yongjie Yang, Huseyin Cimen, Min-Joon Han, Tong Shi, Jian-Hong Deng, Hasan Koc, Orsolya M. Palacios, Laura Montier, Yidong Bai, Qiang Tong* and Emine C. Koc* (2010) NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10. J Biol Chem. 285:7417-7429 (*co-corresponding authors) PMCID: PMC2844190

Yongjie Yang, Basil P. Hubbard, David A. Sinclair, Qiang Tong (2010) Characterization of murine SIRT3 transcript variants and corresponding protein products. J Cell Biochem. 111(4):1051-8. NIHMS272616

Xue Gao, Yong-Hyun Shin, Min Li, Fei Wang, Qiang Tong, and Pumin Zhang (2010) The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice. PLoS One, 5:e14005. PMCID: PMC2982835

Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P, Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA, Tong Q, Tsubota K, Vaquero A, Verdin E. (2010) Dietary restriction: standing up for sirtuins. Science. 329:1012-3

Yongjie Yang, Ke Yun Chen, Qiang Tong (2011) Murine Sirt3 Protein Isoforms Have Variable Half-lives, Gene, 488(1-2):46-51. PMCID: PMC3185158, NIHMS317536

Ligen Lin, Pradip K. Saha, Xiaojun Ma, Iyabo O. Henshaw, Longjiang Shao, Benny H. J. Chang, Eric D. Buras, Qiang Tong, Lawrence Chan, Owen P. McGuinness, and Yuxiang Sun (2011) Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell, 10(6):996-1010. PMCID:PMC3215833

Fei Wang, Chia-Hsin Chan, Keyun Chen, Xinfu Guan, Hui-Kuan Lin, Qiang Tong (2012) Deacetylation of FOXO3 by SIRT1 or SIRT2 Leads to Skp2-Mediated FOXO3 Ubiquitination and Degradation. Oncogene, 31:1546–1557. PMID: 21841822

Ligen Lin, Weijun Pang, Keyun Chen, Fei Wang, Jon Gengler, Yuxiang Sun, and Qiang Tong (2012) Adipocyte Expression of PU.1 Transcription Factor Causes Insulin Resistance through Up-regulation of Inflammatory Cytokine Gene Expression and ROS Production. Am J Physiol-Endocrinology and Metabolism, 302: E1550-E1559. PMCID: PMC3378156

39. Pang WJ, Xiong Y, Wang Y, Tong Q, Yang GS. (2013) Sirt1 attenuates camptothecin-induced apoptosis through caspase-3 pathway in porcine preadipocytes. Exp Cell Res. 319(5):670-83. PMID:23313858

Serrano L, Martínez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, Beck DB, Kane-Goldsmith N, Tong Q, Rabanal RM, Fondevila D, Muñoz P, Krüger M, Tischfield JA, Vaquero A. (2013) The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes & Development. 27(6):639-53. PMID: 23468428, PMCID: PMC3613611

Miao-Hsueh Chen, Qiang Tong (2013) “An Update on the Regulation of Adipogenesis”. Drug Discovery Today: Disease Mechanisms, 10:e15-e19.

Ligen Lin, Keyun Chen, Waed Abdel Khalek, Jack Lee Ward III, Henry Yang, Béatrice Chabi, Chantal Wrutniak-Cabello, Qiang Tong (2014) Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3, PLOS One, 9(1):e85636. PMID: 24454908, PMCID: PMC3893254

Pan JS, Huang L, Belousova T, Lu L, Yang Y, Reddel R, Chang A, Ju H, DiMattia G, Tong Q, Sheikh-Hamad D. (2015) Stanniocalcin-1 Inhibits Renal Ischemia/Reperfusion Injury via an AMP-Activated Protein Kinase-Dependent Pathway. J Am Soc Nephrol. 26(2):364-78.

Cheung KG, Cole LK, Xiang B, Chen K, Ma X, Myal Y, Hatch GM, Tong Q, Dolinsky VW. (2015) SIRT3 attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. J Biol Chem. 290, 10981-10993.

Nosavanh L, Yu DH, Jaehnig EJ, Tong Q, Shen L, Chen MH. (2015) Cell-autonomous activation of Hedgehog signaling inhibits brown adipose tissue development. Proc Natl Acad Sci USA. 112(16):5069-74.

Zhiqiang Liu, Jingda Xu, Jin He, Huan Liu, Pei Lin, Xinhai Wan, Nora M. Navone, Qiang Tong, Larry W. Kwak, Robert Z. Orlowski, Jing Yang (2015) Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation, Oncotarget, 6(33):34329-41. doi: 10.18632/oncotarget.6020.

Rubel CA, Wu SP, Lin L, Wang T, Lanz RB, Li X, Kommagani R, Franco HL, Camper SA, Tong Q, Jeong JW, Lydon JP, DeMayo FJ A (2016) Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function. Cell Rep. 17(5):1414-1425. doi: 10.1016/j.celrep.2016.09.093. PMID: 27783953, PMCID: PMC5084852

de Oliveira RM, Vicente Miranda H, Francelle L, Pinho R, Szegö ÉM, Martinho R, Munari F, Lázaro DF, Moniot S, Guerreiro P, Fonseca-Ornelas L, Marijanovic Z, Antas P, Gerhardt E, Enguita FJ, Fauvet B, Penque D, Pais TF, Tong Q, Becker S, Kügler S, Lashuel HA, Steegborn C, Zweckstetter M, Outeiro TF. (2017) The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease. PLoS Biol. 15(3):e2000374. doi: 10.1371/journal.pbio.2000374, PMID: 28257421 PMCID: PMC5336201

Mo Q, Salley J, Roshan T, Baer LA, May FJ, Jaehnig EJ, Lehnig AC, Guo X, Tong Q, Nuotio-Antar AM, Shamsi F, Tseng YH, Stanford KI, Chen MH (2017) Identification and characterization of a supraclavicular brown adipose tissue in mice. JCI Insight. 2(11). pii: 93166. PMID: 28570265 PMCID: PMC5453704

Liu J, Li D, Zhang T, Tong Q, Ye RD, Lin L. (2017) SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity. Cell Death Dis. 8(10):e3158. doi: 10.1038/cddis.2017.564. PMID: 29072685, PMCID: PMC5680927

Li GL, Chen HJ, Zhang WX, Tong Q, Yan YE. (2017) Effects of maternal omega-3 fatty acids supplementation during pregnancy/lactation on body composition of the offspring: A systematic review and meta-analysis. Clin Nutr. 37(5):1462-1473. doi: 10.1016/j.clnu.2017.08.002. PMID: 28830700

Cao J, Yu Y, Zhang Z, Chen X, Hu Z, Tong Q*, Chang J*, Feng XH*, Lin X*. (2018) SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation. Diabetes. 67(1):46-57. doi: 10.2337/db17-0546, PMID: 28851713, PMCID: PMC5741142 (*co-corresponding authors)

Chabi B, Fouret G, Lecomte J, Cortade F, Pessemesse L, Baati N, Coudray C, Lin L, Tong Q, Wrutniak-Cabello C, Casas F, Feillet-Coudray C. (2018) Skeletal muscle overexpression of short isoform Sirt3 altered mitochondrial cardiolipin content and fatty acid composition. J Bioenerg Biomembr. 50(2):131-142. doi: 10.1007/s10863-018-9752-1. PMID: 29589261

 Li Q, Lei F, Tang Y, Pan JS, Tong Q, Sun Y, Sheikh-Hamad D (2018) Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism. Cell Mol Life Sci. 75(21):4021-4040. doi: 10.1007/s00018-018-2847-3. PMID: 29916093

Liu JX, Shen SN, Tong Q, Wang YT, Lin LG. (2018) Honokiol protects hepatocytes from oxidative injury through mitochondrial deacetylase SIRT3. Eur J Pharmacol. 5;834:176-187. doi: 10.1016/j.ejphar.2018.07.036. PMID: 30036533

Huan Liu , Jin He, Su Pin Koh, Yuping Zhong, Zhiqiang Liu, Zhiqiang Wang, Yujin Zhang, Zongwei Li, Bjorn T. Tam, Pei Lin, Min Xiao, Ken H. Young, Behrang Amini, Michael W. Starbuck, Hans C. Lee, Nora M. Navone, Richard E. Davis, Qiang Tong, P. Leif Bergsagel, Jian Hou, Qing Yi, Robert Z. Orlowski, Robert F. Gagel, Jing Yang (2019) “Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease” Science Translational Medicine  11 (494):eaau9087, DOI: 10.1126/scitranslmed.aau9087, PMID: 31142679

Sebaa R, Johnson J, Pileggi C, Norgren M, Xuan J, Sai Y, Tong Q, Krystkowiak I, Bondy-Chorney E, Davey NE, Krogan N, Downey M, Harper ME. (2019) SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1. Mol Metab. pii: S2212-8778(18)30958-X. doi: 10.1016/j.molmet.2019.04.008. PMID: 31060926

Zhang T, Liu J, Shen S, Tong Q, Ma X, Lin L (2019) SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity. Cell Death Differ. doi: 10.1038/s41418-019-0356-z. PMID: 31160717

Xin Li , Li Yang, Zhengmei Mao, Xueyang Pan, Yueshui Zhao, Xue Gu, Kristin Eckel-Mahan, Zhongyuan Zuo, Qiang Tong, Sean M Hartig, Xiaodong Cheng, Guangwei Du, David D Moore, Hugo J Bellen, Hiromi Sesaki, Kai Sun (2020) Novel role of dynamin-related-protein 1 in dynamics of ER-lipid droplets in adipose tissue. FASEB J, 34(6):8265-8282. doi: 10.1096/fj.201903100RR. PMID: 32294302 PMCID: PMC7336545

Zhang T, Liu J, Tong Q, Lin L. SIRT3 Acts as a Positive Autophagy Regulator to Promote Lipid Mobilization in Adipocytes via Activating AMPK. Int J Mol Sci. 2020 Jan 7;21(2). doi: 10.3390/ijms21020372. PubMed PMID: 31936019; PubMed Central PMCID: PMC7013837.

Liu Z, Liu H, He J, Lin P, Tong Q, Yang J. Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells. Sci Signal. 2020 May 26;13(633). doi: 10.1126/scisignal.aay8203. PubMed PMID: 32457115; PubMed Central PMCID: PMC7376968.

Sarmistha Mukherjee, James Mo, Lauren M Paolella, Caroline E Perry, Jade Toth, Mindy M Hugo, Qingwei Chu, Qiang Tong, Karthikeyani Chellappa, Joseph A Baur (2021) SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside. JCI Insight, 6(7):e147193. doi: 10.1172/jci.insight.147193.PMID: 33690226 PMCID: PMC8119200 DOI: 10.1172/jci.insight.147193

Huiyun Shen, Michael Holliday, David Sheikh-Hamad, Qingtian Li, Qiang Tong, Christopher David Hamad, Jenny S Pan (2021) Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury. Transl Res. 235:15-31. doi: 10.1016/j.trsl.2021.03.015. PMID: 33789208 DOI: 10.1016/j.trsl.2021.03.015

Dan Li, Chao Yang, Jian-Zhong Zhu, Eduardo Lopez, Tian Zhang, Qiang Tong, Cheng Peng, Li-Gen Lin Berberine remodels adipose tissue to attenuate metabolic disorders by activating sirtuin 3. Acta Pharmacol Sin. 2022 May;43(5):1285-1298. doi: 10.1038/s41401-021-00736-y. Epub 2021 Aug 20. PubMed PMID: 34417576; PubMed Central PMCID: PMC9061715.

Chen K, De Angulo A, Guo X, More A, Ochsner SA, Lopez E, Saul D, Pang W, Sun Y, McKenna NJ, Tong Q. Adipocyte-Specific Ablation of PU.1 Promotes Energy Expenditure and Ameliorates Metabolic Syndrome in Aging Mice. Frontiers in Aging. 2022 February; 2.

Guo X, Jiang X, Chen K, Liang Q, Zhang S, Zheng J, Ma X, Jiang H, Wu H, Tong Q. The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice. Nutrients. 2022 Apr 1;14(7). doi: 10.3390/nu14071482. PubMed PMID: 35406095; PubMed Central PMCID: PMC9003329

Tomczyk MM, Cheung KG, Xiang B, Tamanna N, Fonseca Teixeira AL, Agarwal P, Kereliuk SM, Spicer V, Lin L, Treberg J, Tong Q, Dolinsky VW. Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress. Circ Heart Fail. 2022 May;15(5):e008547. doi: 10.1161/CIRCHEARTFAILURE.121.008547. Epub 2022 Apr 14. PubMed PMID: 35418250; PubMed Central PMCID: PMC9117478.