Vol 59, No 4 (2021)
Original paper
Published online: 2021-12-08
New insights into the pathogenesis of cardiac papillary fibroelastomas
1
, 1, 2, 1, 1, 1
, 1, 2, 1, 1, 1
Abstract
Introduction. Cardiac papillary fibroelastomas (CPFs) are rare benign cardiac tumors typically found on the heart valves. The previously published data on the CPF focused on its clinical presentation, optimal management, and prognosis. However, histogenesis of these lesions remains controversial. Accordingly, the aim of this study was to establish the role of endocardial endothelium (EE) in CPF formation.
Materials and methods. Four CPF tumors removed from the right atrioventricular valves were analyzed using hematoxylin & eosin, orcein, and Masson trichrome staining together with immunochemistry for CD-34, CD-68, vimentin, vWF and a-SMA. Moreover, conventional transmission electron microscopy was used for morphological analysis and a-SMA presence confirmation.
Results. Ultrastructural morphology, immunohisto- and immunocytochemical analyses indicated that cells covering collagenous core have an endothelial origin. Some endocardial endothelium cells have the potential to undergo a transition to mesenchymal cells. Moreover, the abundant presence of extracellular vesicles may indicate an active intercellular communication. Within the intermediate translucent zone, amorphous substances with monocytes/macrophage-like cells and fibroblastic cells were found. Finally, within collagenous core activated (myo)fibroblasts were observed.
Conclusions. Our study demonstrated that the endocardial endothelium of the CPF was “double-sided”, i.e., it presented both endothelial and mesenchymal cell characteristics. Another finding was the presence of monocytes, and macrophages which were integrated into CPF core and displayed features of a fibroblast that have been shown to contribute to extracellular matrix production. This could be interpreted as being attributed to the CPF histogenesis.
Keywords: cardiac papillary fibroelastomaendocardial endotheliumendothelial to mesenchymal transitionEMTectosomesmyofibroblastcardiac benign tumorselectron microscopy
References
- Gowda RM, Khan IA, Nair CK, et al. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J. 2003; 146(3): 404–410.
- Park MiY, Shin JS, Park HR, et al. Papillary fibroelastoma of the pulmonary valve. Heart Vessels. 2007; 22(4): 284–286.
- van der Meulen TA, Budde RPJ, Randjgari A, et al. Multimodality imaging of a papillary fibroelastoma of the mitral valve. Eur J Cardiothorac Surg. 2012; 42(4): 747–748.
- Sabet A, Haghighiabyaneh M, Tazelaar H, et al. The Clinical Dilemma of Cardiac Fibroelastic Papilloma. Structural Heart. 2018; 2(4): 274–280.
- Ionescu AA, Radulescu B, Herlea V, et al. Imaging and histology in the diagnosis of multiple papillary fibroelastomas in a patient with hypertrophic obstructive cardiomyopathy. Case report. Med Ultrason. 2017; 19(4): 454–456.
- Popovic C, Yong MS, Saxena P, et al. Papillary fibroelastoma: A unique case of distant recurrence. J Thorac Cardiovasc Surg. 2019; 157(4): e125–e127.
- Malik F, Kalimuddin M, Mam K, et al. Review Article Papillary Fibroelastoma : Review Article. ; 2018: 2–8.
- Darvishian F, Farmer P. Papillary fibroelastoma of the heart: report of two cases and review of the literature. Ann Clin Lab Sci. 2001; 31(3): 291–296.
- Macura O, Paleček T, Hlubocký J, et al. Papillary fibroelastoma originating from the free left ventricular wall as the cause of recurrent stroke: Description of the case and literature review. Cor et Vasa. 2016; 58(5): e466–e469.
- Taguchi E, Nakao K, Sassa T, et al. Resting angina due to papillary fibroelastoma of the right coronary cusp. Heart Vessels. 2016; 31(1): 114–117.
- Fishbein MC, Ferrans VJ, Roberts WC. Endocardial papillary elastofibromas. Histologic, histochemical, and electron microscopical findings. Arch Pathol. 1975; 99(6): 335–341.
- Sánchez-Duffhues G, García de Vinuesa A, Ten Dijke P. Endothelial-to-mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry. Dev Dyn. 2018; 247(3): 492–508.
- Alvandi Z, Bischoff J. Endothelial-Mesenchymal Transition in Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2021; 41(9): 2357–2369.
- Sniegon I, Prieß M, Heger J, et al. Endothelial Mesenchymal Transition in Hypoxic Microvascular Endothelial Cells and Paracrine Induction of Cardiomyocyte Apoptosis Are Mediated via TGFβ₁/SMAD Signaling. Int J Mol Sci. 2017; 18(11).
- Liu ZH, Zhang Y, Wang X, et al. SIRT1 activation attenuates cardiac fibrosis by endothelial-to-mesenchymal transition. Biomed Pharmacother. 2019; 118: 109227.
- Ciavarella C, Motta I, Vasuri F, et al. Involvement of miR-30a-5p and miR-30d in Endothelial to Mesenchymal Transition and Early Osteogenic Commitment under Inflammatory Stress in HUVEC. Biomolecules. 2021; 11(2): 1–20.
- Ranchoux B, Antigny F, Rucker-Martin C, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation. 2015; 131(11): 1006–1018.
- Gasparics Á, Rosivall L, Krizbai IA, et al. When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition. Am J Physiol Heart Circ Physiol. 2016; 310(9): H1055–H1063.
- Zhang H, Lin Y, Ma Y, et al. Protective effect of hydrogen sulfide on monocrotaline‑induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition. Int J Mol Med. 2019; 44(6): 2091–2102.
- Kovacic JC, Dimmeler S, Harvey RP, et al. Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019; 73(2): 190–209.
- Platel V, Faure S, Corre I, et al. Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance. J Oncol. 2019; 2019: 1–13.
- Kaczmarek K, Jakubowski P, Wojnicz R, et al. A local cryotherapy with percutaneous tumour removal as a successful treatment option in patient with tricuspid valve fibroelastoma papillare. Eur Heart J. 2016; 38(18): ehw516.
- Cecoltan S, Ciortan L, Macarie R, et al. High Glucose Induced Changes in Human VEC Phenotype in a 3D Hydrogel Derived From Cell-Free Native Aortic Root. Front Cardiovasc Med. 2021; 8: 1–13.
- van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018; 19(4): 213–228.
- Díaz-Flores L, Gutiérrez R, Alvarez-Argüelles H, et al. Extracellular multivesicular bodies in tissues affected by inflammation/repair and tumors. Ultrastruct Pathol. 2018; 42(5): 448–457.
- Kalra H, Drummen GPC, Mathivanan S. Focus on Extracellular Vesicles: Introducing the Next Small Big Thing. Int J Mol Sci. 2016; 17(2): 170.
- Fu S, Zhang Y, Li Y, et al. Extracellular vesicles in cardiovascular diseases. Cell Death Discovery. 2020; 6(1).
- Loyer X, Vion AC, Tedgui A, et al. Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res. 2014; 114(2): 345–353.
- Mathiesen A, Hamilton T, Carter N, et al. Endothelial Extracellular Vesicles: From Keepers of Health to Messengers of Disease. Int J Mol Sci. 2021; 22(9).
- Ci HB, Ou ZJ, Chang FJ, et al. Endothelial microparticles increase in mitral valve disease and impair mitral valve endothelial function. Am J Physiol Endocrinol Metab. 2013; 304(7): E695–E702.
- Lin ZB, Ci HB, Li Y, et al. Endothelial microparticles are increased in congenital heart diseases and contribute to endothelial dysfunction. J Transl Med. 2017; 15(1): 4.
- Fu Li, Hu XX, Lin ZB, et al. Circulating microparticles from patients with valvular heart disease and cardiac surgery inhibit endothelium-dependent vasodilation. J Thorac Cardiovasc Surg. 2015; 150(3): 666–672.
- Hromada C, Mühleder S, Grillari J, et al. Endothelial Extracellular Vesicles-Promises and Challenges. Front Physiol. 2017; 8: 275.
- Fujimoto S, Fujita Yu, Kadota T, et al. Intercellular Communication by Vascular Endothelial Cell-Derived Extracellular Vesicles and Their MicroRNAs in Respiratory Diseases. Front Mol Biosci. 2021; 7: 1–14.
- Yeon JuH, Jeong HE, Seo H, et al. Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the induction of cancer-associated fibroblasts. Acta Biomater. 2018; 76: 146–153.
- Haynes BA, Yang LiF, Huyck RW, et al. Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction. Arterioscler Thromb Vasc Biol. 2019; 39(10): 2168–2191.
- Akbar N, Digby JE, Cahill TJ, et al. Oxford Acute Myocardial Infarction (OxAMI) Study. Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction. JCI Insight. 2017; 2(17).
- Nikolova-Krstevski V, Leimena C, Fatkin D. Mechanical Stretch Alters the Morphology and Function of Atrial Endocardial Endothelial Cells. Hear Lung Circ [Internet]. 2012 Jan 25;21(1):S61. Available from: http://journals.sagepub.com/doi/10.1177/021849239400200118. .
- Dal-Bianco JP, Aikawa E, Bischoff J, et al. Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation. Circulation. 2009; 120(4): 334–342.
- Cho J, Lee A, Chang W, et al. Endothelial to Mesenchymal Transition Represents a Key Link in the Interaction between Inflammation and Endothelial Dysfunction. Front Immunol. 2018; 9.
- Li Y, Lui KO, Zhou B. Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases. Nat Rev Cardiol. 2018; 15(8): 445–456.
- Bischoff J, Aikawa E. Progenitor cells confer plasticity to cardiac valve endothelium. J Cardiovasc Transl Res. 2011; 4(6): 710–719.
- Bischoff J. Endothelial-to-Mesenchymal Transition. Circ Res. 2019; 124(8): 1163–1165.
- Haack T, Abdelilah-Seyfried S. The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis. Development. 2016; 143(3): 373–386.
- Zhang H, Lui KO, Zhou B. Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration. Circ Res. 2018; 122(5): 774–789.
- Piera-Velazquez S, Jimenez SA. Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases. Fibrogenesis Tissue Repair. 2012; 5(Suppl 1): S7.
- Islam S, Boström KI, Di Carlo D, et al. The Mechanobiology of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease. Front Physiol. 2021; 12: 734215.
- Levine R, Hagége A, Judge D, et al. Mitral valve disease—morphology and mechanisms. Nat Rev Cardiol. 2015; 12(12): 689–710.
- Welch-Reardon KM, Wu N, Hughes CCW. A role for partial endothelial-mesenchymal transitions in angiogenesis? Arterioscler Thromb Vasc Biol. 2015; 35(2): 303–308.
- Paruchuri S, Yang JH, Aikawa E, et al. Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-beta2. Circ Res. 2006; 99(8): 861–869.
- Zhong A, Mirzaei Z, Simmons CA. The Roles of Matrix Stiffness and ß-Catenin Signaling in Endothelial-to-Mesenchymal Transition of Aortic Valve Endothelial Cells. Cardiovasc Eng Technol. 2018; 9(2): 158–167.
- Cieslik KA, Trial J, Crawford JR, et al. Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J Mol Cell Cardiol. 2014; 70: 56–63.
- Bucala R. Review Series--Inflammation & Fibrosis. Fibrocytes and fibrosis. QJM. 2012; 105(6): 505–508.
- Geiger A, Walker A, Nissen E. Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice. Biochem Biophys Res Commun. 2015; 467(2): 303–309.
- Suda S, Williams H, Medbury HJ, et al. A Review of Monocytes and Monocyte-Derived Cells in Hypertrophic Scarring Post Burn. J Burn Care Res. 2016; 37(5): 265–272.
- Alex L, Frangogiannis NG. The Cellular Origin of Activated Fibroblasts in the Infarcted and Remodeling Myocardium. Circ Res. 2018; 122(4): 540–542.
- Meng XM, Wang S, Huang XR, et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis. 2016; 7(12): e2495.
- Liu D, Yan W, Huang J, et al. Macrophages in Ischemic Heart Failure: Yesterday, Today, and Tomorrow. Cardiol Discov. 2021; 1(2): 128–134.
- Moskalik A, Niderla-Bielińska J, Ratajska A. Multiple roles of cardiac macrophages in heart homeostasis and failure. Heart Fail Rev. 2021 [Epub ahead of print].
- Haider N, Boscá L, Zandbergen HR, et al. Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction. J Am Coll Cardiol. 2019; 74(25): 3124–3135.
- Keeley EC, Mehrad B, Strieter RM. The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of fibrotic disorders. Thromb Haemost. 2009; 101(4): 613–618.
- Lin RJ, Su ZZ, Liang SM, et al. Role of Circulating Fibrocytes in Cardiac Fibrosis. Chin Med J (Engl). 2016; 129(3): 326–331.
- Rios FJ, Harvey A, Lopes RA, et al. Progenitor Cells, Bone Marrow-Derived Fibrocytes and Endothelial-to-Mesenchymal Transition: New Players in Vascular Fibrosis. Hypertension. 2016; 67(2): 272–274.
- Grandmougin D, Fayad G, Moukassa D, Decoene C, Abolmaali K, Bodart JC, et al. Cardiac valve papillary fibroelastomas: clinical, histological and immunohistochemical studies and a physiopathogenic hypothesis. J Heart Valve Dis [Internet]. 2000 Nov;9(6):832–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11128794. .
