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Cardiac Sarcoidosis
Abdul Razek Maaty, MD
Professor of Cardiology

Sarcoidosis
 Sarcoidosis is an enigmatic disease for many reasons, not least due to its
exact cause and pathogenesis remaining hidden despite decades of focused
research
 Multi-system disease of unknown etiology characterized by non-caseating
granulomas in various organs.
 Any organ can be affected, leading to its highly variable clinical presentation
(great mimicker).
 ~ 90% of the cases, it affects the lungs and the intrathoracic lymph nodes.

Epidemiology of Sarcoidosis
 Incidence and prevalence vary even within countries (genetics and race,
environmental exposure and diagnosis)
 Not well known b/o presence of mimicking diseases (e.g., tuberculosis), lack
of diagnostic technology, expertise, and limited case registration.
 Annual incidence ~ 10 - 40 per 100,000 depending on the region and ethnicity
Lowest in Eastern Asian countries (0.5–1 per 100,000)
Higher in North America and Australia (5–10)
Highest in Northern European (Scandinavian) countries (11–15)
 Age (bimodal distribution, 25 and 60)
 Women > Men
 5% have a family history of sarcoidosis

Incidence and Prevalence of Sarcoidosis in Europe

Sarcoidosis
Pernio….Bad Nodosum ….Noble

Cardiac Sarcoidosis (CS)
 Patchy granulomatous pancarditis
 Second most common cause of death in sarcoidosis
 Diagnosis is a challenge (No single reliable test for diagnosis)
 Urgent recognition, early detection is mandatory to start therapy
 ~ 5 % of sarcoidosis (clinically evident)
 ~ 25 % of sarcoidosis (subclinical or asymptomatic) based on autopsy series
and recent imaging studies
 Women > men
 Association with HLA DQB*0601 and tumor necrosis factor allele TNFA2 has
been reported
 Prevalence of cardiac sarcoidosis appears to be increasing due to better and
more thorough imaging techniques

Pathophysiology of Sarcoidosis
Immunopathogenesis of Sarcoidosis
 Precise mechanism: Still unknown
 ? Crippled immunologic reaction against a novel and an unidentified antigen in
a genetically susceptible individual
 Antigens are phagocytosed by macrophages→ CD4+ T helper cells → release of
some cytokines
 CD4 activation skew the immune system→ Th1 and Th2 response → many
cytokines as IL-2, and IL-12→ non-caseating granuloma formation
 The human leukocyte antigen (HLA) system encoded by the major
histocompatibility (MHC) gene complex is associated with Sarcoidosis
 CD4+ T-cell immunological response has been linked to HLA genes, and
cardiac involvement is seen in specific subtypes, which include DQB1*0601 and
DRB1*0803 alleles

Different Pathways Through Which Genetic and
Environmental Factors Could Influence Sarcoidosis

Costabel, Eur Respir J 2001; Iannuzzi et al. NEJM 2007

Th1-cells
Th2-cells
Infectious agents Organic particles Inorganic particles
Fibrosis
Resolution
T-cell
HLA
BTNL2 (butyrophilin-like protein 2)
Antigen presenting cell
Granuloma
CD4+
T-cell
TNF-α, interleukins 12, -15, and -18, GM-CFS, MIP, MCP-1
Iannuzzi et al. NEJM 2007
Immunopathogenesis of sarcoidosis

Flowchart Depicting Pathogenesis of CS

Cardiac Sarcoidosis/ Abdul Razek Maaty/ Professor of Cardiology/ Mansoura Faculty of Medicine/ Mansoura/ Egypt 2025.ppt

Pathology of CS
Clinical History
This specimen is from a 30 y/o male who died
suddenly unexpectedly
.
Multiple yellow-white tumor-like infiltrates
(sarcoid lesions) are present throughout the heart
.
Non-caseating granulomas were present in his
heart, lungs, muscle, and other tissues
.
There was total effacement of conduction
system/bundle of His and massive replacement of
myocardium by granulomas and scarred areas
.

Pathology of CS
Gross Pathology
The image shows multiple yellow-
white infiltrates (microscopically -
sarcoid granulomas with scarring)
distributed throughout the
myocardium.
The patient was a 30 y/o who died
suddenly unexpectedly due to
cardiac sarcoidosis.

Pathology of CS
Gross Pathology
 Sarcoid granulomas affects all heart layers,
mainly myocardium .
 Most common sites: LV f free wall, papillary
muscles, and basal IVS, then RV and atria
 Granulomas are often distributed along the
lymphatics, especially numerous around
cardiac conduction system tracts. This
explains the pathogenesis of conduction
blocks and ventricular arrhythmias (which
are often fatal) in cardiac sarcoidosis.
 Grossly, the sarcoid lesions appear as diffuse,
irregular, yellow-gray tumor-like infiltrates
throughout the heart.
 Areas of fibrosis may be seen as slightly
depressed gray-white scars.
 Abnormal thinning of ventricular wall and/or
aneurysms may be present.

Pathology of CS
Microscopic pathology
 Scar-like lesions with non-caseating
epithelioid granulomas and
multinucleated giant cells throughout
the full thickness of the myocardium.
 Granulomas are distributed along the
lymphatics numerous around cardiac
conduction system tracts
 Granulomas are well-demarcated and
associated with a mononuclear
inflammatory infiltrate consisting of
histiocytes and small lymphocytes and
rarely, eosinophils may be present
 The surrounding myocytes are largely
unaffected and without significant
necrosis.
 Diffuse or focal interstitial fibrosis is
usually present

Pathology of CS
Microscopic pathology
The image shows a scar-like area of
interstitial fibrosis with
multinucleated giant cells and
lymphocytic infiltrate

Diagnosis of Cardiac Sarcoidosis
Diagnosis of cardiac sarcoidosis is challenging due to the low yield
of EMB, and the limited accuracy of various clinical criteria. Thus, no
gold standard diagnostic criterion exists.

Symptoms at Presentation and Main Manifestations of CS
in Two Large Cohorts

Biomarkers
Nonspecific and have not been included in any diagnostic algorithms for CS
Anemia, ↓ WBC count, ↑ ESR, ↑ CRP
↑
Troponin (T or I) specially (hs-cTnT)
↑
Plasma B-type natriuretic peptide
↑
Angiotensin-converting enzyme (ACE)
Hypercalcemia and ↑ urinary calcium levels
↑Serum Immunoglobulins
Soluble IL-2 receptor
Others :Th1-related cytokines, myeloid-related protein 8/14 complex,
U-8-OhdG, and microRNA

Echocardiography in CS
Thinning of basal septum in patient
with CS as seen on TTE
.
Thinning (arrow) is obvious when
compared with mid anteroseptum
(double-head arrow)
.

Tissue Biopsy
Extra-cardiac sites Cardiac (EMB)
First choice Second choice
Higher diagnostic yield Low diagnostic yield
Lower procedural risks Higher procedural risks
Lung or lymph node RV biopsy ( sites of lesions free LV wall> IVS> RV >
atria
Low sensitivity (non-caseating granulomas are seen
in less than 25% of cases) b/o focal nature of the
disease
Positive biopsy rate may reach ~ 50% (if we add EP
study, MRI or FDG/PET)
SPPIN and SNNOUT

Advanced Imaging
Delayed-phase contrast-
enhanced CT
“
one-stop shop” for evaluation of coronary artery disease,
systemic disease and cardiac involvement
CMR Anatomy/Function/Edema/Necrosis/Scarring
GE (Early/Late)
18
F-FDG-PET Glucose analog
Caveat: Physiologic glucose uptake→ False +ve results
*
Hybrid PET/CMR Single machine and examination that improves diagnostic
accuracy
*How to reduce physiologic glucose uptake
1-High-fat/ high-protein
2-Low-carbohydrate
3-Fasting
4-IV UFH
5-Novel tracers (somatostatin analogs, that targets
SSTRs and FLT)

Main histopathology features in the different patterns of
cardiac sarcoidosis and corresponding potential PET and MR
imaging findings

Sensitivities and Specificities of Imaging Modalities for the
Detection of CS
SPPIN and SNNOUT

Hybrid CMR/FDG-PET Algorithm for of CS

MRI and Histology Images of a Case of CS

Differential Diagnosis of CS
 Giant Cell Myocarditis Rapidly progressive disease
 Allergic (hypersensitivity)
Myocarditis
Allergic reaction to drugs or other
ingested compounds
 Lymphocytic Myocarditis After a viral infection (most
commonly respiratory)
 Tuberculous Myocarditis Biopsies show caseating granulomas
containing acid-fast bacilli
 Arrhythmogenic right ventricular
cardiomyopathy (ARVC)
 Desmoplakin cardiomyopathy Gene tests
 Hibernating myocardium Due to underlying obstructive CAD

Diagnosis of Cardiac Sarcoidosis
Major guidelines for the diagnosis of Cardiac Sarcoidosis
JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis
Guidelines from the Heart Rhythm Society (HRS 2014)
Guidelines for diagnosing CS from the Japanese Ministry of
Health Welfare 2006 (JMHW)
World Association of Sarcoidosis and Other Granulomatous
Disorders Sarcoidosis Organ (WASOG) Criteria 1999

Algorithm Adapted From the HRS Guidelines

(WASOG) Criteria for the Diagnosis of CS

CS Stepwise Approach to Therapy

Cardiac Sarcoidosis: Treatment (I)
 Disease modifying agent:
Corticosteroids
 Mechanism of action:
Unknown
 May improve prognosis
 Do not reduce the incidence of
VT
 May reduce the incidence of
VT during arrhythmia flare:
Contradictory data
 Disease activity monitoring
required to allow dose
reduction

Treatment (II)
 Treat secondary effects
 Antiarrhythmics
 No systematic studies
 May exacerbate (bradyarrhythmias)
 VT ablation
 PPM
 Frequently required
 ICD
 Recommended in patients with VT, regardless of LVEF
 Heart failure
 GDMT / CRT
 Cardiac transplantation: Rarely performed ( Disease may recur in
transplanted organ)

Current Recommendations by Expert Societies for an ICD in Patients
with CS

Case Presentation
 A 54-year-old man with a medical history of well-controlled hypertension
 Presentation: fatigue of several weeks that limited his usual exercise routine
 He was a long-distance runner/ getting tired easily/ had to walk instead of run
 No chest discomfort, palpitations, light-headedness, syncope, or SOB
 On examination: afebrile/ BP, 162/109 mmHg/ HR, 145 bpm/ no elevated
JVP/ no pedal edema/ lungs were clear to auscultation/ heart exam revealed
an irregular fast rhythm without any murmurs or additional heart sounds
 He did an ECG (comment)
 Laboratory workup, including troponin, was unremarkable
 He was given IV metoprolol in ED with successful conversion to sinus rhythm,
and he was admitted for further evaluation

 (A) ECG demonstrating wide complex tachycardia with right bundle branch
block morphology and superior axis, as well as capture beats, consistent
with ventricular tachycardia.
 (B) ECG taken following administration of beta-blocker and amiodarone
demonstrating sinus rhythm with diffuse repolarization change

Flow Chart Illustrating the Diagnostic Workup

Workup
 Chest CT No parenchymal lung disease/ no subcarinal or hilar
lymphadenopathy
 TTE Moderately depressed LV systolic function, with anterior,
anteroseptal, anterolateral, and apical akinesis
 Coronary angiogram Mild coronary artery disease
 Cardiac MRI Extensive LGE throughout LV and the free wall of the RV with
severe biventricular dysfunction
 SPECT Large resting perfusion defects in the anterior, apical, and
basal inferoseptal segments of LV
 FDG-18 (PET/CT) Marked fluorodeoxyglucose (FDG)-18 uptake in the same
myocardial segments as SPECT
 Transbronchial
biopsy
No target
 EMB Deferred due to overall low yield and convincing
multimodality imaging

Cardiac MRI
Cardiac MRI in the horizontal long-
axis view (A), revealing extensive
LGE in the myocardium of the left
ventricle (red arrows) and the short-
axis view (B), revealing LGE in the
free wall of the right ventricle (red
arrow)

Single Photon-Emitting Computed Tomography (SPECT)
SPECT images from the long-axis view, taken at rest, which
demonstrate large resting perfusion defects in the anterior, apical,
and basal inferoseptal segments of LV

Fluorodeoxyglucose (FDG)-18 PET/CT
(A) showing avid FDG-18 uptake in
the myocardium of the left ventricle
(black arrow) and following 4 months
of treatment with oral steroids
(B), with complete resolution of FDG-
18 uptake in the myocardium.

Follow-up
 The patient underwent placement of an ICD and discharged on amiodarone
and GDMT for LV systolic dysfunction, as well as prednisone 60 mg daily,
with a plan for a slow taper over months
 Four months later, he was readmitted with recurrent VT. On repeat imaging
with FDG-18 PET/CT, he demonstrated complete resolution of FDG-18
myocardial uptake
 However, LV dysfunction and regional wall motion abnormalities remained
unchanged on repeat TTE
 He underwent ablation procedure for VT, which resulted in a lower burden
of ventricular ectopy
 On outpatient follow-up, he is doing well with continued remission of FDG
myocardial uptake 9 months after his initial presentation
 He is still on low-dose steroids

CONCLUSIONS
Clinicians should consider workup for isolated cardiac sarcoidosis with either
cardiac MRI or FDG-PET in patients presenting with arrythmias and without
evidence to suggest other causes.

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Cardiac Sarcoidosis/ Abdul Razek Maaty/ Professor of Cardiology/ Mansoura Faculty of Medicine/ Mansoura/ Egypt 2025.ppt

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