MANAGEMENT OF MYOCARDITIS

MYOCARDITIS

1. Management of myocarditis Murtaza Kamal 26/03/2019

2. Scope of the talk: MINI SEMINAR Diagnosis: Lab evaluation ECX/ CXR/ ECHO CMR EMB Treatment: Activity restrictions Medical management Immunomodulators, Immunosuppressors Antivirals Mechanical circulatory supports Survival and heart transplantation

3. WHO Definition An inflammatory myocardial disease diagnosed by a combination of histologic, immunologic, and immunohistochemical criteria Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation . 1996;93(5):841–842

4. Clinical presentation+ physical examination HF symptoms of short duration—> Days to weeks H/o recent viral prodrome with fever: RTI/ GIT RTI: 80% Vitals: Tachycardia/ Tachypnea/ Hypotention/ Hypoperfusion Lethargy/ Hepatomegaly/ Pallor/ Orthopnea Kids: Non specific symptoms+ variable presentation Freedman SB, Haladyn JK, Floh A, Kirsh JA, Taylor G, Thull-Freedman J. Pediatric myocarditis: emergency department clinical findings and diagnostic evaluation. Pediatrics . 2007;120(6):1278–1285 Kim HJ, Yoo GH, Kil HR. Clinical outcome of acute myocarditis in children according to treatment modalities. Korean J Pediatr . 2010;53(7):745–752 English RF, Janosky JE, Ettedgui JA, Webber SA. Outcomes for children with acute myocarditis. Cardiol Young . 2004;14(5):488–493

5. LAB EVALUATION Non specific: Raised WBCs/ Inflammatory markers/ Liver enzymes Trop T+I: Elevated as a marker of cardiac damage Absence of increased value: Doesn’t rule out Used as a differentiating tool b/w cardiac + non cardiac causes of paediatric chest pain

6. LAB EVALUATION CONT (TROPONINS)… 50% with raised Troponin—> Ultimately have cardiac disease 27%—> Myocarditis 0.052-0.088 ng/ml—> Cutoff (Trop T)

7. NATRIURETIC PEPTIDES High BNP: Helps in differentiation b/w HF + pul disease in kids with RD NT- Pro BNP: Increased in both myocarditis+ idiopathic DCM Levels higher in myocarditis at presentation, trends down over time compared to DCM Adults: Higher levels predictive of cardiac death/ transplant Antibodies to cardiac proteins (myocin+ beta adr receptors): Increased in adults Kids: Unkown/ Experimental

8. Other lab investigations… EMB tissue: Gold standard Cell culture/ PCR: Serum/ respi aspirate/ urine/ stool Peripheral viral PCR: Co-relation with causative agents from EMB—> Not established—> Evaluation complicated by relatively high prevalence of commonly associated viruses in general population Mahfoud F, Gartner B, Kindermann M, et al. Virus serology in patients with suspected myocarditis: utility or futility? Eur Heart J . 2011;32(7):897–903

9. ECG Abnormal in majority—> So—> DO IT ALWAYS Sinus tachycardia/ A+V Tachyarrhythmias Low voltage complexes Non- specific ST segment+ T wave abnormalities Conduction delays/ Blocks (1/2/3rd D HB)—> May require pacemakers in refractory cases Mimics ACS: Adolescents+ young adults

10. ECG

11. CXR Abnormal> 90% Cardiomegaly—> MC Not seen in those presenting with ACS like symptoms Pulmonary edema/ pul infiltrate/ pleural effusion

12. ECHO Ventricular function+ dilatation—> Prognostic value PE/ Intracavitary thrombi Wall thickness/ wall motion abnormalities Distinction of fulminant/acute (non fulminant myocarditis)/ DCM: Acute myocarditis: Normal wall thickness, May have LV dilatation FM: Markedly dec systolic function, Ventricular dysfunction: Global/ regional, normal chamber size, may have inc IVS thickness due to myocardial edema DCM: Markedly abnormal ventricular dilatation+ dysfunction

13. ECHO CONT… Severity of ventricular dysfunction—> Increased mortality+ requirement of heart transplantation Korean review: 72%: Dec EF 64%: Segmental wall abnormality EF< 15%—> More persistent severe cardiac failure RV dysfunction: Independent predictor of adverse outcome Diastolic dysfunction even in presence of normal systolic function Kim HJ, Yoo GH, Kil HR. Clinical outcome of acute myocarditis in children according to treatment modalities. Korean J Pediatr . 2010;53(7):745–752 Mendes LA, Dec GW, Picard MH, Palacios IF, Newell J, Davidoff R. Right ventricular dysfunction: an independent predictor of adverse outcome in patients with myocarditis. Am Heart J . 1994;128(2):301–307 Khoo NS, Smallhorn JF, Atallah J, Kaneko S, Mackie AS, Paterson I. Altered left ventricular tissue velocities, deformation and twist in children and young adults with acute myocarditis and normal ejection fraction. J Am Soc Echocardiog . 2012;25(3):294–303.

14. ECHO

15. CMR Non invasive gold standard for volumes+ function—> Prognostic values Tissue characterisation to evaluate hallmark of myocarditis: Edema/ hyperemia/ fibrosis/ scarring T2 weighted images: Edema, PE T1 weighted images: Hyperemia/ inflammation LGE images: Fibrosis/ scar—> No differentiation b/w acute+ chronic inflammation Sn: 67%; Sp: 91%

16. LAKE LOUISE CRITERIA

17. CMR CONT… Use in differentiation b/w myocarditis vs MI due to CAD: Myocarditis LGE enhancement: Subepicardial/ transmural/ pathcy MI LGE enhancement: Subendocardial/ transmural/ distribution in coronary perfusion territory Repeat CMR b/w 1-2 weeks after disease onset: If non diagnostic CMR changes early ds course, but high clinical suspicion Extent of LGE decreases over time—> Scar contraction

18. EMB: GOLD STANDARD DALLAS CRITERIA

19. EMB: Is it really gold standard?? Limitations: Patchy tissue involvement Preferential LV involvement Difference in inter observer expert interpretation of histopath samples Apparent lack of correlation b/w outcomes/ response to therapy Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circulation . 2006;113(4):593–595 Shanes JG, Ghali J, Billingham ME, et al. Interobserver variability in the pathologic interpretation of endomyocardial biopsy results. Circulation . 1987;75(2):401–405.

20. AHA/ ACC/ESC 2007 Guidelines No recommendation for routine EMB for suspected myocarditis Specific scenarios in which EMB is indicated—> Suspicion of GCM: 1. New onset HF< 2 weeks duration+ Normal sized/ dilated LV+ Heamodynamic compromise 2. New onset HF > 2weeks duration+ Dilated LV+ Ventricular arrhythmias/ HB+ Failure to respond to usual care in 1-2 wks Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J . 2007;28(24):3076–3093

21. 3 TIER CLASSIFICATION: SAGAR ET AL. MAYO CLINIC… (LANCET- 2012) Possible subclinical acute myocarditis: No symptoms+ Elevated biomarkers/ Abnormal ECG of CV injury/ Abnormal cardiac function by ECHO or CMR Probable acute myocarditis: Symptoms+ Any 1/4 of above Definitive myocarditis: Histological/ Immunohistological evidence by EMB Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet . 2012;379(9817):738–747

22. TREATMENT…

23. TREATMENT… Activity restriction Medical management Immunomodulators, Immunosuppressors Antivirals Mechanical circulatory supports Survival and heart transplantation

24. ACTIVITY RESTRICTIONS 2005 Bethesda guidelines: Pt should be restricted from all competitive sports for 6 months after diagnosis Athletes to return after normalisation of LV function+ size, absence of arrhythmias on Holter+ exercise testing, normalization of biomarkers, normalisation of all but relatively minor ECG changes Recommendations based on myocarditis found in athletes with sudden death Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol . 2005;45(8):1340–1345 Harmon KG, Drezner JA, Maleszewski JJ, et al. Pathogeneses of sudden cardiac death in national collegiate athletic association athletes. Circ Arrhythm Electrophysiol . 2014;7(2):198–204 Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation . 2009;119(8):1085–1092.

25. MEDICAL MANAGEMENT Main treatment: Supportive+ symptomatic care 80% pts: Require ICU admission Diuretics/ ACEI/ ARBs/ B- Blockers ACEI/ ARBs: Decreased myocardial fibrosis, inflammation, autoantibody production Adult study: Lack of B-Blocker therapy—> Greater risk of death/ transplantation Carvidelol: Anti- inflammatory+ antiviral effects (Murine) Metoprolol: Less robust response Kindermann I, Kindermann M, Kandolf R, et al. Predictors of outcome in patients with suspected myocarditis. Circulation . 2008;118(6):639–648

26. Medical management cont… CCBs: Decrease in inflammatory cytokines+ increased survival (Murine)—> Effects on production of NO IMAC-2 Trial: Adults/ 373 pts/ 12 centers/ 2014: > 90% patients received ACEI/ ARBs+ B-Blockers—> 94%: Transplant free survival, 88%: HF hospitalization free survival on 1 year follow up Similar data in kids—> Limited

27. Rhythm issues Digoxin: Not recommended: Evidence of worsening viral myocarditisibn murine models—> Increased mortality+ cytokines Matsumori A, Igata H, Ono K, et al. High doses of digitalis increase the myocardial production of proinflammatory cytokines and worsen myocardial injury in viral myocarditis: a possible mechanism of digitalis toxicity. Jpn Circ J . 1999;63(12):934–940 Amiodarone: Inhibits IL6 production, better survival (Murine) Ito H, Ono K, Nishio R, Sasayama S, Matsumori A. Amiodarone inhibits interleukin 6 production and attenuates myocardial injury induced by viral myocarditis in mice. Cytokine . 2002;17(4):197–202 40 kids with CHB: 27%—> PPI for prolonged HB 67%—> Resolution (Av: 3.3 days) Batra AS, Epstein D, Silka MJ. The clinical course of acquired complete heart block in children with acute myocarditis. Pediatr Cardiol . 2003;24(5):495–497

28. ANTI VIRAL THERAPY Ribavarin+ IFN- alpha: Suppresses coxsackie virusin infected cultured human myocardial cells/ Entero virus: Improvement in function and viral clearance IFN- beta: Entero/ adenovirus—> Elimination of virus+ improvement in LV systolic function at 6 Mts follow up Pleconaril: Prevents binding of coxsackie virus to cell receptor CAR Ganciclovir+ Cidofovir: CMV infected—> Reduction in myocarditis

29. Immuno modulatoRs & suppressors Both inflammatory+ AI mediated cellular damage IVIG: Anti inflammatory+ immunomodulatory effects 2g/ kg IV Significantly improved functions+ dimensions+ survival Steroids,Usually in combination with cyclosporin/ azathioprine: Improvement in inflammation on EMB follow up Some also had recurrence of symptoms after discontinuation of therapy

30. IMMUNOADSORPTION Antibody production+ antibody mediated cell signaling—> Participate in myocardial damage Role of immunoadsorption for antibody removal—> Increased LV EF+NCI on follow up IgG3: Role in complement activation—> Reduction Staudt A, Bohm M, Knebel F, et al. Potential role of autoantibodies belonging to the immunoglobulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy. Circulation . 2002;106(19):2448–2453.

31. GCM+ Eosinophilic myocarditis Use of immunosuppressant therapy well established EM: Reduced exposure to inciting exposure/ toxin+ steroids GCM: Steroids+ cyclosporin/ azathioprine—> Av transplant free survival of 12.3 months compared to only 3 months in untreated patients

32. MECHANICAL CIRCULATORY SUPPORT For refractory heart failure, bridge to recovery/ heart transplant ECMO/ VAD Significant morbidity: Major bleeding: 42-50% Infection: 50-63% Stroke: 29% Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med . 2012;367(6):532–541

33. Survival+ heart transplantation Overall transplant free survival: 88% Transplantation: 4.1%-18% Myocarditis patients have worse post transplant survival compared to other DCMs—> 2.7 x Increased mortality risk Cause of death: Rejection Cause: Persistence of infectious and/ or immune mechanisms

34. TAKE HOME MESSAGE Despite controversies in use of immunosuppression+ anti viral therapy—> Primary therapy remains supportive care Long term outcomes in kids still lacking Late cardiac effects of childhood myocarditis: Still poorly understood

35. THANK YOU Joseph Friedrich Sobernheim