Paediatric Myocarditis and Cardiomyopathy - MSICmsic.org.my/sfnag402ndfbqzxn33084mn90a78aas0s9g/SWK_1200... · Paediatric Myocarditis and Cardiomyopathy ... – In children without

Paediatric Myocarditis and Cardiomyopathy

Chor Yek Kee Sarawak General Hospital

Myocarditis

• Myocardial inflammation – Clinically /Histopathlogically – High mortality and morbidity

– Cardiac failure in structurally normal heart without previous heart disease

Cardiomyopathy

• Heart muscle disorder

• Significant mortality and morbidity.

• The most common cause of

heart failure and ventricular dysfunction in children

• Maybe idiopathic, familial and acquired

General

• Myocarditis ‐‐‐‐ viral infection. • Dilated cardiomyopathy – cardiomyopathy (58%) • Myocarditis ‐‐‐ Dilated cardiomyoathy • Myocarditis ++++ dilated cardiomyopathy

– a spectrum of disease – there is considerable overlap

Myocarditis and Cardiomyopathy

• Congestive heart failure • Sudden death • Heart transplantation

Epidemiology

• Underdiagnosed • Estimated incidence 1 to 10 per 100,000

Sudden cardiac death caused by myocarditis

8.6 ‐ 12 % in young adult 16 to 21 % in children

Mortality rate of myocarditis

75% 25%

?? Undiagnosed

• Non specific presentation especially smaller age group, especially gastro‐intestinal and respiratory symptom.

• Robust physiology in children with their ability to compensate for decrease heart function, making minimal cardiovascular symptoms, diagnosis may not even be suspected until acute collapse or sudden death

March 2013

• 39 patients • 18 patients died (46.2%), • 5 patients (12.8%) brought in death. • 12 patients (30.8%) myocarditis was not the admission diagnosis – 4 out of the patients died.

N=21 53.9%

Can you spot anything ?

Rafflesia

Rafflesia

42 non profit Paediatric Hospital. Total 514 patients from Paediatric Health Information System

Presenting signs and symptoms

Pediatrics 2007 Freedman et al : Paediatric myocarditis: clinical finding and diagnostic evaluation in emergency

department

• Pediatrics 2007 Freedman et al : Paediatric myocarditis: clinical finding and • Diagnostic evaluation in emergency department

Etiologies of myocarditis

Pathogenesis

Endothelial cell infection Endothelial cell dysfunction

Chronic ischemia

• Heinz Peter et al. European Heart Journal 2011



Classification of myocarditis

IBAN

Diagnosis and investigation

Diagnosis

• Rule out other causes of myocardial dysfunction – Structural heart lesion :

• left side outflow tract and anomalous coronary arteries. – Pericardial effusion – Arrythmia :

• SVT, permanent form of junctional reciprocating tacchycardia.

– Systemic hypertension – Inherited metabolic cause

Investigation

• Nasopharyngeal and rectal swab • Viral titer • ECG, CXR • Laboratory investigation • ECHO • Endomyocardial biopsy • Non‐invasive diagnostic modalities

Swabs

ECG abnormalities

• Pediatrics 2007 Freedman et al

Near 100% of them has ECG abnormalities Toronto Sick Kids Emergency Department.

Chest X‐ray changes

ECG and CXR in Asian

Laboratory investigation

• Blood investigation : – Aspartate aminotransferase (AST)

• Elevated in 85% of definite and probable case

– Myocardial Muscle creatinine kinase isoenzyme (CKMB)

– ESR/CRP • Elevated in 27‐56%


Troponin

Complex 3 regulatory protein integral actin and tropomyosin

Troponin

Qualitative spot test Quantitative assay

Cardiac Troponin T

• Troponin detect myocardial necrosis • Normal cardiac Troponin I : Less than 0.01 ncg/mL • Normal cardiac Troponin T : 0.001 to 0.01 ncg/mL

– Cardiac Troponin T • >0.026ng/mL has a sensitivity 75%, specificity 75% • > 0.052ng/ml has a sensitivity 71%, specificity 86% • >0.071ng/ml has a sensitivity 63%, specificity 89%

» Soongswang et al Paed cardiol 2005:26:45‐49

– In children without preexisting heart disease, a cTnT level of less than 0.01 ng/mL can be used to exclude myocarditis

• Cardiac troponin T as a screening test for myocarditis in children. • Pediatr Emerg Care. 2012; 28(11):1173‐8 (ISSN: 1535‐1815)

Echocardiography

• Exclude other cause and identify ventricular thrombi.

• No specific echocardiographic feature of myocarditis

• 98% abnormal ECHO – Segmental wall motion abnormalities

• Hypokinesia, akinesia, dyskinesia

• Right ventricular dysfunction is uncommon but important predictor of death and cardiac transplant


Cardiovascular magnetic resonance (CMR)

– Detect subtle patchy myocardial involvement – Localize and quantify tissue injury including edema, hyperaemia and fibrosis

– Monitor the lesion – LGE : Late Gadolinium Enhancement

• Gadolinium penetrate those cell that lost their cell membrane integrity and allow diffusion of the contrast agent into the intracellular space.

• Detect necrosis and fibrosis – First past enhancement and delayed enhancement images

Lake Louise Consesus Criteria

• International consensus group on CMR diagnosis of myocarditis . JACC (Journal of American College of Cardiology ) white paper :2009

• At least 2 or more criteria are positive then diagnostic accuracy of 78% – Regional or global myocardial signal increase in T2 weighted image – Increased global myocardial early gadolinium enhancement ration

between myocardium and skeletal muscle in gadolinium enhanced T1 weighted images

– At least one focal lesion with nonischemic regional distribution in inversion recovery prepared gadolinium enhanced T1 weighted images (late gadolinium enhancement)

Total 82 adult patient Chest pain with positive Trop.T

CMR in paediatric • Paediatric MRI myocarditis characterised by

– subepicardial enhancement – transmural enhancement.

• Vashist S et al Current Treatment Options Cardiovascular Med

2009:11:383‐391

Dallas criteria

• Golden standard of histological classification via endomyocardial biopsy (EMB) – Identification of lymphocyte invasion of cardiac tissue

– Detection of virus by PCR

Dallas criteria

• General definition – Myocardial cell injury with degeneration or necrosis with

inflammatory infiltrate not caused by ischemia • Active myocarditis

– Both myocyte degeneration or necrosis and definite cellular infiltrate ( usually lymphocytes) with or without fibrosis

• Borderline myocarditis – Definite cellular infiltrate without myocyte injury

• Persistent myocarditis – Continued active myocarditis on repeat myocardial biopsy

• Resolving/resolved myocarditis ; – Deminished or absent infiltrate with evidence of connective tissue

healing

Endomyocardial biopsy

• Gold standard – Diagnostic 11% – Helpful 71% – No help 16%

• Schmaltz et al Paed cardio 1990

• Concurrent PCR and in‐situ hybridization – viral genetic material

Disadvantage of EMB

• Invasive and potential dangerous – Pneumothorax, hemothorax, dysrhythmia, heart block, perforation, death.

• Insensitive –patchy inflammation • Perform with strong indication

– Patient of mechanical support – Heart failure did not improve after 15 days

TREATMENT

BIDAYUH

Treatment

• Supportive • Inotropes • Afterload reduction • Mechanical ventilation • Immunotherapies • Extracorporeal membrane oxygenation (ECMO)

Supportive treatment

• Inotropic support – Beta‐agonist : Dobutamine – Phosphodiesterase inhibitor : Milrinone

• PRIMACORP trial (Prophylasis Intravenous Milrinone After Cardiac Operation in Paediatric )

– Low dose adrenaline • More severe cardiogenic shock

– More alpha adrenergic agent; • Dopamine • High dose Adrenaline

Levosimendan

• Calcium sensitizer – increase cardiac contractility

• Open ATP sensitive K channel on smooth muscle – vasodilatation

• LIDO trial : – higher cardiac output and better survival in Levosimendan group as

compare to Dobutamine.

• Namachivayam et al Paed Critical Care 2006: – 15 patient with end stage and acute heart failure, 2 patient with acute

myocarditis – Use of Levosemendan associated with weaning of Dobutamine and better

ejection fraction.

Supportive treatment • Diuretic :

– decrease pulmonary edema and total body water e.g. Frusemide and spironolactone

• ACEIs – Start as soon as renal function is safe and stable, – e.g. Captopril and Enalapril

• Beta‐blocker – Start after stable post cessation of inotropic agent. – Carvedilol ,Metoprolol

• Angiotensinreceptors antagonist – Alternative for patient not tolerate side effect of ACEIs due to kinin i.e.

cough and angioedema – Losartan, Valsartan and Candesartan


• Digoxin – Controversial , Pro‐arrhythmic in the inflamed myocardium.


• Ventilation – Reduced work of breathing – Improve gas exchange – Lessen pulmonary edema – Reduced after‐load on the left ventricle

Immunotherapies

Adjuvant therapeutic intervention Immunotherapies

• Aim – To prevent long term cardiac compromise

• Immunoglobulin • Immunosupressive therapy • Cytokines clearance

Endothelial cell infection Endothelial cell dysfunction

Chronic ischemia

Immunoglobulin

• Autoimmune response responsible for the majority of myocardial damage

• Immunoglobulin – Enhance viral clearance by neutralizing antibodies to the virus

– Reduce inflammatory response triggered by pro‐inflammatory cytokine release

• Circulation 1994, first data • Boston Children Hospital and Los Angeles Children Hospital. • Between 1985 to 1991 • High dose IVIG 2g/Kg over 24 hours • Total 21 patients acute viral myocarditis • 12 months survival (84%vs 60%, p=0.07) not statistically

significant • Left ventricular shortening (p=0.03) • Improve LVEF and better survival after 1 year

Immunoglobulin English et al (Cardiol young 2004) • Retrospective case series

review of 41 children with acute myocarditis

– 1 IVIG – 18 IVIG + Immunosuppressive – 16 no immune therapy

• No different in term out outcome in myocardial function/death/need of transplant

KlugmanD et al 2009 Paediatric cardiology • Multicenter study that

looked at outcome of paediatric patient with myocarditis ,.

• IVIG did not impart a survival advantage.

Adult study in IVIG

• McNamara et al prospective RCT • Circulation 2001

– 62 adult/young adult – IVIG 2g/Kg or placebo – Both treatment group and placebo showed improvement in LVEF

– showed IVIG failed to demonstrate improved survival and LV function

• Intravenous immunoglobulin for presumed viral myocarditis in children and adults

• Robinson J, Hartling L, Vandermeer B, Klassen TP • January 20, 2010

Only one randomized controlled trial (RCT) 62 adults with acute myocarditis no treatment benefit among patients receiving IVIG.

McNamara et al prospective RCT Circulation 2001

Immunosuppressive therapy

• Immunosuppresive therapies – Suppress cell mediated inflammatory reaction within myocardium during subacute phase

– Reduce inflammatory response in chronic myocarditis

– ???suppressing immune responses to an acute viral illness??

– Inhibiting cell mediated immunity and the production of antiviral neutralizing antibodies, viral clearance may be delayed

Immunosuppressive therapies

• Camargo et. al Paediatric Cardiol 1995 – RCT, biopsy proven acute viral myocarditis with immunosuppresive therapy

– 43 paediatric patient ( median age 2.9 years ) – Randomised

• Controlled n=9 • Prednisolone n=12 • Prednisolone + azathioprine n=16 • Prednisolone + Azathioprine + Cyclosporine n=16

– Treatment approximately 8 months after diagnosis – Combination lead to improvement of cardiac outcome –left ventricular function, hemodynamitc and clinical course

Immunosuppressive therapies • Klinert et al (Journal Heart Lung Transplantation 1997)

– Prospective, non‐controlled – 29 paediatric patients with dilated cardiomyopathy – Myocardial biopsy within 72 hours

• Group 1 :Histologic acute viral myocarditis n=9 • Group 2 :Borderline acute viral myocarditis n=2 • Group 3 : Inconclusive histologic finding n=18

– Group 1 treated with Methyprednisolone and Cyclosporine, the rest non.

– All treatment arm have improved left ventricular function – Only 4 out of all patient in group2 and group 3 have improved LVF


The Myocarditis Treatment Trial : • A clinical trial of immunosuppressive therapy in myocarditis. N Eng J Med 1995.

– 111 adults – Histopathology acute viral myocarditis and cardiomyopathy – Randomised to receive conventional or conventional + Prednisolone or Azathioprine for 24

weeks

– No appreciable difference in the recovery of left ventricular ejection fraction between the groups

– No difference in survival


• Frustaci et al (circulation 2003) – 112 adult patients histological proven acute viral myocarditis

– 41 patients put on combination prednisolone and azathioprine because progressive deterioration on conventional therapy

– 21 demonstarted improvement on LVEF and histological

– 90% responder have cardiac autoantibodies, none for the non‐responder

– 17 out of 21 non‐responder demonstrated a viral genome by PCR vs 3 of the responder

Immunoadsorption

• Lower cardiotoxic antibodies, extract antibodies and immune complexes from heart

• Intervention Review

– Corticosteroids for viral myocarditis • Huai‐Sheng Chen1,*, Min Yang2, Jianping Liu3

• Published Online: 21 JAN 2009

• There is no randomised evidence to support the use of corticosteroids for viral myocarditis. Further clinical trials are needed.

• JID 2012:206 (15 September )

• 30 chemokines and cytokines from serum CSF and serum

• Interleukin 1B as pro-inflammatory – Negative inotropic response – Stimulate cardiomyocytes apoptosis

• Interleukin-1Ra and Gcsf as anti-inflammatory and cardiac protective – May potential restorative host responses to minimize

inflammation and tissue damage during EV71 infection

© 2008, Gambro 81

Molecular Weights

“Small”

“Middle”

“Large”

3 category of solutes for removal in CRRT.

Septic Mediators Interleukins TNF

Convection Diffusion

EV71 (HFMD) outbreak 2011, National Hospital of Paediatric, Hanoi, Northen Vietnam

106508 patient, 162 death 36 months old girl with acute cardio‐respiratory shock was put on CVVH for 48 hours Improved heart function after 72 hours EF 37 to 58%, FS 19 to 29% Waiting from Ho Chin Min City, Southern Vietnam result.

Mechanical circulatory support


• Type of support – ECMO, – Centrifugal non‐pulsatile VADs and – Pulsatile paracorporeal VADs

• Bridging to heart transplanation • Class III evidence that most patient will have recovery of cardiac function even in those with cardiac arrest

• Recovery of heart function can be seen even after more than 10 days ( the longest was 68 days in a 12 years old child Davies et al Journal Heart transplant 2002:21:1246‐1249


• Overall survival from ECMO 44% – ELSO (Extracorporeal Life support Organisation.) >3500 patients.

• Outcome remarkably good for myocarditis • Myocarditis as primary diagnosis ‐‐Discharged home 60% – ( ELSO, extracorporeal Life Support Organisation, registry 208 patient )

Temporal trends in medications, care requirements, and outcomes in pediatric myocarditis.

• Total 514 patients – 413 (80.4%) admitted ICU – 228 (44.4%) mechanical ventilated – 97 (18.9%) ECMO – 22 (4.2%) VAD – 15 (2.9%) Both ECMO and VAD

Ghelani S J et al. Circ Cardiovasc Qual Outcomes 2012;5:622-627


• Total 514 patients – 104 patients (20.2%) ECMO /VAD

• 17 (16.3%) : heart transplant • 25 (24%) : Died • 62 (59.6%) : Recovery myocardial function.

– Total death 37 (7.2%) – 21 (4.1%) received heart transplantation




Copyright © American Heart Association

OUTCOME

ORANG ULU

Outcome

• Incidence 1 per 100,000 – The true unknown due to significant number of cases go undiagnosed

– Hence, outcome difficult to characterize • According to Greenwood et al

– 30 year study of outcome of 161 children with primary myocardial disease ( myocarditis, non‐obstructive cardiomyopathy and endomyocardial fibroelastosis)

– Nearly a third had full recovery, a third died and a third had cardiac compromised

Outcome

• Patient survive beyond 72 hours without the need of ECMO had 97% increased likelihood of survival. Lee et al Heart 1999

• Ejection fraction <30%, Shortening fraction <15%, moderate to severe mitral regurgitation were all associated with ultimate development of severe cardiac failure.

Acute fulminant myocarditis

• Patients with had more clearly defined course – Abrupt onset cardiovascular collapse – Aggressive intensive care management – Favorable long term outcome

Thanks for your attention

Cardiomyopathy

• Heart muscle disorder associate with significant mortality and morbidity.

• The most common cause of heart failure and ventricular dysfunction in children

• Maybe idiopathic, familial and acquired

• WHO and Inetrnational Society and Federation of Cardiology task force: 5 forms based on phenotype. 1. Dilated cardiomyopathy (DCM) 51 – 58% 2. Hypertrophy cardiomyopathy(HCM) 25 – 42% 3. Restrictive cardiomyopathy (RCM) 4. Arrhythmogenic right ventricualr dysplasia

(ARVD) 5. Left ventricular non‐compaction (LVNC)

Dilated cardiomyopathy

• ventricular dilation, impaired systolic contractile function, mitral regurgitation, and ventricular arrhythmias in the absence of coronary artery disease, valvular abnormalities, and pericardial disease.

Hypertrophy cardiomyopathy

• LV hypertrophy, a nondilated LV cavity, systolic hypercontractility, diastolic dysfunction, and, in ~20% of cases, obstruction to LV outflow (hypertrophic obstructive cardiomyopathy) secondary to mitral‐septal contact during systole.

• most common genetic cardiovascular disease and is the most common cause of SCD in young healthy subjects, particularly athletes.

Restrictive cardiomyopathy

• restrictive filling and reduced diastolic volume of either or both ventricles, with normal or near‐normal systolic function and wall thicknesses. The prognosis in children with RCM is poor. Half of the children die within 2 years of diagnosis. In RCM, heart failure‐related deaths are the most common

Arrythmogenic Ricght Ventricular Cardiomyopathy (ARVC)

• characterized by fatty‐fibrous replacement of the RV. This gradual process of replacement of normal myocardium with fatty and fibrous tissue predisposes patients to RV dysfunction and life‐threatening ventricular arrhythmias.

Left Ventricular Non‐compaction

• characterized by deep trabeculations in the LV endocardium. These trabeculations are seen particularly in the apex and free wall. Typically, apical hypertrophy with variable systolic dysfunction is also seen.

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