Young Soldier With A Failing Heart Manju Goyal, M.D. Walter Reed Army Medical Center April 2008

Case HPI: 20 year-old male with cough, shortness of breath, intermittent chest pressure and palpitations x 4 days PMhx/PSHx/Shx/Fhx/Meds: negative EXAM: Vitals: 145, 90/58, 95% ra, afebrile Cardiovascular: tachycardic, systolic murmur best heard at the apex, no JVD Lungs: CTAB Extremities: no edema

Case LABS: CBC - nml BMP - nml D-dimer - nml BNP LFTs - 88/136 Cardiac enzymes - 115/2.2/<0.01

Case EKG – sinus tachycardia at 131, inferolateral TWI CXR – AP film with just an enlarged cardiac silhouette Young patient in SHOCK with concerning cardiac exam and EKG

Case ECHO: - Severely dilated left ventricle but normal wall thickness - No LV thrombus - EF in the 10-15% range - Severe global hypokinesis, with mild posterior wall contractility. - Moderate to severe MR due to annular dilatation New onset of Dilated Cardiomyopathy (DCM)

Dilated Cardiomyopathy

Review of 1230 Patients with 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 Etiology NEJM 2000

Additional Tests LABS: ESR - 33 Ferritin - nml TSH - nml ACE level - nml RF - nml ANA - negative Lyme titers - negative HIV - negative Cardiac CATH: Normal Coronaries What’s the differential? Any further tests?

Review of 1230 Patients with DCM Idiopathic — 50 percent Myocarditis — 9 percent Ischemic heart disease — 7 percent Infiltrative disease — 5 percent Peripartum cardiomyopathy — 4 percent Hypertension — 4 percent HIV infection — 4 percent Connective tissue disease — 3 percent Substance abuse — 3 percent Doxorubicin — 1 percent Other — 10 percent NEJM 2000 Endomyocardial Biopsy

Biopsy Results Dr. Brendan Graham Dept. of Pathology

Normal Myocardium

Biopsy – 4x

Biopsy – 20x

Biopsy – 40x

Case of Viral Myocarditis Other infectious etiologies ruled out by special stains/cultures Other infectious etiologies ruled out by special stains/cultures Dallas Criteria: Dallas Criteria: Lymphocytic infiltrates of varying severity Lymphocytic infiltrates of varying severity Myocyte necrosis and cytoskeletal disorganization Myocyte necrosis and cytoskeletal disorganization Interstitial fibrosis seen with subacute/chronic cases Interstitial fibrosis seen with subacute/chronic cases

Objectives: Myocarditis Review etiology and pathophysiology Review etiology and pathophysiology Clinical Manifestations Clinical Manifestations Role of different diagnostic modalities Role of different diagnostic modalities Therapy Therapy 1. Cardiovascular support for an unstable patient (i.e. indications for VAD, ECMO) 2. Role of immunosuppressive/modulating therapies Prognosis Prognosis

Myocarditis Definition: Non-ischemic myocardial inflammation resulting from a variety of infectious, immune and toxic insults.

Epidemiology Precise incidence and prevalence unknown Lack of a non-invasive “gold standard” test for diagnosis Lack of a non-invasive “gold standard” test for diagnosis Not every suspected myocarditis case gets a biopsy Not every suspected myocarditis case gets a biopsy Biopsy itself has low sensitivity Biopsy itself has low sensitivity Present in 1-9% of routine postmortem examinations 1 Present in 1-9% of routine postmortem examinations 1 Accounted for 20% of sudden cardiac deaths in military recruits 2 Accounted for 20% of sudden cardiac deaths in military recruits 2 1. Circulation Ann Intern Med 2004

Etiology Infectious VIRUSES (adeno, coxsackie) VIRUSES (adeno, coxsackie) Bacterial Bacterial Fungal Fungal Protozoal (Chagas disease) Protozoal (Chagas disease) Helminths Helminths Non-infectious Toxins/Drugs (alcohol, anthracyclines) Systemic disorders (sarcoid, lupus, scleroderma)

Etiology

Etiology Braunwald 2007

Pathophysiology of Viral Myocarditis Braunwald 2007

Viral Phase Virus enters (GI/Lungs) Activates proteases  damages cytoskeletan Activates tyrosine kinases  immune system turns ON Replicates and persists  chronic inflammation/fibrosis/DCM Braunwald 2007

Immune Response Braunwald 2007 Autoimmune response: auto-antibodies to myosin and other cardiac proteins Overexpression of cytokines (IL-2, INF-γ, TNF-α)

Pathophysiology

Clinical Presentation AcuteFulminantChronic Nonspecific cardiac symptoms Nonspecific cardiac symptoms Heart failure, Acute MI, or SCD Heart failure, Acute MI, or SCD More common in children/teenagers More common in children/teenagers +/- viral prodrome +/- viral prodrome Cardiogenic shock +/- acute heart failure Cardiogenic shock +/- acute heart failure Biopsy doesn’t match the clinical severity. Biopsy doesn’t match the clinical severity. High levels of cytokines  reversible cardiac depression  better prognosis High levels of cytokines  reversible cardiac depression  better prognosis Subtle, insidious onset Subtle, insidious onset Already have DCM  HF symptoms Already have DCM  HF symptoms Biopsy with fibrosis usually Biopsy with fibrosis usually

Diagnosis Symptoms: non-specific Laboratory Testing: also non-specific Positive cardiac biomarkers Positive cardiac biomarkers ECG: T wave inversion, ST segment elevation, bundle branch blocks ECG: T wave inversion, ST segment elevation, bundle branch blocksECHO Differentiate fulminant from acute myocarditis Differentiate fulminant from acute myocarditis Detect thrombi, valvular abnormalities, and pericardial involvement Detect thrombi, valvular abnormalities, and pericardial involvement Rule out other cardiomyopathies (HOCM, Takotsubo) Rule out other cardiomyopathies (HOCM, Takotsubo)

Diagnosis: Cardiac MRI WITH ContrastWITHOUT Contrast Non-invasive Non-invasive Visualize entire myocardium Visualize entire myocardium Use to guide biopsy Use to guide biopsy Follow disease course and response to therapy Follow disease course and response to therapy Eur Heart J 1994 LVRV LV

Diagnosis: Coronary Angiography Rule out other congenital, rheumatic, or ischemic heart disease Rule out other congenital, rheumatic, or ischemic heart disease Determine need for inotropic or mechanical support based on hemodynamic parameters Determine need for inotropic or mechanical support based on hemodynamic parameters Elevated pulmonary artery pressures are independent predictors of mortality Elevated pulmonary artery pressures are independent predictors of mortality

Diagnosis: Endomyocardial Biopsy Although controversial, still the current gold-standard test for diagnosis Although controversial, still the current gold-standard test for diagnosis 1-6% complication rate 1-6% complication rate Consider when suspicious for: Consider when suspicious for: Giant cell myocarditis Giant cell myocarditis Hypersensitivity/eosinophilic myocarditis Hypersensitivity/eosinophilic myocarditis Cardiac involvement in a systemic disease Cardiac involvement in a systemic disease All other patients, consider only if pt is deteriorating All other patients, consider only if pt is deteriorating

When to consider biopsy? Mayo Clin Proc 2001

Circulation 2007

Treatment Dr. Barnett Gibbs Dept. of Cardiology

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

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

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 therapy Prednisone Azathioprine Cyclosporine IVIG

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 case Stabilized initially with LVAD and ECMO Stabilized initially with LVAD and ECMO EF increased to 40-45% EF increased to 40-45% Started on coreg, lisinopril, and aldactone Started on coreg, lisinopril, and aldactone Multiple complications during the hospital course Multiple complications during the hospital course Cardiac tamponade s/p thoracotomy Cardiac tamponade s/p thoracotomy Hemorrhagic CVA s/p craniotomy, tracheostomy and a PEG Hemorrhagic CVA s/p craniotomy, tracheostomy and a PEG Multiple Infections Multiple Infections Currently, at a rehab facility due to residual neurologic deficit and deconditioning Currently, at a rehab facility due to residual neurologic deficit and deconditioning

Conclusion Most common cause is viruses (adeno and coxsackie) Most common cause is viruses (adeno and coxsackie) Highly variable clinical manifestations Highly variable clinical manifestations Cardiac MRI looks promising for diagnosis Cardiac MRI looks promising for diagnosis Biopsy is the gold standard but should be pursued in only select patients Biopsy is the gold standard but should be pursued in only select patients Aggressive, supportive care is the first line therapy because of high incidence of recovery Aggressive, supportive care is the first line therapy because of high incidence of recovery Immunosuppressive therapy does not affect mortality Immunosuppressive therapy does not affect mortality

References 1. Felker GM et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000 Apr; 342(15): Cooper LT et al. 2. Cooper LT et al. The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease. Circulation 2007 Nov; 116: Baughman KL: Diagnosis of myocarditis: Death of Dallas criteria. Circulation 2006; 113: Wu LA et al. Current role of endomyocardial biopsy in the management of patients with dilated cardiomyopathy and myocarditis. Mayo Clin Proc 2001; 76: 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 Cardiology, and the European Society of Cardiology. Circulation 2007; 116: Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed. 8. Goldberg LR et al. Predictors of adverse outcome in biopsy-proven myocarditis. JACC 1999; 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– Blankenhorn MA, Gall EA. Myocarditis and myocardosis; a clinicopathologic appraisal. Circulation. 1956;13:217– Kuhl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation. 2005;112:1965– Fuse K, Kodama M, Okura Y, et al. Predictors of disease course in patients with acute myocarditis. Circulation. 2000;102:2829 – Ellis CR, et al. Myocarditis basic and clinical aspects. 13. Ellis CR, et al. Myocarditis basic and clinical aspects. Cardiology in Review 2007;15: 170–177

Biopsy - 2-5% complication rate Venous access: inadvertent arterial puncture, pneumothorax, vasovagal reaction, or bleeding after sheath removal Venous access: inadvertent arterial puncture, pneumothorax, vasovagal reaction, or bleeding after sheath removal Procedure itself: arrhythmias, conduction abnormalities, and cardiac perforation  to pericardial tamponade and rarely, death. Procedure itself: arrhythmias, conduction abnormalities, and cardiac perforation  to pericardial tamponade and rarely, death. - Patchy infiltrates  lower sensitivity - Lateral wall most common  hard to access

Diagnosis Expanded Criteria Expanded Criteria Suspicious for myocarditis = 2 positive categories Suspicious for myocarditis = 2 positive categories Compatible with myocarditis = 3 positive categories Compatible with myocarditis = 3 positive categories High probability of being myocarditis = all 4 categories positive High probability of being myocarditis = all 4 categories positive Category I: Clinical symptoms Category II: Evidence of Cardiac dysfunction in the Absence of regional coronary ischemia Category III: Cardiac MRI Category IV: Myocardial biopsy - Pathological or Molecular Analysis