What is the recommended diagnostic workup for suspected cardiac sarcoidosis in a 20‑ to 50‑year‑old adult presenting with unexplained atrioventricular block, ventricular arrhythmias, heart failure, or syncope, especially when extracardiac sarcoidosis is known?

Diagnosis of Cardiac Sarcoidosis

Direct Answer

In adults aged 20-50 presenting with unexplained AV block, ventricular arrhythmias, heart failure, or syncope, perform baseline ECG screening immediately, followed by cardiac MRI with late gadolinium enhancement if the ECG is abnormal or clinical suspicion remains high despite a normal ECG, and pursue tissue diagnosis from the most accessible site to confirm noncaseating granulomas while excluding alternative causes. 1, 2

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Diagnostic Algorithm

Step 1: Initial Clinical Recognition and ECG Screening

• Maintain high clinical suspicion in patients aged ≤60 years presenting with unexplained high-grade AV block (Mobitz type II or third-degree) or ventricular tachycardia, as approximately 30-34% of such patients have cardiac sarcoidosis. 3, 4

• Perform baseline ECG immediately on all patients with suspected cardiac involvement, even if asymptomatic, as this is inexpensive, noninvasive, and widely accessible. 1, 2

• Recognize ECG limitations: ECG has low sensitivity for detecting cardiac sarcoidosis, and a normal ECG does NOT exclude the diagnosis; combined ECG and echocardiography sensitivity is only 32%. 2

Step 2: Advanced Cardiac Imaging

• If ECG is abnormal, cardiac symptoms are present, or clinical suspicion remains high despite normal ECG, proceed immediately to cardiac MRI with late gadolinium enhancement (LGE) as the first-line advanced imaging modality. 1, 2

• Cardiac MRI is superior to echocardiography for detecting myocardial inflammation and fibrosis; abnormal LGE predicts 9-fold increased cardiac mortality, 11.7-fold increased ventricular arrhythmias, and 11.9-fold increased heart failure events. 2

• If cardiac MRI is unavailable or contraindicated, use dedicated cardiac PET scan with FDG as the second-choice imaging modality to identify active inflammation. 1, 2

• Do NOT perform routine transthoracic echocardiography or 24-hour Holter monitoring in asymptomatic patients with normal ECG, as these have insufficient sensitivity. 1, 2

Step 3: Tissue Diagnosis and Histopathologic Confirmation

• Pursue tissue sampling for histopathologic confirmation of noncaseating granulomas from the most accessible involved site to establish definitive diagnosis. 1

• Endomyocardial biopsy (EMB) is reasonable in patients with unexplained heart failure >3 months' duration associated with dilated left ventricle and new ventricular arrhythmias, Mobitz type II or third-degree AV block, or failure to respond to usual care within 1-2 weeks. 5

• Recognize EMB limitations: The sensitivity of EMB for cardiac sarcoidosis is only 20-30% due to the heterogeneous, patchy distribution of granulomas in the myocardium, leading to sampling error. 5

• If extracardiac sarcoidosis is known, combine extracardiac histology with cardiac clinical manifestations and imaging findings to achieve sufficient diagnostic likelihood without requiring cardiac biopsy. 6

• Exception to tissue requirement: For patients presenting with Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome, tissue sampling is NOT required due to sufficiently high diagnostic specificity. 1

Step 4: Systematic Screening for Multiorgan Involvement

Even in patients presenting with isolated cardiac symptoms, systematically screen for extracardiac involvement:

• Chest imaging: High-resolution CT scan to detect bilateral hilar adenopathy, perilymphatic nodules, and parenchymal infiltrates. 1

• Serum calcium: Screen for abnormal calcium metabolism, which occurs even without symptoms. 1

• Serum creatinine: Screen for renal involvement. 1

• Serum alkaline phosphatase: Screen for hepatic involvement. 1

• Vitamin D levels: Measure both 25-OH and 1,25-OH vitamin D if assessment is needed, as granulomas produce excess 1α-hydroxylase causing hypercalcemia. 1

• Ophthalmologic examination: Screen for uveitis, optic neuritis, scleritis, or retinitis. 1

• Whole-body FDG-PET scan: Consider for detecting multiorgan involvement and guiding biopsy sites, particularly when isolated cardiac sarcoidosis is suspected. 1, 4

Step 5: Establish Definitive Diagnosis

The diagnosis of cardiac sarcoidosis requires three pillars:

1. Compatible clinical and radiologic presentation (AV block, ventricular arrhythmias, heart failure, abnormal cardiac imaging). 1

2. Pathologic evidence of noncaseating granulomas (either from cardiac or extracardiac tissue). 1

3. Exclusion of alternative causes of granulomatous disease, including infections (tuberculosis), berylliosis, hypersensitivity pneumonitis, vasculitis, and drug-induced sarcoid-like reactions. 1

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Critical Diagnostic Pitfalls to Avoid

• Do not rely solely on serum ACE levels, as they lack adequate sensitivity and specificity for diagnosis. 1

• Do not assume isolated cardiac disease will remain isolated: Approximately 50% of patients with granulomatous inflammation in the heart have no evidence of extracardiac disease at presentation, but many develop systemic involvement over time. 5

• Do not miss cardiac involvement in patients with known extracardiac sarcoidosis: Cardiac involvement occurs in approximately 25% of sarcoidosis patients and is the second leading cause of death after pulmonary involvement. 5, 2

• Do not delay investigation in young patients with unexplained conduction disease: In the prospective study by Nery et al., 34% of patients aged ≤60 years with unexplained AVB had previously undiagnosed cardiac sarcoidosis, and 27% of those with CS experienced adverse events including heart failure and recurrent VT. 4

• Consider the "presumed cardiac sarcoidosis" category for patients without histologic evidence but with unexplained high-grade AV block or ventricular arrhythmia plus suggestive findings on cardiac MRI or PET, as these patients have similar high-risk outcomes to those with biopsy-proven disease. 7

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Specialist Referrals

• Cardiologist: Refer all patients with ECG abnormalities, cardiac symptoms, or abnormal cardiac imaging for management of conduction disturbances, arrhythmias, and heart failure. 1

• Pulmonologist: Refer for bronchoscopy with BAL and transbronchial biopsy if pulmonary involvement is suspected, as EBUS-guided lymph node sampling has 87% diagnostic yield. 1

• Ophthalmologist: Refer for baseline eye examination even in asymptomatic patients. 1

• Nephrologist: Refer if elevated creatinine, hypercalciuria, or nephrolithiasis are present. 1