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 - 397 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

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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

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 Endomyocardial Biopsy NEJM 2000

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  Dallas Criteria:  Lymphocytic infiltrates of varying severity  Myocyte necrosis and cytoskeletal disorganization  Interstitial fibrosis seen with subacute/chronic cases

Objectives: Myocarditis

     Review etiology and pathophysiology Clinical Manifestations Role of different diagnostic modalities Therapy 1.

2.

Cardiovascular support for an unstable patient (i.e. indications for VAD, ECMO) Role of immunosuppressive/modulating therapies 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 Not every suspected myocarditis case gets a biopsy  Biopsy itself has low sensitivity   Present in 1-9% of routine postmortem examinations 1 Accounted for 20% of sudden cardiac deaths in military recruits 2 1. Circulation 1976 2. Ann Intern Med 2004

Infectious

     VIRUSES (adeno, coxsackie) Bacterial Fungal Protozoal (Chagas disease) Helminths

Etiology

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

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

Pathophysiology

Clinical Presentation

Acute

 Nonspecific cardiac symptoms

Fulminant

 Cardiogenic shock +/- acute heart failure

Chronic

 Subtle, insidious onset  Heart failure, Acute MI, or SCD  Biopsy doesn’t match the clinical severity.  Already have DCM  HF symptoms  More common in children/teenagers  +/- viral prodrome  High levels of cytokines 

reversible

cardiac depression  better prognosis  Biopsy with fibrosis usually

Diagnosis

Symptoms:

non-specific

Laboratory Testing:

also non-specific   Positive cardiac biomarkers ECG: T wave inversion, ST segment elevation, bundle branch blocks

ECHO

   Differentiate fulminant from acute myocarditis Detect thrombi, valvular abnormalities, and pericardial involvement Rule out other cardiomyopathies (HOCM, Takotsubo)

RV LV

Diagnosis: Cardiac MRI

 Non-invasive  Visualize entire myocardium RV LV  Use to guide biopsy  Follow disease course and response to therapy Eur Heart J 1994 WITHOUT Contrast WITH Contrast



Diagnosis: Coronary Angiography

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

Diagnosis: Endomyocardial Biopsy

    Although controversial, still the current gold-standard test for diagnosis 1-6% complication rate Consider when suspicious for:  Giant cell myocarditis  Hypersensitivity/eosinophilic myocarditis  Cardiac involvement in a systemic disease 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

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

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 CID. 2005;40:1108.

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

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 Int Heart J. 2005;46:113.

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.

NEJM. 2000;342:1077.

Prognosis

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

Conclusion

      Most common cause is viruses (adeno and coxsackie) Highly variable clinical manifestations Cardiac MRI looks promising for diagnosis 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 Immunosuppressive therapy does not affect mortality

References

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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. Cooper LT et al. The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease. Circulation 2007 Nov; 116: 2216-2233.

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Baughman KL: Diagnosis of myocarditis: Death of Dallas criteria. Circulation 2006; 113:593.

Wu LA et al. Current role of endomyocardial biopsy in the management of patients with dilated cardiomyopathy and myocarditis. Mayo Clin Proc 2001; 76:1030 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: 2216 Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.

Goldberg LR et al. Predictors of adverse outcome in biopsy-proven myocarditis. JACC 1999; 33 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.

Blankenhorn MA, Gall EA. Myocarditis and myocardosis; a clinicopathologic appraisal. Circulation. 1956;13:217–223.

Kuhl U, Pauschinger M, Seeberg B, et al. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation. 2005;112:1965–1970.

Fuse K, Kodama M, Okura Y, et al. Predictors of disease course in patients with acute myocarditis. Circulation. 2000;102:2829 –2835.

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 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 

Suspicious

myocarditis = 2 positive categories for  Category I: Clinical symptoms  Category II: Evidence of Cardiac dysfunction in the Absence of regional coronary ischemia 

Compatible

myocarditis = 3 positive categories with  Category III: Cardiac MRI 

High probability

being myocarditis = all 4 categories positive of  Category IV: Analysis Myocardial biopsy - Pathological or Molecular