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Cited by 17Cardiovascular Effects of ExerciseCardiac electrophysiology and arrhythmiasCardiomyopathy and Myosin Studies

Cardiac sympathetic neurons are additional cells affected in genetically determined arrhythmogenic cardiomyopathy

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Vanaja, Induja Perumal, Scalco, Arianna, Ronfini, Marco, Bona, Anna Di, Olianti, Camilla, Rizzo, Stefania, Chelko, Stephen P., Corrado, Domenico +4 more·2025·The Journal of Physiology
DOI 10.1113/jp286845PMC PMC11955870
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Abstract

Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes, which accounts for most cases of stress‐related arrhythmic sudden death, in young and athletes. AC hearts display fibro‐fatty lesions that generate the arrhythmic substrate and cause contractile dysfunction. A correlation between physical/emotional stresses and arrhythmias supports the involvement of sympathetic neurons (SNs) in the disease, but this has not been confirmed previously. Here, we combined molecular, in vitro and ex vivo analyses to determine the role of AC‐linked DSG2 downregulation on SN biology and assess cardiac sympathetic innervation in desmoglein‐2 mutant (Dsg2 mut/mut) mice. Molecular assays showed that SNs express DSG2, implying that DSG2‐mutation carriers would harbour the mutant protein in SNs. Confocal immunofluorescence of heart sections and 3‐D reconstruction of SN network in clarified heart blocks revealed significant changes in the physiologialc SN topology, with massive hyperinnervation of the intact subepicardial layers and heterogeneous distribution of neurons in fibrotic areas. Cardiac SNs isolated from Dsg2 mut/mut neonatal mice, prior to the establishment of cardiac innervation, show alterations in axonal sprouting, process development and distribution of varicosities. Consistently, virus‐assisted DSG2 downregulation replicated, in PC12‐derived SNs, the phenotypic alterations displayed by Dsg2 mut/mut primary neurons, corroborating that AC‐linked Dsg2 variants may affect SNs. Our results reveal that altered sympathetic innervation is an unrecognized feature of AC hearts, which may result from the combination of cell‐autonomous and context‐dependent factors implicated in myocardial remodelling. Our results favour the concept that AC is a disease of multiple cell types also hitting cardiac SNs. image Key points: Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress‐related arrhythmic sudden death. Arrhythmogenic cardiomyopathy linked to mutations in desmoglein‐2 (DSG2) is frequent and leads to a left‐dominant form of the disease. Arrhythmogenic cardiomyopathy has been approached thus far as a disease of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by cardiac and extracardiac sympathetic neurons, although not organized into desmosomes. AC‐linked DSG2 downregulation primarily affect sympathetic neurons, resulting in the significant increase in cardiac innervation density, accompanied by alterations in sympathetic neuron distribution. Our data supports the notion that AC develops with the contribution of several ‘desmosomal protein‐carrying’ cell types and systems.

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  • DSG2 variants are characterized by extensive left ventricular involvement, demonstrating substantial fibro-inflammatory remodeling, as well as an unrecognized multicellular pathology involving the autonomic nervous system.

    “DSG2 variants are also characterized by extensive left ventricular involvement, demonstrating substantial fibro-inflammatory remodeling [62], as well as an unrecognized multicellular pathology involving the autonomic nervous system [62].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [62]

    The Results (pages unavailable) describe extensive heart remodelling in six-month-old Dsg2-mutant mice, examine lesions in the left ventricle, and document altered sympathetic innervation. The Abstract also identifies sympathetic neurons as an additional cell type affected. The paper does not establish extensive left ventricular involvement or specifically characterize the remodelling as fibro-inflammatory across DSG2 variants; its direct evidence is chiefly from a mouse model. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Neuronal remodeling provides an independent, early-stage substrate for stress-induced arrhythmias.

    “This neuronal remodeling provides an independent, early-stage substrate for stress-induced arrhythmias [62] and serves as an additional reminder of the importance of germline mutations in disease modeling as opposed to cardiomyocyte-specific KO models.”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [62]

    The Discussion reports sympathetic-innervation abnormalities at an early disease stage, before detectable myocardial remodelling, and suggests they may be an independent event. It also links sympathetic activity and stress to arrhythmias, but does not establish that the neuronal remodelling itself provides an independent substrate for stress-induced arrhythmias; the claim states that possibility more firmly than the paper does. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Cardiac sympathetic neurons expressing desmosomal gene variants exhibited decreased axonal sprouting alongside abnormal varicosity patterning in ACM subjects.

    “Additionally, as stated above, cardiac sympathetic neurons expressing desmosomal gene variants exhibited decreased axonal sprouting alongside abnormal varicosity patterning in ACM subjects.”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [62]

    The Results section (‘DSG2 downregulation affects sympathetic neurons’; page unavailable) reports that cultured neurons from Dsg2-mutant mice had shorter, less-ramified axons and fewer, irregularly distributed varicosities. That supports the claim for isolated mouse neurons, but not as a finding in human ACM subjects. The Discussion (page unavailable) instead reports increased axonal sprouting in mutant mouse hearts. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • DSG2 is expressed in human cardiac sympathetic neurons, and its deficiency leads to massive subepicardial sympathetic hyperinnervation that precedes overt structural remodeling, potentially serving as an early arrhythmic substrate.

    “Recent work by Vanaja IP et al. demonstrated DSG2 is expressed in human cardiac sympathetic neurons, and its deficiency leads to massive subepicardial sympathetic hyperinnervation that precedes overt structural remodeling [62], potentially serving as an early arrhythmic substrate.”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [62]

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Research works printed but not linked: 95

  1. Arshadi, C., Günther, U., Eddison, M., Harrington, K. I. S., & Ferreira, T. A. (2021). SNT: A unifying toolbox for quantification of neuronal anatomy. Nature Methods, 18(4), 374– 377. 33795878
  2. Asimaki, A., & Saffitz, J. E. (2014). Remodeling of cell‐cell junctions in arrhythmogenic cardiomyopathy. Cell Communication & Adhesion, 21(1), 13– 23. 24460198 PMC4466113
  3. Asimaki, A., Kapoor, S., Plovie, E., Karin Arndt, A., Adams, E., Liu, Z., James, C. A., Judge, D. P., Calkins, H., Churko, J., Wu, J. C., MacRae, C. A., Kléber, A. G., & Saffitz, J. E. (2014). Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Science Translational Medicine, 6(240), 240ra74. PMC4471875 24920660
  4. Asimaki, A., Kleber, A. G., & Saffitz, J. E. (2015). Pathogenesis of arrhythmogenic cardiomyopathy. The Canadian Journal of Cardiology, 31(11), 1313– 1324. 26199027 PMC4619183
  5. Basso, C., Corrado, D., Marcus, F. I., Nava, A., & Thiene, G. (2009). Arrhythmogenic right ventricular cardiomyopathy. Lancet (London, England), 373(9671), 1289– 1300. 19362677
  6. Basso, C., Bauce, B., Corrado, D., & Thiene, G. (2011). Pathophysiology of arrhythmogenic cardiomyopathy. Nature reviews Cardiology, 9(4), 223– 233. 22124316
  7. Boriani, G., Artale, P., Biffi, M., Martignani, C., Frabetti, L., Valzania, C., Diemberger, I., Ziacchi, M., Bertini, M., Rapezzi, C., Parlapiano, M., & Branzi, A. (2007). Outcome of cardioverter‐defibrillator implant in patients with arrhythmogenic right ventricular cardiomyopathy. Heart and Vessels, 22(3), 184– 192. 17533523
  8. Calore, M., Lorenzon, A., De Bortoli, M., Poloni, G., & Rampazzo, A. (2015). Arrhythmogenic cardiomyopathy: A disease of intercalated discs. Cell and Tissue Research, 360(3), 491– 500. 25344329
  9. Cerrone, M., Noorman, M., Lin, X., Chkourko, H., Liang, F. X., van der Nagel, R., Hund, T., Birchmeier, W., Mohler, P., van Veen, T. A., van Rijen, H. V., & Delmar, M. (2012). Sodium current deficit and arrhythmogenesis in a murine model of plakophilin‐2 haploinsufficiency. Cardiovascular Research, 95(4), 460– 468. 22764151 PMC3422082
  10. Cerrone, M., & Delmar, M. (2014). Desmosomes and the sodium channel complex: Implications for arrhythmogenic cardiomyopathy and Brugada syndrome. Trends in Cardiovascular Medicine, 24(5), 184– 190. 24656989 PMC4099253
  11. Chevalier, P., Moreau, A., Richard, S., Janin, A., Millat, G., Bessière, F., & Delinière, A. (2021). Short QT interval as a harbinger of an arrhythmogenic cardiomyopathy. HeartRhythm Case Reports, 7(11), 734– 738. 34820269 PMC8602084
  12. Chua, C. J., Morrissette‐McAlmon, J., Tung, L., & Boheler, K. R. (2023). Understanding arrhythmogenic cardiomyopathy: Advances through the use of human pluripotent stem cell models. Genes, 14(10), 1864. 37895213 PMC10606441
  13. Chung, K., & Deisseroth, K. (2013). CLARITY for mapping the nervous system. Nature Methods, 10(6), 508– 513. 23722210
  14. Corrado, D., Basso, C., Thiene, G., McKenna, W. J., Davies, M. J., Fontaliran, F., Nava, A., Silvestri, F., Blomstrom‐Lundqvist, C., Wlodarska, E. K., Fontaine, G., & Camerini, F. (1997). Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. Journal of the American College of Cardiology, 30(6), 1512– 1520. 9362410
  15. Corrado, D., Basso, C., & Thiene, G. (2001). Sudden cardiac death in young people with apparently normal heart. Cardiovascular Research, 50(2), 399– 408. 11334844
  16. Corrado, D., Basso, C., Leoni, L., Tokajuk, B., Bauce, B., Frigo, G., Tarantini, G., Napodano, M., Turrini, P., Ramondo, A., Daliento, L., Nava, A., Buja, G., Iliceto, S., & Thiene, G. (2005). Three‐dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation, 111(23), 3042– 3050. 15939822
  17. Corrado, D., Basso, C., Pavei, A., Michieli, P., Schiavon, M., & Thiene, G. (2006). Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. The Journal of The American Medical Association, 296(13), 1593– 1601. 17018804
  18. Corrado, D., & Zorzi, A. (2015). Arrhythmogenic right ventricular cardiomyopathy and sports activity. European Heart Journal, 36(27), 1708– 1710. 25971286
  19. Corrado, D., Link, M. S., & Calkins, H. (2017). Arrhythmogenic right ventricular cardiomyopathy. The New England Journal of Medicine, 376(1), 61– 72. 28052233
  20. Corrado, D., Migliore, F., & Zorzi, A. (2019). Sport activity in patients with implantable defibrillator: Playing with death? European Journal of Preventive Cardiology, 26(7), 760– 763. 30335508
  21. Corrado, D., Drezner, J. A., D'Ascenzi, F., & Zorzi, A. (2020). How to evaluate premature ventricular beats in the athlete: Critical review and proposal of a diagnostic algorithm. British Journal of Sports Medicine, 54(19), 1142– 1148. 31481389 PMC7513269
  22. Costantini, I., Ghobril, J. P., Giovanna D.I. A. P., Mascaro A. A. L., Silvestri, L., Müllenbroich, M. C., Onofri, L., Conti, V., Vanzi, F., Sacconi, L., Guerrini, R., Markram, H., Iannello, G., & Pavone, F. S. (2015). A versatile clearing agent for multi‐modal brain imaging. Scientific Reports, 5, 9808. 25950610 PMC4423470
  23. de Coster, T., Claus, P., Kazbanov, I. V., Haemers, P., Willems, R., Sipido, K. R., & Panfilov, A. V. (2018). Arrhythmogenicity of fibro‐fatty infiltrations. Scientific Reports, 8(1), 2050. 29391548 PMC5795000
  24. Denis, A., Sacher, F., Derval, N., Lim, H. S., Cochet, H., Shah, A. J., Daly, M., Pillois, X., Ramoul, K., Komatsu, Y., Zemmoura, A., Amraoui, S., Ritter, P., Ploux, S., Bordachar, P., Hocini, M., Jaïs, P., & Haïssaguerre, M. (2014). Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy. Circulation Arrhythmia and Electrophysiology, 7(4), 590– 597. 24970294
  25. di Gioia, C. R., Giordano, C., Cerbelli, B., Pisano, A., Perli, E., de Dominicis, E., Poscolieri, B., Palmieri, V., Ciallella, C., Zeppilli, P., & d'Amati, G. (2016). Nonischemic left ventricular scar and cardiac sudden death in the young. Human Pathology, 58, 78– 89. 27569295
  26. Dokshokova, L., Franzoso, M., Di Bona, A., Moro, N., Sanchez Alonso, J. L., Prando, V., Sandre, M., Basso, C., Faggian, G., Abriel, H., Marin, O., Gorelik, J., Zaglia, T., & Mongillo, M. (2022). Nerve growth factor transfer from cardiomyocytes to innervating sympathetic neurons activates TrkA receptors at the neuro‐cardiac junction. The Journal of Physiology, 600(12), 2853– 2875. 35413134 PMC9321700
  27. Franzoso, M., Zaglia, T., & Mongillo, M. (2016). Putting together the clues of the everlasting neuro‐cardiac liaison. Biochimica et biophysica acta, 1863(7 Pt B), 1904– 1915. 26778332
  28. Gardner, R. T., Ripplinger, C. M., Myles, R. C., & Habecker, B. A. (2016). Molecular mechanisms of sympathetic remodeling and arrhythmias. Circulation Arrhythmia and Electrophysiology, 9(2), e001359. 26810594 PMC4730917
  29. Gehmlich, K., Syrris, P., Peskett, E., Evans, A., Ehler, E., Asimaki, A., Anastasakis, A., Tsatsopoulou, A., Vouliotis, A. I., Stefanadis, C., Saffitz, J. E., Protonotarios, N., & McKenna, W. J. (2011). Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin‐2 mutations. Cardiovascular Research, 90(1), 77– 87. 21062920 PMC3058729
  30. Gerull, B., Heuser, A., Wichter, T., Paul, M., Basson, C. T., McDermott, D. A., Lerman, B. B., Markowitz, S. M., Ellinor, P. T., MacRae, C. A., Peters, S., Grossmann, K. S., Drenckhahn, J., Michely, B., Sasse‐Klaassen, S., Birchmeier, W., Dietz, R., Breithardt, G., Schulze‐Bahr, E., & Thierfelder, L. (2004). Mutations in the desmosomal protein plakophilin‐2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature Genetics, 36(11), 1162– 1164. 15489853
  31. Giardini, F., Lazzeri, E., Olianti, C., Beconi, G., Costantini, I., Silvestri, L., Cerbai, E., Pavone, F. S., & Sacconi, L. (2021). Mesoscopic optical imaging of whole mouse heart. Journal of Visualized Experiments: JoVE, (176). 10.3791/62795 34723943 · DOI
  32. Giuliodori, A., Beffagna, G., Marchetto, G., Fornetto, C., Vanzi, F., Toppo, S., Facchinello, N., Santimaria, M., Vettori, A., Rizzo, S., Della Barbera, M., Pilichou, K., Argenton, F., Thiene, G., Tiso, N., & Basso, C. (2018). Loss of cardiac Wnt/β‐catenin signalling in desmoplakin‐deficient AC8 zebrafish models is rescuable by genetic and pharmacological intervention. Cardiovascular Research, 114(8), 1082– 1097. 29522173
  33. Grundy, D. (2015). Principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology. The Journal of Physiology, 593(12), 2547– 2549. 26095019 PMC4500341
  34. Habecker, B. A., Anderson, M. E., Birren, S. J., Fukuda, K., Herring, N., Hoover, D. B., Kanazawa, H., Paterson, D. J., & Ripplinger, C. M. (2016). Molecular and cellular neurocardiology: Development, and cellular and molecular adaptations to heart disease. The Journal of Physiology, 594(14), 3853– 3875. 27060296 PMC4945713
  35. Habecker, B. A., Bers, D. M., Birren, S. J., Chang, R., Herring, N., Kay, M. W., Li, D., Mendelowitz, D., Mongillo, M., Montgomery, J. M., Ripplinger, C. M., Tampakakis, E., Winbo, A., Zaglia, T., Zeltner, N., & Paterson, D. J. (2025). Molecular and cellular neurocardiology in heart disease. The Journal of Physiology, 603(7), 1689– 1728. PMC11582088 38778747
  36. Herring, N., Kalla, M., & Paterson, D. J. (2019). The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies. Nature Reviews Cardiology, 16(12), 707– 726. 31197232
  37. Hodgkinson, K. A., Parfrey, P. S., Bassett, A. S., Kupprion, C., Drenckhahn, J., Norman, M. W., Thierfelder, L., Stuckless, S. N., Dicks, E. L., McKenna, W. J., & Connors, S. P. (2005). The impact of implantable cardioverter‐defibrillator therapy on survival in autosomal‐dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). Journal of the American College of Cardiology, 45(3), 400– 408. 15680719 PMC3133766
  38. Ieda, M., Kanazawa, H., Kimura, K., Hattori, F., Ieda, Y., Taniguchi, M., Lee, J. K., Matsumura, K., Tomita, Y., Miyoshi, S., Shimoda, K., Makino, S., Sano, M., Kodama, I., Ogawa, S., & Fukuda, K. (2007). Sema3a maintains normal heart rhythm through sympathetic innervation patterning. Nature Medicine, 13(5), 604– 612. 17417650
  39. Kam, C. Y., Dubash, A. D., Magistrati, E., Polo, S., Satchell, K. J. F., Sheikh, F., Lampe, P. D., & Green, K. J. (2018). Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin‐43. The Journal of Cell Biology, 217(9), 3219– 3235. 29959233 PMC6123000
  40. Kant, S., Holthöfer, B., Magin, T. M., Krusche, C. A., & Leube, R. E. (2015). Desmoglein 2‐dependent arrhythmogenic cardiomyopathy is caused by a loss of adhesive function. Circulation Cardiovascular Genetics, 8(4), 553– 563. 26085008
  41. Kim, J. C., Pérez‐Hernández, M., Alvarado, F. J., Maurya, S. R., Montnach, J., Yin, Y., Zhang, M., Lin, X., Vasquez, C., Heguy, A., Liang, F. X., Woo, S. H., Morley, G. E., Rothenberg, E., Lundby, A., Valdivia, H. H., Cerrone, M., & Delmar, M. (2019). Disruption of Ca2+ i homeostasis and connexin 43 hemichannel function in the right ventricle precedes overt arrhythmogenic cardiomyopathy in plakophilin‐2‐deficient mice. Circulation, 140(12), 1015– 1030. 31315456 PMC6746608
  42. Kimura, K., Ieda, M., & Fukuda, K. (2012). Development, maturation, and transdifferentiation of cardiac sympathetic nerves. Circulation Research, 110(2), 325– 336. 22267838
  43. Kohela, A., van Kampen, S. J., Moens, T., Wehrens, M., Molenaar, B., Boogerd, C. J., Monshouwer‐Kloots, J., Perini, I., Goumans, M. J., Smits, A. M., van Tintelen, J. P., & van Rooij, E. (2021). Epicardial differentiation drives fibro‐fatty remodeling in arrhythmogenic cardiomyopathy. Science Translational Medicine, 13(612), eabf2750. 34550725
  44. Larsen, H. E., Lefkimmiatis, K., & Paterson, D. J. (2016). Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease. Scientific Reports, 6, 38898. 27966588 PMC5155272
  45. Li, J., Swope, D., Raess, N., Cheng, L., Muller, E. J., & Radice, G. L. (2011). Cardiac tissue‐restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}‐catenin signaling. Molecular and Cellular Biology, 31(6), 1134– 1144. 21245375 PMC3067899
  46. Link, M. S., Wang, P. J., Haugh, C. J., Homoud, M. K., Foote, C. B., Costeas, X. B., & Estes, N. A. 3rd (1997). Arrhythmogenic right ventricular dysplasia: Clinical results with implantable cardioverter defibrillators. Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing, 1(1), 41– 48. 9869950
  47. Lombardi, R., Dong, J., Rodriguez, G., Bell, A., Leung, T. K., Schwartz, R. J., Willerson, J. T., Brugada, R., & Marian, A. J. (2009). Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circulation Research, 104(9), 1076– 1084. 19359597 PMC2767296
  48. Lombardi, R., da Graca Cabreira‐Hansen, M., Bell, A., Fromm, R. R., Willerson, J. T., & Marian, A. J. (2011). Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circulation Research, 109(12), 1342– 1353. 22021931 PMC3237769
  49. Lyon, R. C., Mezzano, V., Wright, A. T., Pfeiffer, E., Chuang, J., Banares, K., Castaneda, A., Ouyang, K., Cui, L., Contu, R., Gu, Y., Evans, S. M., Omens, J. H., Peterson, K. L., McCulloch, A. D., & Sheikh, F. (2014). Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model. Human Molecular Genetics, 23(5), 1134– 1150. 24108106 PMC3919010
  50. Martherus, R., Jain, R., Takagi, K., Mendsaikhan, U., Turdi, S., Osinska, H., James, J. F., Kramer, K., Purevjav, E., & Towbin, J. A. (2016). Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/β‐catenin signaling. American Journal of Physiology Heart and Circulatory Physiology, 310(2), H174– H187. 26545710 PMC4796627
  51. Matthes, S. A., Taffet, S., & Delmar, M. (2011). Plakophilin‐2 and the migration, differentiation and transformation of cells derived from the epicardium of neonatal rat hearts. Cell Communication & Adhesion, 18(4), 73– 84. 21985446 PMC3208727
  52. Mazzanti, A., Ng, K., Faragli, A., Maragna, R., Chiodaroli, E., Orphanou, N., Monteforte, N., Memmi, M., Gambelli, P., Novelli, V., Bloise, R., Catalano, O., Moro, G., Tibollo, V., Morini, M., Bellazzi, R., Napolitano, C., Bagnardi, V., & Priori, S. G. (2016). Arrhythmogenic right ventricular cardiomyopathy: Clinical course and predictors of arrhythmic risk. Journal of the American College of Cardiology, 68(23), 2540– 2550. 27931611
  53. McKoy, G., Protonotarios, N., Crosby, A., Tsatsopoulou, A., Anastasakis, A., Coonar, A., Norman, M., Baboonian, C., Jeffery, S., & McKenna, W. J. (2000). Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet (London, England), 355(9221), 2119– 2124. 10902626
  54. Migliore, F., Zorzi, A., Silvano, M., Bevilacqua, M., Leoni, L., Marra, M. P., Elmaghawry, M., Brugnaro, L., Dal Lin, C., Bauce, B., Rigato, I., Tarantini, G., Basso, C., Buja, G., Thiene, G., Iliceto, S., & Corrado, D. (2013). Prognostic value of endocardial voltage mapping in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation Arrhythmia and Electrophysiology, 6(1), 167– 176. 23392584
  55. Moncayo‐Arlandi, J., Guasch, E., Sanz‐de la Garza, M., Casado, M., Garcia, N. A., Mont, L., Sitges, M., Knöll, R., Buyandelger, B., Campuzano, O., Diez‐Juan, A., & Brugada, R. (2016). Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model. Human Molecular Genetics, 25(17), 3676– 3688. 27412010
  56. Myles, R. C., Wang, L., Kang, C., Bers, D. M., & Ripplinger, C. M. (2012). Local β‐adrenergic stimulation overcomes source‐sink mismatch to generate focal arrhythmia. Circulation Research, 110(11), 1454– 1464. 22539768 PMC3396564
  57. Olianti, C., Costantini, I., Giardini, F., Lazzeri, E., Crocini, C., Ferrantini, C., Pavone, F. S., Camici, P. G., & Sacconi, L. (2020). 3D imaging and morphometry of the heart capillary system in spontaneously hypertensive rats and normotensive controls. Scientific Reports, 10(1), 14276. 32868776 PMC7459314
  58. Olianti, C., Giardini, F., Lazzeri, E., Costantini, I., Silvestri, L., Coppini, R., Cerbai, E., Pavone, F. S., & Sacconi, L. (2022). Optical clearing in cardiac imaging: A comparative study. Progress in Biophysics and Molecular Biology, 168, 10– 17. 34358555
  59. Oxford, E. M., Musa, H., Maass, K., Coombs, W., Taffet, S. M., & Delmar, M. (2007). Connexin43 remodeling caused by inhibition of plakophilin‐2 expression in cardiac cells. Circulation Research, 101(7), 703– 711. 17673670
  60. Patel, D. M., & Green, K. J. (2014). Desmosomes in the heart: A review of clinical and mechanistic analyses. Cell Communication & Adhesion, 21(3), 109– 128. 24754498
  61. Pianca, N., Di Bona, A., Lazzeri, E., Costantini, I., Franzoso, M., Prando, V., Armani, A., Rizzo, S., Fedrigo, M., Angelini, A., Basso, C., Pavone, F. S., Rubart, M., Sacconi, L., Zaglia, T., & Mongillo, M. (2019). Cardiac sympathetic innervation network shapes the myocardium by locally controlling cardiomyocyte size through the cellular proteolytic machinery. The Journal of Physiology, 597(14), 3639– 3656. 31116413
  62. Pilichou, K., Nava, A., Basso, C., Beffagna, G., Bauce, B., Lorenzon, A., Frigo, G., Vettori, A., Valente, M., Towbin, J., Thiene, G., Danieli, G. A., & Rampazzo, A. (2006). Mutations in desmoglein‐2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation, 113(9), 1171– 1179. 16505173
  63. Pilichou, K., Remme, C. A., Basso, C., Campian, M. E., Rizzo, S., Barnett, P., Scicluna, B. P., Bauce, B., van den Hoff, M. J., de Bakker, J. M., Tan, H. L., Valente, M., Nava, A., Wilde, A. A., Moorman, A. F., Thiene, G., & Bezzina, C. R. (2009). Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2‐related arrhythmogenic right ventricular cardiomyopathy. The Journal of Experimental Medicine, 206(8), 1787– 1802. 19635863 PMC2722163
  64. Pilichou, K., Bezzina, C. R., Thiene, G., & Basso, C. (2011). Arrhythmogenic cardiomyopathy: transgenic animal models provide novel insights into disease pathobiology. Circulation Cardiovascular Genetics, 4(3), 318– 326. 21673311
  65. Pilichou, K., Thiene, G., Bauce, B., Rigato, I., Lazzarini, E., Migliore, F., Perazzolo Marra, M., Rizzo, S., Zorzi, A., Daliento, L., Corrado, D., & Basso, C. (2016). Arrhythmogenic cardiomyopathy. Orphanet Journal of Rare Diseases, 11, 33. 27038780 PMC4818879
  66. Prando, V., da Broi, F., Franzoso, M., Plazzo, A. P., Pianca, N., Francolini, M., Basso, C., Kay, M. W., Zaglia, T., & Mongillo, M. (2018). Dynamics of neuroeffector coupling at cardiac sympathetic synapses. The Journal of Physiology, 596(11), 2055– 2075. 29524231 PMC5983210
  67. Priori, S. G., Blomström‐Lundqvist, C., Mazzanti, A., Blom, N., Borggrefe, M., Camm, J., Elliott, P. M., Fitzsimons, D., Hatala, R., Hindricks, G., Kirchhof, P., Kjeldsen, K., Kuck, K.‐H., Hernandez‐Madrid, A., Nikolaou, N., Norekvål, T. M., Spaulding, C., & van Veldhuisen, D. J. & ESC Scientific Document Group. (2015). 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). European Heart Journal, 36, 2793– 2867. 26320108
  68. Rampazzo, A., Nava, A., Malacrida, S., Beffagna, G., Bauce, B., Rossi, V., Zimbello, R., Simionati, B., Basso, C., Thiene, G., Towbin, J. A., & Danieli, G. A. (2002). Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. American Journal of Human Genetics, 71(5), 1200– 1206. 12373648 PMC385098
  69. Rasmussen, T. B., Nissen, P. H., Palmfeldt, J., Gehmlich, K., Dalager, S., Jensen, U. B., Kim, W. Y., Heickendorff, L., Mølgaard, H., Jensen, H. K., Baandrup, U. T., Bross, P., & Mogensen, J. (2014). Truncating plakophilin‐2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. Circulation Cardiovascular Genetics, 7(3), 230– 240. 24704780
  70. Reisqs, J. B., Moreau, A., Sleiman, Y., Boutjdir, M., Richard, S., & Chevalier, P. (2023). Arrhythmogenic cardiomyopathy as a myogenic disease: Highlights from cardiomyocytes derived from human induced pluripotent stem cells. Frontiers in Physiology, 14, 1191965. 37250123 PMC10210147
  71. Ripplinger, C. M., Noujaim, S. F., & Linz, D. (2016). The nervous heart. Progress in Biophysics and Molecular Biology, 120(1–3), 199– 209. 26780507 PMC4808395
  72. Rizzo, S., Lodder, E. M., Verkerk, A. O., Wolswinkel, R., Beekman, L., Pilichou, K., Basso, C., Remme, C. A., Thiene, G., & Bezzina, C. R. (2012). Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein‐2 mutant mice prior to cardiomyopathic changes. Cardiovascular Research, 95(4), 409– 418. 22764152
  73. Saberniak, J., Hasselberg, N. E., Borgquist, R., Platonov, P. G., Sarvari, S. I., Smith, H. J., Ribe, M., Holst, A. G., Edvardsen, T., & Haugaa, K. H. (2014). Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members. European Journal of Heart Failure, 16(12), 1337– 1344. 25319773 PMC4278531
  74. Schindelin, J., Arganda‐Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., Tinevez, J. Y., White, D. J., Hartenstein, V., Eliceiri, K., Tomancak, P., & Cardona, A. (2012). Fiji: An open‐source platform for biological‐image analysis. Nature Methods, 9(7), 676– 682. 22743772 PMC3855844
  75. Schinner, C., Vielmuth, F., Rötzer, V., Hiermaier, M., Radeva, M. Y., Co, T. K., Hartlieb, E., Schmidt, A., Imhof, A., Messoudi, A., Horn, A., Schlipp, A., Spindler, V., & Waschke, J. (2017). Adrenergic signaling strengthens cardiac myocyte cohesion. Circulation Research, 120(8), 1305– 1317. 28289018
  76. Schuler, P. K., Haegeli, L. M., Saguner, A. M., Wolber, T., Tanner, F. C., Jenni, R., Corti, N., Lüscher, T. F., Brunckhorst, C., & Duru, F. (2012). Predictors of appropriate ICD therapy in patients with arrhythmogenic right ventricular cardiomyopathy: Long term experience of a tertiary care center. PLoS ONE, 7(9), e39584. 23028419 PMC3459957
  77. Sommariva, E., Brambilla, S., Carbucicchio, C., Gambini, E., Meraviglia, V., Dello Russo, A., Farina, F. M., Casella, M., Catto, V., Pontone, G., Chiesa, M., Stadiotti, I., Cogliati, E., Paolin, A., Ouali Alami, N., Preziuso, C., d'Amati, G., Colombo, G. I., Rossini, A., Capogrossi, M. C., … Pompilio, G. (2016). Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy. European Heart Journal, 37(23), 1835– 1846. 26590176 PMC4912024
  78. Stadiotti, I., Di Bona, A., Pilato, C. A., Scalco, A., Guarino, A., Micheli, B., Casella, M., Tondo, C., Rizzo, S., Pilichou, K., Thiene, G., Frigo, A. C., Pompilio, G., Basso, C., Sommariva, E., Mongillo, M., & Zaglia, T. (2021). Neuropeptide Y promotes adipogenesis of human cardiac mesenchymal stromal cells in arrhythmogenic cardiomyopathy. International Journal of Cardiology, 342, 94– 102. 34400166
  79. Stevens, T. L., Manring, H. R., Wallace, M. J., Argall, A., Dew, T., Papaioannou, P., Antwi‐Boasiako, S., Xu, X., Campbell, S. G., Akar, F. G., Borzok, M. A., Hund, T. J., Mohler, P. J., Koenig, S. N., & El Refaey, M. (2022). Humanized Dsp ACM mouse model displays stress‐induced cardiac electrical and structural phenotypes. Cells, 11(19), 3049. 36231013 PMC9562631
  80. Syrris, P., Ward, D., Evans, A., Asimaki, A., Gandjbakhch, E., Sen‐Chowdhry, S., & McKenna, W. J. (2006). Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin‐2. American journal of human genetics, 79(5), 978– 984. 17033975 PMC1698574
  81. Thiene, G., Nava, A., Corrado, D., Rossi, L., & Pennelli, N. (1988). Right ventricular cardiomyopathy and sudden death in young people. The New England Journal of Medicine, 318(3), 129– 133. 3336399
  82. Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., & Rampazzo, A. (2001). Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Human Molecular Genetics, 10(3), 189– 194. 11159936
  83. Tolstik, E., Lehnart, S. E., Soeller, C., Lorenz, K., & Sacconi, L. (2024). Cardiac multiscale bioimaging: from nano‐ through micro‐ to mesoscales. Trends in Biotechnology, 42(2), 212– 227. 37806897
  84. Vallverdú‐Prats, M., Carreras, D., Pérez, G. J., Campuzano, O., Brugada, R., & Alcalde, M. (2023). Alterations in calcium handling are a common feature in an arrhythmogenic cardiomyopathy cell model triggered by desmosome genes loss. International Journal of Molecular Sciences, 24(3), 2109. 36768439 PMC9917020
  85. van der Voorn, S. M., Te Riele, A. S. J. M., Basso, C., Calkins, H., Remme, C. A., & van Veen, T. A. B. (2020). Arrhythmogenic cardiomyopathy: Pathogenesis, pro‐arrhythmic remodeling, and novel approaches for risk stratification and therapy. Cardiovascular Research, 116(9), 1571– 1584. 32246823 PMC7526754
  86. van der Zwaag, P. A., van Rijsingen, I. A., Asimaki, A., Jongbloed, J. D., van Veldhuisen, D. J., Wiesfeld, A. C., Cox, M. G., van Lochem, L. T., de Boer, R. A., Hofstra, R. M., Christiaans, I., van Spaendonck‐Zwarts, K. Y., Lekanne dit Deprez, R. H., Judge, D. P., Calkins, H., Suurmeijer, A. J., Hauer, R. N., Saffitz, J. E., Wilde, A. A., van den Berg, M. P., … van Tintelen, J. P. (2012). Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: Evidence supporting the concept of arrhythmogenic cardiomyopathy. European Journal of Heart Failure, 14(11), 1199– 1207. 22820313 PMC3475434
  87. Vanzi, F., Sacconi, L., Cicchi, R., & Pavone, F. S. (2012). Protein conformation and molecular order probed by second‐harmonic‐generation microscopy. Journal of biomedical optics, 17(6), 060901. 22734730
  88. Wichter, T., Schäfers, M., Rhodes, C. G., Borggrefe, M., Lerch, H., Lammertsma, A. A., Hermansen, F., Schober, O., Breithardt, G., & Camici, P. G. (2000). Abnormalities of cardiac sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy: Quantitative assessment of presynaptic norepinephrine reuptake and postsynaptic beta‐adrenergic receptor density with positron emission tomography. Circulation, 101(13), 1552– 1558. 10747349
  89. Wichter, T., Paul, M., Wollmann, C., Acil, T., Gerdes, P., Ashraf, O., Tjan, T. D., Soeparwata, R., Block, M., Borggrefe, M., Scheld, H. H., Breithardt, G., & Böcker, D. (2004). Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: Single‐center experience of long‐term follow‐up and complications in 60 patients. Circulation, 109(12), 1503– 1508. 15007002
  90. Zaglia, T., Milan, G., Franzoso, M., Bertaggia, E., Pianca, N., Piasentini, E., Voltarelli, V. A., Chiavegato, D., Brum, P. C., Glass, D. J., Schiaffino, S., Sandri, M., & Mongillo, M. (2013). Cardiac sympathetic neurons provide trophic signal to the heart via β2‐adrenoceptor‐dependent regulation of proteolysis. Cardiovascular Research, 97(2), 240– 250. 23090606
  91. Zaglia, T., Milan, G., Ruhs, A., Franzoso, M., Bertaggia, E., Pianca, N., Carpi, A., Carullo, P., Pesce, P., Sacerdoti, D., Sarais, C., Catalucci, D., Krüger, M., Mongillo, M., & Sandri, M. (2014). Atrogin‐1 deficiency promotes cardiomyopathy and premature death via impaired autophagy. The Journal of Clinical Investigation, 124(6), 2410– 2424. 24789905 PMC4038560
  92. Zaglia, T., Di Bona, A., Chioato, T., Basso, C., Ausoni, S., & Mongillo, M. (2016). Optimized protocol for immunostaining of experimental GFP‐expressing and human hearts. Histochemistry and Cell Biology, 146(4), 407– 419. 27311322
  93. Zaglia, T., & Mongillo, M. (2017). Cardiac sympathetic innervation, from a different point of (re)view. The Journal of Physiology, 595(12), 3919– 3930. 28240352 PMC5471365
  94. Zaklyazminskaya, E., & Dzemeshkevich, S. (2016). The role of mutations in the SCN5A gene in cardiomyopathies. Biochimica et biophysica acta, 1863(7 Pt B), 1799– 1805. 26916278
  95. Zorzi, A., Perazzolo Marra, M., Rigato, I., de Lazzari, M., Susana, A., Niero, A., Pilichou, K., Migliore, F., Rizzo, S., Giorgi, B., de Conti, G., Sarto, P., Serratosa, L., Patrizi, G., de Maria, E., Pelliccia, A., Basso, C., Schiavon, M., Bauce, B., Iliceto, S., … Corrado, D. (2016). Nonischemic left ventricular scar as a substrate of life‐threatening ventricular arrhythmias and sudden cardiac death in competitive athletes. Circulation Arrhythmia and Electrophysiology, 9(7), e004229. 27390211 PMC4956679

Cited by

Sorted by citations

Authors
Vanaja, I. P., Scalco, A., Ronfini, M., Bona, A. D., Olianti, C., Rizzo, S., Chelko, S. P., Corrado, D., Sacconi, L., Basso, C., Mongillo, M., & Zaglia, T.
Affiliations
  • University of Padua (IT)
  • Istituto di Fisiologia Clinica (IT)
  • Florida State University (US)
  • University of Freiburg (DE)
Corresponding author
Zaglia, Tania
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2024-08-14
Volume
603
Issue
7
Pages
1959-1982
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jp286845
PMC
PMC11955870
OpenAlex
W4401566911
Cited by
17
References
7
Citations by year
2026: 8 · 2025: 8 · 2024: 1
FWCI
5.11
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
European Commission (HORIZON2020, 101034319)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
arrhythmogenic cardiomyopathy, desmoglein 2, cardiac sympathetic neurons, sympathetic innervation, desmosomes, desmosomal gene mutations, myocardial remodelling, axonal sprouting, varicosities, sudden cardiac death, arrhythmogenic substrate, cardiomyocytes
MeSH terms
Animals, Arrhythmias, Cardiac, Heart, Male, Mice, Inbred C57BL, Mutation, Cardiomyopathies, Myocardium, Neurons, Sympathetic Nervous System, Arrhythmogenic Right Ventricular Dysplasia, Desmoglein 2, Mice, Rats, Adrenergic Neurons

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