Carta Acesso aberto Revisado por pares

The Changing Face of Cardiac Inflammation

2017; Lippincott Williams & Wilkins; Volume: 10; Issue: 11 Linguagem: Inglês

10.1161/circheartfailure.117.004528

ISSN

1941-3297

Autores

Leslie T. Cooper,

Tópico(s)

Cardiac Structural Anomalies and Repair

Resumo

HomeCirculation: Heart FailureVol. 10, No. 11The Changing Face of Cardiac Inflammation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Changing Face of Cardiac InflammationNew Opportunities in the Management of Myocarditis Leslie T. CooperJr., MD Leslie T. CooperJr.Leslie T. CooperJr. From the Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL. Originally published20 Nov 2017https://doi.org/10.1161/CIRCHEARTFAILURE.117.004528Circulation: Heart Failure. 2017;10:e004528See Articles by Berg et al and Müller et alThe search for noninvasive tests to diagnose myocardial inflammation has developed from the use of 67Gallium through antimyosin antibodies to the current standards of 18fluorodeoxyglucose positron emission tomography and cardiac magnetic resonance imaging (CMR).1,2 In CMR, a combination of 2 of 3 signal intensity measurements from native T2-weighted images and T1-weighted images obtained before and after gadolinium contrast provides a reasonable diagnostic performance with an estimated sensitivity of 67% and specificity of 91%.3 Since these original Lake Louise criteria were published, newer mapping techniques that quantify T1 and T2 relaxation times have significantly improved the performance of CMR for the diagnosis of inflammation.4Early in the course of suspected myocarditis, CMR can predict meaningful clinical outcomes. In most but not all studies, the risk of ventricular arrhythmias is increased in patients with delayed gadolinium enhancement.5–7 CMR sequences that estimate extracellular volume and edema can also inform management decisions. For example, an increase in T2 relaxation time may suggest greater myocardial water content and a greater likelihood of improved cardiac function.8 Because exercise can trigger arrhythmias in the setting of acute myocarditis, current American Heart Association scientific and European Society of Cardiology position statements recommend abstention from competitive sports while there is evidence of myocardial inflammation.9,10In this issue, Berg et al11 describe the clinical course and serial CMR imaging in 24 subjects with acute myocarditis. The cohort was 75% male with a preserved mean left ventricular ejection fraction of 55%. The imaging diagnosis relied on older sequences, and 79% of subjects also had pericardial involvement, suggesting a diagnosis of myopericarditis. Quantitative T1 and T2 parametric mapping was not performed. Only a minority were treated with colchicine, and 29% had persistent or recurrent atypical chest pain. It is not clear whether these symptoms were because of persistent or recurrent inflammation.Their novel observation is that delayed gadolinium enhancement (DGE) remained present by visual estimate in the majority of patients with acute myocarditis despite normalization of troponin and inflammatory biomarkers. The only cardiac arrest, because of polymorphic ventricular tachycardia, occurred in a subject with increasing DGE 3 months after presentation. Because the diagnosis was not confirmed by biopsy, a more aggressive form of eosinophilic or granulomatous myocarditis could have caused a minority of the CMR-diagnosed inflammation.Because DGE signal increases in scar as well as inflammation, DGE persistence in their cohort may reflect a greater tendency for scar formation rather than ongoing myocardial damage. This is consistent with the observed normalization of troponin and inflammatory markers. Previous studies have shown that men with more severe forms of myocarditis tend to have larger areas of DGE and less functional recovery than women. Men with acute myocarditis probably experience cardiovascular sudden death more often than women.10 However, the risk of subsequent systolic heart failure or transplantation is small in myopericarditis patients with preserved left ventricular ejection fraction.12,13This study highlights important and unanswered questions about the role of CMR in risk stratification after myocarditis. We do not know whether the presence of DGE after clinical recovery from myocarditis predicts cardiovascular events or should prevent clearance for sports participation. Perhaps in certain patients at high risk with increasing DGE, implantation of a defibrillator might be indicated. Larger studies using parametric mapping CMR techniques to increase diagnostic accuracy are needed to confirm the predictive value of DGE persistence after recovery. Endomyocardial biopsy in high-risk cohorts together with CMR may help to reveal the mechanisms of ventricular arrhythmias after acute myocarditis.14The challenges of myocarditis management include the optimal use of biomarkers. A second article in this issue by Müller et al15 describes the association of 2 proinflammatory proteins, S100A8 and s100A9 with coxsackie B virus myocarditis in 5 patients. When acutely ill, their 5 patients had elevated mRNA and protein levels of S100A8 and S100A9 in heart tissue. After recovery, the levels went down significantly as the left ventricular function improved. In a male C57BL mouse model of fulminant coxsackie B virus myocarditis, they observed a similar pattern. In this model, knockout of S100A9 eliminated both S100A8 and s100A9 protein expression, reduced coxsackie B virus 3 copy number, reduced inflammation, and the degree of left ventricular impairment. Addition of exogenous S100A8 and s100A9 to the knockout mice restored the injury pattern.Early clinical trials of immunosuppression were designed on the hypotheses that selective alteration of proinflammatory pathways early in the course of myocarditis could modify the course of the disease.16,17 Alterations in myocardial damage in multiple small animal experimental models of infectious and autoimmune myocarditis suggested that these pathways could be therapeutic targets in man; however, clinical trials blocking inflammation in acute myocarditis were largely negative.18,19 Recently, as our understanding of innate and adaptive immunity has increased, more individualized approaches that target specific pathways based on person-specific immunophenotype have also shown promise in preclinical experiments and observational patient studies.20,21Together with prior experimental studies, the study by Müller et al15 adds to our knowledge of myocarditis by demonstrating that the injurious or protective effect of SA100A8 and SA100A9 depends on genetic background and environmental factors, such as the nature of the injury. For example, Otsuka et al22 demonstrated essentially opposite results in a prior autoimmune myocarditis experiment in the Lewis rat. Furthermore, the Mueller and Otsuka studies were performed in males, and the impact of immunologic interventions often depends on the specific hormonal mileu at the time of intervention.23The reports by Berg et al11 and Müller et al15 highlight trends in the design of clinical myocarditis studies. Novel and better predictors of arrhythmia risk, including CMR tissue imaging, should refine subject selection in treatment trials. Pathogen-specific biomarkers like SA100A8 and SA100A9 may provide an individualized approached to therapy and the possibility of mechanistically focused interventions in smaller cohorts. The path from preclinical discovery into first in man trials remains time consuming and costly. More streamlined development and individualized interventions are needed to select the best drug candidates and accelerate focused trials in subjects with the greatest likelihood of benefit.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circ Heart Fail is available at http://circheartfailure.ahajournals.org.Correspondence to: Leslie T. Cooper, Jr., MD, Department of Cardiovascular Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. E-mail [email protected]References1. Skouri HN, Dec GW, Friedrich MG, Cooper LT. Noninvasive imaging in myocarditis.J Am Coll Cardiol. 2006; 48:2085–2093. doi: 10.1016/j.jacc.2006.08.017.CrossrefMedlineGoogle Scholar2. Kadkhodayan A, Chareonthaitawee P, Raman SV, Cooper LT. Imaging of inflammation in unexplained cardiomyopathy.JACC Cardiovasc Imaging. 2016; 9:603–617. doi: 10.1016/j.jcmg.2016.01.010.CrossrefMedlineGoogle Scholar3. 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November 2017Vol 10, Issue 11 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.117.004528PMID: 29158438 Originally publishedNovember 20, 2017 KeywordsEditorialsarrhythmias, cardiacgadoliniumcoxsackie B virusmyocarditismagnetic resonance imagingPDF download Advertisement SubjectsCardiomyopathyHeart FailureInflammatory Heart Disease

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