Demystifying Cardiac Sarcoidosis: A Global Clinician’s Guide

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 Demystifying Cardiac Sarcoidosis: A Global Clinician’s Guide

Introduction

Cardiac sarcoidosis (CS), a serious manifestation of systemic sarcoidosis, is characterized by granulomatous infiltration of the heart. Though only 5 % of sarcoidosis patients have clinically overt cardiac involvement, up to 25–30 % are found to have cardiac lesions on autopsy or advanced imaging frontiersin.org. CS is globally underrecognized but can result in conduction blocks, arrhythmias, heart failure, and sudden death if not promptly diagnosed and managed mdpi.com+1en.wikipedia.org+1.

This article explores the latest science, guided by the recent work “Serial 18F-FDG PET to evaluate infliximab in steroid‑refractory cardiac sarcoidosis” sciencedirect.com+1cdt.amegroups.org+1, and synthesizes current understanding across disease domains.

Epidemiology

·         Incidence & Prevalence

o    Sarcoidosis affects approximately 10–40 per 100,000 in Europe/USA, with African Americans at 3.8× increased risk ncbi.nlm.nih.gov+13cdt.amegroups.org+13mdpi.com+13.

o    CS presents clinically in ~5 % of sarcoidosis cases; subclinical cardiac involvement may reach 25 % or higher frontiersin.org+2pmc.ncbi.nlm.nih.gov+2mdpi.com+2.

o    Japanese autopsy data suggest up to 58 % cardiac involvement, with CS accounting for up to 85 % of sarcoidosis-related deaths pmc.ncbi.nlm.nih.gov.

·         Age and Gender Trends

o    Peak onset between ages 20–34, with a second smaller peak in females over 50.

o    Slight male predominance; lifetime risk ~1–1.3 % in adults frontiersin.org.

Etiology & Pathophysiology

·         Unknown Etiology

o    CS arises in genetically predisposed individuals exposed to environmental triggers, leading to exaggerated T-cell–mediated granulomatous inflammation ncbi.nlm.nih.gov+5frontiersin.org+5academic.oup.com+5.

·         Genetic Factors

o    HLA associations: HLA-A1, B8, DR3, -DQB1*0601, and TNFA2 correlate with higher CS risk frontiersin.org.

o    Familial and twin studies highlight strong heritable risk .

·         Environmental & Infectious Triggers

o    Possible antigens: mycobacteria, Propionibacterium acnes, beryllium, fungal elements frontiersin.orgen.wikipedia.org.

·         Pathologic Cascade

o    Heart involvement begins with myocardial edema, progresses to non-caseating granulomas, then fibrosis and scarring arxiv.org+14frontiersin.org+14cdt.amegroups.org+14.

o    Granulomas develop patchily, primarily in the left ventricular septum and free wall arxiv.org+4frontiersin.org+4cdt.amegroups.org+4.

Clinical Presentation

CS manifestations are diverse:

1.       Conduction Abnormalities

o    AV block (first-degree to complete), bundle branch block, and bradyarrhythmias sciencedirect.com+11ncbi.nlm.nih.gov+11academic.oup.com+11.

2.       Ventricular Arrhythmias

o    Ventricular tachycardia or fibrillation, sometimes leading to sudden cardiac death cdt.amegroups.org.

3.       Heart Failure

o    Progressive LV dysfunction due to granuloma replacement fibrosis .

4.       Other Presentations

o    Syncope, palpitations, dyspnea, chest pain, orthopnea, peripheral edema .

Notably, 37 % of CS patients may be asymptomatic frontiersin.org+1mdpi.com+1.

Diagnostic Imaging Features

1.       ECG & Echocardiography

Spectrum of cardiac sarcoidosis by echocardiography.doi:10.1161/CIRCIMAGING.113.000867

·         ECG: PR prolongation, QRS changes, non-specific ST abnormalities; 20–50 % of sarcoidosis patients have ECG changes frontiersin.org.

A 33-year-old female with cardiac sarcoidosis and sustained ventricular tachyarrhythmia (VT). Panel A shows the patient’s resting electrocardiogram (ECG) with T-wave inversions in the inferolateral leads. Panel B shows left ventricular voltage MAP with red regions indicating low voltage areas with myocardial scar. Cardiac echo showed a slightly reduced left ventricular ejection fraction with inferobasal hypokinesia framed in blue color (C). A 12-lead ECG shows the clinical VT (D) from the basal posterolateral region, which was successfully ablated.

·         Transthoracic echo: wall motion abnormalities, septal thinning, aneurysms, LV dilation, RV dysfunction. Sensitivity ~70–84 %.

2. Cardiac Magnetic Resonance (CMR)


·         Detects edema (T2-weighted) and fibrosis/scar (late gadolinium enhancement, LGE).

·         CMR has high negative predictive value; the presence of LGE is a strong predictor of adverse events cdt.amegroups.org+1en.wikipedia.org+1.

3. 18F‑FDG PET

18F-FDG PET/CT false positive for cardiac sarcoidosis. Left panel: MIPs of patient no. 15 scanned after injection of ~370 MBq 18F-FDG and ~300 MBq 68Ga-DOTANOC. There was avid 18F-FDG uptake in all areas of the bone marrow and the spleen, indicating long-term infection. A few lymph nodes are visible in the upper mediastinum on the 68Ga-DOTANOC scan. Right panel: transaxial and coronal slices of the cardiac region revealed avid 18F-FDG uptake in the area around the aortic ostium (yellow arrows), which is often seen in aortic valve sclerosis, but can also be mistaken for uptake in a sarcoid lesion (SUVmax 7.6). Clear calcifications are seen around the posterior valve on the low-dose CT. On the 68Ga-DOTANOC scan (bottom), there is no activity above background in the myocardium. By contrast, activity is increased in the pericardium (yellow arrows), and some pericardial fluid is visible, indicating pericarditis. doi:10.1186/s13550-016-0207-6

·         Highlights myocardial inflammation with standardized uptake value (SUV).

·         Allows assessment of metabolic-inflammatory activity and guides immunosuppression cdt.amegroups.org+1frontiersin.org+1.

4. Endomyocardial Biopsy

·         Gold standard but limited sensitivity (<20–30 %) due to patchy disease cdt.amegroups.org.

5. Other Imaging

·         CT and nuclear scans (gallium, Thallium-201) can support diagnosis arxiv.org+14cdt.amegroups.org+14pmc.ncbi.nlm.nih.gov+14.

Discussion

Etiology & Pathophysiology

CS results from a complex interplay between genetic predisposition (e.g., HLA variants), environmental exposures (e.g., silica, microbial antigens), and dysregulated immunity, particularly Th1/Th17-mediated granuloma formation en.wikipedia.org+4frontiersin.org+4en.wikipedia.org+4. In the heart, this process leads to myocardial inflammation, granuloma development, edema, and subsequent fibrosis.

Epidemiology

Variable incidence worldwide—more common in high-latitude countries and certain ethnic groups, especially African Americans and Japanese pmc.ncbi.nlm.nih.gov+9cdt.amegroups.org+9frontiersin.org+9. Many cases remain subclinical, discovered only through imaging or autopsy.

Clinical Presentation

CS can be asymptomatic or manifest with conduction defects, sudden arrhythmias, heart block, or progressive heart failure. There's often a mismatch between symptom severity and disease burden mdpi.com+1pmc.ncbi.nlm.nih.gov+1en.wikipedia.org.

Imaging Features

CMR and PET are central to diagnosing and monitoring CS. CMR identifies inflammation/scarring via T2-weighted imaging and LGE; FDG-PET quantifies inflammatory activity. Echo and ECG are key initial screens en.wikipedia.org+3cdt.amegroups.org+3mdpi.com+3.

Treatment

·         First-line: High-dose corticosteroids—typically prednisone 0.5–1 mg/kg/day .

·         Steroid-sparing/immunosuppressants: Methotrexate, azathioprine, mycophenolate, cyclophosphamide (selective), calcineurin inhibitors, anti-TNF agents like infliximab for refractory cases .

·         Device therapy: Pacemakers for AV block, ICDs for ventricular arrhythmias or reduced LVEF en.wikipedia.org+2cdt.amegroups.org+2frontiersin.org+2.

·         Advanced intervention: Ablation for recurrent arrhythmia; heart transplant if CHF is terminal .

The referenced study highlights infliximab’s efficacy in steroid-refractory cardiac sarcoidosis via serial FDG-PET sciencedirect.com+4sciencedirect.com+4cdt.amegroups.org+4.

Prognosis

·         Presence of myocardial scar and active inflammation predicts higher risk of arrhythmia, sudden death, and heart failure cdt.amegroups.org+1en.wikipedia.org+1.

·         Mortality remains substantial in untreated cases—prompt diagnosis and tailored immunosuppression plus device support improve outcomes.

Quiz:

1.       What is the first-line pharmacologic treatment for cardiac sarcoidosis?

o    A) Infliximab

o    B) Prednisone

o    C) Methotrexate

o    D) Cyclophosphamide

Answer: B) Prednisone
Explanation: Glucocorticoids (e.g., prednisone) are the primary therapy due to their effectiveness in reducing myocardial inflammation. Other immunosuppressants are used as adjuncts or steroid-sparing agents.

2.       Which advanced cardiac imaging modality is most sensitive for detecting myocardial inflammation in CS?

o    A) Endomyocardial biopsy

o    B) Transthoracic echocardiography

o    C) ^18F‑FDG PET

o    D) Non-contrast MRI

Answer: C) ^18F‑FDG PET
Explanation: ^18F‑FDG PET is highly sensitive in detecting active granulomatous inflammation (cellular activity), while MRI shows edema and scar, and biopsy has limited sensitivity due to patchy involvement.

3.       Which ECG finding is most commonly associated with cardiac sarcoidosis?

o    A) Atrial fibrillation

o    B) Left bundle branch block

o    C) Second- or third-degree AV block

o    D) Prolonged QT interval

Answer: C) AV Block
Explanation: AV conduction abnormalities (e.g., first-to-complete block) are among the most frequent ECG findings in CS due to granulomatous infiltration of the conduction system.

Summary

Cardiac sarcoidosis is a global health concern marked by granulomatous myocardial involvement, often underdiagnosed due to its subtle presentation. Key diagnostic tools—ECG, echo, CMR, and FDG-PET—are central to assessment. First-line therapy with corticosteroids, supplemented as needed with immunosuppressants and device interventions, aims to quell inflammation, prevent arrhythmia, and improve survival. Advanced therapies like infliximab are promising for steroid-refractory cases. Early detection and treatment are paramount in altering the course of this potentially fatal condition.

References

1.       Osborne MT, Hulten E, et al. Cardiac sarcoidosis—state of the art review. Cardiovasc Diagn Ther. 2016;6(3):201–215.

2.       Birnie DH, Sauer WH, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11(7):1305–1323.

3.       Hulten EA, Molina DR, et al. Cardiovascular diagnosis & therapy: Cardiac sarcoidosis review. Cardiovasc Diagn Ther. 2016;6(3):201–215.

4.       Shah HH, Zehra SA, et al. Cardiac sarcoidosis: a comprehensive review of risk factors, pathogenesis, diagnosis, clinical manifestations, and treatment strategies. Front Cardiovasc Med. 2023;10:1156474.

5.       Crouser ED, Ono C, Tran T, et al. Improved detection of cardiac sarcoidosis using magnetic resonance with myocardial T2 mapping. Am J Respir Crit Care Med. 2014;189(1):109–112.

6.       Yodogawa K, Seino Y, Ohara T, et al. Effect of corticosteroid therapy on ventricular arrhythmias in patients with cardiac sarcoidosis. Ann Noninvasive Electrocardiol. 2011;16(2):140–147.

7.       Myung‑Jin Cha, et al. Histopathologic indicators in cardiac sarcoidosis biopsies. J Pathol Transl Med. 2014;48(4):345–352.

8.       Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with ^18F‑FDG PET and MRI in sarcoidosis. Eur J Nucl Med Mol Imaging. 2008;35(5):933–941.

9.       Osborne MT, et al. MRI predicts survival free of arrhythmia in CS. J Am Heart Assoc. 2016;5(1):e003022.

10.    Youssef G, Leung E, Mylonas I, et al. The use of ^18F‑FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and meta‑analysis. J Nucl Med. 2012;53(2):241–248.

11.    Nery PB, Beanlands RS, Nair GM, et al. AV block as initial manifestation of CS. J Cardiovasc Electrophysiol. 2014;25(8):875–881.


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