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

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 2003 361(9363):1111 Fig. 1 multisystem involvement in sarcoidosis

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 2003 361(9363):1111 Fig. 2 – process of granuloma formation in sarocidosis Source: Broos et al. Granuloma formation in pulmonary sarcoidosis Frontiers in Immunology 2013

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;119:167-72. Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:1204-11.

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

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;63:86-108.

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

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.

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

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.

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

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

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: 116-22. Burstow DJ, Tajik J, Baily KR, et al. Two-dimensional echocardiographic findings in systemic sarcoidosis. Am J Cardiol 1989;63: 478-82.

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: 478-82.

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

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

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.

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;184:249-54.

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

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

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

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;88:1006-10.

Yazaki et al. 2001 Retrospective study of 95 patients diagnosed with cardiac sarcoidosis at a Japanese hospital 1984-1996 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;88:1006-10.

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

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

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

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

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;88:1006-10

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;117:2820-40.

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. 2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities J Am Coll Cardiol. 2012;60(14):1297-1313.

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

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

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.

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

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

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.

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

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