CASE REPORT

Cardiac Sarcoidosis – Diagnosis, Risk Stratification and Management

Dr Joanna Grogono
ST6 Cardiology, John Radcliffe Hospital

The Case
36yr old man presented to GP with 2-3 month history of shortness of breath on exertion and reduced exercise tolerance.  He did not have any cough/wheeze/chest pains/palpitations/joint pains/swelling or neurological symptoms.  An ECG performed at his GP surgery showed complete heart block.  He had a normal calcium, thyroid function and white cell count.  He had a CXR (Figure A) followed by a CT that showed bilateral hilar lymphadenopathy.  His echocardiogram showed a dilated LV with low normal systolic function and mild concentric left ventricular hypertrophy.  A CMR showed a moderately dilated LV with normal systolic function and relative wall thinning.  On late gadolinium imaging there were multiple areas of hyper-enhancement consistent with an infiltrative process.  On the basis of this information a probable diagnosis of sarcoid with cardiac involvement was made.  A bronchoscopy and lung biopsy was performed with non-caseating granuloma seen on histology.  Due to the demonstration of extensive infiltration and persistent complete heart block a dual chamber internal cardioverter defibrillator (ICD) was implanted for primary prevention.  The device was programmed to DDD 50 to 150 with first VT zone of 165bpm (monitoring only), the second VT zone 185 with two scans, 2 ramps and shocks, and a VF zone of 240bpm with ATP during charging and shocks. 


Figure A: CXR

This article is based on the 2014 HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated with Cardiac Sarcoidosis1.  It addresses the difficulties in diagnosing and investigating for cardiac sarcoidosis and finally focuses on the management options including which patients are suitable for complex device therapy. 

Question 1: How is cardiac sarcoidosis (CS) diagnosed?

Background
Sarcoidosis is a non-caseating, granulomatous disorder of unknown aetiology and causes an infiltrative cardiomyopathy.  CS can occur prior, after or concurrently with involvement of the lungs or other organs.  

Prevalence is 4.7 to 64/100,000.  Highest prevalence in Northern European and African American individuals, especially women.  70% occur in the 25-45year group with a second peak in women >50yrs in Europe and Japan. 

Studies have suggested that symptomatic CS occurs in ~5% of patients with sarcoidosis with many remaining asymptomatic with autopsy studies showing cardiac involvement in ~25% of patients with sarcoidosis.

Prognosis
There is minimal data to guide risk stratification and management with no clear identifiable risk stratification method to predict sudden death risk in patients with CS.  The prognosis of sarcoidosis is worse with cardiac involvement especially if symptomatic.  The extent of the LV dysfunction appears to be the most important predictor of survival.  (Normal vs reduced EF 10yr survival 89% vs 27%2)

In CS sudden death due to ventricular tachyarrhythmias or conduction block account for 30-65% of deaths.  There are high rates of recurrent VT or sudden death with anti-arrhythmic drug therapy. 

Asymptomatic myocardial involvement with sarcoidosis is common and includes:
- conduction abnormalities
- tachyarrhythmias
- cardiomyopathy
- cardiac failure – with reduced and preserved ejection fraction
- sudden cardiac death – which can occur without any prior symptoms of conduction disorder and normal ventricular function, therefore it is important to try and detect ‘at risk’ patients. 

Criteria for the Diagnosis for Cardiac Sarcoid
1. Non-caseating granuloma on histological examination from myocardial tissue with no alternative cause identified
2. Probable involvement (in general, adequate to establish clinical diagnosis) if:
a. Histological diagnosis of extra-cardiac sarcoidosis
AND
b. 1+ of:
i. corticosteroid +/- immunosuppressant responsive cardiomyopathy of heart block
ii. unexplained reduced LVEF <40%
iii. unexplained sustained (spontaneous or induced) VT
iv. Mobitz II second-degree heart block or third degree heart block
v. patchy uptake on cardiac PET
vi. late gadolinium enhancement on CMR
vii. positive gallium uptake
AND
c. Other causes for the cardiac manifestations have been reasonably excluded.

Who and How to Screen
There are 2 distinct groups when it comes to screening for cardiac sarcoidosis:
1) those with no known history of sarcoidosis
2) those that have been diagnosed with sarcoidosis in another organ

In those with no previous diagnosis of sarcoidosis investigate for cardiac sarcoid if:
• <60yrs with unexplained sustained Mobitz II or third degree heart block (Class IIa)
• Sustained monomorphic VT +/- cardiomyopathy
Perform a CT chest +/- advanced imaging such as CMR or FDG-PET.  If either of these are suggestive of sarcoidosis then biopsies can be useful, extra-cardiac if feasible, otherwise guided endomyocardial biopsy. 

In those with biopsy proven diagnosis of extra-cardiac sarcoid (Figure B)
• Assess for unexplained syncope/presyncope/significant palpitations
• Perform a 12 lead ECG (ClassI)
• Echocardiogram can be useful (Class IIa)
• Advanced cardiac imaging (CMR or FDG-PET at experienced centres) can be useful in patients with abnormalities detected on initial screening of symptoms / ECG / echocardiogram (Class IIa) but is not recommended if these are absent (Class IIIa)

Figure B: Flow chart for cardiac sarcoidosis in biopsy proven extra-cardiac sarcoidosis. 

When used together ECG, Holter monitoring, and echocardiogram are highly sensitive for detecting cardiac involvement, but these modalities are not specific for CS.  If these investigations are normal the prognosis is very good and further immediate testing is not required3.  If there are abnormalities detected, then more definitive imaging is necessary, such as CMR or cardiac PET-CT. 

Question 2: What investigations are helpful in risk stratifying in CS?

Investigations
Non-invasive
• ECG - AV block, bundle branch block, non-specific interventricular conduction delay, PVCs = 30%+ in patients with CS (NB 10-15% in normal population). 
• Holter monitoring
• Echo
• CMR – perform if any abnormality on Holter (more than 10/hour or >100/day premature ventricular contractions, more than 3 beats of nonsustained VT or supraventricular tachycardia, VT or VF4) or any abnormality on echo.  CMR appears to be more specific than PET
• PET – useful to assess disease activity, appears to be more sensitive than CMR.  Assessment of myocardial inflammation with FDG-PET can be useful in CS patients with ventricular arrhythmias (Class IIa). 
• Radionuclide imaging
• Exercise testing

Invasive
• Angiogram: exclude coronary artery disease as CS can mimic this.
• Endomyocardial biopsy: ‘gold standard.’ Low sensitivity with high false negative results due to patchy distribution of disease. 
• EPS:  assessment of sinus node or conduction system (not needed if symptomatic bradycardia or heart block).  This may aid in risk stratification of sudden death in those who do not meet criteria for conventional ICD indications.

Question 3: What is the management of CS focussing on device therapy?

Treatment of CS
There is a lack of evidence to produce specific guidance on routine use of immunosuppressive therapy.  Corticosteroids are the mainstay of immunosuppressive therapy.  These are most beneficial when commenced early in the inflammatory phase of the disease and are less effective once fibrosis has occurred.  Steroids appear to prevent adverse ventricular remodelling in those with normal, or mild to moderate LV impairment5.  Steroids reduce refractory atrial and ventricular arrhythmias.  Those most likely to respond to steroids are those with preserved LV function and evidence of active inflammation on imaging6  Therefore a trial of corticosteroids is recommended  in most patients with newly diagnosed CS although the dose, use of steroid sparing agent and duration of treatment is not agreed upon and varies significantly throughout clinical practice.  There is no proof of survival benefit although it has been used for >50years.  If intolerant to steroids, alternatives include methotrexate, azathioprine, cyclophosphamide and hydroxychloroquine.  
Steroids may suppress malignant ventricular arrhythmias or partially reverse high grade AV block in some patients but they cannot be relied upon as sole therapy and in nearly all of these patients cardiac device therapy is also recommended. 

The HRS expert consensus statement states that steroids 'may be useful' in patients with Mobitz II or third degree heart block. 

Monitoring response to treatment: There is a lack of specific guidelines for monitoring response to therapy.  Options for monitor include assessing clinical response, arrhythmia burden (ECG, Holter), LV and RV function (echo), resolution of oedema (CMR) and decrease in metabolic activity (PET-CT).  If decision made to stop steroids then close monitoring for disease reactivation needs be in place.

Device Therapy
Pacing:
Permanent pacemaker if complete heart block or high degree AV block, even if transient.
In one retrospective study7 of 45 patients with cardiac sarcoidosis and ICDs for both primary and secondary prevention those patients with complete heart block were at increased risk for appropriate ICD therapies.  This suggests that an ICD with appropriate pacing therapy would be the preferred approach in most patients. 
ICD (Figure C):
Secondary prevention in those who have spontaneous sustained VT or VF or prior cardiac arrest (Class I)
Primary prevention:
• NYHA II-III with LVEF <35% despite optimal medical therapy and a period of immunosuppression (Class I) 
• Inducible ventricular arrhythmia at EPS performed for symptoms or NSVT
• Extensive LGE of LV CMR or PET abnormalities, particularly if indication for PPM.   (Class IIa)
• If unexplained syncope or near-syncope, felt to be arrhythmic in aetiology
• If inducible sustained ventricular arrhythmias (>30sec of monomorphic or polymorphic VT) or clinically relevant VF
• ICD may be considered in patients with LVEF in range of 36-49% +/- RV ejection fraction <40%, despite optimal medical therapy for heart failure and a period of immunosuppression (if active inflammation).  (Class IIb)
• ICD is not immediately recommended in patients with no history of syncope, normal LVEF/RV ejection fraction, no LGE on CMR, a negative EP study, and no indication for permanent pacing.  However these patients should be followed closely for deterioration in ventricular function (Class III)
• ICD is not recommended for incessant ventricular arrhythmias or if severe NYHA IV heart failure. 


Figure C

Management of Ventricular Arrhythmias of CS (Expert Consensus Recommendations)
• Immunosuppression can be useful in CS patients with frequent ventricular ectopy or non-sustained/sustained ventricular arrhythmias and evidence of myocardial inflammation. (IIa)
• Antiarrhythmics can be useful in patient with ventricular arrhythmias refractory to immunosuppressive therapy (IIa)
• Catheter ablation can be useful in patients with CS and ventricular arrhythmias refractive to immunosuppressive therapy AND antiarrhythmic therapy. (IIa) or in patients with incessant ventricular arrhythmias. 

Our Case
Diagnosis: clinical diagnosis of cardiac sarcoid with a) Histological diagnosis of extra-cardiac sarcoidosis AND b) third degree heart block AND c) Other causes for the cardiac manifestations have been reasonably excluded.
Treatment: corticosteroids and ICD as there was an extensive LGE of LV on CMR and an indication for PPM.   (Class IIa)

Summary
For patients with cardiac sarcoidosis, an ICD is not immediately indicated in asymptomatic patients with completely normal investigations (normal LV and RV ejection fraction, no LGE on CMR, a negative EP study) and no indication for permanent pacing.  Although it should be appreciated that the assessment is performed at one snapshot in time, and the condition may continue to progress despite medical therapy and therefore regular follow up is recommended. 

References
1. HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated with Cardiac Sarcoidosis.  2014

2. Yazaki, Y.; Isobe, M.; Hiroe, M.; Morimoto, S.; Hiramitsu, S.; Nakano, T.; Izumi, T.; Sekiguchi, M. Prognostic Determinants of Long-Term Survival in Japanese Patients with Cardiac Sarcoidosis Treated with Prednisone. The American journal of cardiology. 2001, 88, 1006–10.

3. Huang, PL, Brooks R, Capenter C, Garan H. Antiarrhythmic therapy guided by programmed electrical stimulation in cardiac sarcoidosis with ventricular tachycardia.  Am Heart J. 1991 Feb;121 (2 Pt 1):599-601

4. Suzuki T, Kanda T, Kubota S, et al.  Holter monitoring as a noninvasive indicator of cardiac involvement in sarcoidosis.  Chest 1994;106:1021-1435

5. Chiu CZ, Katnai S, Zhang G et al.  Prevention of left ventricular remodelling by long-term corticosteroid therapy in patients with cardiac sarcoidosis.  AM J Cardiol 2001; 88:1006-1010. 

6. Banba K, Kusano KF, Nakamura K, et al.  Relationship between arrhythmogenesis and disease activity in cardiac sarcoidosis.  Heart Rhythm 2007; 4:1292-1299

7. Betensky, BP, Tschabrunn C, Zado S et al.  Long-term follow-up of patients with cardiac sarcoidosis and implantable cardioverter-defibrillators.  Heart Rhythm v.9,p.884-91

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