1. Themes Case which presented a diagnostic challenge
when to suspect sarcoid?
Demonstrates sequelae of the disease when untreated
decline in ejection fraction and ventricular arrhythmias
Highlights severe manifestations of underlying disease process
refractory ventricular tachycardia
Provides an example of how these are complications are managed
multiple antiarrhythmics, AICD, RFA and transplantation

2. Overview Multisystem disorder of unknown etiology
Characterized by noncaseating granulomas in involved tissues composed of T lymphocytes and monocytes
The lungs are affected in approximately 90 percent of patients, other tissues commonly involved include the skin, eyes, heart and lymph nodes
Baughman RP et al. Sarcoidosis Lancet (9363):1111
Fig. 1 multisystem involvement in sarcoidosis

3. Eitiology
Thought to be an immunological response to an unidentified antigenic trigger or triggers
Disease prevalence follows geographical, seasonal, and occupational clustering suggesting possible infectious, environmental or occupational eitiologies
Baughman RP et al. Sarcoidosis Lancet (9363):1111
Fig. 2 – process of granuloma formation in sarocidosis
Source: Broos et al. Granuloma formation in pulmonary sarcoidosis Frontiers in Immunology 2013

4. Prevalence
Autopsy studies estimate the prevalence of cardiac involvement in at least 25% of patients with sarcoidosis
Imaging studies have found asymptomatic cardiac involvement in 3.7%–54.9% of the patients with extra-cardiac sarcoidosis
Cardiac sarcoidosis accounts for 13% to 25% of deaths from the disease
Perry A, Vuitch F. Causes of death in patients with sarcoidosis. A morphologic study of 38 autopsies with clinicopathologic correlations.Arch Pathol Lab Med 1995;119:
Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:

5. Clinical Presentation
The typical presentation of cardiac sarcoid is initial conduction block then progressing to ventricular tachycardia and heart failure
However very heterogeneous with a significant proportion presenting with sudden cardiac death
Kim et al. Cardiac Sarcoidosis. Am Heart J, 01/2009, Volume 157, Issue 1

6. Arrhythmia
Supraventricular arrhythmias are less common than ventricular arrhythmias
Thought to be related to atrial dilatation secondary to left ventricular dysfunction
Ventricular arrhythmias more common and caused by direct granulomatous involvement of the myocardium
Roberts WC, McAllister HA, Ferrans VJ. Sarcoidosis of the heart: a clinicopathologic study of 35 necropsy patients and review of 78 previously described necropsy patients. Am J Med 1977;63:

7. Heart Failure
Congestive heart failure is common and due to direct granulomatous involvement of the myocardium or valvular regurgitation
Ventricular dysfunction is systolic or diastolic or both
Does not follow coronary artery distribution
Mitral valve regurgitation is the most common valvular lesion due to papillary muscle dysfunction
Kim et al. Cardiac Sarcoidosis. Am Heart J, 01/2009, Volume 157, Issue 1

8. Effusions
Pericardial effusions detected by echocardiography have been reported in up to 19% of patients with cardiac sarcoid
Although the effusions are usually small, cases of very large effusions with associated tamponade have been reported
Kinney E, Murthy R, Ascunce G, et al. Pericardial effusions in sarcoidosis. Chest 1979;76:476-8.
Zelcer AA, LeJemtel TH, Jones J, et al. Pericardial tamponade in sarcoidosis. Can J Cardiol 1987;3:12-3.

9. Diagnosis
Because of the potential life-threatening complications and potential benefit of treatment, all patients diagnosed with sarcoidosis should be screened for cardiac involvement
Kim et al. Cardiac Sarcoidosis.
Am Heart J, 01/2009, Volume 157, Issue 1

10. Gold Standard
The diagnostic approach has not been standardized, and the most commonly accepted guidelines written in 1993 by the Japanese Ministry Of Health and Welfare are now outdated
Positive biopsy or
BBB, AV block or VT
+ 1 or more of
RWMAs, decreased LVEF, non specific inflammatory
biopsy, MPS perfusion defect
Hiraga H et al. Guideline for diagnosis of cardiac sarcoidosis: study
report on diffuse pulmonary diseases from the Japanese Ministry of
Health and Welfare. Tokyo: Japanese Ministry of Health and Welfare;
1993. pp. 23Q4.

11. Heart Rhythm Society Consensus
Latest expert consensus guidelines
Heart Rhythm Society in 2014
Histological diagnosis of cardiac sarcoid Or
B. Histological diagnosis of extra cardiac sarcoid +
Conduction abnormality, reduced EF, increased uptake on PET, late Gd enhancement on MRI
Bimie et al. HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated With Cardiac Sarcoidosis 2014 Heart Rhythm Society

12. Endomyocardial Biopsy
Gold Standard for diagnosis
Prognostic indicator - a positive biopsy is associated with a shorter median survival time
Limitations:
Not sensitive as may not capture parts of the heart with sarcoid
Risks of invasive procedure – tamponade
Fig 2. Non caseating granulomas seen on RV biopsy
Ardehali H, Howard DL, Hariri A, et al. A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J 2005;150:459-63

13. ECHO
Although characteristic findings on imaging are known, there is no pathognomonic for diagnosis
Echocardiographic abnormalities have been reported in 14-56% of patients with sarcoidosis
Regional wall motion abnormalities, ventricular systolic or diastolic dysfunction, valvular abnormalities or abnormal ventricular wall thickness (thick or thin)
Lewin RF, Mor R, Spitzer S, et al. Echocardiographic evaluation of patients with systemic sarcoidosis. Am Heart J 1985;110:
Burstow DJ, Tajik J, Baily KR, et al. Two-dimensional echocardiographic findings in systemic sarcoidosis. Am J Cardiol 1989;63:

14. Thinned akinetic basal inferolateral wall and papillary muscle
Dilated LV
Thinned akinetic basal inferolateral wall and papillary muscle
Burstow DJ, Tajik J, Baily KR, et al. Two-dimensional echocardiographic findings in systemic sarcoidosis. Am J Cardiol 1989;63:

15. FDG-PET
FDG PET may provide both a measure of disease activity via FDG uptake, as well as a measure of fibrogranulomatous replacement of the myocardium using perfusion imaging
Essentially get an overlap of areas of reduced perfusion (scar) with areas of inflammation
Kaminaga T, Takeshita T, Yamauchi T, et al. The role of iodine-123– labeled 15-(p-iodophenyl)-3R, S-methylpentadecanoic acid scintigraphy in the detection of local myocardial involvement of sarcoidosis. Int J Cardiol 2004;94:99-103

16. Early in disease process normal perfusion with high FDG uptake secondary to inflammation
Late in the disease after scarring low perfusion with high FDG uptake

17. FDG-PET
Increased FDG uptake is assumed to be associated with areas of inflammation and is postulated to identify patients at higher risk of sudden cardiac death given increased disease activity and risk of progression
Blankstein et al. found the
presence of both a
perfusion defect and an
abnormal FDG uptake was
associated with death or
sustained VT, even after
adjusting for LVEF
Blankstein R et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2013;October 1.

18. MRI MRI has the advantage of superior spatial resolution
Areas of inflammation are seen with increased signal intensity on T2-weighted images and early gadolinium-DTPA (Gd)-enhanced images
Sarcoid granulomas may also be seen in the myocardium, appearing as nodules on T2-weighted and Gd-enhanced images
Matsuki M, Matsuo M. MR findings of myocardial sarcoidosis. Clin Radiol 2000;55:323-5.
Vignaux O. Cardiac sarcoidosis: spectrum of MRI features. AJR Am J Roentgenol 2005;184:

19. MRI vs PET Ideal imaging modality is contentious
MRI benefit of greater sensitivity in subclinical disease while FDG-PET provides better information on inflammation/acitivity
Whether MRI or PET scanning should be performed as initial screening tests in this asymptomatic population is unknown
Unknown whether treating such asymptomatic patients is of benefit
Kim et al. Cardiac Sarcoidosis. Am Heart J, 01/2009, Volume 157, Issue

20. Patel et al. 2009
Followed 81 patients with biopsy-proven extracardiac sarcoidosis.
Followed for major adverse events (death, defibrillator shock, or pacemaker requirement)
At 5 years, 6 of 8 patients in the group with LGE had ventricular arrhythmia or died compared with 1 death in the group without LGE
Patel etal.Detection of myocardialdamage in patients with sarcoidosis.Circulation2009;120:1969–1977

21. Contrast ECHO
Contrast ECHO not been studied extensively in this setting
Potential to be used to track disease progression in patients with non-MRI compatible devices
Can also be used to target areas for biopsy to increase diagnostic yield

22. Prognosis
The data on prognosis is quite variable, with 5-year survival ranging from 60% to 90% in patients with treatment and preserved systolic function, to 10% in autopsy subjects
LVEF involvement and response to steroids appear to be two most significant prognostic indicators
Yazaki Y, Isobe M, Hiroe M, et al. Prognostic determinants of longterm survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001;88:

23. Yazaki et al. 2001
Retrospective study of 95 patients diagnosed with cardiac sarcoidosis at a Japanese hospital
A - Overall, patients had survival rates of 50% at 10 years
C – (top) Steroid treated patients with LVEF>50% 89% survival rate at 10 years, LVEF <50% had 27% at 10 years, those diagnosed at autopsy (aka no cardiac treatment) had survival rate 10% at 5 years
Yazaki Y, Isobe M, Hiroe M, et al. Prognostic determinants of longterm survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001;88:

24. Greulich et al. 2013
155 consecutive patients with systemic sarcoid underwent cMRI for evaluation of cardiac sarcoid
Median follow up time 2.6 years
Primary endpoints: death, aborted sudden cardiac death, appropriate ICD discharge

25. The present of LGE yields a hazard ratio of 31.9 for primary outcome
Superior to parameters including LVEF, presentation with heart failure
No patient without LGE experienced any event or died in the follow up even if the LV was enlarged or reduced EF

26. Corticosteroids
Corticosteroid therapy is the mainstay of treatment for cardiac sarcoidosis
The effects of corticosteroid treatment on the clinical course have not been studied in large, randomized, prospective trials.
To date, no study has prospectively compared different corticosteroid dosing regimens and no study has compared corticosteroids to alternative immunosuppressants such as methotrexate or azathioprine.
The optimal dose, when to begin treatment, and the duration of treatment all remain undetermined
Kim et al. Cardiac Sarcoidosis. Am Heart J, 01/2009, Volume 157, Issue 1

27. Corticosteroids
Review article 2013 Canadian Journal of Cardiology which evaluated corticosteroid therapy in cardiac sarcoidosis
10 publications identified
None randomised control trials
Doses ranged from 20mg alternate days – to 60mg daily
Duration ranged from 3 to 168 months
No definite conclusions were able to be drawn due to heterogeneity between studies

28. Corticosteroids
One study showed no significant difference in prognosis in those patients treated with greater than 40 mg or prednisone per day compared to those treated with 30 mg of prednisone or less
One study suggested that patients with severe left ventricular dysfunction should be offered a corticosteroid trial for one to three months (30 to 40 mg/day of prednisone equivalent) then taper over 12 months, with or without a steroid sparing agent
Immunosuppressive agents such as infliximab, methotrexate, azathioprine and cyclophosphamide have been used with reported success in the treatment of sarcoidosis
Yazaki Y, Isobe M, Hiroe M, et al. Prognostic determinants of longterm survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001;88:

29. Arrythmia - ?ICD
ICD recommended for patients with cardiac sarcoid and spontaneous sustained ventricular tachycardia or ventricular fibrillation
Unknown whether patients without functional impairment and without spontaneous significant arrhythmias should be considered for ICD therapy or at least some risk-stratification strategy
Epstein AE, Dimarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. Circulation 2008;117:

30. ACCF/AHA/HRS
2012 Focussed update still did not make any firm recommendation regarding device therapy in sarcoidosis
Sufficient data is not available to stratify risk of sudden cardiac death among patients with sarcoidosis
Tracy et al ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities
J Am Coll Cardiol. 2012;60(14):

31. ICD Heart Rhythm Society Consensus 2014 indicated
EF<35% or sustained VT = ICD
EF>40% no late Gd enhancement = do not put in an ICD
Everything in between it can be considered but no strong recommendation made
Bimie et al. HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated With Cardiac Sarcoidosis 2014 Heart Rhythm Society

32. Ventricular Arrhythmias
Class IIa recommendation from HRS 2014
Immunosuppression, can be useful – evidence of inflammation
Antiarrhythmic medication can be useful – if refractory to immunosuppression
Catheter ablation can be useful – if refractory to both of the above
Bimie et al. HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated With Cardiac Sarcoidosis 2014 Heart Rhythm Society

33. VT Ablation
Kumar et al. Ventricular tachycardia in cardiac sarcoidosis Characterization of Ventricular Substrate and Outcomes of Catheter Ablation Circ Arrhythm Electrophysiol. 2015;8:87-93.

34. VT Ablation 21 patients with cardiac sarcoidosis
EPS confirmed scar mediated re-entry
Catheter ablation is effective in eliminating VT storm and >=1 inducible VT in the majority of patients but recurrences
are common

35. Heart Failure & Transplantation
Heart failure due to cardiac sarcoidosis should be treated in the same manner as heart failure due to other causes
Including: angiotensin converting enzyme inhibitors, diuretics and β-blockers
Studies report that patients with sarcoidosis undergoing heart transplant have better mean short- and intermediate-term survival than patients undergoing transplant due to other causes
Recurrence of sarcoidosis in the transplanted heart has been documented
All recurrences can be treated with steroids usually with good outcome
Kim et al. Cardiac Sarcoidosis. Am Heart J, 01/2009, Volume 157, Issue 1

36. Zaidi et al. 2007
Analysed 65 patients over an 18 year period who underwent orthotopic heart transplantation for cardiac sarcoid
One year post transplant survival was significantly better in sarcoid patients versus patients receiving transplants for all other diagnosis
No difference in baseline characteristics
No difference in incidence of rejection
Zaidi AR, Zaidi A, Vaitkus PT. Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J Heart Lung Transplant 2007;26:714-7.

37. Themes Case which presented a diagnostic challenge
when to suspect sarcoid?
Demonstrates sequelae of the disease when untreated
?any predictors of who will decline vs respond to therapy
Highlights severe manifestations of underlying disease process
Optimal treatment regime unknown
Example of how these are complications are managed
multiple antiarrhythmics, AICD, RFA and transplantation

38. Thank You