What are the cardiac effects of pulmonary sarcoidosis and how are they managed?

Cardiac Effects of Pulmonary Sarcoidosis and Management

Cardiac Involvement and Clinical Significance

Cardiac involvement occurs in 20-55% of patients with pulmonary sarcoidosis based on autopsy and imaging studies, though only 5% develop clinically manifest cardiac disease, making it the second leading cause of death in sarcoidosis patients after pulmonary complications. 1, 2

• Cardiac sarcoidosis presents with conduction abnormalities (including high-degree AV block), ventricular arrhythmias, heart failure with reduced ejection fraction, and sudden cardiac death 1
• Approximately 30% of patients under 60 years presenting with unexplained high-degree AV block or ventricular tachycardia have cardiac sarcoidosis 2
• Up to two-thirds of clinically manifest cardiac sarcoidosis cases are isolated cardiac disease without significant pulmonary symptoms 3
• The extent of left ventricular dysfunction (LVEF <35%) is the most important predictor of adverse outcomes and mortality 1, 3

Diagnostic Approach

All patients with pulmonary sarcoidosis and cardiac symptoms, abnormal ECG, or cardiomegaly on chest radiograph must undergo transthoracic echocardiography, 24-hour Holter monitoring, and cardiac MRI with late gadolinium enhancement as the preferred advanced imaging modality. 4

Initial Screening Tests:

• Transthoracic echocardiography to assess ventricular systolic/diastolic dysfunction, wall-motion abnormalities, abnormal septal thickness, and measure LVEF 4
• 24-hour Holter monitoring to identify ventricular tachycardia and >100 ventricular ectopic beats in 24 hours 4
• ECG to detect conduction abnormalities, particularly AV block 4

Advanced Imaging:

• Cardiac MRI with late gadolinium enhancement is the imaging study of choice, showing mid-myocardial or subepicardial enhancement patterns and early T2-weighted enhancement indicating active inflammation 4
• Late gadolinium enhancement presence increases all-cause mortality and ventricular arrhythmia risk, with 4.9% per year risk of death or VT when present versus 0.24% per year when absent 1
• FDG-PET imaging serves as complementary or alternative imaging when MRI is contraindicated, identifying active myocardial inflammation and predicting adverse clinical events 4
• The presence of inflammation and right ventricular involvement on PET scanning increases risk of death 1

Risk Stratification with Electrophysiology Study:

• Electrophysiological study may identify inducible ventricular arrhythmias in patients with documented cardiac sarcoidosis but without spontaneous arrhythmias 1
• In one study, 11% of patients were inducible for sustained VAs, and 75% of inducible patients had spontaneous VT or died during 5-year follow-up versus minimal events in non-inducible patients 1
• However, inducibility correlates inversely with LVEF, and it remains unclear if EPS adds predictive value beyond LVEF alone 1

High-Risk Features Requiring Aggressive Treatment

The following features mandate immediate initiation of high-dose corticosteroids and consideration for device therapy: 4, 5

• Left ventricular ejection fraction <40% 5
• NYHA Functional Class III or IV 5
• Increased left ventricular end-diastolic diameter 5
• Late gadolinium enhancement on cardiac MRI 5
• Ventricular tachycardia 5
• Cardiac inflammation on FDG-PET scan 5
• Abnormal global longitudinal strain on echocardiography 5
• Interventricular septal thinning 5
• Elevated troponin or brain natriuretic peptide 5

Immunosuppressive Treatment

High-dose corticosteroids (prednisone 40-60 mg daily or 0.5 mg/kg/day, maximum 30 mg) should be initiated immediately in all patients with clinically manifest cardiac sarcoidosis, symptomatic patients with any cardiac involvement, and patients with high-risk features. 5

• Corticosteroid treatment improves survival, with 75% of steroid-treated patients surviving 5 years 5
• Taper slowly over months only if clinical and imaging features stabilize or improve 5
• Avoid rapid steroid tapers as this increases risk of disease relapse 5
• Steroids are most effective when given in early stages of disease; those with advanced LV dysfunction do not experience benefit 1
• Steroids do not reverse advanced ventricular dysfunction once present, supporting the importance of early diagnosis and intervention 1

Steroid-Sparing Agents:

• Methotrexate is the preferred first-line steroid-sparing agent, with evidence showing improved ejection fraction and brain natriuretic peptide when added to prednisone after 5 years 5
• Other agents (azathioprine, mycophenolate mofetil, cyclophosphamide, pentoxifylline, thalidomide) are reasonable in patients who cannot tolerate corticosteroids or continue to worsen despite treatment 1, 5

Important Caveats About Immunosuppression:

• Results with immunosuppression for reducing ventricular arrhythmias have been inconsistent 1
• Worsening of ventricular arrhythmias, including electrical storm, has been reported within 12 months of initiating glucocorticoid therapy in some patients 1
• A systematic combined approach using steroids plus antiarrhythmic medications, followed by radiofrequency catheter ablation if needed, was successful in 63% of patients 1

Heart Failure Management

Standard guideline-directed medical therapy for heart failure with reduced ejection fraction must be implemented, including ACE inhibitors/ARBs, beta-blockers, and aldosterone antagonists, regardless of immunosuppressive regimen. 1, 4, 5

• Duration of standard heart failure medications should be indefinite when left ventricular function fails to normalize 1
• Cardiac MRI or FDG-PET imaging should be used to follow response to therapy 5

Device Therapy

ICD placement is reasonable for all patients with cardiac sarcoidosis due to the high risk of sudden cardiac death, with several reports showing high frequency of appropriate ICD therapies for both primary and secondary prevention. 1, 4, 5

ICD Indications:

• Sudden cardiac arrest survivors 1
• Syncope and/or sustained ventricular tachycardia 1
• LVEF <35% 1
• Patients who are candidates for permanent pacemaker with cardiac sarcoidosis 1

Timing Considerations:

• It is reasonable to allow ≥6 months of standard medical therapy to allow for possible myocardial recovery before permanent device placement 1, 5
• Wearable defibrillator vests may be considered for patients with LVEF <35% while waiting for response to medical therapy 1, 5

Cardiac Resynchronization Therapy:

• CRT should be considered when ventricular function fails to normalize 1, 4, 5
• The frequency of conduction abnormalities often warrants a device that provides bradycardia pacing as well 1

Conduction Abnormalities

Patients presenting with high-degree atrioventricular block as the initial manifestation have similar risk of fatal cardiac events (including sustained VAs) as those presenting with VT and/or heart failure, despite fewer heart failure hospitalizations. 1

• Administration of steroids led to some clinical improvement with recovery of conduction in some patients, but effectiveness was not universal and did not appear protective against adverse cardiac events 1

Advanced Heart Failure Management

Referral for cardiac transplantation or mechanical circulatory support should be made for patients with advanced heart failure without significant extracardiac sarcoidosis. 5

• Patients with cardiac sarcoidosis undergoing transplantation have better short- and intermediate-term survival than patients transplanted for other reasons 5
• Sarcoidosis can recur in the transplanted heart as early as 24 weeks post-transplantation but usually responds to steroids 5
• Consider transplantation for end-stage heart failure or intractable arrhythmias 5

Critical Pitfalls to Avoid

The degree of pulmonary impairment does not predict cardiac involvement—patients with minimal pulmonary disease can have significant cardiac sarcoidosis. 6

• Isolated cardiac sarcoidosis occurs in approximately 5% of patients without pulmonary involvement and is particularly challenging to diagnose, requiring high index of suspicion 4, 5, 2
• Asymptomatic patients with concerning imaging features (late gadolinium enhancement or FDG-PET inflammation) represent diagnostic uncertainty, but lean toward treatment given high mortality stakes even when cardiac function is preserved and electrical abnormalities are absent 4, 5
• Cardiac sarcoidosis can mimic arrhythmogenic cardiomyopathy, giant cell myocarditis, dilated, restrictive, and hypertrophic cardiomyopathies 2
• Ventricular arrhythmias can occur in patients with relatively normal LV function, some with right ventricular involvement mimicking arrhythmogenic right ventricular cardiomyopathy 1