Case 1

 17-year-old girl with a PMHx significant only for asthma presented with a chief complaint of fatigue. Her mother noticed she had been having unintentional weight loss of 10 pounds over 2 weeks and brought her to a doctor who diagnosed her with (asymptomatic) UTI and treated her with Bactrim. After 1 week, she represents with fever, abdominal pain, nausea and vomiting.

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Case 1

 A CT of the abdomen and pelvis showed no abnormalities and she is discharged with Keflex for pyelonephritis.

 She returns in 24 hours hypotensive with the following ECG.

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Case 1 :

Troponin 13 3

Case 1

 On arrival to VCU she is hypotensive with a SBP in the 60-80s despite 4L IVF  Dobutamine 5mcg/kg/min is running  HR 140s  Lactate 7.2

 Troponin >50 4

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Acute and fulminant VIRAL Myocarditis

Frances Canet, MD Cath Conference August 18, 2011 7

Outline

 Definition  Incidence  Clinical presentation  Etiologies  Pathogenesis  Diagnostics  Treatment  Prognosis 8

Definition of mycocarditis

 Inflammation of the heart muscle secondary to injury  Ischemic damage  Mechanical trauma  Genetic cardiomyopathies  Exposure to discrete external antigens ○ Viruses , bacteria, parasites, toxins drugs  Internal triggers ○ Autoimmune activation against self antigens 9

Dallas criteria



Active myocarditis:

the presence of an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary artery disease (CAD).



Borderline myocarditis:

the presence of an inflammatory infiltrate of the myocardium without necrosis or degeneration of adjacent myocytes. 10

Incidence

 Difficult to ascertain, depends on criteria used  Estimated 8 to 10 per 100,000  Unselected autopsy series as high as 1 to 4 per 100  Young adults with sudden cardiac death, estimated 8.6%  Idiopathic dilated cardiomyopathy patients only  10-40% are secondary to myocarditis 11

Population

 Bimodal age distribution  Young children and teenagers: acute presentation  Exuberant response to initial exposure of antigen  Older adults: Subtle and insidious symptoms of dilated cardiomyopathy and heart failure  Mature immune system with greater tolerance 12

Clinical presentation

 Wide-ranging clinical presentation contributes to difficult diagnosis and classification  Asymptomatic ECG or echocardiographic abnormalities  Cardiac dysfunction, arrhythmias, heart failure and hemodynamic collapse 13

Acute Myocarditis Presentation

 Fatigue 82%  Dyspnea on exertion 81%  Arrhythmias 55%  Palpitations 49%  Chest pain at rest 26% 14

Acute Myocarditis Presentation

 Acute ischemic syndrome type symptoms  Elevated troponin  ST-segment elevation on ECG  Segmental wall motion abnormalities on echocardiography  Viral prodrome symptoms 20-80%  Fever  Chills  Myalgias  Constitutional symptoms 15

Fulminant Myocarditis Presentation

 Abrupt onset within 2 weeks of a viral illness  Hemodynamic compromise  Hypotension requiring pressors and mechanical support  Echocardiogram reveals diffuse global hypofunction  Thickening of the ventricular wall probably due to myocardial edema from myocardial inflammation and cytokine release 16

Case 1

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Endomyocardial biopsy in fulminant myocarditis

 Typical and diffuse myocarditis in each histologic section 18

Infectious Etiologies

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Non-infectious Etiologies

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Pathogenesis of viral myocarditis caused by coxsackievirus

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Pathogenesis

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Pathogenesis

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Diagnostics: Expanded Criteria for Diagnosis of Myocarditis

 Category I: Clinical Symptoms  Clinical heart failure  Fever  Viral prodrome  Fatigue  Dyspnea on exertion  Chest pain  Palpitations  Pre-syncope or syncope 24

Category II: Evidence of Cardiac Structural or Functional Perturbation in the absence of Regional Coronary Ischemia  Echocardiography evidence    Regional wall motion abnormalities Cardiac dilation Regional cardiac hypertrophy    Troponin release  High sensitivity (>0.1 ng/mL) Positive indium In 111 antimyosin scintigraphy and Normal coronary angiography or  Absence of reversible ischemia by coronary distribution on perfusion scan 25

Category III: Cardiac Magnetic Resonance Imaging

 Increased myocardial T2 signal on inversion recovery sequence  Delayed contrast enhancement after gadolinium-DTPA infusion 26

Category IV: Myocardial biopsy – Pathologic or Molecular Analysis

 Pathology findings compatible with Dallas criteria  Presence of viral genome of polymerase chain reaction or in situ hybridization  80-100% specificity when performed from myocardial biopsy 27

Enzyme biomarkers

 Elevated secondary to myocardial damage from inflammatory cell infiltrates, cytokine activation and virus- mediated cell death  More useful when high sensitivity thresholds are used  Troponin T threshold of >0.1mg/mL increases sensitivity from 34% to 53% 28

ECG Findings

 T wave inversions  ST-segment elevation  Bundle branch block  Supraventricular arrhythmias  Ventricular arrhythmias  47% sensitivity, indeterminate/poor specificity 29

Echocardiography

     Regional ventricular dysfunction Ventricular remodeling    Chamber dilation Regional hypertrophy Regional wall motion abnormalities May not be able to distinguish from myocardial ischemia or infarction Useful as follow-up to monitor natural history and response to treatment Helps distinguish fulminant from acute myocarditis 30

Cardiac MRI

 Characterizes tissue according to water content and changes in contrast kinetics (T2 imaging)  Can detect local patchy nature of myocarditic lesions  Extracellular contrast agents such as gadolinium-DTPA distribute and clear differently in inflamed or scarred tissue compared to normal tissue (T1 imaging) 31

Cardiac MRI

 T2 weighted imaging has a sensitivity of 84% and specificity of 74% based on biopsy or natural history evidence of myocarditis  Delayed enhancement increases diagnostic accuracy to 90%  Deposition of collagen bundles in healing binds gadolinium and decreases its clearance 32

Cardiac MRI

 Helpful in guiding biopsy  CMR suggests the lateral wall is a common location for lesion development (not the septum) 33

Case 2

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Case 2

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Case 3

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Case 3

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Case 4

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Role of CMR in myocarditis 2009

 Indications for CMR include  New-onset or persisting symptoms suggestive of myocarditis  Evidence of recent or ongoing myocardial injury or dysfunction  Suspected viral or non-ischemic etiology 39

Criteria for myocarditis

 At least 2 of the following indicators of inflammation  Regional or global myocardial signaling intensity increase in T2-weighted images  Increased global myocardial early gadolinium enhancement between myocardium and skeletal muscle in gadolinium-enhanced T1 weighted images  At least one focal lesion with non-ischemic regional distribution in inversion recovery prepared gadolinium-enhanced T1-weighted images 40

Myocardial Biopsy

 The Dallas criteria are the gold standard for diagnosis, however there are many reasons for insensitivity  Patchy nature of disease  Of postmortem hearts of patients with known myocarditis, only 25% of single endomyocardial biopsies showed myocarditis  66% if 5 biopsies were taken  Most inflammation is in the lateral wall 41

The Role of Endomyocardial Biopsy

 AHA/ACC/European Society of Cardiology released a scientific statement in 2007 with 14 clinical scenarios  Only the first 2 scenarios are class 1 recommendations with B level of evidence 42

Clinical Scenarios for Biopsy

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New-onset heart failure of <2 weeks duration associated with a normal sized or dilated left ventricle and hemodynamic compromise 2.

New-onset heart failure of 2 weeks to 3 months duration associated with a dilated left ventricle and new ventricular arrhythmias, second- or third-degree heart block, or failure to responds to usual care with 1-2 weeks 43

Risks of endomyocardial biopsy

 Complications occur in 2-5% of patients with a dilated cardiomyopathy  Half of these are related to venous access  Arterial puncture  Pneumothorax  Vasovagal reaction  Bleeding after sheath removal 44

Risks of endomyocardial biopsy

 Related to the biopsy itself  Arrhythmias  Cardiac conduction abnormalities  Cardiac perforation ○ Pericardial tamponade  Death 45

Molecular evaluation of biopsy

 Combined with Dallas criteria, improves sensitivity of the biopsy as a diagnostic tool  Detect viral myocarditis  Delineate potential viral etiology  In-situ hybridization, PCR  PCR is limited by requirement of the viral pathogen must be declared in advance  Helps with prognosis and to guide therapy 46

Treatments/Therapeutic Approaches

 Supportive Therapy  Immunosuppression  Interferon  Intravenous Immune Globulin  Immune Adsorption Therapy  Hemodynamic Support  Vaccination 47

Supportive Therapy

 First-line therapy  Only a small proportion of patient require hemodynamic support  Treat this group same as for clinical heart failure  Diuretics  IV Vasodilators: Nitroglycerin, Nesiritide  ACEi, ARBs, B-blockers when stable ○ Anti-inflammatory properties 48

Immunosuppression

 Unproven hypothesis  No shortage of short trials, limited by  High degree of spontaneous improvement in the control and treatment arms  Small sample size with heterogenous population  Patchy nature of myocardial biopsy  Lack of relationship between pathologic abnormalities and clinical prognosis 49

NIH-sponsored Myocardial Treatment Trial

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Interferon

 Type 1 interferons (IFN of viral RNA   and IFN host innate immune system   phosphorylate interferon-stimulated genes in the degradation of foreign viral RNA and interfere with accumulation  2003, Kuhl et. Al. evaluated 22 patients with dilated cardiomyopathy and biopsy evidence of viral persistence  24 weeks of IFN   Eliminated the viral genome in all 22 patients  LVEF improved from 44.6% to 53.1% in 15 of 22 patients.  NYHA class also improved 51

Intravenous Immune Globulin

 Passive immunization with IVIG  2001 Controlled trial of IVIG in recent onset dilated cardiomyopathy, McNamara et. Al.

 62 patients  IVIG or Placebo  LVEF improved 25 to 41% at 6 months  LVEF improved to 42% at 12 months  Same improvement seen in both IVIG and Placebo group 52

Intravenous Immune Globulin

 No primary indication except:  Pediatric population  Patients refractory to immunosuppressive therapy  Need to obtain viral studies prior to administering 53

Immune Adsorption Therapy

 Plasmapheresis of peripheral blood  Cytokines, circulating antibodies may target specific components of the myocyte under stress  Beta-adrenergic receptor  ATP carrier  Myosin molecule  Leads to cell dysfunction and cell death 54

2001 Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution, Staudt at. al  34 patients, randomized  Standard therapy or immune adsorption therapy aimed at removal of antibodies against the beta-adrenergic receptor  After 1 year, treatment group LVEF improved from a mean of 22 to 38%.

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Hemodynamic Support

 Patients with fulminant myocarditis and cardiogenic shock may require  Intra-aortic balloon pump  Ventricular assist devices  Extracoporeal membrane oxygenation (ECMO) 56

Vaccination

 Targeted vaccination in the future  Patients genetically susceptible to myocarditis  After the mumps vaccination  Disappearance of endocardial fibroelastosis causing dilated cardiomyopathy 57

Prognosis

    Most patients with acute myocarditis and mild cardiac involvement recover without long-term sequelae Patient with advance cardiac dysfunction, varied outlook Patients with severe hemodynamic collapse at presentation actually have a good prognosis  93% transplant-free survival in 11 years 30% of those with chronic myocarditis may recover 58

Prognosis

     Several studies have looked at clinical variables that predict adverse outcomes (death and transplantation) Syncope Bundle branch block EF <40%    Other factors    NYHA Class III or IV PCWP <15mmHg Immunopathologic evidence of myocardial inflammation Failure to use B-blockers BiV failure Giant cell or viral genome on biopsy 59

Other poor prognostic signs

 Dilated cardiomyopathy with positive enteroviral genome  Viral genome persistence on myocardial biopsy  Excessive apoptosis  Myocardial expression of Fas ligand or tumor necrosis factor receptor 1 showed minimal recovery 60

Good prognosis

 Echo evidence of small left atrial and LV size was predictive of recovery in one small study 61

Summary

 Myocarditis is a model study of host injury and repair  Diagnosis was classically dependent on Dallas criteria  Newer modalities of testing such as cardiac MRI and PCR will help pinpoint diagnosis thus facilitating treatment and prognosis 62

Summary

 Understanding the pathophysiologic mechanisms of infection and injury has led to new treatments.

 Interferon and immune-modifying agents as well as advanced modes of hemodynamic support will offer patients the best chances of full recovery. 63