Letter by Gutmann et al Regarding Article, "Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles".

HomeCirculationVol. 147, No. 4Letter by Gutmann et al Regarding Article, “Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Gutmann et al Regarding Article, “Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles” Clemens Gutmann, Stefan Stojkovic and Manuel Mayr Clemens GutmannClemens Gutmann https://orcid.org/0000-0003-0675-8632 King’s College London, School of Cardiovascular and Metabolic Medicine and Sciences, United Kingdom (C.G., M.M.). Department of Cardiology, Innere Medizin II, Medical University Vienna, Austria (C.G., S.S., M.M). Search for more papers by this author , Stefan StojkovicStefan Stojkovic Department of Cardiology, Innere Medizin II, Medical University Vienna, Austria (C.G., S.S., M.M). Search for more papers by this author and Manuel MayrManuel Mayr https://orcid.org/0000-0002-0597-829X King’s College London, School of Cardiovascular and Metabolic Medicine and Sciences, United Kingdom (C.G., M.M.). Department of Cardiology, Innere Medizin II, Medical University Vienna, Austria (C.G., S.S., M.M). Search for more papers by this author Originally published23 Jan 2023https://doi.org/10.1161/CIRCULATIONAHA.122.062334Circulation. 2023;147:e68–e69To the Editor:We have read the study by Hosen et al1 with great interest and deem the finding that circulating microRNA-122 (miR-122) is associated with a lack of improvement in left ventricular function after transcatheter aortic valve replacement of substantial clinical relevance. However, we advise caution regarding the interpretation that miR-122 is carried by endothelial cell (EC)–derived extracellular vesicles and that miR-122 levels within extracellular vesicles are sufficiently high to affect cardiomyocyte function in vivo through horizontal miRNA transfer. Instead, we argue that circulating miR-122 is a marker of hepatic congestion attributable to increased central venous pressure in heart failure.MiR-122 represents a well-characterized miRNA, which has been found to be highly expressed in the liver,2 where its transcription is controlled by hepatocyte nuclear factor 4 alpha.3 MiR-122 accounts for >70% of miRNA expression in the liver, and non-human primate models have shown a regulatory role in cholesterol and fatty acid metabolism.4 Hepatic miR-122 is constantly secreted into the circulation, where it ranks among the most readily detectable miRNAs, with levels increasing further on liver injury.4 Therefore, circulating miR-122 levels correlate strongly with hepatic miR-122 expression, as well as conventional liver parameters measured in blood such as alanine and aspartate aminotransferases.4 Moreover, miR-122 has previously been associated with both right and left ventricular dysfunction and with adverse outcome in patients with heart failure with reduced ejection fraction. An increase in miR-122 predates overt liver failure and might indicate beginning liver injury attributable to hepatic congestion.5Hosen et al1 have investigated left ventricular dysfunction. Although isolated left-sided heart failure predominantly affects the lungs with minor effects on central venous pressure, information on right ventricular function, central venous pressure, or liver parameters is not included in the article. Given that the focus of the article is on the most severely affected patients after transcatheter aortic valve replacement, one can assume that hepatic miR-122 release attributable to hepatic congestion represents the primary source of variation.Regarding the in vitro data, a likely source of miR-122 in cell cultures is fetal calf or bovine serum. The authors report miR-122 expression in ECs and cardiomyocytes, but it remains unclear how many copy numbers were detected per cell and how abundant miR-122 was compared with other well-characterized ECs or cardiomyocyte miRNAs. Moreover, in vitro models with donor cells overexpressing candidate miRNAs that are then detected in cocultured recipient cells are not proof that horizontal miRNA transfer exists in vivo at relevant levels. Likewise, the authors did not investigate whether modulation of miR-122 levels affects cardiac function in vivo.In summary, we deem the finding that miR-122 is associated with a lack of improvement in left ventricular function after transcatheter aortic valve replacement of great interest. It expands on our previous finding of elevated miR-122 in patients with chronic systolic heart failure.5 However, we disagree with the interpretation that lack of improvement in cardiac function after transcatheter aortic valve replacement is explained by shuttling of EC-derived miR-122 to cardiomyocytes. MiR-122 has exquisite tissue specificity, and circulating miR-122 levels are determined by hepatic secretion, not by EC-derived extracellular vesicles.FootnotesCirculation is available at www.ahajournals.org/journal/circREFERENCES1. Hosen MR, Goody PR, Zietzer A, Xiang X, Niepmann ST, Sedaghat A, Tiyerili V, Chennupati R, Moore JB, Boon RA, et al. Circulating microRNA-122-5p is associated with a lack of improvement in left ventricular function after transcatheter aortic valve replacement and regulates viability of cardiomyocytes through extracellular vesicles.Circulation. 2022; 146:1836–1854. doi: 10.1161/CIRCULATIONAHA.122.060258LinkGoogle Scholar2. Ludwig N, Leidinger P, Becker K, Backes C, Fehlmann T, Pallasch C, Rheinheimer S, Meder B, Stähler C, Meese E, et al. Distribution of miRNA expression across human tissues.Nucleic Acids Res. 2016; 44:3865–3877. doi: 10.1093/nar/gkw116CrossrefMedlineGoogle Scholar3. Li Z-Y, Xi Y, Zhu W-N, Zeng C, Zhang Z-Q, Guo Z-C, Hao D-L, Liu G, Feng L, Chen H-Z, et al. Positive regulation of hepatic miR-122 expression by HNF4α.J Hepatol. 2011; 55:602–611. doi: 10.1016/j.jhep.2010.12.023CrossrefMedlineGoogle Scholar4. Willeit P, Skroblin P, Kiechl S, Fernández-Hernando C, Mayr M. Liver microRNAs: potential mediators and biomarkers for metabolic and cardiovascular disease?.Eur Heart J. 2016; 37:3260–3266. doi: 10.1093/eurheartj/ehw146CrossrefMedlineGoogle Scholar5. Stojkovic S, Koller L, Sulzgruber P, Hülsmann M, Huber K, Mayr M, Hengstenberg C, Wojta J, Niessner A. Liver-specific microRNA-122 as prognostic biomarker in patients with chronic systolic heart failure.Int J Cardiol. 2020; 303:80–85. doi: 10.1016/j.ijcard.2019.11.090CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails January 24, 2023Vol 147, Issue 4 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.062334PMID: 36689571 Originally publishedJanuary 23, 2023 PDF download Advertisement SubjectsCatheter-Based Coronary and Valvular InterventionsValvular Heart Disease