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• W2893213731 abstract "Blood, serum and plasma represent accessible sources of data about physiological and pathologic status. In arrhythmogenic cardiomyopathy (ACM), circulating nucleated cells are routinely used for detection of germinal genetic mutations. In addition, different biomarkers have been proposed for diagnostic purposes and for monitoring disease progression, including inflammatory cytokines, markers of myocardial dysfunction and damage, and microRNAs. This review summarizes the current information that can be retrieved from the blood of ACM patients and considers the future prospects. Improvements in current knowledge of circulating factors may provide noninvasive means to simplify and improve the diagnosis, prognosis prediction, and management of ACM patients. Blood, serum and plasma represent accessible sources of data about physiological and pathologic status. In arrhythmogenic cardiomyopathy (ACM), circulating nucleated cells are routinely used for detection of germinal genetic mutations. In addition, different biomarkers have been proposed for diagnostic purposes and for monitoring disease progression, including inflammatory cytokines, markers of myocardial dysfunction and damage, and microRNAs. This review summarizes the current information that can be retrieved from the blood of ACM patients and considers the future prospects. Improvements in current knowledge of circulating factors may provide noninvasive means to simplify and improve the diagnosis, prognosis prediction, and management of ACM patients. Blood is an easily accessible tissue, widely exploited in medicine to obtain clinical information at different levels. It serves as a window to monitor health or disease states because of its complex and “flexible” composition. Indeed, the whole set of molecules present in the blood originates from all body tissues, thus reflecting their fitness. In particular, several blood-based tests are routinely used to diagnose a wide number of pathologies, to understand their possible causes, to monitor the state of progression/remission and outcomes after treatment, and to help the choice of appropriate specific therapies as tools for theranostics. Thus, research is continuously making remarkable efforts to improve the quantity and quality of information retrieved from this tissue. Blood complexity can be unraveled using different approaches, either omics- or hypothesis-driven, the latter usually originating from known molecular mechanisms involved in a specific disease. Biomarkers are defined as disease indicators that can be measured accurately and reproducibly.1Strimbu K. Tavel J.A. What are biomarkers?.Curr Opin HIV AIDS. 2010; 5: 463-466Crossref PubMed Scopus (1138) Google Scholar In particular, circulating biomarkers have the unquestionable advantage of being noninvasive and usually inexpensive. Despite these advantages, the number of clinical-grade biomarkers is limited, and the validation path of biomarkers possessing high sensitivity and/or specificity for a defined disease is challenging. This issue may be overcome by using a combination of different molecules. In this review, we applied a structured literature search (Supplementary Methods and Supplemental Figure S1) to summarize the most up-to-date information retrievable from blood samples with regard to arrhythmogenic cardiomyopathy (ACM) patients (Figure 1). Because of their genetic basis, germinal mutations are routinely assessed in blood cells. However, much more information can be potentially unraveled. ACM inflammatory components can be studied through circulating lymphocytes–monocytes and cytokines, as well as possible systemic concomitant infective agents. Cardiac damage can be monitored by detecting released factors as well as circulating microRNAs (miRNAs). Sex prevalence is reflected in blood hormonal modulation. To date, no validated circulating biomarkers are available for ACM, and the few new candidates that have been proposed mainly provide indications about disease progression rather than onset. We speculate that advances beyond the current knowledge will translate into future extensive exploitation of noninvasive blood tests in ACM. ACM is a genetic and relatively rare cardiac disease characterized by ventricular fibrofatty substitution and arrhythmias.2Stadiotti I. Catto V. Casella M. Tondo C. Pompilio G. Sommariva E. Arrhythmogenic cardiomyopathy: the guilty party in adipogenesis.J Cardiovasc Transl Res. 2017; 10: 446-454Crossref PubMed Scopus (16) Google Scholar In the majority of cases, involvement of the right ventricle (RV) is predominant, with a lesser representation of left dominant and biventricular forms.3McNally E. MacLeod H. Dellefave-Castillo L. Arrhythmogenic right ventricular cardiomyopathy. April 18, 2005. Updated May 25, 2017.in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews. University of Washington, Seattle, Seattle, WA1993–2018https://www.ncbi.nlm.nih.gov/books/NBK1131/Google Scholar It mostly affects young men, particularly athletes, as intense physical exercise worsens the disease phenotype.4Castanos Gutierrez S.L. Kamel I.R. Zimmerman S.L. Current concepts on diagnosis and prognosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia.J Thorac Imaging. 2016; 31: 324-335Crossref PubMed Scopus (9) Google Scholar Sustained myocardium workload provokes a training-induced heart remodeling that, despite being generally considered as physiological, can induce adverse alterations in predisposed subjects. ACM onset usually occurs during adolescence and early adulthood.4Castanos Gutierrez S.L. Kamel I.R. Zimmerman S.L. Current concepts on diagnosis and prognosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia.J Thorac Imaging. 2016; 31: 324-335Crossref PubMed Scopus (9) Google Scholar In many cases, nonspecific symptoms, such as syncope and palpitations, arise before the manifestation of overt myocardial dysfunction. Even in the context of well-preserved morphology, histology, and ventricular function, ACM patients may die of sudden cardiac death.5Sommariva E. Stadiotti I. Perrucci G.L. Tondo C. Pompilio G. Cell models of arrhythmogenic cardiomyopathy: advances and opportunities.Dis Model Mech. 2017; 10: 823-835Crossref PubMed Scopus (24) Google Scholar As the disease progresses, the myocardial damage becomes evident, and structural anomalies such as regional wall-motion abnormalities, increased myocardial trabeculation, ventricular dilation, and dysfunction appear. At the histologic level, cardiomyocyte death, inflammation, and fibro-adipose substitution are observed.6Saguner A.M. Brunckhorst C. Duru F. Arrhythmogenic ventricular cardiomyopathy: a paradigm shift from right to biventricular disease.World J Cardiol. 2014; 6: 154-174Crossref PubMed Google Scholar Currently there is no single gold standard diagnostic test for ACM. The diagnosis is based on a scoring system of “major” and “minor” criteria that include structural and electrocardiographic alterations, tissue characterization, previous arrhythmic events, and family history. In selected cases, a genetic test is recommended.7Marcus F.I. McKenna W.J. Sherrill D. et al.Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.Circulation. 2010; 121: 1533-1541Crossref PubMed Scopus (1430) Google Scholar Genetic tests are increasingly performed in the diagnostic process for inherited cardiovascular diseases. The opportunity to confirm diagnostic suspects or to identify at-risk relatives using blood samples is widely used in ACM, allowing etiologically based differential diagnosis if clinical presentation is not specific.8Marcus F.I. Edson S. Towbin J.A. Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide for physicians.J Am Coll Cardiol. 2013; 61: 1945-1948Crossref PubMed Scopus (116) Google Scholar Since 2000, molecular genetic analysis led to the discovery of many genes associated with ACM. To date, it is known that ACM has mostly a familial occurrence with an autosomal dominant inheritance.3McNally E. MacLeod H. Dellefave-Castillo L. Arrhythmogenic right ventricular cardiomyopathy. April 18, 2005. Updated May 25, 2017.in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews. University of Washington, Seattle, Seattle, WA1993–2018https://www.ncbi.nlm.nih.gov/books/NBK1131/Google Scholar Recessive forms are also present, namely, Naxos and Carvajal syndromes, and are associated with a cutaneous phenotype.9Protonotarios N. Tsatsopoulou A. Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy.Cardiovasc Pathol. 2004; 13: 185-194Crossref PubMed Scopus (153) Google Scholar The most frequently mutated genes encode for desmosomal proteins, but mutations in nondesmosomal genes are also known.3McNally E. MacLeod H. Dellefave-Castillo L. Arrhythmogenic right ventricular cardiomyopathy. April 18, 2005. Updated May 25, 2017.in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews. University of Washington, Seattle, Seattle, WA1993–2018https://www.ncbi.nlm.nih.gov/books/NBK1131/Google Scholar Desmosomes are intercellular junctions that provide cell-to-cell adhesion and influence intracellular transduction signals, through the Wnt pathway, which is impaired in ACM patients.10Garcia-Gras E. Lombardi R. Giocondo M.J. Willerson J.T. Schneider M.D. Khoury D.S. Marian A.J. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.J Clin Invest. 2006; 116: 2012-2021Crossref PubMed Scopus (459) Google Scholar These mutations lead to electrical and mechanical dysfunction of the myocardium. For a list of genes associated with ACM, see Supplemental Table S1. Genetic testing is initially recommended in 1 proband per family.11Cirino A.L. Harris S. Lakdawala N.K. et al.Role of genetic testing in inherited cardiovascular disease: a review.JAMA Cardiol. 2017; 2: 1153-1160Crossref PubMed Scopus (50) Google Scholar For each screened individual, cardiomyopathy gene panels could be used when clinical features overlap with other cardiac diseases or, when the phenotype is indisputable, a selected ACM-specific panel could be used.11Cirino A.L. Harris S. Lakdawala N.K. et al.Role of genetic testing in inherited cardiovascular disease: a review.JAMA Cardiol. 2017; 2: 1153-1160Crossref PubMed Scopus (50) Google Scholar When a causative mutation is identified, predictive genetic testing is applied to ascertain the presence of the disease in apparently healthy relatives, in order to adopt preventive/follow-up strategies in individuals at risk. Unfortunately, the genetic cause remains unknown in approximately 50% of probands with routine screening.12Fedida J. Fressart V. Charron P. Surget E. Hery T. Richard P. Donal E. Keren B. Duthoit G. Hidden-Lucet F. Villard E. Gandjbakhch E. Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia.PLoS One. 2017; 12: e0181840Crossref PubMed Scopus (8) Google Scholar The success rate of genotyping could depend on several variables, such as cohort ethnicity, proband selection criteria, and the standards applied to understand the pathogenicity of the detected variants. Negative results could be due to the use of techniques that do not allow the detection of copy number variations.13Pilichou K. Lazzarini E. Rigato I. et al.Large genomic rearrangements of desmosomal genes in italian arrhythmogenic cardiomyopathy patients.Circ Arrhythm Electrophysiol. 2017; 10: e005324Crossref PubMed Scopus (32) Google Scholar, 14Roberts J. Herkert J. Rutberg J. Nikkel S. Wiesfeld A. Dooijes D. Gow R. van Tintelen J. Gollob M. Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy.Clin Genet. 2013; 83: 452-456Crossref PubMed Scopus (30) Google Scholar Moreover, phenotype misclassification could represent a considerable limit of this analysis.15Ott P. Marcus F.I. Sobonya R.E. Morady F. Knight B.P. Fuenzalida C.E. Cardiac sarcoidosis masquerading as right ventricular dysplasia.Pacing Clin Electrophysiol. 2003; 26: 1498-1503Crossref PubMed Scopus (62) Google Scholar Furthermore, the presence of mutations in genes not yet associated with ACM could be an additional reason for low efficiency.12Fedida J. Fressart V. Charron P. Surget E. Hery T. Richard P. Donal E. Keren B. Duthoit G. Hidden-Lucet F. Villard E. Gandjbakhch E. Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia.PLoS One. 2017; 12: e0181840Crossref PubMed Scopus (8) Google Scholar Notably, compound or digenic heterozygosity is present in up to 18% of ACM patients, indicating that more than 1 pathogenic allele may be involved.16Xu T. Yang Z. Vatta M. et al.Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy.J Am Coll Cardiol. 2010; 55: 587-597Crossref PubMed Scopus (250) Google Scholar, 17König E. Volpato C.B. Motta B.M. et al.Exploring digenic inheritance in arrhythmogenic cardiomyopathy.BMC Med Genet. 2017; 18: 145Crossref PubMed Scopus (9) Google Scholar Even if the value of genetics in risk stratification is poorly understood, multiple mutations18Rigato I. Bauce B. Rampazzo A. et al.Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.Circ Cardiovasc Genet. 2013; 6: 533-542Crossref PubMed Scopus (179) Google Scholar and, possibly, mutations in the PKP2 gene19Sommariva E. Brambilla S. Carbucicchio C. et al.Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy.Eur Heart J. 2016; 37: 1835-1846Crossref PubMed Scopus (65) Google Scholar, 20Bao J. Wang J. Yao Y. Wang Y. Fan X. Sun K. He D.S. Marcus F.I. Zhang S. Hui R. Song L. Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy.Circ Cardiovasc Genet. 2013; 6: 552-556Crossref PubMed Scopus (48) Google Scholar are predictors of more severe prognoses. Because of this variability, even after genetic tests, ACM diagnosis and risk stratification are still challenging. Recently, different variants previously linked to ACM have been reclassified as variants of uncertain pathogenicity because they have been found also in large screenings of healthy subjects (see the ARVD/C Genetic Variants Database at http://www.arvcdatabase.info for indications on variant pathogenicity).21Hall C.L. Sutanto H. Dalageorgou C. McKenna W.J. Syrris P. Futema M. Frequency of genetic variants associated with arrhythmogenic right ventricular cardiomyopathy in the genome aggregation database.Eur J Hum Genet. 2018; 26: 1312-1318Crossref PubMed Scopus (22) Google Scholar, 22van der Zwaag P.A. Jongbloed J.D. van den Berg M.P. van der Smagt J.J. Jongbloed R. Bikker H. Hofstra R.M. van Tintelen J.P. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy.Hum Mutat. 2009; 30: 1278-1283Crossref PubMed Scopus (98) Google Scholar The possible false-positive rate seems to be particularly high.23Kapplinger J.D. Landstrom A.P. Salisbury B.A. et al.Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.J Am Coll Cardiol. 2011; 57: 2317-2327Crossref PubMed Scopus (235) Google Scholar However, when a causal mutation is not detected, the complete exclusion of the disease is not possible. Genetic and phenotypic overlap between ACM and other types of cardiomyopathy have been reported, particularly with dilated cardiomyopathy, Brugada syndrome, and hypertrophic cardiomyopathy (Supplemental Table S1).24Murray B. Hoorntje E.T. Te Riele A. et al.Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).J Cardiovasc Electrophysiol. 2018; 29: 1004-1009Crossref PubMed Scopus (12) Google Scholar In these cases, differential diagnosis is challenging even with the help of blood genetic tests. The amount of implicated variables clearly defines how complex it is to obtain useful information on ACM genetics. Therefore, a great effort in the interpretation of the results is necessary to define their clinical significance, in addition to constant technical progresses. The advent of low-cost next-generation sequencing, the development of sophisticated analytics tools and models to test the pathogenicity of ACM mutations, and the increased knowledge about disease-associated genes represent significant steps forward in providing genetic diagnosis to patients. An inflammatory milieu with patchy infiltrates in the RV has been observed in ACM hearts.25Campuzano O. Alcalde M. Iglesias A. Barahona-Dussault C. Sarquella-Brugada G. Benito B. Arzamendi D. Flores J. Leung T.K. Talajic M. Oliva A. Brugada R. Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation.J Clin Pathol. 2012; 65: 1077-1083Crossref PubMed Scopus (54) Google Scholar Thus, an inflammation theory was formulated to explain ACM etiology. In particular, it has been proposed that genetic mutations could induce immune alterations contributing to heart-specific inflammatory conditions.26Cooper Jr., L.T. Myocarditis. N Engl J Med. 2009; 360: 1526-1538Crossref PubMed Scopus (926) Google Scholar The inflammatory process could provoke myocardial injury, followed by a genetically determined aberrant fibro-adipose repair. However, whether inflammation is a primary mechanism or a consequence of mutation-dependent cardiomyocyte death is still unknown.25Campuzano O. Alcalde M. Iglesias A. Barahona-Dussault C. Sarquella-Brugada G. Benito B. Arzamendi D. Flores J. Leung T.K. Talajic M. Oliva A. Brugada R. Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation.J Clin Pathol. 2012; 65: 1077-1083Crossref PubMed Scopus (54) Google Scholar Indeed, inflammation related to necrosis and apoptosis has been reported, involving a feed-forward loop.27Haanen C. Vermes I. Apoptosis and inflammation.Mediators Inflamm. 1995; 4: 5-15Crossref PubMed Scopus (114) Google Scholar Most of the studies investigating ACM cardiac inflammation are based on invasive endomyocardial biopsy analysis to evaluate the presence of macrophages, neutrophils, and mast cells in the RV of ACM patients.25Campuzano O. Alcalde M. Iglesias A. Barahona-Dussault C. Sarquella-Brugada G. Benito B. Arzamendi D. Flores J. Leung T.K. Talajic M. Oliva A. Brugada R. Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation.J Clin Pathol. 2012; 65: 1077-1083Crossref PubMed Scopus (54) Google Scholar Also, the presence of cardiotropic viruses has been reported in the ACM myocardium, possibly contributing to the inflammatory environment.28Bowles N.E. Ni J. Marcus F. Towbin J.A. The detection of cardiotropic viruses in the myocardium of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.J Am Coll Cardiol. 2002; 39: 892-895Crossref PubMed Scopus (160) Google Scholar In fact, a correlation between genetic predisposition and viral susceptibility has been proposed.29Calabrese F. Basso C. Carturan E. Valente M. Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: is there a role for viruses?.Cardiovasc Pathol. 2006; 15: 11-17Crossref PubMed Scopus (94) Google Scholar Because the use of cardiac biopsy is limited by its invasiveness, noninvasive techniques based on blood analysis to monitor cardiac inflammation are desirable. The detection of viruses and bacteria in the blood of ACM patients could reflect a cardiac infection. Chronic infections with Bartonella henselae, a bacterial agent associated with endocarditis detected in serum samples, have been proposed to be linked to ACM as a possible cause of nonfamilial ACM cases.30H Fischer A. van der Loo B. M Shar G. Zbinden R. Duru F. Brunckhorst C. Rousson V. Delacretaz Y.E. Stuber T. Oechslin E.N. Follath F. Jenni R. Serological evidence for the association of Bartonella henselae infection with arrhythmogenic right ventricular cardiomyopathy.Clin Cardiol. 2008; 31: 469-471Crossref PubMed Scopus (9) Google Scholar To date, circulating inflammatory mediators in ACM patients have been tested measuring different parameters. The plasmatic levels of the inflammatory marker C-reactive protein (CRP) are higher in the blood of patients with ACM than in those with idiopathic ventricular tachycardia (IVT), often in differential diagnosis. The association of an inflammatory status with the occurrence of arrhythmic events has been postulated because CRP levels significantly increase just after ventricular arrhythmia (VA) occurrence in ACM patients.31Bonny A. Lellouche N. Ditah I. Hidden-Lucet F. Yitemben M.T. Granger B. Larrazet F. Frank R. Fontaine G. C-reactive protein in arrhythmogenic right ventricular dysplasia/cardiomyopathy and relationship with ventricular tachycardia.Cardiol Res Pract. 2010; 2010: 919783Crossref PubMed Scopus (22) Google Scholar However, because the CRP values of nonarrhythmic ACM patient subgroups have not been shown as well as those of the IVT cohort immediately after VA, CRP increase might be associated with VA and not with ACM. In addition, higher levels of circulating proinflammatory cytokines have been found in ACM patients compared to healthy controls.32Campian M.E. Verberne H.J. Hardziyenka M. de Groot E.A. van Moerkerken A.F. van Eck-Smit B.L. Tan H.L. Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.Eur J Nucl Med Mol Imaging. 2010; 37: 2079-2085Crossref PubMed Scopus (42) Google Scholar, 33Asimaki A. Tandri H. Duffy E.R. et al.Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy.Circ Arrhythm Electrophysiol. 2011; 4: 743-752Crossref PubMed Scopus (125) Google Scholar Although the inflammatory status of the heart has been associated with disease severity,25Campuzano O. Alcalde M. Iglesias A. Barahona-Dussault C. Sarquella-Brugada G. Benito B. Arzamendi D. Flores J. Leung T.K. Talajic M. Oliva A. Brugada R. Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation.J Clin Pathol. 2012; 65: 1077-1083Crossref PubMed Scopus (54) Google Scholar no studies have correlated circulating cytokine levels to myocardial damage degree. Myocarditis is often in the differential diagnosis with ACM. However, it has been postulated that myocarditis is a superimposed phenomenon during the natural history of ACM, being associated with an active progression phase.34Pilichou K. Thiene G. Bauce B. Rigato I. Lazzarini E. Migliore F. Perazzolo Marra M. Rizzo S. Zorzi A. Daliento L. Corrado D. Basso C. Arrhythmogenic cardiomyopathy.Orphanet J Rare Dis. 2016; 11: 33Crossref PubMed Scopus (99) Google Scholar To date, no study has addressed the role of circulating factors in the differential diagnosis between these 2 diseases. Recently, an autoimmune etiology has been proposed35Chatterjee D. Fatah M. Adkis D. Spears D.A. Koopmann T. Mittal K. Brunckhorst C. Duri F. Saguner A. Hamilton R. A novel serum biomarker identifying arrhythmogenic right ventricular cardiomyopathy (ARVC).Eur Heart J. 2017; 38 (https://doi.org/10.1093/eurheartj/ehx494.2889)Crossref Google Scholar; however, the presence of autoantibodies against desmosomal components in ACM plasma needs to be confirmed in larger cohorts. Thus, to date, a complete characterization of circulating inflammatory/immune response in ACM is still lacking. A large analysis of inflammatory cell mediators, antibodies, and cytokines may help define an ACM-specific inflammatory cascade36Ciulla M.M. De Marco F. Montelatici E. Lazzari L. Perrucci G.L. Magrini F. Assessing cytokines' talking patterns following experimental myocardial damage by applying Shannon's information theory.J Theor Biol. 2014; 343: 25-31Crossref PubMed Scopus (5) Google Scholar and improve diagnostic and prognostic processes along with pathogenic mechanisms. Heart failure (HF) in ACM is a severe consequence of an advanced cardiac remodeling process. Thus, the exploitation of different HF biomarkers are proposed for the characterization of ACM late phases. Circulating brain natriuretic peptide (BNP) is routinely used to evaluate the presence and progression of HF and has been shown to be a useful indicator of RV dysfunction in ACM patients due to the reported negative correlation with RV ejection fraction.37Matsuo K. Nishikimi T. Yutani C. Kurita T. Shimizu W. Taguchi A. Suyama K. Aihara N. Kamakura S. Kangawa K. Takamiya M. Shimomura K. Diagnostic value of plasma levels of brain natriuretic peptide in arrhythmogenic right ventricular dysplasia.Circulation. 1998; 98: 2433-2440Crossref PubMed Scopus (58) Google Scholar Of note, BNP is higher in the plasma of ACM vs IVT patients, which aids differential diagnosis. Accordingly, immunohistochemistry performed on endomyocardial biopsies showed no detectable BNP in the RV of IVT patients, whereas positive results were obtained in ACM patients.37Matsuo K. Nishikimi T. Yutani C. Kurita T. Shimizu W. Taguchi A. Suyama K. Aihara N. Kamakura S. Kangawa K. Takamiya M. Shimomura K. Diagnostic value of plasma levels of brain natriuretic peptide in arrhythmogenic right ventricular dysplasia.Circulation. 1998; 98: 2433-2440Crossref PubMed Scopus (58) Google Scholar Similar experiments using the N-terminal fragment of BNP, NT-proBNP, showed its association with RV dysfunction and volumes in ACM.38Cheng H. Lu M. Hou C. Chen X. Wang J. Yin G. Chu J. Zhang S. Prasad S.K. Pu J. Zhao S. Relation between N-terminal pro-brain natriuretic peptide and cardiac remodeling and function assessed by cardiovascular magnetic resonance imaging in patients with arrhythmogenic right ventricular cardiomyopathy.Am J Cardiol. 2015; 115: 341-347Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar This observation has been confirmed in other studies.39Akdis D. Saguner A.M. Shah K. Wei C. Medeiros-Domingo A. von Eckardstein A. Luscher T.F. Brunckhorst C. Chen H.S.V. Duru F. Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.Eur Heart J. 2017; 38: 1498-1508Crossref PubMed Scopus (80) Google Scholar The major limitation of the use of BNP and NT-proBNP in association with ACM is its low specificity due to the well-known association with a large number of HF-related cardiac conditions. In 2009, the chaperone heat shock protein 70 (HSP70) was found to be differentially expressed in failing hearts of ACM patients in comparison to nonfailing hearts, with similar results at the systemic level.40Wei Y.J. Huang Y.X. Shen Y. Cui C.J. Zhang X.L. Zhang H. Hu S.S. Proteomic analysis reveals significant elevation of heat shock protein 70 in patients with chronic heart failure due to arrhythmogenic right ventricular cardiomyopathy.Mol Cell Biochem. 2009; 332: 103-111Crossref PubMed Scopus (29) Google Scholar Based on in vitro results, circulating HSP70 was proposed to originate from damaged myocardial cells. Other evidences associated HSP70 with inflammation and apoptosis.41Snoeckx L.H. Cornelussen R.N. Van Nieuwenhoven F.A. Reneman R.S. Van Der Vusse G.J. Heat shock proteins and cardiovascular pathophysiology.Physiol Rev. 2001; 81: 1461-1497Crossref PubMed Scopus (331) Google Scholar Similarly to BNP, HSP70 usage is limited by its lack of ACM specificity because it is elevated in patients with dilated cardiomyopathy and ischemic cardiomyopathy. Likewise, cardiac troponin I (cTnI), a structural protein released into circulation after cardiomyocyte death and a well-established marker of cardiac muscle injury, has been proposed to be associated with ACM.42Adams 3rd, J.E. Bodor G.S. Davila-Roman V.G. Delmez J.A. Apple F.S. Ladenson J.H. Jaffe A.S. Cardiac troponin I. A marker with high specificity for cardiac injury.Circulation. 1993; 88: 101-106Crossref PubMed Google Scholar The first evidence was observed in ACM boxer dogs, in which a correlation between cTnI levels and premature ventricular contractions was demonstrated.43Baumwart R.D. Orvalho J. Meurs K.M. Evaluation of serum cardiac troponin I concentration in Boxers with arrhythmogenic right ventricular cardiomyopathy.Am J Vet Res. 2007; 68: 524-528Crossref PubMed Scopus (56) Google Scholar This was confirmed in humans, highlighting a correlation of cTnI with major arrhythmic events.39Akdis D. Saguner A.M. Shah K. Wei C. Medeiros-Domingo A. von Eckardstein A. Luscher T.F. Brunckhorst C. Chen H.S.V. Duru F. Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.Eur Heart J. 2017; 38: 1498-1508Crossref PubMed Scopus (80) Google Scholar However, its use in ACM is questionable because troponin increase also has been observed in athletes with ischemia44Mahajan N. Mehta Y. Rose M. Shani J. Lichstein E. Elevated troponin level is not synonymous with myocardial infarction.Int J Cardiol. 2006; 111: 442-449Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar or myocarditis45Smith S.C. Ladenson J.H. Mason J.W. Jaffe A.S. Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates.Circulation. 1997; 95: 163-168Crossref PubMed Scopus (449) Google Scholar and in agonist athletes after strenuous physical activity.46Saenz A.J. Lee-Lewandrowski E. Wood M.J. Neilan T.G. Siegel" @default.
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• W2893213731 date "2019-03-01" @default.
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• W2893213731 title "Arrhythmogenic cardiomyopathy: what blood can reveal?" @default.
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• W2893213731 doi "https://doi.org/10.1016/j.hrthm.2018.09.023" @default.
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