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

2. 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

3. Case LABS: CBC - nml BMP - nml D-dimer - nml BNP - 397 LFTs - 88/136
Cardiac enzymes - 115/2.2/<0.01

4. Young patient in SHOCK with concerning cardiac exam and EKG
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

5. New onset of Dilated Cardiomyopathy (DCM)
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)

6. Dilated Cardiomyopathy

7. 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

8. Importance of Etiology
NEJM 2000

9. Additional Tests LABS: Cardiac CATH: ESR - 33 Normal Coronaries
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?

10. 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

11. Dr. Brendan Graham Dept. of Pathology
Biopsy Results
Dr. Brendan Graham
Dept. of Pathology

12. Normal Myocardium

13. Biopsy – 4x

14. Biopsy – 20x

15. Biopsy – 40x

16. 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

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

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

19. 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 examinations1
Accounted for 20% of sudden cardiac deaths in military recruits2
1. Circulation 1976
2. Ann Intern Med 2004

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

21. Etiology

22. Etiology
Braunwald 2007

23. Pathophysiology of Viral Myocarditis
Braunwald 2007

24. 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

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

26. Pathophysiology

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

28. 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)

29. Diagnosis: Cardiac MRI
Non-invasive
Visualize entire myocardium
Use to guide biopsy
Follow disease course and response to therapy RV LV RV LV
WITHOUT Contrast
WITH Contrast
Eur Heart J 1994

30. 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

31. 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

32. When to consider biopsy?
Mayo Clin Proc 2001

33. Circulation 2007

34. Dr. Barnett Gibbs Dept. of Cardiology
Treatment
Dr. Barnett Gibbs
Dept. of Cardiology

35. Treatment

36. Treatment

37. Treatment ABC’s Circulation:
Intra-aortic balloon pump counterpulsation
Ventricular assist device
Cardiopulmonary assist device
Improved survival in patients with acute myocarditis using external pulsatile mechanical ventricular assistance.
AU Chen JM; Spanier TB; Gonzalez JJ; Marelli D; Flannery MA; Tector KA; Cullinane S; Oz MC
SO J Heart Lung Transplant 1999 Apr;18(4):351-7.
BACKGROUND: Acute myocarditis remains a disease with a variable clinical course, from full ventricular recovery to complete heart failure; to date, few cases have been reported that describe the efficacy of temporary mechanical ventricular assistance for its treatment. METHODS: We evaluated the voluntary world registry with the use of an external pulsatile ventricular assist device (the ABIOMED BVS 5000 [BVS]) for acute myocarditis to determine the impact of mechanical ventricular assistance on outcome. Variables analyzed included patient demographics, serum chemistries, and overall hemodynamics prior to BVS, while on BVS support, and after BVS explanation. Postoperative parameters included re-operation, bleeding, respiratory failure, renal failure, and infections, neurologic, or embolic events. RESULTS: Eighteen patients in the ABIOMED world registry underwent BVS implantation for myocarditis; 11 (61.1%) had complete pre-operative and hemodynamic data for analysis. Patients were supported for / days, after which time 7 (63.6%) patients survived to explanation of the device and 2 (18.2%) underwent transplantation. Elevated admission serum chemistries (blood ureanitrogen [BUN], creatinine, transaminases) and hemodynamics (central venous pressure [CVP], mean pulmonary arterial pressure [PAP], pulmonary capillary wedge pressure [PCW], cardiac index [CI], all normalized during the period of device support. Estimated ejection fractions in the 7 explanted patients ranged between 50 to 60% at routine evaluation 3 years after device removal. CONCLUSIONS: Temporary mechanical ventricular assistance represents an efficacious therapy for acute myocarditis in patients with hemodynamic decompensation despite maximal medical therapy. Failure to achieve full ventricular recovery while on device support still allows for other surgical alternatives, including implantation of a long-term implantable ventricular assist device, or cardiac transplantation.

38. 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

39. 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

40. 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

41. *
*Centrifugal pump vs. corkscrew

42. 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

43. 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 ;40:1108.

44. Treatment

45. Treatment ABC’s Circulation: Medical therapy
Intra-aortic balloon pump counterpulsation
Ventricular assist device
Cardiopulmonary assist device
Medical therapy
ACE-inhibitors
Beta-blockers

46. 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
High doses of digitalis increase the myocardial production of proinflammatory cytokines and worsen myocardial injury in viral myocarditis: a possible mechanism of digitalis toxicity. (AUMatsumori A; Igata H; Ono K; Iwasaki A; Miyamoto T; Nishio R; Sasayama S SO. Jpn Circ J 1999 Dec;63(12):934-40).   Results of recent studies suggest that proinflammatory cytokines cause myocardial contractile dysfunction, and that the drugs used to treat heart failure modulate the production of cytokines. This study was designed to examine the effects of digoxin in a murine model of heart failure induced by viral myocarditis. Four-week-old inbred DBA/2 mice were inoculated intraperitoneally with encephalomyocarditis virus (EMCV). Digoxin was given orally in doses of 0.1, 1 or 10 mg/kg daily from the day of virus inoculation. Interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha production in the heart were measured on day 5 after EMCV inoculation by enzyme-linked immunosorbent assay. The 14-day mortality tended to be increased in mice treated with 1 mg/kg, and was significantly increased in the group treated with 10 mg/kg per day. Myocardial necrosis and cellular infiltration on day 6 were significantly more severe in the high-dose digoxin group than in the control group. In the animals treated with 1 mg/kg digoxin, IL-1beta was significantly higher than in the control group. Intracardiac TNF-alpha levels were increased in a dose-dependent manner. These results suggest that digoxin worsens viral myocarditis, and that its use in high doses should be avoided in patients suffering from heart failure due to viral myocarditis.

47. 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 ;120:1377.

48. Medical therapy
Animal models appear to demonstrate improved function with use of beta-blockers
Circulation ;83:2021..

49. Treatment

50. Treatment ABC’s Circulation: Medical therapy Immunosuppressive therapy
Intra-aortic balloon pump counterpulsation
Ventricular assist device
Cardiopulmonary assist device
Medical therapy
ACE-inhibitors
Beta-blockers
Immunosuppressive therapy

51. 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 ;46:113.

52. Immunosuppressive Therapies
Int Heart J ;46:113.

53. 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 ;46:113.
NEJM ;343:1388.

54. 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 ;342:1077.

55. Prognosis Idiopathic CM acted as the reference category
No difference in survival between idiopathic CM and cardiomyopathy due to myocarditis
NEJM ;342:1077.

56. Prognosis
NEJM ;342:1077.

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

58. 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

59. 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

60. 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

61. References
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. 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; 113:593.
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

62. Biopsy 2-5% complication rate Patchy infiltrates  lower sensitivity
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

63. Diagnosis Expanded Criteria Category I: Clinical symptoms
Suspicious for myocarditis = 2 positive categories
Compatible with myocarditis = 3 positive categories
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