Young Soldier Young Soldier With A Failing With A Failing

HeartHeartManju Goyal, M.D.Manju Goyal, M.D.

Walter Reed Army Medical Walter Reed Army Medical CenterCenter

April 2008April 2008

CaseCase

HPI: HPI: 20 year-old male with cough, 20 year-old male with cough, shortness of breath, intermittent chest shortness of breath, intermittent chest pressure and palpitations x 4 dayspressure and palpitations x 4 days

PMhx/PSHx/Shx/Fhx/Meds: PMhx/PSHx/Shx/Fhx/Meds: negativenegative

EXAM: EXAM: Vitals: Vitals: 145, 90/58, 145, 90/58, 95% ra, afebrile95% ra, afebrileCardiovascular: Cardiovascular: tachycardic, systolic tachycardic, systolic

murmur murmur best heard at the apex, no JVDbest heard at the apex, no JVDLungs: CTABLungs: CTABExtremities: no edemaExtremities: no edema

CaseCase

LABS:LABS:CBC - nmlCBC - nml

BMP - nmlBMP - nml

D-dimer - nmlD-dimer - nml

BNP - 397BNP - 397

LFTs - 88/136LFTs - 88/136

Cardiac enzymes - 115/2.2/<0.01Cardiac enzymes - 115/2.2/<0.01

CaseCase

EKGEKG – – sinus tachycardia at 131, sinus tachycardia at 131, inferolateral TWI inferolateral TWI

CXRCXR – – AP film with just an enlarged AP film with just an enlarged cardiac silhouettecardiac silhouette

Young patient in SHOCK with concerning cardiac exam and EKG

CaseCase

ECHO: ECHO: - Severely dilated left ventricleSeverely dilated left ventricle but normal wall but normal wall

thicknessthickness- No LV thrombus No LV thrombus - EF in the 10-15% rangeEF in the 10-15% range- Severe global hypokinesis, with mild Severe global hypokinesis, with mild

posterior wall contractility.posterior wall contractility.- Moderate to severe MRModerate to severe MR due to annular due to annular

dilatationdilatation

New onset of Dilated Cardiomyopathy (DCM)

Dilated CardiomyopathyDilated Cardiomyopathy

www.uptodate.com

Review of 1230 Patients Review of 1230 Patients with DCMwith DCM

Idiopathic — 50 percent Idiopathic — 50 percent Myocarditis — 9 percent Myocarditis — 9 percent Ischemic heart disease — 7 percent Ischemic heart disease — 7 percent Infiltrative disease — 5 percent Infiltrative disease — 5 percent Peripartum cardiomyopathy — 4 percent Peripartum cardiomyopathy — 4 percent Hypertension — 4 percent Hypertension — 4 percent HIV infection — 4 percent HIV infection — 4 percent Connective tissue disease — 3 percent Connective tissue disease — 3 percent Substance abuse — 3 percent Substance abuse — 3 percent Doxorubicin — 1 percent Doxorubicin — 1 percent Other — 10 percent Other — 10 percent

NEJM 2000

Importance of EtiologyImportance of Etiology

NEJM 2000

Additional TestsAdditional Tests

LABS:LABS:ESR - 33ESR - 33Ferritin - nmlFerritin - nmlTSH - nmlTSH - nmlACE level - nmlACE level - nmlRF - nmlRF - nmlANA - negativeANA - negativeLyme titers - Lyme titers -

negativenegativeHIV - negativeHIV - negative

Cardiac CATH:Cardiac CATH:Normal CoronariesNormal Coronaries

What’s the differential?Any further tests?

Review of 1230 Patients Review of 1230 Patients with DCMwith DCM

Idiopathic — 50 percent Idiopathic — 50 percent Myocarditis — 9 percent Myocarditis — 9 percent Ischemic heart disease — 7 percent Ischemic heart disease — 7 percent Infiltrative disease — 5 percent Infiltrative disease — 5 percent Peripartum cardiomyopathy — 4 percent Peripartum cardiomyopathy — 4 percent Hypertension — 4 percent Hypertension — 4 percent HIV infection — 4 percent HIV infection — 4 percent Connective tissue disease — 3 percent Connective tissue disease — 3 percent Substance abuse — 3 percent Substance abuse — 3 percent Doxorubicin — 1 percent Doxorubicin — 1 percent Other — 10 percent Other — 10 percent

NEJM 2000

Endomyocardial

Biopsy

Biopsy ResultsBiopsy Results

Dr. Brendan GrahamDr. Brendan Graham

Dept. of PathologyDept. of Pathology

Normal MyocardiumNormal Myocardium

Biopsy – 4xBiopsy – 4x

Biopsy – 20xBiopsy – 20x

Biopsy – 40xBiopsy – 40x

Case of Viral MyocarditisCase of Viral Myocarditis

Other infectious etiologies ruled out Other infectious etiologies ruled out by special stains/culturesby special stains/cultures

Dallas Criteria:Dallas Criteria: Lymphocytic infiltratesLymphocytic infiltrates of varying of varying

severityseverity Myocyte necrosisMyocyte necrosis and cytoskeletal and cytoskeletal

disorganizationdisorganization Interstitial fibrosis seen with Interstitial fibrosis seen with

subacute/chronic casessubacute/chronic cases

Objectives: MyocarditisObjectives: Myocarditis

Review etiology and pathophysiologyReview etiology and pathophysiology Clinical ManifestationsClinical Manifestations Role of different diagnostic modalitiesRole of different diagnostic modalities TherapyTherapy

1.1. Cardiovascular support for an unstable Cardiovascular support for an unstable patient (i.e. indications for VAD, ECMO)patient (i.e. indications for VAD, ECMO)

2.2. Role of immunosuppressive/modulating Role of immunosuppressive/modulating therapiestherapies

PrognosisPrognosis

Myocarditis

Definition: Non-ischemic myocardial

inflammation resulting from a variety of infectious, immune and toxic insults.

EpidemiologyEpidemiology

Precise incidence and prevalence unknownPrecise incidence and prevalence unknown Lack of a Lack of a non-invasivenon-invasive “gold standard” “gold standard”

test for diagnosistest for diagnosis Not every suspected myocarditis case gets a Not every suspected myocarditis case gets a

biopsybiopsy Biopsy itself has low sensitivityBiopsy itself has low sensitivity

Present in 1-9% of routine postmortem Present in 1-9% of routine postmortem examinationsexaminations11

Accounted for 20% of sudden cardiac Accounted for 20% of sudden cardiac deaths in military recruitsdeaths in military recruits22

1. Circulation 1976

2. Ann Intern Med 2004

EtiologyEtiology

InfectiousInfectious VIRUSESVIRUSES (adeno, (adeno,

coxsackie)coxsackie) BacterialBacterial FungalFungal Protozoal (Chagas Protozoal (Chagas

disease)disease) HelminthsHelminths

Non-infectiousNon-infectious Toxins/Drugs Toxins/Drugs

(alcohol, (alcohol, anthracyclines)anthracyclines)

Systemic disorders Systemic disorders (sarcoid, lupus, (sarcoid, lupus, scleroderma)scleroderma)

Etiology

EtiologyEtiology

Braunwald 2007

Pathophysiology of Viral Pathophysiology of Viral MyocarditisMyocarditis

Braunwald 2007

Viral PhaseViral Phase

Virus enters (GI/Lungs)Virus enters (GI/Lungs)

Activates Activates proteasesproteases damages cytoskeletan damages cytoskeletan

Activates Activates tyrosine kinasestyrosine kinases immune system immune system turns ONturns ON

Replicates and persistsReplicates and persists chronic chronic inflammation/fibrosis/DCMinflammation/fibrosis/DCM

Braunwald 2007

Immune ResponseImmune Response

Braunwald 2007

Autoimmune response: auto-antibodies to myosin and other cardiac proteins

Overexpression of cytokines (IL-2, INF-γ, TNF-α)

PathophysiologyPathophysiology

Clinical PresentationClinical PresentationAcuteAcute FulminantFulminant ChronicChronic

Nonspecific Nonspecific cardiac cardiac symptomssymptoms

Heart failure, Heart failure, Acute MI, or SCDAcute MI, or SCD

More common More common in in children/teenagerchildren/teenagers s

+/- viral +/- viral prodromeprodrome

Cardiogenic Cardiogenic shock +/- acute shock +/- acute heart failure heart failure

Biopsy doesn’t Biopsy doesn’t match the clinical match the clinical severity. severity.

High levels of High levels of cytokines cytokines reversiblereversible cardiac cardiac depression depression better prognosisbetter prognosis

Subtle, Subtle, insidious onsetinsidious onset

Already have Already have DCM DCM HF HF symptomssymptoms

Biopsy with Biopsy with fibrosis usuallyfibrosis usually

DiagnosisDiagnosis

Symptoms:Symptoms: non-specificnon-specific

Laboratory Testing: Laboratory Testing: also non-specificalso non-specific Positive cardiac biomarkersPositive cardiac biomarkers ECG: T wave inversion, ST segment elevation, ECG: T wave inversion, ST segment elevation,

bundle branch blocksbundle branch blocks

ECHOECHO Differentiate fulminant from acute myocarditisDifferentiate fulminant from acute myocarditis Detect thrombi, valvular abnormalities, and Detect thrombi, valvular abnormalities, and

pericardial involvementpericardial involvement Rule out other cardiomyopathies (HOCM, Rule out other cardiomyopathies (HOCM,

Takotsubo)Takotsubo)

Diagnosis: Cardiac MRIDiagnosis: Cardiac MRI

WITH ContrastWITHOUT Contrast

Non-invasiveNon-invasive

Visualize entire Visualize entire myocardiummyocardium

Use to guide biopsyUse to guide biopsy

Follow disease Follow disease course and response course and response to therapyto therapy

Eur Heart J 1994

LVRV

RV

LV

Diagnosis: Coronary Diagnosis: Coronary AngiographyAngiography

Rule out other congenital, rheumatic, or Rule out other congenital, rheumatic, or ischemic heart disease ischemic heart disease

Determine need for inotropic or Determine need for inotropic or mechanical support based on mechanical support based on hemodynamic parametershemodynamic parameters

Elevated pulmonary artery pressures are Elevated pulmonary artery pressures are independent predictors of mortalityindependent predictors of mortality

Diagnosis: Diagnosis: Endomyocardial BiopsyEndomyocardial Biopsy

Although controversial, still the Although controversial, still the current current gold-standard testgold-standard test for diagnosis for diagnosis

1-6% complication rate1-6% complication rate Consider when suspicious for:Consider when suspicious for:

Giant cell myocarditisGiant cell myocarditis Hypersensitivity/eosinophilic myocarditis Hypersensitivity/eosinophilic myocarditis Cardiac involvement in a systemic diseaseCardiac involvement in a systemic disease

All other patients, All other patients, consider only if pt is consider only if pt is deterioratingdeteriorating

When to consider biopsy?When to consider biopsy?

Mayo Clin Proc 2001

Circulation 2007

TreatmentTreatment

Dr. Barnett GibbsDr. Barnett Gibbs

Dept. of CardiologyDept. of Cardiology

Treatment

Treatment

Treatment

ABC’s Circulation:

Intra-aortic balloon pump counterpulsation Ventricular assist device Cardiopulmonary assist device

Intra-aortic balloon pump

Electrocardiographic synchronized phased pulsation Inflation with aortic valve closure Deflation just before systole

Reduce systolic arterial pressure (afterload) Reduces myocardial oxygen consumption

Augment diastolic arterial pressure Enhances coronary blood flow

Mean pressure unchanged

Intra-aortic balloon pump

Benefits: Diminish

myocardial ischemia

10-20% increase in CO

Diminish heart rate Increase urine

output

Risks: Damage/

perforation of aorta Distal ischemia Thrombocytopenia Hemolysis Renal emboli Mechanical failure

– balloon rupture

Ventricular-assist device

Centrifugal pump or Archimedes’ screw type

Inflow from LV and outflow into aorta

Has been used as a bridge in myocarditis until recovery or transplant

**Centrifugal pump vs. corkscrew

Ventricular-assist device

Centrifugal pump or Archimedes’ screw type

Inflow from LV and outflow into aorta Has been used as a bridge in myocarditis

until recovery or transplant Disadvantages:

Surgical implantation infection thrombosis hemolysis

CID. 2005;40:1108.

Ventricular-assist device

Infection: Review of 76 patients using LVAD to

bridge to cardiac transplant LVAD-related infection:

38 patients (50%) 29 bloodstream infections (including 5

cases of endocarditis) 17 local infections

Treatment

Treatment

ABC’s Circulation:

Intra-aortic balloon pump counterpulsation Ventricular assist device Cardiopulmonary assist device

Medical therapy ACE-inhibitors Beta-blockers

Medical therapy

Most therapy used in HF patients appears to benefit those with HF due to myocarditis – with the exception of digoxin ACE-inhibitors Beta-blockers No RCT reviewing spironolactone or

ARBs but these as well as other HF meds have been used successfully in case reports

Medical therapy

Animal models appear to demonstrate improved function with use of ACE inhibitors 32 mice infected with Coxsakie B3 virus Randomized to captopril vs. placebo on

day 3 This evidence has been extrapolated to

humans

Am Heart J. 1990;120:1377.

Medical therapy

Animal models appear to demonstrate improved function with use of beta-blockers

Circulation. 1991;83:2021..

Treatment

Treatment

ABC’s Circulation:

Intra-aortic balloon pump counterpulsation Ventricular assist device Cardiopulmonary assist device

Medical therapy ACE-inhibitors Beta-blockers

Immunosuppressive therapy

Int Heart J. 2005;46:113.

Immunosuppressive Therapies

Recent meta-analysis of placebo-controlled RCT of immune therapy for myocarditis Five trials; 316 total patients Single or combination

immunosuppressive therapyPrednisoneAzathioprineCyclosporineIVIG

Immunosuppressive Therapies

Int Heart J. 2005;46:113.

Immunosuppressive Therapies

End-points: All cause death Heart transplantation Secondary:

Change in LVEF and LVEDD

Summary: No statistically significant benefit in

treatment of myocarditis with immunosuppressive therapy

Int Heart J. 2005;46:113.NEJM. 2000;343:1388.

Prognosis Review of 1230 patients with

cardiomyopathy Idiopathic cardiomyopathy (n=616 patients) Peripartum cardiomyopathy (51) Myocarditis (111) Ischemic heart disease (91) Infiltrative myocardial disease (59) Hypertension (49) Human immunodeficiency virus (45) Connective-tissue disease (39) Substance abuse (37) Therapy with doxorubicin (15) Other causes (117)

NEJM. 2000;342:1077.

Prognosis

Idiopathic CM acted as the reference category No difference in survival between idiopathic CM

and cardiomyopathy due to myocarditis

NEJM. 2000;342:1077.

Prognosis

NEJM. 2000;342:1077.

Prognosis

“Loose” rule of third’s… 1/3: recover 1/3: residual ventricular dysfunction 1/3: transplantation or death

SUMMARY

ABC’s Supportive therapy is mainstay

therapy Most medical therapies for HF seem

to benefit myocarditis patients with the exception of digoxin

Immunosuppressive therapy does not seem to play a role in survival

Back to the caseBack to the case

Stabilized initially with LVAD and ECMOStabilized initially with LVAD and ECMO EF increased to 40-45%EF increased to 40-45% Started on coreg, lisinopril, and aldactoneStarted on coreg, lisinopril, and aldactone Multiple complications during the hospital Multiple complications during the hospital

coursecourse Cardiac tamponade s/p thoracotomyCardiac tamponade s/p thoracotomy Hemorrhagic CVA s/p craniotomy, tracheostomy and Hemorrhagic CVA s/p craniotomy, tracheostomy and

a PEGa PEG Multiple Infections Multiple Infections

Currently, at a rehab facility due to residual Currently, at a rehab facility due to residual neurologic deficit and deconditioningneurologic deficit and deconditioning

ConclusionConclusion

Most common cause is viruses (adeno and Most common cause is viruses (adeno and coxsackie)coxsackie)

Highly variable clinical manifestationsHighly variable clinical manifestations Cardiac MRI looks promising for diagnosisCardiac MRI looks promising for diagnosis Biopsy is the gold standard but should be Biopsy is the gold standard but should be

pursued in only select patientspursued in only select patients Aggressive, supportive care is the first line Aggressive, supportive care is the first line

therapy because of high incidence of recoverytherapy because of high incidence of recovery Immunosuppressive therapy does not affect Immunosuppressive therapy does not affect

mortalitymortality

ReferencesReferences1.1. Felker GM et al. Underlying causes and long-term survival in patients with initially Felker GM et al. Underlying causes and long-term survival in patients with initially

unexplained cardiomyopathy. N Engl J Med 2000 Apr; 342(15): 1077-84. unexplained cardiomyopathy. N Engl J Med 2000 Apr; 342(15): 1077-84. 2.2. Cooper LT et al. Cooper LT et al. The Role of Endomyocardial Biopsy in the Management of Cardiovascular

Disease. Circulation 2007 Nov; 116: 2216-2233.3. www.uptodate.com4.4. Baughman KL:  Diagnosis of myocarditis: Death of Dallas criteria.   Baughman KL:  Diagnosis of myocarditis: Death of Dallas criteria.   CirculationCirculation   

 2006; 113:593. 2006; 113:593.5.5. Wu LA et al. Current role of endomyocardial biopsy in the management of patients with Wu LA et al. Current role of endomyocardial biopsy in the management of patients with

dilated cardiomyopathy and myocarditis. Mayo Clin Proc 2001; 76:1030dilated cardiomyopathy and myocarditis. Mayo Clin Proc 2001; 76:10306.6. Cooper LT et al. The role of endomyocardial biopsy in the management of cardiovascular Cooper LT 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 disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116: 2216Cardiology, and the European Society of Cardiology. Circulation 2007; 116: 2216

7.7. Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.8.8. Goldberg LR et al. Predictors of adverse outcome in biopsy-proven myocarditis. JACC 1999; Goldberg LR et al. Predictors of adverse outcome in biopsy-proven myocarditis. JACC 1999;

33339. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review

of autopsies in military recruits. Ann Intern Med. 2004;141:829–834.10. Blankenhorn MA, Gall EA. Myocarditis and myocardosis; a clinicopathologic appraisal.

Circulation. 1956;13:217–223.11. Kuhl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated

with progressive cardiac dysfunction. Circulation. 2005;112:1965–1970.12. Fuse K, Kodama M, Okura Y, et al. Predictors of disease course in patients with acute

myocarditis. Circulation. 2000;102:2829 –2835.13.13. Ellis CR, et al. Myocarditis basic and clinical aspects. Ellis CR, et al. Myocarditis basic and clinical aspects. Cardiology in Review 2007;15:

170–177

BiopsyBiopsy

- 2-5% complication rate2-5% complication rate Venous accessVenous access: inadvertent arterial : inadvertent arterial

puncture, pneumothorax, vasovagal reaction, puncture, pneumothorax, vasovagal reaction, or bleeding after sheath removal or bleeding after sheath removal

Procedure itselfProcedure itself: arrhythmias, conduction : arrhythmias, conduction abnormalities, and cardiac perforation abnormalities, and cardiac perforation to to pericardial tamponade and rarely, death.pericardial tamponade and rarely, death.

- Patchy infiltrates Patchy infiltrates lower sensitivity lower sensitivity- Lateral wall most common Lateral wall most common hard to hard to

accessaccess

DiagnosisDiagnosis Expanded CriteriaExpanded Criteria

SuspiciousSuspicious for for myocarditis = 2 myocarditis = 2 positive categoriespositive categories

CompatibleCompatible with with myocarditis = 3 myocarditis = 3 positive categoriespositive categories

High probabilityHigh probability of of being myocarditis = being myocarditis = all 4 categories all 4 categories positivepositive

Category ICategory I: : Clinical Clinical

symptomssymptoms

Category IICategory II: : Evidence of Evidence of Cardiac dysfunction Cardiac dysfunction in the in the AbsenceAbsence of regional coronary of regional coronary ischemiaischemia

Category IIICategory III: : Cardiac MRICardiac MRI

Category IVCategory IV: : Myocardial Myocardial biopsy - Pathological or biopsy - Pathological or Molecular AnalysisMolecular Analysis