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Definitions

3

2014 Heart Rhythm Society (HRS) expert consensus criteria

The 2014 HRS international expert consensus statement is the most widely used framework in Europe and North America. It allows a clinical diagnosis of cardiac sarcoidosis from histologically proven extracardiac sarcoidosis plus a qualifying cardiac abnormality (high-grade AV block, ventricular arrhythmia, reduced LVEF, or characteristic CMR/FDG-PET findings), with histologic diagnosis reserved for myocardial biopsy. Its screening arm is symptoms plus electrocardiography plus conventional echocardiography.

DIAGNOSTIC_CRITERIA Clinical and histologic diagnosis of cardiac involvement in sarcoidosis

Show evidence (2 references)

PMID:37123482 SUPPORT Human Clinical

"Also, in 2014, the Heart Rhythm Society (HRS) published their international guideline document."

Establishes the 2014 HRS document as one of the three standing cardiac-sarcoidosis guideline frameworks.

PMID:40445485 SUPPORT Human Clinical

"Heart Rhythm Society (HRS) screening algorithm is commonly used and comprises the presence of cardiac symptoms, electrocardiography and conventional echocardiography."

Specifies the three components of the HRS screening arm, which is why echocardiography is curated as a first-line diagnostic rung in this entry.

2016 Japanese Circulation Society (JCS) guideline criteria

The JCS guideline is the Japanese national framework, developed by a community that has led cardiac-sarcoidosis guideline work. It differs from HRS in both diagnostic thresholds and management triggers - for example it recommends an electrophysiological study in all patients with LVEF 35-50% - and it is markedly more restrictive than HRS when both are applied to the same cohort.

DIAGNOSTIC_CRITERIA Clinical and histologic diagnosis and management of cardiac sarcoidosis

Show evidence (2 references)

PMID:37123482 SUPPORT Human Clinical

"The Japanese Circulation Society (JCS) recently published new guidelines for the diagnosis and treatment of Cardiac Sarcoidosis (CS)."

Establishes the JCS guideline as a distinct diagnostic and treatment framework.

PMID:37123482 SUPPORT Human Clinical

"The 2016 JCS document is broadly similar, with the major exception that it is recommended that all patients with LVEF 35-50% should have an EP study."

Documents a concrete management divergence between the JCS and HRS frameworks, supporting the description's claim that they differ in practice and not only in wording.

WASOG Sarcoidosis Organ Assessment Instrument

The WASOG instrument is not a cardiac-specific guideline but an organ-involvement probability tool covering all sarcoidosis organs, grading each clinical manifestation as highly probable, probable, or possible evidence of sarcoidosis involvement in that organ. It requires histologic granulomatous inflammation in some other organ and exclusion of alternative causes, so it classifies cardiac involvement probabilistically rather than issuing a binary cardiac diagnosis.

DIAGNOSTIC_CRITERIA Probability of sarcoidosis involvement of a given organ, including the heart

Show evidence (3 references)

PMID:24751450 SUPPORT Human Clinical

"the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) developed a new sarcoidosis organ assessment instrument"

Establishes the instrument and its issuing body.

PMID:24751450 SUPPORT Human Clinical

"Clinical manifestations were assessed as either: a) highly probable: likelihood of sarcoidosis causing this manifestation of at least 90%.; b) probable: likelihood of sarcoidosis causing this manifestation of between 50 and 90%; c) possible: likelihood of sarcoidosis causing this manifestation..."

Gives the probabilistic grading that distinguishes WASOG from the binary HRS and JCS cardiac diagnoses.

PMID:37123482 SUPPORT Human Clinical

"There are two other guideline documents, the World Association of Sarcoidosis and Other Granulomatous Disorders Sarcoidosis Organ (WASOG) Assessment Instrument created in 1999 and updated in 2014."

Places WASOG alongside HRS and JCS as one of the three standing frameworks.

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Inheritance

1

Multifactorial susceptibility

Cardiac sarcoidosis is not a Mendelian disorder. It arises in genetically susceptible individuals as an organ-specific expression of systemic sarcoidosis, whose susceptibility is polygenic (HLA and non-HLA alleles); no causal gene is established for the cardiac phenotype specifically, and MONDO:0001707 records no causal gene relation.

Show evidence (1 reference)

PMID:36924191 SUPPORT Human Clinical

"Major progress in the care of CS awaits the key to its molecular-genetic pathogenesis and large-scale controlled clinical trials."

Supports the absence of an established molecular-genetic basis for cardiac sarcoidosis indirectly, by naming it as an outstanding research need rather than asserting a specific inheritance model.

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Subtypes

2

Isolated cardiac sarcoidosis

Sarcoid granulomatous disease confined to the heart, without demonstrable extracardiac organ involvement. Diagnostically the hardest form (no extracardiac biopsy target) and prognostically the worst.

Show evidence (2 references)

PMID:41193496 SUPPORT Human Clinical

"Isolated cardiac sarcoidosis is a distinct entity of sarcoidosis characterized by disease confined exclusively to the heart, without involvement of other organs."

Defines the isolated cardiac subtype as a distinct entity.

PMID:41193496 SUPPORT Human Clinical

"Compared with multi-organ cardiac sarcoidosis, isolated cardiac sarcoidosis is associated with lower left ventricular ejection fraction and poorer survival."

Establishes the prognostic separation of the isolated subtype from multi-organ disease.

Cardiac sarcoidosis with extracardiac involvement

Cardiac involvement occurring in a patient with demonstrable extracardiac sarcoidosis, either as the presenting organ or superimposed on established systemic disease. Extracardiac histology can substitute for myocardial biopsy in the diagnostic pathway.

Show evidence (1 reference)

PMID:36924191 SUPPORT Human Clinical

"CS can appear as the first or only organ manifestation of sarcoidosis or on top of pre-existing extracardiac disease."

Distinguishes cardiac-first and superimposed presentations from isolated disease.

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Discussions and Knowledge Gaps

3

Does immunosuppression in cardiac sarcoidosis reduce ventricular arrhythmia burden or mortality, or only recover atrioventricular conduction and stabilize left ventricular function?

KNOWLEDGE GAP OPEN gap_cardiac_sarcoidosis_immunosuppression_arrhythmia_mortality

Attached to

pathophysiology#Active Granulomatous Myocardial Inflammation pathophysiology#Scar-Mediated Re-entrant Ventricular Tachyarrhythmia

The curated treatment chain models corticosteroids as inhibiting the active inflammatory node, which is well supported for AV conduction recovery and for prevention of LV functional deterioration. It is deliberately NOT extended to the scar-mediated arrhythmia node, because the systematic review of 34 publications and 1297 patients found no randomized trials and explicitly declined to draw conclusions for ventricular arrhythmia and mortality. This matters mechanistically: if arrhythmic risk is carried by fixed scar rather than by active inflammation, suppressing inflammation should not be expected to abolish it, and the persistence of VT after PET normalization is consistent with that. Curators must not add a treatment edge from immunosuppression to the arrhythmia node on current evidence.

Proposed experiments

Randomized trial of immunosuppression with arrhythmic endpoints

exp_cardiac_sarcoidosis_rct_arrhythmic_endpoints

A randomized controlled trial of corticosteroid-based versus steroid-sparing immunosuppression in clinically manifest cardiac sarcoidosis, powered for device-detected ventricular arrhythmia burden and all-cause mortality rather than for imaging surrogates.

Show evidence (1 reference)

PMID:34472360 SUPPORT Human Clinical

"The data quality is too limited to draw conclusions for ventricular arrhythmias and mortality."

The systematic review's own statement of the evidence gap this discussion records.

Why do sex and race modify the presenting phenotype and arrhythmic risk of cardiac sarcoidosis, and does this reflect biology or differential ascertainment and treatment?

KNOWLEDGE GAP OPEN gap_cardiac_sarcoidosis_sex_race_phenotype_modifiers

Attached to

pathophysiology#Myocardial Non-Caseating Granuloma Formation pathophysiology#Progressive Ventricular Dysfunction and Heart Failure

A tertiary-center cohort of 252 patients found that women and Black patients more often presented with symptomatic heart failure, while male sex carried more than twice the adjusted hazard of ventricular arrhythmia - i.e. the same granulomatous lesion appears to distribute its downstream consequences differently by sex and race. Treatment also differed by group. Nothing in the curated mechanism explains this, and the study cannot separate a biological modifier of the granulomatous or fibrotic response from differences in referral, diagnosis, and management.

Show evidence (2 references)

PMID:37062472 SUPPORT Human Clinical

"At presentation with CS, females vs males (P = 0.001) and Black vs White individuals (P = 0.001) more commonly had symptomatic heart failure (HF), with HF most common in Black females"

Documents the sex and race differences in presenting phenotype.

PMID:37062472 SUPPORT Human Clinical

"Male sex had an adjusted hazard ratio of 2.34 (95% CI 1.13, 4.80; P = 0.021) for ventricular arrhythmia."

Quantifies the sex difference in arrhythmic risk that this gap concerns.

Which of the three competing cardiac sarcoidosis criteria frameworks (2014 HRS, 2016 JCS, WASOG) identifies the patients who actually have myocardial granulomas, given that they classify substantially different fractions of the same cohort?

KNOWLEDGE GAP OPEN gap_cardiac_sarcoidosis_criteria_framework_discordance

Attached to

pathophysiology#Myocardial Non-Caseating Granuloma Formation pathophysiology#Active Granulomatous Myocardial Inflammation

This entry curates three diagnostic frameworks because no one of them is authoritative, and they are not interchangeable. Applied to the same 324-patient cohort of histologically proven sarcoidosis with suspected cardiac involvement, the HRS consensus criteria classified 22.7% of women and 36.0% of men as having cardiac sarcoidosis, while the 2016 JCS criteria classified 8.0% and 19.3% - roughly a two- to threefold difference in the same patients. Because definite diagnosis requires myocardial biopsy and biopsy sensitivity is low, there is no accessible gold standard against which to adjudicate, so the disagreement cannot currently be resolved by comparison to truth. This is not a curation gap in this entry; it is the defining clinical problem of the disease, and it propagates into every cohort-derived number curated here - prevalence, phenotype frequencies, and treatment-response rates all depend on which framework selected the cohort.

Proposed experiments

Outcome-anchored head-to-head comparison of HRS, JCS and WASOG criteria

exp_cardiac_sarcoidosis_criteria_head_to_head_outcome_anchored

Apply all three frameworks prospectively to a single multicentre cohort of patients with suspected cardiac sarcoidosis and adjudicate them not against each other but against hard downstream outcomes (device-detected ventricular arrhythmia, heart failure hospitalization, sudden cardiac death) and, where tissue becomes available through transplantation or autopsy, against myocardial histology. Report reclassification between frameworks and the outcome yield of the patients each framework uniquely captures or uniquely misses.

Show evidence (2 references)

PMID:34546787 SUPPORT Human Clinical

"less often met criteria for a clinical diagnosis of cardiac sarcoidosis (Heart Rhythm Society consensus criteria, 22.7% versus 36.0%; P=0.012 and 2016 Japanese Circulation Society guideline criteria, 8.0% versus 19.3%; P=0.005), indicating lesser cardiac involvement"

Reports both frameworks applied to the same cohort, giving the paired percentages that quantify their discordance. The paper's own subject is sex differences, so the framework comparison is read off its data rather than being its stated conclusion.

PMID:36924191 SUPPORT Human Clinical

"Definite diagnosis of CS requires myocardial biopsy and histopathology, but a sufficient diagnostic likelihood can be achieved by combining extracardiac histology of sarcoidosis with clinical manifestations and findings on cardiac imaging."

Establishes that the frameworks exist precisely because the histologic gold standard is usually unavailable, which is why the discordance cannot be adjudicated directly.

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Pathophysiology

7

Antigen-Driven CD4+ T-Cell and Macrophage Activation

As in sarcoidosis at any other site, an unidentified poorly degradable antigen encountered by a genetically susceptible host drives antigen presentation to CD4+ T cells, Th1-skewed cytokine production (IL-2, TNF, IFN-gamma), and sustained macrophage activation. This upstream immune program is shared with systemic sarcoidosis and is not cardiac-specific; it is curated here because it is the trigger of the cardiac chain that follows.

CD4-positive helper T cell CL:0000492 T-helper 1 cell CL:0000545 macrophage CL:0000235

T cell activation GO:0042110 ↑ INCREASED antigen processing and presentation GO:0019882 ↑ INCREASED macrophage activation GO:0042116 ↑ INCREASED cytokine production GO:0001816 ↑ INCREASED

Downstream

Myocardial Non-Caseating Granuloma Formation Sustained Th1/macrophage activation in the myocardium organizes into epithelioid-cell granulomas, the defining lesion of cardiac sarcoidosis.

Show evidence (1 reference)

ORPHA:797 SUPPORT Other

"A rare multisystemic, autoinflammatory disorder of unknown etiology characterized by the formation of immune, non-caseating granulomas in any organ(s), leading to variable clinical symptoms and severity."

Orphanet establishes the systemic autoinflammatory granuloma-forming process that this node represents upstream of cardiac localization.

Myocardial Non-Caseating Granuloma Formation

Activated macrophages within the myocardium undergo the defining granulomatous transformations - differentiation into tightly packed epithelioid cells and fusion into multinucleated giant cells - producing compact non-caseating granulomas cuffed by lymphocytes. Distribution is characteristically patchy and multifocal, favouring the left ventricular free wall, the interventricular septum, and the right ventricle. This patchiness is directly responsible for the low sensitivity of endomyocardial biopsy.

epithelioid macrophage CL:0000235 CD4-positive helper T cell CL:0000492

granuloma formation GO:0002432 ↑ INCREASED Macrophage fusion into multinucleated giant cells GO:0000768 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

myocardium UBERON:0002349 interventricular septum UBERON:0002094

Downstream

Active Granulomatous Myocardial Inflammation Established granulomas sustain an actively inflamed, oedematous myocardial focus with inflammatory-cell infiltration of surrounding working myocardium and conduction tissue.

Show evidence (3 references)

PMID:31769474 SUPPORT Human Clinical

"Although granulomas are often composed of tight epithelioid macrophage aggregates, early granulomas comprise loosely associated macrophages with lymphocyte predominance."

Pathology series documents the epithelioid macrophage aggregate that defines the myocardial granuloma, and its lymphocyte-predominant early form.

PMID:31769474 SUPPORT Human Clinical

"Irregular left ventricular free wall involvement is most common, followed by the interventricular septum and right ventricle."

Establishes the anatomical distribution and the irregular (patchy) character of myocardial involvement curated on this node.

PMID:36924191 SUPPORT Human Clinical

"Definite diagnosis of CS requires myocardial biopsy and histopathology, but a sufficient diagnostic likelihood can be achieved by combining extracardiac histology of sarcoidosis with clinical manifestations and findings on cardiac imaging."

Confirms that the granulomatous lesion of this node is the histopathologic referent that defines the disease.

Active Granulomatous Myocardial Inflammation

An actively inflamed myocardial focus - oedema, glucose-avid inflammatory cells, and injury to adjacent cardiomyocytes and specialized conduction tissue. This is the potentially reversible stage: conduction disturbance arising from inflammation rather than from established scar can recover under immunosuppression. FDG avidity of these lesions is the basis of PET imaging and of treatment monitoring.

cardiac muscle cell CL:0000746 macrophage CL:0000235

inflammatory response GO:0006954 ↑ INCREASED cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED

myocardium UBERON:0002349

Downstream

Conduction System Involvement and Atrioventricular Block Active inflammation involving the basal septum and the atrioventricular conduction axis impairs AV conduction. Because this arm is inflammatory rather than fibrotic, it is the arm that can reverse with corticosteroid therapy.

Post-Inflammatory Replacement Fibrosis and Myocardial Scar Granulomas that persist rather than resolve evolve into replacement fibrosis, converting a reversible inflammatory lesion into fixed myocardial scar.

Show evidence (1 reference)

PMID:28501519 SUPPORT Human Clinical

"Late gadolinium enhancement was present in 22%, indicating myocardial involvement, and 70% had corresponding hyper-intense T2 signal indicating active inflammation."

T2 hyper-intensity co-localizing with sarcoid myocardial involvement is the imaging correlate of the active inflammatory state this node represents.

Conduction System Involvement and Atrioventricular Block

Granulomatous inflammation and scar involving the basal interventricular septum and the atrioventricular conduction axis interrupt AV conduction, producing Mobitz II second-degree or third-degree block. High-grade AV block is the single most common presenting manifestation of cardiac sarcoidosis and is frequently the only one at presentation ("lone AVB"). It is the cardiac consequence that most sharply distinguishes this entry from sarcoidosis at other sites.

cardiac conduction GO:0061337 ↓ DECREASED

atrioventricular node UBERON:0002352 interventricular septum UBERON:0002094

Downstream

Atrioventricular Block Conduction-axis involvement manifests clinically as symptomatic high-grade atrioventricular block.

Show evidence (2 references)

PMID:31230070 SUPPORT Human Clinical

"High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%)"

Quantifies high-grade AV block as the most frequent first sign of cardiac sarcoidosis in a nationwide series of 351 cases.

PMID:27443438 SUPPORT Human Clinical

"The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure."

Names conduction abnormality as one of the three principal manifestations that this and the two sibling consequence nodes represent.

Post-Inflammatory Replacement Fibrosis and Myocardial Scar

Persistent granulomas are replaced by collagenous scar. The resulting fibrosis is patchy and multifocal - confluent in the right ventricle, patchier in the left with a predilection for the basal septum, anterior wall, and perivalvular regions - and it is fixed: unlike the inflammatory stage it does not regress with immunosuppression. Scar burden on late gadolinium enhancement is the durable arrhythmic and functional substrate of the disease.

fibroblast of cardiac tissue CL:0002548 myofibroblast CL:0000186

extracellular matrix organization GO:0030198 ↑ INCREASED collagen fibril organization GO:0030199 ↑ INCREASED

myocardium UBERON:0002349

Downstream

Scar-Mediated Re-entrant Ventricular Tachyarrhythmia Patchy scar interleaved with surviving myocyte bundles creates zones of slow conduction and unidirectional block, the classic substrate for macro-re-entrant ventricular tachycardia.

Progressive Ventricular Dysfunction and Heart Failure Loss of contractile myocardium to granuloma and scar, together with adverse remodeling of the residual myocardium, produces progressive ventricular dysfunction.

Show evidence (3 references)

PMID:25527825 SUPPORT Human Clinical

"Left ventricular scarring was patchy with a predilection for the basal septum, anterior wall, and perivalvular regions."

Voltage mapping characterizes the patchy distribution and regional predilection of the scar curated on this node.

PMID:28501519 SUPPORT Human Clinical

"Late gadolinium enhancement was 18%+/-9.7% of overall left ventricular (LV) mass and most commonly located in the basal to mid septum."

Cardiac MRI localizes the late gadolinium enhancement (scar) of this node to the basal-to-mid septum, matching the electroanatomic findings.

PMID:31769474 SUPPORT Human Clinical

"Chronic disease leads to fibrosis and end-stage heart failure."

Pathology review anchors replacement fibrosis as the chronic-stage lesion.

Scar-Mediated Re-entrant Ventricular Tachyarrhythmia

Fixed myocardial scar sustains multiple macro-re-entrant circuits. Both ventricles contribute: right ventricular scar is widespread and confluent (with epicardial extent exceeding the endocardial), while left ventricular scar is patchy. Because the substrate is structural rather than a primary channelopathy, arrhythmia can persist after inflammation has resolved on PET - which is why suppressing inflammation does not by itself abolish arrhythmic risk.

cardiac conduction GO:0061337 ⚠ ABNORMAL regulation of heart rate GO:0002027 ⚠ ABNORMAL

myocardium UBERON:0002349

Downstream

Ventricular Tachycardia Re-entrant circuits within sarcoid scar generate sustained and non-sustained ventricular tachycardia.

Sudden Cardiac Death Degeneration of scar-mediated ventricular tachycardia to fibrillation, and high-grade conduction block, underlie sudden death - which is frequently the first recognized event and often occurs in patients whose cardiac granulomas were never diagnosed in life.

Show evidence (2 references)

PMID:25527825 SUPPORT Human Clinical

"Voltage maps showed widespread and confluent right ventricular scarring."

Documents the confluent right ventricular scar component of the arrhythmogenic substrate this node represents.

PMID:28501519 SUPPORT Human Clinical

"The presence of LGE was highly correlated with clinically significant arrhythmias and lower LVEF."

Links imaging-quantified scar burden to clinically significant arrhythmia, supporting scar as the arrhythmic substrate.

Progressive Ventricular Dysfunction and Heart Failure

Cumulative replacement of contractile myocardium by granuloma and scar, together with remodeling of the residual myocardium, produces falling ejection fraction and clinical heart failure. The extent of left ventricular dysfunction is the strongest prognostic determinant in clinically manifest disease, and end-stage cases proceed to mechanical support or transplantation.

cardiac muscle contraction GO:0060048 ↓ DECREASED heart contraction GO:0060047 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Congestive Heart Failure Progressive contractile failure manifests clinically as congestive heart failure.

Show evidence (3 references)

PMID:27443438 SUPPORT Human Clinical

"In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis."

Establishes left ventricular dysfunction - the state this node represents - as the dominant prognostic variable.

PMID:31769474 SUPPORT Human Clinical

"Chronic disease leads to fibrosis and end-stage heart failure."

Pathologic confirmation of the fibrosis-to-end-stage-heart-failure endpoint.

PMID:33059834 SUPPORT Human Clinical

"CS is problematic to diagnose and may cause significant morbidity and death from heart failure or ventricular arrhythmias."

Names heart failure alongside ventricular arrhythmia as the two dominant causes of death, the two terminal arms of this pathograph.

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Histopathology

1

Non-caseating granulomatous myocarditis

Compact non-caseating granulomas of epithelioid macrophages and multinucleated giant cells with a lymphocytic cuff, distributed irregularly through the left ventricular free wall, interventricular septum, and right ventricle, with replacement fibrosis in chronic disease. The patchiness is the reason endomyocardial biopsy is insensitive despite being highly specific.

Show evidence (3 references)

PMID:31769474 SUPPORT Human Clinical

"Although granulomas are often composed of tight epithelioid macrophage aggregates, early granulomas comprise loosely associated macrophages with lymphocyte predominance."

Describes the granuloma cellular composition and its early/late variation.

PMID:31769474 SUPPORT Human Clinical

"Sampling errors and variable histology cause low endomyocardial biopsy sensitivity."

Directly attributes the low biopsy sensitivity to sampling error against patchy lesions, the claim made in this entry's description.

PMID:31769474 SUPPORT Human Clinical

"Irregular left ventricular free wall involvement is most common, followed by the interventricular septum and right ventricle."

Gives the anatomical distribution of the histopathologic lesion.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 7

Atrioventricular Block FREQUENT HP:0001678

Show evidence (2 references)

PMID:31230070 SUPPORT Human Clinical

"High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%)"

Nationwide series of 351 cases gives 42% as the proportion presenting with high-grade AV block, supporting the FREQUENT (30-79%) band directly.

PMID:30354309 SUPPORT Human Clinical

"Symptomatic high-grade atrioventricular block (AVB) is the most common and often the only presenting manifestation (lone AVB) of cardiac sarcoidosis."

Independently confirms high-grade AV block as the dominant presentation.

Ventricular Tachycardia OCCASIONAL HP:0004756

Show evidence (2 references)

PMID:31230070 SUPPORT Human Clinical

"unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%)"

Nationwide series gives 14% presenting with sustained VT, which maps to the OCCASIONAL (5-29%) band. Note this counts VT as the *presenting* manifestation; lifetime VT burden is higher.

PMID:25527825 SUPPORT Human Clinical

"Multiple inducible VTs were observed with mechanism consistent with scar-mediated re-entry in all VTs."

Characterizes the mechanism of the VT phenotype as scar-mediated re-entry.

Congestive Heart Failure OCCASIONAL HP:0001635

Show evidence (2 references)

PMID:31230070 SUPPORT Human Clinical

"High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%)"

17% of 351 cases presented with heart failure, supporting the OCCASIONAL (5-29%) band. Note this counts heart failure as the *presenting* manifestation, so it is a lower bound on lifetime frequency.

PMID:33070538 SUPPORT Human Clinical

"Cardiac fibrosis leads to congestive heart failure, arrhythmias and sudden cardiac death."

Links the fibrotic mechanism curated in the pathograph to this phenotype.

Sudden Cardiac Death OCCASIONAL HP:0001645

Show evidence (2 references)

PMID:31230070 SUPPORT Human Clinical

"unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%)"

Fatal or aborted sudden cardiac death accounted for 14% of presentations in 351 nationwide cases, supporting the OCCASIONAL (5-29%) band. As with the other bands here this counts the *presenting* event, so it is a lower bound on lifetime risk.

PMID:31230070 SUPPORT Human Clinical

"Nearly two-thirds of all fatalities from CS are caused by undiagnosed granulomas in the heart."

Supports the description's claim that sudden death frequently occurs in undiagnosed disease.

Reduced Left Ventricular Ejection Fraction HP:0012664

Show evidence (2 references)

PMID:27443438 SUPPORT Human Clinical

"In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis."

Establishes LV dysfunction as a curated phenotype with prognostic weight.

PMID:41193496 SUPPORT Human Clinical

"Compared with multi-organ cardiac sarcoidosis, isolated cardiac sarcoidosis is associated with lower left ventricular ejection fraction and poorer survival."

Supports the subtype-dependent severity of reduced LVEF stated in the description.

Syncope HP:0001279

Show evidence (1 reference)

PMID:33687942 SUPPORT Human Clinical

"A 53-year-old man was admitted for recurrent syncope and found to have complete heart block (CHB)."

Case report documents syncope as the presenting symptom of conduction-block cardiac sarcoidosis. Single-case evidence, so no frequency band is asserted.

Atrial Fibrillation HP:0005110

Show evidence (2 references)

PMID:33059834 SUPPORT Human Clinical

"atrial fibrillation (AF) can occur as well (up to 32% of subjects)"

Establishes atrial fibrillation as a recognized manifestation and gives an upper-bound cumulative estimate.

PMID:36924191 SUPPORT Human Clinical

"Atrial fibrillation is rare at presentation but has a considerable later incidence."

Supplies the temporal qualification stated in the description, and is why no frequency band is asserted for this phenotype.

Other 2

Myocardial Fibrosis HP:0001685

Show evidence (2 references)

PMID:28501519 SUPPORT Human Clinical

"The presence of LGE was highly correlated with clinically significant arrhythmias and lower LVEF."

Late gadolinium enhancement is the in-vivo readout of myocardial fibrosis, and correlates with the arrhythmic and functional consequences.

PMID:31769474 SUPPORT Human Clinical

"Chronic disease leads to fibrosis and end-stage heart failure."

Histopathologic confirmation of myocardial fibrosis in chronic cardiac sarcoidosis.

Bundle Branch Block HP:0011710

Show evidence (1 reference)

PMID:33059834 SUPPORT Human Clinical

"Right bundle branch block (RBBB) and atrioventricular block (AVB), ranging from first to third degree, are the most common manifestation"

Names right bundle branch block alongside AV block as the most common conduction manifestation of cardiac sarcoidosis.

💊

Medical Actions

7

Corticosteroid Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Corticosteroids are first-line therapy for clinically manifest cardiac sarcoidosis, aimed at suppressing active granulomatous myocardial inflammation before it converts to fixed scar. The best-quality evidence is for recovery of atrioventricular conduction and prevention of deterioration in left ventricular function; evidence is explicitly inadequate to claim a ventricular-arrhythmia or mortality benefit, and no randomized trial exists.

Mechanism Target:

INHIBITS Active Granulomatous Myocardial Inflammation — Corticosteroids suppress the active granulomatous inflammatory lesion. The therapeutic window is the inflammatory stage: AV conduction impaired by active septal inflammation can recover, whereas established fibrosis cannot.

Show evidence (2 references)

PMID:34472360 SUPPORT Human Clinical

"There were 178 patients treated for atrioventricular conduction disease, with 76/178 (42.7%) improving."

Systematic review quantifies AV conduction recovery under corticosteroid/immunosuppressant therapy, the effect of inhibiting this node.

PMID:33687942 SUPPORT Human Clinical

"This highlights the importance of immediate therapy in reversing AV conduction abnormalities in CS."

Case-level demonstration that the reversible target is the inflammatory, not the fibrotic, lesion.

Show evidence (4 references)

PMID:34472360 SUPPORT Human Clinical

"In contrast, 21 patients were not treated with corticosteroids and/or immunosuppressant therapy, and none of them improved."

Provides the untreated comparator (0/21 improved) against which the 42.7% treated improvement rate is read.

PMID:34472360 SUPPORT Human Clinical

"Therapy was associated with the prevention of deterioration in left ventricular function."

Supports the second of the two outcomes for which evidence quality is adequate.

PMID:34472360 SUPPORT Human Clinical

"The data quality is too limited to draw conclusions for ventricular arrhythmias and mortality."

Records the explicit limit of the evidence base, so this treatment entry does not overstate benefit beyond conduction and LV function.

+ 1 more reference

Methotrexate Corticosteroid-Sparing Maintenance

Action: Immunosuppressive Therapy NCIT:C15261

Agent: methotrexate CHEBI:44185

Methotrexate, with or without low-dose prednisone, is used as maintenance therapy after an initial corticosteroid response, reducing cumulative steroid exposure. Efficacy is judged by suppression of myocardial FDG uptake; relapse after cessation supports ongoing surveillance.

Mechanism Target:

INHIBITS Active Granulomatous Myocardial Inflammation — Steroid-sparing immunosuppression suppresses the same active granulomatous lesion as corticosteroids, measured as reduction or elimination of myocardial FDG uptake.

Show evidence (1 reference)

PMID:31538835 SUPPORT Human Clinical

"Methotrexate±low-dose prednisone resulted in initial reduction (88%) or elimination (60%) of 18-fluorodeoxyglucose uptake"

Quantifies suppression of the active inflammatory node under methotrexate-based maintenance specifically. The adalimumab arm of the same study is curated separately under TNF Inhibitor Therapy.

Show evidence (2 references)

PMID:31538835 SUPPORT Human Clinical

"Corticosteroid-sparing regimens containing methotrexate with or without adalimumab is an effective maintenance therapy in patients after an initial response is confirmed."

States the maintenance role and the precondition (confirmed initial response).

PMID:31538835 SUPPORT Human Clinical

"Disease recurrence in patients on and off immunosuppression support need for ongoing radiologic surveillance regardless of immunosuppression regimen."

Supports the surveillance requirement stated in the description.

TNF Inhibitor Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: adalimumab NCIT:C65216 infliximab NCIT:C1789

TNF-neutralizing biologics - infliximab (chimeric) and adalimumab (fully human) - are used in cardiac sarcoidosis refractory to corticosteroids and conventional steroid-sparing agents. This instantiates the granuloma-formation drug-target design pattern: TNF is the non-redundant amplifier that drives macrophage accumulation and activation, so its blockade acts on the Th1/TNF node rather than on the mature granuloma. Safety caveat specific to this disease: anti-TNF therapy carries a risk of increased mortality in patients with severe cardiomyopathy, so it must be used with caution in exactly the cardiac sarcoidosis patients whose ventricular function is most impaired.

Mechanism Target:

INHIBITS Antigen-Driven CD4+ T-Cell and Macrophage Activation — TNF neutralization removes the amplifier that drives macrophage accumulation and activation, the mechanism by which anti-TNF agents prevent granuloma formation. This is the same node that conforms to granuloma_formation#Th1 and TNF-Driven Macrophage Recruitment and Activation, which the module's own TNF-inhibitor pattern targets.

Show evidence (2 references)

PMID:36924191 SUPPORT Human Clinical

"Biologic anti-tumor necrosis factor (TNF) agents can prevent granuloma formation, and observational data support their efficacy in CS when other therapies have failed."

States both the mechanism (prevention of granuloma formation) and the cardiac-sarcoidosis-specific efficacy setting for this edge.

PMID:33059834 SUPPORT Human Clinical

"IFN-γ and TNF-α promote the accumulation and activation of macrophages"

Identifies TNF as a driver of the macrophage accumulation and activation that this node represents, so neutralizing it acts here.

INHIBITS Active Granulomatous Myocardial Inflammation — Adalimumab-containing regimens suppress the active myocardial lesion, measured as improvement or resolution of myocardial FDG uptake.

Show evidence (1 reference)

PMID:31538835 SUPPORT Human Clinical

"patients receiving adalimumab-containing regimens experienced improved (84%) or resolved (63%) 18-fluorodeoxyglucose uptake"

Quantifies suppression of the active inflammatory node under adalimumab-containing therapy.

Show evidence (3 references)

PMID:36924191 SUPPORT Human Clinical

"Infliximab is a chimeric TNF antibody which in doses <10 mg/kg is well tolerated even in patients with impaired LV function."

Establishes infliximab as one of the two agents in this treatment class.

PMID:36924191 SUPPORT Human Clinical

"Adalimumab, a human monoclonal TNF antibody, is a subcutaneously administered alternative."

Establishes adalimumab as the second agent in this treatment class.

PMID:33059834 SUPPORT Human Clinical

"However, because of the risk of increased mortality associated with use of anti-TNF therapy in patients with severe CMP (130), one must use with caution."

Source for the disease-specific safety caveat stated in the description. Note the two cited reviews are not fully concordant on tolerability in impaired ventricular function, which is why the caveat is curated rather than only the favourable statement.

Implantable Cardioverter-Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

ICD implantation for prevention of sudden cardiac death. Because arrhythmic risk arises from fixed scar and persists even when conduction recovers, an ICD rather than a pacemaker is recommended whenever permanent pacing is needed in cardiac sarcoidosis. Device therapy addresses the arrhythmic consequence; it does not modify the granulomatous disease.

Mechanism Target:

INHIBITS Scar-Mediated Re-entrant Ventricular Tachyarrhythmia — The device terminates scar-mediated ventricular tachyarrhythmia when it occurs, preventing progression to sudden death, without altering the underlying scar substrate.

Show evidence (1 reference)

PMID:32062788 SUPPORT Human Clinical

"Appropriate and inappropriate ICD treatments (AT and IAT) were reported in 39% and 15% of patients respectively"

Meta-analysis documents that 39% of implanted patients received appropriate device therapy for the arrhythmia this node represents.

Show evidence (3 references)

PMID:30354309 SUPPORT Human Clinical

"The consensus recommendation to implant an intracardiac cardioverter defibrillator whenever permanent pacing is needed seems well-founded."

Nationwide outcome data support ICD over pacemaker whenever pacing is indicated, the recommendation stated in this treatment entry.

PMID:32062788 SUPPORT Human Clinical

"High degree AV block appears to be predictive of appropriate ICD therapy."

Supports the link between the conduction-block presentation and subsequent arrhythmic events that motivates ICD rather than pacemaker selection.

PMID:27443438 SUPPORT Human Clinical

"Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease."

Independent statement of the device recommendation in manifest disease.

Permanent Pacing

Action: pacemaker placement Ontology label: Pacemaker Placement NCIT:C80434

Pacemaker implantation for symptomatic high-grade atrioventricular block. In cardiac sarcoidosis, current recommendation is that a defibrillator be implanted instead of a pacemaker whenever permanent pacing is indicated, because of the persisting risk of ventricular tachyarrhythmia.

Mechanism Target:

BYPASSES Conduction System Involvement and Atrioventricular Block — Pacing bypasses the interrupted atrioventricular conduction axis, treating the bradyarrhythmic consequence without addressing the granulomatous cause.

Show evidence (1 reference)

PMID:30354309 SUPPORT Human Clinical

"Implantation of an intracardiac cardioverter defibrillator instead of a pacemaker is recommended, but the true risk of fatal arrhythmia, one incident to lone AVB in particular, remains poorly known."

Establishes permanent pacing as the indicated therapy for this node while recording the device-selection caveat stated in the description.

Catheter Ablation for Ventricular Tachycardia

Action: cardiac ablation Ontology label: Cardiac Ablation NCIT:C100068

Catheter ablation of scar-mediated ventricular tachycardia circuits, used for recurrent VT or VT storm alongside antiarrhythmic drugs. It is palliative: acute success is high but recurrence is common, because septal intramural circuits and extensive right ventricular scar leave residual inducible circuits.

Mechanism Target:

INHIBITS Scar-Mediated Re-entrant Ventricular Tachyarrhythmia — Ablation interrupts individual re-entrant circuits within sarcoid scar, controlling VT burden without eliminating the substrate.

Show evidence (1 reference)

PMID:25527825 SUPPORT Human Clinical

"Catheter ablation is effective in terminating VT storm and eliminating ≥1 inducible VT in the majority of patients, but recurrences are common."

Reports ablation efficacy against the scar-mediated arrhythmia of this node, in the same cohort in which the mechanism was mapped, together with the recurrence caveat that makes the effect palliative.

Show evidence (2 references)

PMID:25527825 SUPPORT Human Clinical

"Failure to abolish all inducible VTs was because of septal intramural circuits or extensive right ventricular scarring."

Names the anatomical reasons ablation is palliative rather than curative, as stated in the description.

PMID:25527825 SUPPORT Human Clinical

"Multiple procedure VT-free survival was 37% at 1 year, but VT control was achievable in the majority of patients with fewer antiarrhythmic drugs compared with preablation"

Quantifies the recurrence rate that makes this a palliative rather than curative therapy.

Heart Transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Cardiac transplantation for end-stage cardiac sarcoidosis refractory to immunosuppression and device therapy.

Show evidence (1 reference)

PMID:33059834 SUPPORT Human Clinical

"Treatment of CS is often multifactorial, involving a combination of antigranulomatous therapy and pharmacotherapy for cardiac arrhythmias and/or heart failure in addition to device placement and cardiac transplantation."

Places cardiac transplantation within the treatment repertoire for cardiac sarcoidosis.

🔬

Biochemical Markers

2

Elevated high-sensitivity cardiac troponin (Elevated)

Context: High-sensitivity cardiac troponin reports ongoing cardiomyocyte injury from the active granulomatous lesion, and is repeatable enough to follow disease activity serially under immunosuppression. Cumulative troponin release after prednisolone initiation - rather than any single pre- or post-treatment value - predicts ventricular arrhythmia, worsening heart failure, and sudden cardiac death, which fits the entry's model in which the reversible inflammatory arm and the fixed scar arm diverge over time.

Pathograph Readouts

Readout Of Active Granulomatous Myocardial Inflammation Positive Prognostic

Rising cumulative troponin reports continuing cardiomyocyte injury from the active granulomatous lesion this node represents.

Show evidence (1 reference)

PMID:37591415 SUPPORT Human Clinical

"A higher area under the cTnT trajectory was significantly associated with an increased incidence of the primary outcome (P = 0.027)"

The specific measurement behind this readout: cumulative troponin release predicted the composite of sustained VT/VF, worsening heart failure, and sudden cardiac death.

Show evidence (3 references)

PMID:37591415 SUPPORT Human Clinical

"Although high-sensitivity cardiac troponins may be sensitive and easily repeatable markers of disease activity in patients with cardiac sarcoidosis (CS), the association between longitudinal cardiac troponin trajectory and adverse events remains unclear."

Establishes hs-cardiac troponin as a repeatable marker of cardiac sarcoidosis disease activity, the basis for attaching it to the active-inflammation node.

PMID:37591415 SUPPORT Human Clinical

"Longitudinal cTnT trajectory following PSL initiation was associated with adverse cardiac events in patients with CS"

Supports the prognostic endpoint context: it is the cumulative trajectory, not a single value, that carries the signal.

PMID:40445485 SUPPORT Human Clinical

"16% and 19% of patients were positive for Troponin I and NT-Pro BNP respectively"

Gives the proportion of a screened sarcoidosis cohort positive for troponin. Partial because this quantifies screening yield in sarcoidosis generally rather than troponin behaviour within established cardiac sarcoidosis.

Elevated NT-proBNP (Elevated)

Context: N-terminal pro-B-type natriuretic peptide reports ventricular wall stress and is elevated in cardiac sarcoidosis independently of ejection fraction and pulmonary artery pressure. It discriminates cardiac involvement well (AUC 0.913) but does not identify pulmonary hypertension in the same patients, so it is a cardiac-involvement marker rather than a general sarcoidosis severity marker.

Pathograph Readouts

Readout Of Progressive Ventricular Dysfunction and Heart Failure Positive Diagnostic

Elevated NT-proBNP reports the ventricular wall stress and contractile failure that this node represents.

Show evidence (1 reference)

PMID:21086902 SUPPORT Human Clinical

"Plasma NT-proBNP showed good accuracy in identifying patients with cardiac sarcoidosis (area under the ROC curve; AURC = 0.913)."

The specific measurement behind this readout, with its discrimination quantified as an area under the ROC curve.

Show evidence (3 references)

PMID:21086902 SUPPORT Human Clinical

"Plasma NT-proBNP levels were significantly higher in patients with cardiac sarcoidosis (p < 0.0001)."

Directly establishes NT-proBNP elevation in cardiac sarcoidosis.

PMID:21086902 SUPPORT Human Clinical

"Stepwise regression analysis showed that presence of cardiac sarcoidosis, decreased ejection fraction and increased sPAP were all independently associated with higher plasma NT-proBNP levels."

Supports the independence claim in the context field, and ties the marker to reduced ejection fraction - the phenotype of the target node.

PMID:21086902 SUPPORT Human Clinical

"In patients with sarcoidosis, plasma NT-proBNP levels are a useful biomarker to identify cardiac involvement, but not to identify PH."

Records the specific scope of the marker, preventing it being read as a general sarcoidosis-severity readout.

🔬

Diagnosis

5

Cardiac magnetic resonance imaging

CMR with late gadolinium enhancement detects myocardial scar and, with T2 imaging, active oedema. It uncovers cardiac involvement far more often than clinical criteria do, and LGE burden carries arrhythmic and functional prognostic weight.

magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:28501519 SUPPORT Human Clinical

"Late gadolinium enhancement was present in 22%, indicating myocardial involvement, and 70% had corresponding hyper-intense T2 signal indicating active inflammation."

Demonstrates CMR detection of both scar (LGE) and active inflammation (T2) in a biopsy-proven sarcoidosis cohort.

PMID:28501519 SUPPORT Human Clinical

"Using CMR, we identified a higher prevalence of cardiac sarcoidosis than previously reported clinical studies, a prevalence which is more consistent with autopsy data."

Supports CMR as the modality that closes the clinical-versus-autopsy detection gap.

FDG-PET assessment of myocardial inflammation

18F-FDG PET detects glucose-avid inflammatory cells in active granulomatous lesions, and is used both diagnostically and to monitor response to immunosuppression. It is a surrogate imaging biomarker, adopted because endomyocardial biopsy yield is low.

FDG-positron emission tomography NCIT:C103400

Show evidence (2 references)

PMID:33059834 SUPPORT Human Clinical

"The diagnosis of CS usually requires surrogate cardiac imaging biomarkers, as endomyocardial biopsy has relatively low yield, even with directed electrophysiological mapping."

Establishes the reliance on surrogate cardiac imaging biomarkers in place of biopsy, the rationale for this diagnostic modality.

PMID:31538835 SUPPORT Human Clinical

"Methotrexate±low-dose prednisone resulted in initial reduction (88%) or elimination (60%) of 18-fluorodeoxyglucose uptake"

Demonstrates FDG uptake being used as the treatment-response readout, the monitoring role described here.

Endomyocardial biopsy

Histologic demonstration of non-caseating myocardial granulomas is the only route to a definite diagnosis, but sensitivity is low because lesions are patchy; electroanatomic- or image-guided sampling improves but does not solve the yield problem.

endomyocardial biopsy NCIT:C51674

Show evidence (2 references)

PMID:36924191 SUPPORT Human Clinical

"Definite diagnosis of CS requires myocardial biopsy and histopathology"

States the role of myocardial biopsy in establishing a definite diagnosis.

PMID:31769474 SUPPORT Human Clinical

"Sampling errors and variable histology cause low endomyocardial biopsy sensitivity."

Quantifies the limitation of the modality described here.

Electrocardiography

ECG identifies the conduction abnormalities that most often bring cardiac sarcoidosis to attention - high-grade AV block, bundle branch block, and ventricular arrhythmia - and is the entry point for screening patients with known systemic sarcoidosis.

electrocardiography NCIT:C38053

Show evidence (1 reference)

PMID:33687942 SUPPORT Human Clinical

"Three weeks later, ECG with pacing inhibited showed second-degree AV block Mobitz type II and 4 weeks later, AV conduction recovery."

Illustrates ECG being used to grade and follow the conduction abnormality that defines the cardiac presentation.

Echocardiography

Transthoracic echocardiography is the first-line imaging rung of the HRS screening algorithm, ahead of CMR and FDG-PET. Typical findings are regional wall thinning and contraction abnormalities in basal, septal, and lateral segments. Sensitivity is low - a normal echocardiogram does not exclude cardiac sarcoidosis - so it triages patients toward advanced imaging rather than settling the diagnosis.

echocardiography NCIT:C16525

Show evidence (3 references)

PMID:37682338 SUPPORT Human Clinical

"Typical echocardiographic findings include regional thinning and contraction abnormalities particularly in basal, septal and lateral locations."

Gives the characteristic echocardiographic findings, whose regional distribution matches the granuloma and scar distribution curated in the pathograph.

PMID:37682338 SUPPORT Human Clinical

"the sensitivity of echocardiography is low and cardiac sarcoidosis can be present even when an echocardiogram is unrevealing"

Records the limitation that makes echocardiography a triage rather than a confirmatory modality.

PMID:40445485 SUPPORT Human Clinical

"Of the 100 patients screened, 23% had cardiac symptoms, 23% had ECG changes, 16% had abnormalities on conventional echocardiography, 32% of patients had abnormal GLS, 16% and 19% of patients were positive for Troponin I and NT-Pro BNP respectively."

Quantifies the yield of conventional echocardiography within a prospective sarcoidosis screening cohort, alongside the other screening rungs curated in this entry.

📈

Progression

1

Survival in clinically manifest disease

Contemporary survival in manifest cardiac sarcoidosis is reported as roughly 90-96% at 5 years and 80-90% at 10 years in specialist series; a nationwide Finnish series including autopsy-detected cases reported 85% at 5 years and 76% at 10 years from symptom onset. The difference between these figures reflects ascertainment - the nationwide series includes cases first identified at death.

Show evidence (2 references)

PMID:36924191 SUPPORT Human Clinical

"Recent outcome data indicate 90% to 96% 5-year survival in manifest CS with the 10-year figures ranging from 80% to 90%."

Gives the specialist-series survival estimates.

PMID:31230070 SUPPORT Human Clinical

"The Kaplan-Meier estimate (95% CI) of survival from symptom onset was 85% (80-90%) at 5 years and 76% (68-84%) at 10 years."

Gives the nationwide-registry survival estimates for contrast.

📊

Prevalence

2

Patients with systemic/pulmonary sarcoidosis (clinically manifest cardiac involvement)

Point Prevalence Rare

Clinically manifest cardiac involvement in approximately 5% of sarcoidosis patients. This is a proportion of the sarcoidosis population, not a general population rate, so no rate_per_100000 is asserted.

Show evidence (1 reference)

PMID:27443438 SUPPORT Human Clinical

"Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis."

States the proportion of sarcoidosis patients with clinically manifest cardiac disease.

Patients with systemic/pulmonary sarcoidosis (clinically silent cardiac involvement)

Point Prevalence Unknown

Occult (imaging- or autopsy-detected) cardiac involvement in 20-25% of sarcoidosis patients - four to five times the clinically detectable rate. Again a within-sarcoidosis proportion, not a population rate.

Show evidence (3 references)

PMID:27443438 SUPPORT Human Clinical

"An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease)."

Quantifies clinically silent cardiac involvement among sarcoidosis patients.

PMID:28501519 SUPPORT Human Clinical

"Autopsy reports suggest that cardiac sarcoidosis occurs in 20 to 25% of patients with pulmonary sarcoidosis, yet the clinical ante-mortem diagnosis is made in only 5% of cases."

Independently corroborates the autopsy-versus-clinical detection gap that separates the two prevalence records.

PMID:36924191 SUPPORT Human Clinical

"Manifest CS, however, constitutes only the top of an iceberg as advanced imaging uncovers cardiac involvement 4 to 5 times more commonly than what is clinically detectable."

Quantifies the ratio of imaging-detected to clinically detected cardiac involvement.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Cardiac Sarcoidosis:

Arrhythmogenic right ventricular cardiomyopathy MONDO:0016587

Overlapping Features Isolated cardiac sarcoidosis and ARVC overlap closely: both produce right ventricular scar, ventricular arrhythmia, and conduction abnormality in a structurally abnormal heart. The dismech ARVC entry reciprocally lists cardiac sarcoidosis as one of its own key differentials.

Show evidence (1 reference)

PMID:33070538 SUPPORT Human Clinical

"isolated cardiac sarcoidosis is difficult to differentiate from other causes of arrhythmogenic cardiomyopathy"

Directly states the diagnostic difficulty separating isolated cardiac sarcoidosis from arrhythmogenic cardiomyopathy.

📊

Related Datasets

4

Transcriptional and immune landscape of cardiac sarcoidosis geo:GSE205734

human SPATIAL TRANSCRIPTOMICS n=7

PMID:36111531

Identified by GEO DataSets index search for Cardiac_Sarcoidosis (scripts/discover_datasets.py) and verified with just verify-datasets. Relevance triaged manually: cardiac sarcoidosis is named in the GEO series title and the material is human cardiac tissue, so this is a DIRECT match rather than a gene- or word-only hit. Title, sample count, and organism are GEO's own values. No evidence block: a bulk-generated dataset record carries provenance notes rather than a manufactured abstract quote.

Spatial transcriptomic signatures of cardiac sarcoidosis geo:GSE314910

human SPATIAL TRANSCRIPTOMICS n=12

Identified by GEO DataSets index search for Cardiac_Sarcoidosis (scripts/discover_datasets.py) and verified with just verify-datasets. Cardiac sarcoidosis is named in the GEO series title. No linked publication was indexed at the time of curation.

Integrative Molecular Analyses of Inflammatory and Autoimmune Signals in Cardiac Sarcoidosis [snRNA-Seq] geo:GSE319770

human SINGLE CELL RNA SEQ n=41

PMID:42206386

Identified by GEO DataSets index search for Cardiac_Sarcoidosis (scripts/discover_datasets.py) and verified with just verify-datasets. Cardiac sarcoidosis is named in the GEO series title. Companion Xenium series of the same study is geo:GSE319771.

Integrative Molecular Analyses of Inflammatory and Autoimmune Signals in Cardiac Sarcoidosis [Xenium] geo:GSE319771

human MICROARRAY n=18

PMID:42206386

Identified by GEO DataSets index search for Cardiac_Sarcoidosis (scripts/discover_datasets.py) and verified with just verify-datasets. Cardiac sarcoidosis is named in the GEO series title. Companion snRNA-seq series of the same study is geo:GSE319770. GEO's own platform typing for this Xenium in-situ series is recorded as MICROARRAY by the discovery index.

🔬

Clinical Trials

4

NCT06660732 PHASE_II RECRUITING

REPAIR-CS - a randomized Phase II trial (n=60) of the IL-1 trap rilonacept added to standard therapy versus standard therapy alone, with the primary endpoint being improvement in myocardial inflammation at 24 weeks. It targets the active granulomatous inflammation node of this entry's pathograph, and is the design that would begin to answer the randomized-evidence gap recorded in the immunosuppression KNOWLEDGE_GAP - though its endpoint is imaging inflammation, not arrhythmia or mortality.

Target Phenotypes: Myocardial fibrosis HP:0001685

Show evidence (1 reference)

clinicaltrials:NCT06660732 SUPPORT Human Clinical

"The primary objective of this study is to evaluate the effect of rilonacept, added to standard therapy and compared with standard therapy alone, on improvement in myocardial inflammation in subjects with cardiac sarcoidosis after 24 weeks of therapy."

States the randomized comparison and the myocardial-inflammation endpoint that make this trial relevant to the active-inflammation node.

NCT04017936 PHASE_II COMPLETED

MAGiC-ART - a completed pilot (n=17) of IL-1 blockade with anakinra in cardiac sarcoidosis. Its rationale rests on inflammasome components being demonstrable in cardiac sarcoid granulomas, making it a direct test of the granulomatous inflammation arm.

Show evidence (2 references)

clinicaltrials:NCT04017936 SUPPORT Human Clinical

"In the current study, researchers aim to evaluate the safety and efficacy of IL-1 blockade with anakinra (IL-1 receptor antagonist) in patients with cardiac sarcoidosis."

States the intervention and objective of the trial.

clinicaltrials:NCT04017936 SUPPORT Human Clinical

"cardiac disease generally progresses from areas of focal inflammation to scar"

The trial registration independently states the focal-inflammation-to-scar progression that is the backbone of this entry's pathograph.

NCT06868381 PHASE_II NOT_RECRUITING

A single-site open-label Phase IIa trial (n=10) of the JAK inhibitor baricitinib added to steroid-sparing therapy in active cardiac sarcoidosis, with cardiac FDG-PET/CT change as the primary endpoint. Status is not-yet-recruiting.

Show evidence (1 reference)

clinicaltrials:NCT06868381 SUPPORT Human Clinical

"In patients with active cardiac sarcoidosis, does treatment with baricitinib improve cardiac sarcoidosis disease activity as assessed by changes on cardiac FDG-PET/CT?"

States the intervention and the FDG-PET activity endpoint, the same readout used for the curated immunosuppression treatments.

NCT07159074 PHASE_II RECRUITING

A Phase II diagnostic study (n=15) testing whether Tc 99m tilmanocept SPECT/CT - a macrophage-mannose-receptor-directed tracer - can identify cardiac sarcoidosis. Unlike FDG, which reports generic glucose-avid inflammation and needs demanding dietary preparation, this tracer targets the macrophage lineage that forms the granuloma itself.

Show evidence (1 reference)

clinicaltrials:NCT07159074 SUPPORT Human Clinical

"The purpose of this study is to see if Tc 99m Tilmanocept SPECT/CT imaging can be used to identify cardiac sarcoidosis."

States the diagnostic objective of the trial.

{ }

Source YAML

click to show

name: Cardiac Sarcoidosis
creation_date: "2026-08-19T00:00:00Z"
category: Immune
description: >-
  Cardiac sarcoidosis is myocardial involvement by sarcoidosis, in which
  non-caseating epithelioid-cell granulomas infiltrate the heart. Granulomatous
  infiltration follows the same antigen-driven CD4+ T-cell / Th1 / macrophage
  program as sarcoidosis elsewhere, but in the myocardium it acquires an
  organ-specific consequence set that no other sarcoid organ shares: the
  granulomas and the patchy replacement fibrosis they leave behind disrupt the
  atrioventricular conduction axis (producing high-grade AV block), create the
  fixed scar substrate for macro-re-entrant ventricular tachyarrhythmia, and
  drive progressive ventricular dysfunction and heart failure. Sudden cardiac
  death may be the first recognized manifestation. Lesions favour the left
  ventricular free wall, basal interventricular septum, and right ventricle, and
  are characteristically patchy - which is why endomyocardial biopsy has low
  sensitivity and diagnosis rests on cardiac MRI and FDG-PET. Clinically manifest
  cardiac involvement is recognized in roughly 5% of sarcoidosis patients, while
  imaging and autopsy detect involvement in 20-25%. Disease may also be confined
  to the heart (isolated cardiac sarcoidosis), where it carries a worse prognosis
  and is difficult to distinguish from arrhythmogenic cardiomyopathy.
disease_term:
  preferred_term: cardiac sarcoidosis
  term:
    id: MONDO:0001707
    label: cardiac sarcoidosis
parents:
- Sarcoidosis
- Immune-Mediated Disease
- Granulomatous Disease
- Cardiovascular Disease
inheritance:
- name: Multifactorial susceptibility
  description: >-
    Cardiac sarcoidosis is not a Mendelian disorder. It arises in genetically
    susceptible individuals as an organ-specific expression of systemic
    sarcoidosis, whose susceptibility is polygenic (HLA and non-HLA alleles); no
    causal gene is established for the cardiac phenotype specifically, and
    MONDO:0001707 records no causal gene relation.
  evidence:
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Major progress in the care of CS awaits the key to its molecular-genetic
      pathogenesis and large-scale controlled clinical trials.
    explanation: >-
      Supports the absence of an established molecular-genetic basis for cardiac
      sarcoidosis indirectly, by naming it as an outstanding research need rather
      than asserting a specific inheritance model.
prevalence:
- population: Patients with systemic/pulmonary sarcoidosis (clinically manifest cardiac involvement)
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  notes: >-
    Clinically manifest cardiac involvement in approximately 5% of sarcoidosis
    patients. This is a proportion of the sarcoidosis population, not a general
    population rate, so no rate_per_100000 is asserted.
  evidence:
  - reference: PMID:27443438
    reference_title: Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis.
    explanation: States the proportion of sarcoidosis patients with clinically manifest cardiac disease.
- population: Patients with systemic/pulmonary sarcoidosis (clinically silent cardiac involvement)
  measure_type: POINT_PREVALENCE
  prevalence_class: UNKNOWN
  notes: >-
    Occult (imaging- or autopsy-detected) cardiac involvement in 20-25% of
    sarcoidosis patients - four to five times the clinically detectable rate.
    Again a within-sarcoidosis proportion, not a population rate.
  evidence:
  - reference: PMID:27443438
    reference_title: Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis
      have asymptomatic cardiac involvement (clinically silent disease).
    explanation: Quantifies clinically silent cardiac involvement among sarcoidosis patients.
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autopsy reports suggest that cardiac sarcoidosis occurs in 20 to 25% of
      patients with pulmonary sarcoidosis, yet the clinical ante-mortem diagnosis
      is made in only 5% of cases.
    explanation: >-
      Independently corroborates the autopsy-versus-clinical detection gap that
      separates the two prevalence records.
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Manifest CS, however, constitutes only the top of an iceberg as advanced
      imaging uncovers cardiac involvement 4 to 5 times more commonly than what
      is clinically detectable.
    explanation: Quantifies the ratio of imaging-detected to clinically detected cardiac involvement.
has_subtypes:
- name: Isolated CS
  display_name: Isolated cardiac sarcoidosis
  description: >-
    Sarcoid granulomatous disease confined to the heart, without demonstrable
    extracardiac organ involvement. Diagnostically the hardest form (no
    extracardiac biopsy target) and prognostically the worst.
  evidence:
  - reference: PMID:41193496
    reference_title: "Isolated cardiac sarcoidosis: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated cardiac sarcoidosis is a distinct entity of sarcoidosis
      characterized by disease confined exclusively to the heart, without
      involvement of other organs.
    explanation: Defines the isolated cardiac subtype as a distinct entity.
  - reference: PMID:41193496
    reference_title: "Isolated cardiac sarcoidosis: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with multi-organ cardiac sarcoidosis, isolated cardiac
      sarcoidosis is associated with lower left ventricular ejection fraction and
      poorer survival.
    explanation: Establishes the prognostic separation of the isolated subtype from multi-organ disease.
- name: Systemic CS
  display_name: Cardiac sarcoidosis with extracardiac involvement
  description: >-
    Cardiac involvement occurring in a patient with demonstrable extracardiac
    sarcoidosis, either as the presenting organ or superimposed on established
    systemic disease. Extracardiac histology can substitute for myocardial biopsy
    in the diagnostic pathway.
  evidence:
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CS can appear as the first or only organ manifestation of sarcoidosis or on
      top of pre-existing extracardiac disease.
    explanation: Distinguishes cardiac-first and superimposed presentations from isolated disease.
definitions:
- name: 2014 Heart Rhythm Society (HRS) expert consensus criteria
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The 2014 HRS international expert consensus statement is the most widely
    used framework in Europe and North America. It allows a clinical diagnosis
    of cardiac sarcoidosis from histologically proven extracardiac sarcoidosis
    plus a qualifying cardiac abnormality (high-grade AV block, ventricular
    arrhythmia, reduced LVEF, or characteristic CMR/FDG-PET findings), with
    histologic diagnosis reserved for myocardial biopsy. Its screening arm is
    symptoms plus electrocardiography plus conventional echocardiography.
  scope: Clinical and histologic diagnosis of cardiac involvement in sarcoidosis
  evidence:
  - reference: PMID:37123482
    reference_title: Comparing and Contrasting Guidelines for the Management of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also, in 2014, the Heart Rhythm Society (HRS) published their
      international guideline document.
    explanation: >-
      Establishes the 2014 HRS document as one of the three standing
      cardiac-sarcoidosis guideline frameworks.
  - reference: PMID:40445485
    reference_title: Screening for cardiac involvement in patients with sarcoidosis using AIIMS algorithm.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heart Rhythm Society (HRS) screening algorithm is commonly used and
      comprises the presence of cardiac symptoms, electrocardiography and
      conventional echocardiography.
    explanation: >-
      Specifies the three components of the HRS screening arm, which is why
      echocardiography is curated as a first-line diagnostic rung in this entry.
- name: 2016 Japanese Circulation Society (JCS) guideline criteria
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The JCS guideline is the Japanese national framework, developed by a
    community that has led cardiac-sarcoidosis guideline work. It differs from
    HRS in both diagnostic thresholds and management triggers - for example it
    recommends an electrophysiological study in all patients with LVEF 35-50%
    - and it is markedly more restrictive than HRS when both are applied to the
    same cohort.
  scope: Clinical and histologic diagnosis and management of cardiac sarcoidosis
  evidence:
  - reference: PMID:37123482
    reference_title: Comparing and Contrasting Guidelines for the Management of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Japanese Circulation Society (JCS) recently published new guidelines
      for the diagnosis and treatment of Cardiac Sarcoidosis (CS).
    explanation: Establishes the JCS guideline as a distinct diagnostic and treatment framework.
  - reference: PMID:37123482
    reference_title: Comparing and Contrasting Guidelines for the Management of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 2016 JCS document is broadly similar, with the major exception that it
      is recommended that all patients with LVEF 35-50% should have an EP study.
    explanation: >-
      Documents a concrete management divergence between the JCS and HRS
      frameworks, supporting the description's claim that they differ in
      practice and not only in wording.
- name: WASOG Sarcoidosis Organ Assessment Instrument
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The WASOG instrument is not a cardiac-specific guideline but an
    organ-involvement probability tool covering all sarcoidosis organs,
    grading each clinical manifestation as highly probable, probable, or
    possible evidence of sarcoidosis involvement in that organ. It requires
    histologic granulomatous inflammation in some other organ and exclusion of
    alternative causes, so it classifies cardiac involvement probabilistically
    rather than issuing a binary cardiac diagnosis.
  scope: Probability of sarcoidosis involvement of a given organ, including the heart
  evidence:
  - reference: PMID:24751450
    reference_title: "The WASOG Sarcoidosis Organ Assessment Instrument: An update of a previous clinical tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the World Association of Sarcoidosis and Other Granulomatous Diseases
      (WASOG) developed a new sarcoidosis organ assessment instrument
    explanation: Establishes the instrument and its issuing body.
  - reference: PMID:24751450
    reference_title: "The WASOG Sarcoidosis Organ Assessment Instrument: An update of a previous clinical tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical manifestations were assessed as either: a) highly probable:
      likelihood of sarcoidosis causing this manifestation of at least 90%.; b)
      probable: likelihood of sarcoidosis causing this manifestation of between
      50 and 90%; c) possible: likelihood of sarcoidosis causing this
      manifestation of less than 50%.
    explanation: >-
      Gives the probabilistic grading that distinguishes WASOG from the binary
      HRS and JCS cardiac diagnoses.
  - reference: PMID:37123482
    reference_title: Comparing and Contrasting Guidelines for the Management of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are two other guideline documents, the World Association of
      Sarcoidosis and Other Granulomatous Disorders Sarcoidosis Organ (WASOG)
      Assessment Instrument created in 1999 and updated in 2014.
    explanation: Places WASOG alongside HRS and JCS as one of the three standing frameworks.
pathophysiology:
- name: Antigen-Driven CD4+ T-Cell and Macrophage Activation
  conforms_to: "granuloma_formation#Th1 and TNF-Driven Macrophage Recruitment and Activation"
  biological_scale: CELLULAR
  description: >-
    As in sarcoidosis at any other site, an unidentified poorly degradable
    antigen encountered by a genetically susceptible host drives antigen
    presentation to CD4+ T cells, Th1-skewed cytokine production (IL-2, TNF,
    IFN-gamma), and sustained macrophage activation. This upstream immune
    program is shared with systemic sarcoidosis and is not cardiac-specific; it
    is curated here because it is the trigger of the cardiac chain that follows.
  cell_types:
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  - preferred_term: T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: T cell activation
    modifier: INCREASED
    term:
      id: GO:0042110
      label: T cell activation
  - preferred_term: antigen processing and presentation
    modifier: INCREASED
    term:
      id: GO:0019882
      label: antigen processing and presentation
  - preferred_term: macrophage activation
    modifier: INCREASED
    term:
      id: GO:0042116
      label: macrophage activation
  - preferred_term: cytokine production
    modifier: INCREASED
    term:
      id: GO:0001816
      label: cytokine production
  downstream:
  - target: Myocardial Non-Caseating Granuloma Formation
    description: >-
      Sustained Th1/macrophage activation in the myocardium organizes into
      epithelioid-cell granulomas, the defining lesion of cardiac sarcoidosis.
    evidence:
    - reference: PMID:36924191
      reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac sarcoidosis (CS) results from epithelioid cell granulomas
        infiltrating the myocardium and predisposing to conduction disturbances,
        ventricular tachyarrhythmias, and heart failure.
      explanation: >-
        Establishes myocardial epithelioid-cell granuloma formation as the
        proximate lesion of cardiac sarcoidosis, the target of this edge.
  evidence:
  - reference: ORPHA:797
    reference_title: Sarcoidosis
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare multisystemic, autoinflammatory disorder of unknown etiology
      characterized by the formation of immune, non-caseating granulomas in any
      organ(s), leading to variable clinical symptoms and severity.
    explanation: >-
      Orphanet establishes the systemic autoinflammatory granuloma-forming
      process that this node represents upstream of cardiac localization.
- name: Myocardial Non-Caseating Granuloma Formation
  conforms_to: "granuloma_formation#Epithelioid Transformation and Multinucleated Giant Cell Formation"
  biological_scale: TISSUE
  description: >-
    Activated macrophages within the myocardium undergo the defining
    granulomatous transformations - differentiation into tightly packed
    epithelioid cells and fusion into multinucleated giant cells - producing
    compact non-caseating granulomas cuffed by lymphocytes. Distribution is
    characteristically patchy and multifocal, favouring the left ventricular free
    wall, the interventricular septum, and the right ventricle. This patchiness
    is directly responsible for the low sensitivity of endomyocardial biopsy.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  cell_types:
  - preferred_term: epithelioid macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  biological_processes:
  - preferred_term: granuloma formation
    modifier: INCREASED
    term:
      id: GO:0002432
      label: granuloma formation
  - preferred_term: Macrophage fusion into multinucleated giant cells
    modifier: INCREASED
    term:
      id: GO:0000768
      label: syncytium formation by cell-cell fusion
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Active Granulomatous Myocardial Inflammation
    description: >-
      Established granulomas sustain an actively inflamed, oedematous myocardial
      focus with inflammatory-cell infiltration of surrounding working myocardium
      and conduction tissue.
    evidence:
    - reference: PMID:28501519
      reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Late gadolinium enhancement was present in 22%, indicating myocardial
        involvement, and 70% had corresponding hyper-intense T2 signal indicating
        active inflammation.
      explanation: >-
        Imaging demonstrates that myocardial sarcoid involvement co-localizes
        with an active inflammatory (oedematous, T2-bright) signal, the target of
        this edge.
  evidence:
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although granulomas are often composed of tight epithelioid macrophage
      aggregates, early granulomas comprise loosely associated macrophages with
      lymphocyte predominance.
    explanation: >-
      Pathology series documents the epithelioid macrophage aggregate that
      defines the myocardial granuloma, and its lymphocyte-predominant early
      form.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Irregular left ventricular free wall involvement is most common, followed
      by the interventricular septum and right ventricle.
    explanation: >-
      Establishes the anatomical distribution and the irregular (patchy)
      character of myocardial involvement curated on this node.
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Definite diagnosis of CS requires myocardial biopsy and histopathology,
      but a sufficient diagnostic likelihood can be achieved by combining
      extracardiac histology of sarcoidosis with clinical manifestations and
      findings on cardiac imaging.
    explanation: >-
      Confirms that the granulomatous lesion of this node is the histopathologic
      referent that defines the disease.
- name: Active Granulomatous Myocardial Inflammation
  biological_scale: TISSUE
  description: >-
    An actively inflamed myocardial focus - oedema, glucose-avid inflammatory
    cells, and injury to adjacent cardiomyocytes and specialized conduction
    tissue. This is the potentially reversible stage: conduction disturbance
    arising from inflammation rather than from established scar can recover under
    immunosuppression. FDG avidity of these lesions is the basis of PET imaging
    and of treatment monitoring.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: cardiac muscle cell apoptotic process
    modifier: INCREASED
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
  downstream:
  - target: Conduction System Involvement and Atrioventricular Block
    description: >-
      Active inflammation involving the basal septum and the atrioventricular
      conduction axis impairs AV conduction. Because this arm is inflammatory
      rather than fibrotic, it is the arm that can reverse with corticosteroid
      therapy.
    evidence:
    - reference: PMID:33687942
      reference_title: "Complete heart block in cardiac sarcoidosis reversed by corticosteroid therapy: time course of resolution."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Imaging suggested active inflammation in the septum affecting
        atrioventricular (AV) conduction but no irreversible fibrosis.
      explanation: >-
        Directly attributes AV conduction impairment to active septal
        inflammation, distinct from fixed fibrosis, in a case with imaging
        separation of the two.
  - target: Post-Inflammatory Replacement Fibrosis and Myocardial Scar
    description: >-
      Granulomas that persist rather than resolve evolve into replacement
      fibrosis, converting a reversible inflammatory lesion into fixed
      myocardial scar.
    evidence:
    - reference: PMID:31769474
      reference_title: The Many Faces of Cardiac Sarcoidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic disease leads to fibrosis and end-stage heart failure.
      explanation: >-
        Pathology review states the progression from chronic granulomatous
        disease to fibrosis, the target of this edge.
  evidence:
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late gadolinium enhancement was present in 22%, indicating myocardial
      involvement, and 70% had corresponding hyper-intense T2 signal indicating
      active inflammation.
    explanation: >-
      T2 hyper-intensity co-localizing with sarcoid myocardial involvement is the
      imaging correlate of the active inflammatory state this node represents.
- name: Conduction System Involvement and Atrioventricular Block
  biological_scale: TISSUE
  description: >-
    Granulomatous inflammation and scar involving the basal interventricular
    septum and the atrioventricular conduction axis interrupt AV conduction,
    producing Mobitz II second-degree or third-degree block. High-grade AV block
    is the single most common presenting manifestation of cardiac sarcoidosis and
    is frequently the only one at presentation ("lone AVB"). It is the cardiac
    consequence that most sharply distinguishes this entry from sarcoidosis at
    other sites.
  locations:
  - preferred_term: atrioventricular node
    term:
      id: UBERON:0002352
      label: atrioventricular node
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  biological_processes:
  - preferred_term: cardiac conduction
    modifier: DECREASED
    term:
      id: GO:0061337
      label: cardiac conduction
  downstream:
  - target: Atrioventricular Block
    description: >-
      Conduction-axis involvement manifests clinically as symptomatic high-grade
      atrioventricular block.
    evidence:
    - reference: PMID:30354309
      reference_title: Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Symptomatic high-grade atrioventricular block (AVB) is the most common
        and often the only presenting manifestation (lone AVB) of cardiac
        sarcoidosis.
      explanation: >-
        Nationwide registry analysis establishes symptomatic high-grade AV block
        as the dominant clinical expression of this node.
  evidence:
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High-grade atrioventricular block was the most common first sign of CS
      (n = 147, 42%) followed by heart failure (n = 58, 17%)
    explanation: >-
      Quantifies high-grade AV block as the most frequent first sign of cardiac
      sarcoidosis in a nationwide series of 351 cases.
  - reference: PMID:27443438
    reference_title: Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction
      abnormalities, ventricular arrhythmias, and heart failure.
    explanation: >-
      Names conduction abnormality as one of the three principal manifestations
      that this and the two sibling consequence nodes represent.
- name: Post-Inflammatory Replacement Fibrosis and Myocardial Scar
  conforms_to: "granuloma_formation#Tissue Containment versus Destruction and Fibrosis"
  biological_scale: TISSUE
  description: >-
    Persistent granulomas are replaced by collagenous scar. The resulting
    fibrosis is patchy and multifocal - confluent in the right ventricle,
    patchier in the left with a predilection for the basal septum, anterior wall,
    and perivalvular regions - and it is fixed: unlike the inflammatory stage it
    does not regress with immunosuppression. Scar burden on late gadolinium
    enhancement is the durable arrhythmic and functional substrate of the
    disease.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: fibroblast of cardiac tissue
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: collagen fibril organization
    modifier: INCREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  downstream:
  - target: Scar-Mediated Re-entrant Ventricular Tachyarrhythmia
    description: >-
      Patchy scar interleaved with surviving myocyte bundles creates zones of
      slow conduction and unidirectional block, the classic substrate for
      macro-re-entrant ventricular tachycardia.
    evidence:
    - reference: PMID:25527825
      reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Multiple inducible VTs were observed with mechanism consistent with
        scar-mediated re-entry in all VTs.
      explanation: >-
        Electroanatomic mapping in cardiac sarcoidosis established scar-mediated
        re-entry as the mechanism of every induced VT, the target of this edge.
  - target: Progressive Ventricular Dysfunction and Heart Failure
    description: >-
      Loss of contractile myocardium to granuloma and scar, together with adverse
      remodeling of the residual myocardium, produces progressive ventricular
      dysfunction.
    evidence:
    - reference: PMID:33070538
      reference_title: "Cardiac sarcoidosis: diagnosis and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cardiac fibrosis leads to congestive heart failure, arrhythmias and sudden cardiac death.
      explanation: >-
        Directly states the causal step from cardiac fibrosis to congestive heart
        failure that this edge represents.
  evidence:
  - reference: PMID:25527825
    reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Left ventricular scarring was patchy with a predilection for the basal
      septum, anterior wall, and perivalvular regions.
    explanation: >-
      Voltage mapping characterizes the patchy distribution and regional
      predilection of the scar curated on this node.
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late gadolinium enhancement was 18%+/-9.7% of overall left ventricular
      (LV) mass and most commonly located in the basal to mid septum.
    explanation: >-
      Cardiac MRI localizes the late gadolinium enhancement (scar) of this node
      to the basal-to-mid septum, matching the electroanatomic findings.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Chronic disease leads to fibrosis and end-stage heart failure.
    explanation: Pathology review anchors replacement fibrosis as the chronic-stage lesion.
- name: Scar-Mediated Re-entrant Ventricular Tachyarrhythmia
  biological_scale: ORGANISM
  description: >-
    Fixed myocardial scar sustains multiple macro-re-entrant circuits. Both
    ventricles contribute: right ventricular scar is widespread and confluent
    (with epicardial extent exceeding the endocardial), while left ventricular
    scar is patchy. Because the substrate is structural rather than a primary
    channelopathy, arrhythmia can persist after inflammation has resolved on PET
    - which is why suppressing inflammation does not by itself abolish arrhythmic
    risk.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: cardiac conduction
    modifier: ABNORMAL
    term:
      id: GO:0061337
      label: cardiac conduction
  - preferred_term: regulation of heart rate
    modifier: ABNORMAL
    term:
      id: GO:0002027
      label: regulation of heart rate
  downstream:
  - target: Ventricular Tachycardia
    description: >-
      Re-entrant circuits within sarcoid scar generate sustained and
      non-sustained ventricular tachycardia.
    evidence:
    - reference: PMID:25527825
      reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with cardiac sarcoidosis and VT exhibit ventricular substrate
        characterized by confluent right ventricular scarring and patchy left
        ventricular scarring capable of sustaining a large number of re-entrant
        circuits.
      explanation: >-
        Characterizes the sarcoid ventricular substrate as able to sustain many
        re-entrant circuits, the immediate cause of the VT phenotype.
  - target: Sudden Cardiac Death
    description: >-
      Degeneration of scar-mediated ventricular tachycardia to fibrillation, and
      high-grade conduction block, underlie sudden death - which is frequently
      the first recognized event and often occurs in patients whose cardiac
      granulomas were never diagnosed in life.
    evidence:
    - reference: PMID:31230070
      reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nearly two-thirds of all fatalities from CS are caused by undiagnosed
        granulomas in the heart.
      explanation: >-
        Nationwide cause-of-death linkage attributes most cardiac sarcoidosis
        fatalities to undiagnosed cardiac granulomas, supporting sudden death as
        the terminal event of this node.
  evidence:
  - reference: PMID:25527825
    reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Voltage maps showed widespread and confluent right ventricular scarring.
    explanation: >-
      Documents the confluent right ventricular scar component of the
      arrhythmogenic substrate this node represents.
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of LGE was highly correlated with clinically significant
      arrhythmias and lower LVEF.
    explanation: >-
      Links imaging-quantified scar burden to clinically significant arrhythmia,
      supporting scar as the arrhythmic substrate.
  notes: >-
    Deliberately NOT declared as conforming to cardiac_ion_channel_repolarization.
    That module models arrhythmia arising from an ion-channel or calcium-handling
    variant in a structurally normal heart; cardiac sarcoidosis arrhythmia is
    structural, arising from macro-re-entry around fixed granulomatous scar
    (PMID:25527825). Forcing conformance would misstate the mechanism.
- name: Progressive Ventricular Dysfunction and Heart Failure
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  description: >-
    Cumulative replacement of contractile myocardium by granuloma and scar,
    together with remodeling of the residual myocardium, produces falling
    ejection fraction and clinical heart failure. The extent of left ventricular
    dysfunction is the strongest prognostic determinant in clinically manifest
    disease, and end-stage cases proceed to mechanical support or
    transplantation.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  - preferred_term: heart contraction
    modifier: ABNORMAL
    term:
      id: GO:0060047
      label: heart contraction
  downstream:
  - target: Congestive Heart Failure
    description: >-
      Progressive contractile failure manifests clinically as congestive heart
      failure.
    evidence:
    - reference: PMID:33070538
      reference_title: "Cardiac sarcoidosis: diagnosis and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cardiac fibrosis leads to congestive heart failure, arrhythmias and sudden cardiac death.
      explanation: States the progression to congestive heart failure that this edge represents.
  evidence:
  - reference: PMID:27443438
    reference_title: Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with clinically manifest CS, the extent of left ventricular
      dysfunction seems to be the most important predictor of prognosis.
    explanation: >-
      Establishes left ventricular dysfunction - the state this node represents -
      as the dominant prognostic variable.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Chronic disease leads to fibrosis and end-stage heart failure.
    explanation: Pathologic confirmation of the fibrosis-to-end-stage-heart-failure endpoint.
  - reference: PMID:33059834
    reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CS is problematic to diagnose and may cause significant morbidity and death
      from heart failure or ventricular arrhythmias.
    explanation: >-
      Names heart failure alongside ventricular arrhythmia as the two dominant
      causes of death, the two terminal arms of this pathograph.
phenotypes:
- name: Atrioventricular Block
  category: Cardiac
  frequency: FREQUENT
  description: >-
    Mobitz type II second-degree or third-degree atrioventricular block from
    granulomatous involvement of the basal septum and AV conduction axis. The
    most common presenting manifestation of cardiac sarcoidosis, and often the
    only one at presentation.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High-grade atrioventricular block was the most common first sign of CS
      (n = 147, 42%) followed by heart failure (n = 58, 17%)
    explanation: >-
      Nationwide series of 351 cases gives 42% as the proportion presenting with
      high-grade AV block, supporting the FREQUENT (30-79%) band directly.
  - reference: PMID:30354309
    reference_title: Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptomatic high-grade atrioventricular block (AVB) is the most common and
      often the only presenting manifestation (lone AVB) of cardiac sarcoidosis.
    explanation: Independently confirms high-grade AV block as the dominant presentation.
- name: Ventricular Tachycardia
  category: Cardiac
  frequency: OCCASIONAL
  description: >-
    Sustained or non-sustained ventricular tachycardia arising from
    macro-re-entrant circuits within granulomatous myocardial scar. May be the
    presenting event or emerge later, and may persist after myocardial
    inflammation has been suppressed.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained
      ventricular tachycardia (n = 48, 14%)
    explanation: >-
      Nationwide series gives 14% presenting with sustained VT, which maps to the
      OCCASIONAL (5-29%) band. Note this counts VT as the *presenting*
      manifestation; lifetime VT burden is higher.
  - reference: PMID:25527825
    reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multiple inducible VTs were observed with mechanism consistent with
      scar-mediated re-entry in all VTs.
    explanation: Characterizes the mechanism of the VT phenotype as scar-mediated re-entry.
- name: Congestive Heart Failure
  category: Cardiac
  frequency: OCCASIONAL
  description: >-
    Heart failure from cumulative granulomatous and fibrotic replacement of
    contractile myocardium. Presents with dyspnoea and exercise intolerance; in a
    minority progresses to end-stage disease requiring mechanical support or
    transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High-grade atrioventricular block was the most common first sign of CS
      (n = 147, 42%) followed by heart failure (n = 58, 17%)
    explanation: >-
      17% of 351 cases presented with heart failure, supporting the OCCASIONAL
      (5-29%) band. Note this counts heart failure as the *presenting*
      manifestation, so it is a lower bound on lifetime frequency.
  - reference: PMID:33070538
    reference_title: "Cardiac sarcoidosis: diagnosis and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiac fibrosis leads to congestive heart failure, arrhythmias and sudden cardiac death.
    explanation: Links the fibrotic mechanism curated in the pathograph to this phenotype.
- name: Sudden Cardiac Death
  category: Cardiac
  frequency: OCCASIONAL
  description: >-
    Sudden death from ventricular tachyarrhythmia degenerating to fibrillation,
    or from high-grade conduction block. Frequently the first recognized
    manifestation, and most cardiac sarcoidosis deaths occur in patients whose
    cardiac granulomas were never diagnosed during life.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained
      ventricular tachycardia (n = 48, 14%)
    explanation: >-
      Fatal or aborted sudden cardiac death accounted for 14% of presentations in
      351 nationwide cases, supporting the OCCASIONAL (5-29%) band. As with the
      other bands here this counts the *presenting* event, so it is a lower
      bound on lifetime risk.
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly two-thirds of all fatalities from CS are caused by undiagnosed
      granulomas in the heart.
    explanation: >-
      Supports the description's claim that sudden death frequently occurs in
      undiagnosed disease.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiac
  description: >-
    Depressed left ventricular systolic function from myocardial replacement by
    granuloma and scar. The extent of LV dysfunction is the most important
    prognostic determinant in clinically manifest disease, and is more severe in
    isolated cardiac sarcoidosis than in multi-organ disease.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:27443438
    reference_title: Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with clinically manifest CS, the extent of left ventricular
      dysfunction seems to be the most important predictor of prognosis.
    explanation: Establishes LV dysfunction as a curated phenotype with prognostic weight.
  - reference: PMID:41193496
    reference_title: "Isolated cardiac sarcoidosis: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with multi-organ cardiac sarcoidosis, isolated cardiac
      sarcoidosis is associated with lower left ventricular ejection fraction and
      poorer survival.
    explanation: Supports the subtype-dependent severity of reduced LVEF stated in the description.
- name: Myocardial Fibrosis
  category: Cardiac
  description: >-
    Patchy replacement fibrosis of the myocardium, detected in life as late
    gadolinium enhancement on cardiac MRI, typically in the basal-to-mid septum
    and left ventricular free wall. Scar burden correlates with arrhythmia and
    with reduced ejection fraction.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of LGE was highly correlated with clinically significant
      arrhythmias and lower LVEF.
    explanation: >-
      Late gadolinium enhancement is the in-vivo readout of myocardial fibrosis,
      and correlates with the arrhythmic and functional consequences.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Chronic disease leads to fibrosis and end-stage heart failure.
    explanation: Histopathologic confirmation of myocardial fibrosis in chronic cardiac sarcoidosis.
- name: Syncope
  category: Cardiac
  description: >-
    Loss of consciousness from bradyarrhythmia (high-grade AV block) or from
    ventricular tachyarrhythmia. Recurrent syncope in a patient without an
    established cardiac diagnosis is a recognized trigger for evaluating cardiac
    sarcoidosis.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:33687942
    reference_title: "Complete heart block in cardiac sarcoidosis reversed by corticosteroid therapy: time course of resolution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 53-year-old man was admitted for recurrent syncope and found to have
      complete heart block (CHB).
    explanation: >-
      Case report documents syncope as the presenting symptom of conduction-block
      cardiac sarcoidosis. Single-case evidence, so no frequency band is asserted.
- name: Bundle Branch Block
  category: Cardiac
  description: >-
    Right bundle branch block and other intraventricular conduction delay from
    granulomatous involvement of the distal conduction system, reported alongside
    atrioventricular block as the most common conduction manifestation. No
    frequency band is asserted: the cited source ranks it as most common without
    giving a proportion of patients.
  phenotype_term:
    preferred_term: Bundle branch block
    term:
      id: HP:0011710
      label: Bundle branch block
  evidence:
  - reference: PMID:33059834
    reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Right bundle branch block (RBBB) and atrioventricular block (AVB), ranging
      from first to third degree, are the most common manifestation
    explanation: >-
      Names right bundle branch block alongside AV block as the most common
      conduction manifestation of cardiac sarcoidosis.
- name: Atrial Fibrillation
  category: Cardiac
  description: >-
    Atrial fibrillation and other supraventricular arrhythmias occur in cardiac
    sarcoidosis, attributable to atrial granulomatous involvement and to atrial
    stretch from ventricular dysfunction. It is uncommon as a presenting feature
    but accumulates over the disease course, so the two cited sources describe
    different time points and no single frequency band is asserted.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:33059834
    reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      atrial fibrillation (AF) can occur as well (up to 32% of subjects)
    explanation: >-
      Establishes atrial fibrillation as a recognized manifestation and gives an
      upper-bound cumulative estimate.
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atrial fibrillation is rare at presentation but has a considerable later
      incidence.
    explanation: >-
      Supplies the temporal qualification stated in the description, and is why
      no frequency band is asserted for this phenotype.
histopathology:
- name: Non-caseating granulomatous myocarditis
  description: >-
    Compact non-caseating granulomas of epithelioid macrophages and
    multinucleated giant cells with a lymphocytic cuff, distributed irregularly
    through the left ventricular free wall, interventricular septum, and right
    ventricle, with replacement fibrosis in chronic disease. The patchiness is
    the reason endomyocardial biopsy is insensitive despite being highly
    specific.
  diagnostic: true
  context: Endomyocardial biopsy or explanted/autopsy heart
  evidence:
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although granulomas are often composed of tight epithelioid macrophage
      aggregates, early granulomas comprise loosely associated macrophages with
      lymphocyte predominance.
    explanation: Describes the granuloma cellular composition and its early/late variation.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sampling errors and variable histology cause low endomyocardial biopsy sensitivity.
    explanation: >-
      Directly attributes the low biopsy sensitivity to sampling error against
      patchy lesions, the claim made in this entry's description.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Irregular left ventricular free wall involvement is most common, followed
      by the interventricular septum and right ventricle.
    explanation: Gives the anatomical distribution of the histopathologic lesion.
diagnosis:
- name: Cardiac magnetic resonance imaging
  description: >-
    CMR with late gadolinium enhancement detects myocardial scar and, with T2
    imaging, active oedema. It uncovers cardiac involvement far more often than
    clinical criteria do, and LGE burden carries arrhythmic and functional
    prognostic weight.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late gadolinium enhancement was present in 22%, indicating myocardial
      involvement, and 70% had corresponding hyper-intense T2 signal indicating
      active inflammation.
    explanation: >-
      Demonstrates CMR detection of both scar (LGE) and active inflammation (T2)
      in a biopsy-proven sarcoidosis cohort.
  - reference: PMID:28501519
    reference_title: The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using CMR, we identified a higher prevalence of cardiac sarcoidosis than
      previously reported clinical studies, a prevalence which is more consistent
      with autopsy data.
    explanation: Supports CMR as the modality that closes the clinical-versus-autopsy detection gap.
- name: FDG-PET assessment of myocardial inflammation
  description: >-
    18F-FDG PET detects glucose-avid inflammatory cells in active granulomatous
    lesions, and is used both diagnostically and to monitor response to
    immunosuppression. It is a surrogate imaging biomarker, adopted because
    endomyocardial biopsy yield is low.
  diagnosis_term:
    preferred_term: FDG-positron emission tomography
    term:
      id: NCIT:C103400
      label: FDG-Positron Emission Tomography
  evidence:
  - reference: PMID:33059834
    reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of CS usually requires surrogate cardiac imaging biomarkers,
      as endomyocardial biopsy has relatively low yield, even with directed
      electrophysiological mapping.
    explanation: >-
      Establishes the reliance on surrogate cardiac imaging biomarkers in place
      of biopsy, the rationale for this diagnostic modality.
  - reference: PMID:31538835
    reference_title: Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Methotrexate±low-dose prednisone resulted in initial reduction (88%) or
      elimination (60%) of 18-fluorodeoxyglucose uptake
    explanation: >-
      Demonstrates FDG uptake being used as the treatment-response readout, the
      monitoring role described here.
- name: Endomyocardial biopsy
  description: >-
    Histologic demonstration of non-caseating myocardial granulomas is the only
    route to a definite diagnosis, but sensitivity is low because lesions are
    patchy; electroanatomic- or image-guided sampling improves but does not solve
    the yield problem.
  diagnosis_term:
    preferred_term: endomyocardial biopsy
    term:
      id: NCIT:C51674
      label: Endomyocardial Biopsy
  evidence:
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Definite diagnosis of CS requires myocardial biopsy and histopathology
    explanation: States the role of myocardial biopsy in establishing a definite diagnosis.
  - reference: PMID:31769474
    reference_title: The Many Faces of Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sampling errors and variable histology cause low endomyocardial biopsy sensitivity.
    explanation: Quantifies the limitation of the modality described here.
- name: Electrocardiography
  description: >-
    ECG identifies the conduction abnormalities that most often bring cardiac
    sarcoidosis to attention - high-grade AV block, bundle branch block, and
    ventricular arrhythmia - and is the entry point for screening patients with
    known systemic sarcoidosis.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:33687942
    reference_title: "Complete heart block in cardiac sarcoidosis reversed by corticosteroid therapy: time course of resolution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three weeks later, ECG with pacing inhibited showed second-degree AV block
      Mobitz type II and 4 weeks later, AV conduction recovery.
    explanation: >-
      Illustrates ECG being used to grade and follow the conduction abnormality
      that defines the cardiac presentation.
- name: Echocardiography
  description: >-
    Transthoracic echocardiography is the first-line imaging rung of the HRS
    screening algorithm, ahead of CMR and FDG-PET. Typical findings are regional
    wall thinning and contraction abnormalities in basal, septal, and lateral
    segments. Sensitivity is low - a normal echocardiogram does not exclude
    cardiac sarcoidosis - so it triages patients toward advanced imaging rather
    than settling the diagnosis.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:37682338
    reference_title: "[Imaging diagnostics of cardiac sarcoidosis]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical echocardiographic findings include regional thinning and
      contraction abnormalities particularly in basal, septal and lateral
      locations.
    explanation: >-
      Gives the characteristic echocardiographic findings, whose regional
      distribution matches the granuloma and scar distribution curated in the
      pathograph.
  - reference: PMID:37682338
    reference_title: "[Imaging diagnostics of cardiac sarcoidosis]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the sensitivity of echocardiography is low and cardiac sarcoidosis can be
      present even when an echocardiogram is unrevealing
    explanation: >-
      Records the limitation that makes echocardiography a triage rather than a
      confirmatory modality.
  - reference: PMID:40445485
    reference_title: Screening for cardiac involvement in patients with sarcoidosis using AIIMS algorithm.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 100 patients screened, 23% had cardiac symptoms, 23% had ECG
      changes, 16% had abnormalities on conventional echocardiography, 32% of
      patients had abnormal GLS, 16% and 19% of patients were positive for
      Troponin I and NT-Pro BNP respectively.
    explanation: >-
      Quantifies the yield of conventional echocardiography within a
      prospective sarcoidosis screening cohort, alongside the other screening
      rungs curated in this entry.
treatments:
- name: Corticosteroid Therapy
  description: >-
    Corticosteroids are first-line therapy for clinically manifest cardiac
    sarcoidosis, aimed at suppressing active granulomatous myocardial
    inflammation before it converts to fixed scar. The best-quality evidence is
    for recovery of atrioventricular conduction and prevention of deterioration
    in left ventricular function; evidence is explicitly inadequate to claim a
    ventricular-arrhythmia or mortality benefit, and no randomized trial exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  target_mechanisms:
  - target: Active Granulomatous Myocardial Inflammation
    treatment_effect: INHIBITS
    description: >-
      Corticosteroids suppress the active granulomatous inflammatory lesion. The
      therapeutic window is the inflammatory stage: AV conduction impaired by
      active septal inflammation can recover, whereas established fibrosis
      cannot.
    evidence:
    - reference: PMID:34472360
      reference_title: "Corticosteroid and Immunosuppressant Therapy for Cardiac Sarcoidosis: A Systematic Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There were 178 patients treated for atrioventricular conduction disease,
        with 76/178 (42.7%) improving.
      explanation: >-
        Systematic review quantifies AV conduction recovery under
        corticosteroid/immunosuppressant therapy, the effect of inhibiting this
        node.
    - reference: PMID:33687942
      reference_title: "Complete heart block in cardiac sarcoidosis reversed by corticosteroid therapy: time course of resolution."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This highlights the importance of immediate therapy in reversing AV
        conduction abnormalities in CS.
      explanation: >-
        Case-level demonstration that the reversible target is the inflammatory,
        not the fibrotic, lesion.
  evidence:
  - reference: PMID:34472360
    reference_title: "Corticosteroid and Immunosuppressant Therapy for Cardiac Sarcoidosis: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, 21 patients were not treated with corticosteroids and/or
      immunosuppressant therapy, and none of them improved.
    explanation: >-
      Provides the untreated comparator (0/21 improved) against which the 42.7%
      treated improvement rate is read.
  - reference: PMID:34472360
    reference_title: "Corticosteroid and Immunosuppressant Therapy for Cardiac Sarcoidosis: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Therapy was associated with the prevention of deterioration in left ventricular function.
    explanation: Supports the second of the two outcomes for which evidence quality is adequate.
  - reference: PMID:34472360
    reference_title: "Corticosteroid and Immunosuppressant Therapy for Cardiac Sarcoidosis: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data quality is too limited to draw conclusions for ventricular
      arrhythmias and mortality.
    explanation: >-
      Records the explicit limit of the evidence base, so this treatment entry
      does not overstate benefit beyond conduction and LV function.
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, the treatment involves corticosteroid-based, tiered
      immunosuppression to control myocardial inflammation with medical and
      device-based therapy for symptomatic atrioventricular block, ventricular
      tachyarrhythmias, and heart failure.
    explanation: Confirms corticosteroid-based immunosuppression as the therapeutic backbone.
- name: Methotrexate Corticosteroid-Sparing Maintenance
  description: >-
    Methotrexate, with or without low-dose prednisone, is used as maintenance
    therapy after an initial corticosteroid response, reducing cumulative steroid
    exposure. Efficacy is judged by suppression of myocardial FDG uptake; relapse
    after cessation supports ongoing surveillance.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Immunosuppressive Therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
  target_mechanisms:
  - target: Active Granulomatous Myocardial Inflammation
    treatment_effect: INHIBITS
    description: >-
      Steroid-sparing immunosuppression suppresses the same active granulomatous
      lesion as corticosteroids, measured as reduction or elimination of
      myocardial FDG uptake.
    evidence:
    - reference: PMID:31538835
      reference_title: Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Methotrexate±low-dose prednisone resulted in initial reduction (88%) or
        elimination (60%) of 18-fluorodeoxyglucose uptake
      explanation: >-
        Quantifies suppression of the active inflammatory node under
        methotrexate-based maintenance specifically. The adalimumab arm of the
        same study is curated separately under TNF Inhibitor Therapy.
  evidence:
  - reference: PMID:31538835
    reference_title: Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corticosteroid-sparing regimens containing methotrexate with or without
      adalimumab is an effective maintenance therapy in patients after an initial
      response is confirmed.
    explanation: States the maintenance role and the precondition (confirmed initial response).
  - reference: PMID:31538835
    reference_title: Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease recurrence in patients on and off immunosuppression support need
      for ongoing radiologic surveillance regardless of immunosuppression
      regimen.
    explanation: Supports the surveillance requirement stated in the description.
- name: TNF Inhibitor Therapy
  description: >-
    TNF-neutralizing biologics - infliximab (chimeric) and adalimumab (fully
    human) - are used in cardiac sarcoidosis refractory to corticosteroids and
    conventional steroid-sparing agents. This instantiates the granuloma-formation
    drug-target design pattern: TNF is the non-redundant amplifier that drives
    macrophage accumulation and activation, so its blockade acts on the
    Th1/TNF node rather than on the mature granuloma. Safety caveat specific to
    this disease: anti-TNF therapy carries a risk of increased mortality in
    patients with severe cardiomyopathy, so it must be used with caution in
    exactly the cardiac sarcoidosis patients whose ventricular function is most
    impaired.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
  target_mechanisms:
  - target: Antigen-Driven CD4+ T-Cell and Macrophage Activation
    treatment_effect: INHIBITS
    description: >-
      TNF neutralization removes the amplifier that drives macrophage
      accumulation and activation, the mechanism by which anti-TNF agents
      prevent granuloma formation. This is the same node that conforms to
      granuloma_formation#Th1 and TNF-Driven Macrophage Recruitment and
      Activation, which the module's own TNF-inhibitor pattern targets.
    evidence:
    - reference: PMID:36924191
      reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biologic anti-tumor necrosis factor (TNF) agents can prevent granuloma
        formation, and observational data support their efficacy in CS when
        other therapies have failed.
      explanation: >-
        States both the mechanism (prevention of granuloma formation) and the
        cardiac-sarcoidosis-specific efficacy setting for this edge.
    - reference: PMID:33059834
      reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IFN-γ and TNF-α promote the accumulation and activation of macrophages
      explanation: >-
        Identifies TNF as a driver of the macrophage accumulation and activation
        that this node represents, so neutralizing it acts here.
  - target: Active Granulomatous Myocardial Inflammation
    treatment_effect: INHIBITS
    description: >-
      Adalimumab-containing regimens suppress the active myocardial lesion,
      measured as improvement or resolution of myocardial FDG uptake.
    evidence:
    - reference: PMID:31538835
      reference_title: Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        patients receiving adalimumab-containing regimens experienced improved
        (84%) or resolved (63%) 18-fluorodeoxyglucose uptake
      explanation: >-
        Quantifies suppression of the active inflammatory node under
        adalimumab-containing therapy.
  evidence:
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infliximab is a chimeric TNF antibody which in doses <10 mg/kg is well
      tolerated even in patients with impaired LV function.
    explanation: Establishes infliximab as one of the two agents in this treatment class.
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adalimumab, a human monoclonal TNF antibody, is a subcutaneously
      administered alternative.
    explanation: Establishes adalimumab as the second agent in this treatment class.
  - reference: PMID:33059834
    reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, because of the risk of increased mortality associated with use of
      anti-TNF therapy in patients with severe CMP (130), one must use with
      caution.
    explanation: >-
      Source for the disease-specific safety caveat stated in the description.
      Note the two cited reviews are not fully concordant on tolerability in
      impaired ventricular function, which is why the caveat is curated rather
      than only the favourable statement.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    ICD implantation for prevention of sudden cardiac death. Because arrhythmic
    risk arises from fixed scar and persists even when conduction recovers, an
    ICD rather than a pacemaker is recommended whenever permanent pacing is
    needed in cardiac sarcoidosis. Device therapy addresses the arrhythmic
    consequence; it does not modify the granulomatous disease.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Scar-Mediated Re-entrant Ventricular Tachyarrhythmia
    treatment_effect: INHIBITS
    description: >-
      The device terminates scar-mediated ventricular tachyarrhythmia when it
      occurs, preventing progression to sudden death, without altering the
      underlying scar substrate.
    evidence:
    - reference: PMID:32062788
      reference_title: "Outcome of implantable cardioverter defibrillator in cardiac sarcoidosis: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Appropriate and inappropriate ICD treatments (AT and IAT) were reported
        in 39% and 15% of patients respectively
      explanation: >-
        Meta-analysis documents that 39% of implanted patients received
        appropriate device therapy for the arrhythmia this node represents.
  evidence:
  - reference: PMID:30354309
    reference_title: Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The consensus recommendation to implant an intracardiac cardioverter
      defibrillator whenever permanent pacing is needed seems well-founded.
    explanation: >-
      Nationwide outcome data support ICD over pacemaker whenever pacing is
      indicated, the recommendation stated in this treatment entry.
  - reference: PMID:32062788
    reference_title: "Outcome of implantable cardioverter defibrillator in cardiac sarcoidosis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: High degree AV block appears to be predictive of appropriate ICD therapy.
    explanation: >-
      Supports the link between the conduction-block presentation and subsequent
      arrhythmic events that motivates ICD rather than pacemaker selection.
  - reference: PMID:27443438
    reference_title: Cardiac Sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Device therapy, primarily with implantable cardioverter-defibrillators, is
      often recommended for patients with clinically manifest disease.
    explanation: Independent statement of the device recommendation in manifest disease.
- name: Permanent Pacing
  description: >-
    Pacemaker implantation for symptomatic high-grade atrioventricular block.
    In cardiac sarcoidosis, current recommendation is that a defibrillator be
    implanted instead of a pacemaker whenever permanent pacing is indicated,
    because of the persisting risk of ventricular tachyarrhythmia.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: pacemaker placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  target_mechanisms:
  - target: Conduction System Involvement and Atrioventricular Block
    treatment_effect: BYPASSES
    description: >-
      Pacing bypasses the interrupted atrioventricular conduction axis, treating
      the bradyarrhythmic consequence without addressing the granulomatous cause.
    evidence:
    - reference: PMID:30354309
      reference_title: Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Implantation of an intracardiac cardioverter defibrillator instead of a
        pacemaker is recommended, but the true risk of fatal arrhythmia, one
        incident to lone AVB in particular, remains poorly known.
      explanation: >-
        Establishes permanent pacing as the indicated therapy for this node while
        recording the device-selection caveat stated in the description.
- name: Catheter Ablation for Ventricular Tachycardia
  description: >-
    Catheter ablation of scar-mediated ventricular tachycardia circuits, used for
    recurrent VT or VT storm alongside antiarrhythmic drugs. It is palliative:
    acute success is high but recurrence is common, because septal intramural
    circuits and extensive right ventricular scar leave residual inducible
    circuits.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_mechanisms:
  - target: Scar-Mediated Re-entrant Ventricular Tachyarrhythmia
    treatment_effect: INHIBITS
    description: >-
      Ablation interrupts individual re-entrant circuits within sarcoid scar,
      controlling VT burden without eliminating the substrate.
    evidence:
    - reference: PMID:25527825
      reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Catheter ablation is effective in terminating VT storm and eliminating
        ≥1 inducible VT in the majority of patients, but recurrences are common.
      explanation: >-
        Reports ablation efficacy against the scar-mediated arrhythmia of this
        node, in the same cohort in which the mechanism was mapped, together
        with the recurrence caveat that makes the effect palliative.
  evidence:
  - reference: PMID:25527825
    reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Failure to abolish all inducible VTs was because of septal intramural
      circuits or extensive right ventricular scarring.
    explanation: >-
      Names the anatomical reasons ablation is palliative rather than curative,
      as stated in the description.
  - reference: PMID:25527825
    reference_title: "Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multiple procedure VT-free survival was 37% at 1 year, but VT control was
      achievable in the majority of patients with fewer antiarrhythmic drugs
      compared with preablation
    explanation: Quantifies the recurrence rate that makes this a palliative rather than curative therapy.
- name: Heart Transplantation
  description: >-
    Cardiac transplantation for end-stage cardiac sarcoidosis refractory to
    immunosuppression and device therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:33059834
    reference_title: "Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of CS is often multifactorial, involving a combination of
      antigranulomatous therapy and pharmacotherapy for cardiac arrhythmias
      and/or heart failure in addition to device placement and cardiac
      transplantation.
    explanation: >-
      Places cardiac transplantation within the treatment repertoire for cardiac
      sarcoidosis.
clinical_trials:
- name: NCT06660732
  phase: PHASE_II
  status: RECRUITING
  description: >-
    REPAIR-CS - a randomized Phase II trial (n=60) of the IL-1 trap rilonacept
    added to standard therapy versus standard therapy alone, with the primary
    endpoint being improvement in myocardial inflammation at 24 weeks. It targets
    the active granulomatous inflammation node of this entry's pathograph, and
    is the design that would begin to answer the randomized-evidence gap recorded
    in the immunosuppression KNOWLEDGE_GAP - though its endpoint is imaging
    inflammation, not arrhythmia or mortality.
  target_phenotypes:
  - preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: clinicaltrials:NCT06660732
    reference_title: "A RandomizEd PhAse II TrIal of Rilonacept in Subjects With Cardiac Sarcoidosis (REPAIR-CS)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary objective of this study is to evaluate the effect of
      rilonacept, added to standard therapy and compared with standard therapy
      alone, on improvement in myocardial inflammation in subjects with cardiac
      sarcoidosis after 24 weeks of therapy.
    explanation: >-
      States the randomized comparison and the myocardial-inflammation endpoint
      that make this trial relevant to the active-inflammation node.
- name: NCT04017936
  phase: PHASE_II
  status: COMPLETED
  description: >-
    MAGiC-ART - a completed pilot (n=17) of IL-1 blockade with anakinra in
    cardiac sarcoidosis. Its rationale rests on inflammasome components being
    demonstrable in cardiac sarcoid granulomas, making it a direct test of the
    granulomatous inflammation arm.
  evidence:
  - reference: clinicaltrials:NCT04017936
    reference_title: "Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the current study, researchers aim to evaluate the safety and efficacy
      of IL-1 blockade with anakinra (IL-1 receptor antagonist) in patients with
      cardiac sarcoidosis.
    explanation: States the intervention and objective of the trial.
  - reference: clinicaltrials:NCT04017936
    reference_title: "Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cardiac disease generally progresses from areas of focal inflammation to
      scar
    explanation: >-
      The trial registration independently states the focal-inflammation-to-scar
      progression that is the backbone of this entry's pathograph.
- name: NCT06868381
  phase: PHASE_II
  status: NOT_RECRUITING
  description: >-
    A single-site open-label Phase IIa trial (n=10) of the JAK inhibitor
    baricitinib added to steroid-sparing therapy in active cardiac sarcoidosis,
    with cardiac FDG-PET/CT change as the primary endpoint. Status is
    not-yet-recruiting.
  evidence:
  - reference: clinicaltrials:NCT06868381
    reference_title: "A Phase IIa, Single-Site, Open-Label Trial of Baricitinib in Patients With Cardiac Sarcoidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with active cardiac sarcoidosis, does treatment with
      baricitinib improve cardiac sarcoidosis disease activity as assessed by
      changes on cardiac FDG-PET/CT?
    explanation: >-
      States the intervention and the FDG-PET activity endpoint, the same
      readout used for the curated immunosuppression treatments.
- name: NCT07159074
  phase: PHASE_II
  status: RECRUITING
  description: >-
    A Phase II diagnostic study (n=15) testing whether Tc 99m tilmanocept
    SPECT/CT - a macrophage-mannose-receptor-directed tracer - can identify
    cardiac sarcoidosis. Unlike FDG, which reports generic glucose-avid
    inflammation and needs demanding dietary preparation, this tracer targets
    the macrophage lineage that forms the granuloma itself.
  evidence:
  - reference: clinicaltrials:NCT07159074
    reference_title: "Repurposing Tc 99m Tilmanocept Imaging for Cardiac Sarcoidosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to see if Tc 99m Tilmanocept SPECT/CT imaging
      can be used to identify cardiac sarcoidosis.
    explanation: States the diagnostic objective of the trial.
biochemical:
- name: Elevated high-sensitivity cardiac troponin
  presence: Elevated
  context: >-
    High-sensitivity cardiac troponin reports ongoing cardiomyocyte injury from
    the active granulomatous lesion, and is repeatable enough to follow disease
    activity serially under immunosuppression. Cumulative troponin release after
    prednisolone initiation - rather than any single pre- or post-treatment
    value - predicts ventricular arrhythmia, worsening heart failure, and sudden
    cardiac death, which fits the entry's model in which the reversible
    inflammatory arm and the fixed scar arm diverge over time.
  readouts:
  - target: Active Granulomatous Myocardial Inflammation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Rising cumulative troponin reports continuing cardiomyocyte injury from the
      active granulomatous lesion this node represents.
    evidence:
    - reference: PMID:37591415
      reference_title: Association of longitudinal cardiac troponin trajectory with adverse events in patients with cardiac sarcoidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A higher area under the cTnT trajectory was significantly associated with
        an increased incidence of the primary outcome (P = 0.027)
      explanation: >-
        The specific measurement behind this readout: cumulative troponin release
        predicted the composite of sustained VT/VF, worsening heart failure, and
        sudden cardiac death.
  evidence:
  - reference: PMID:37591415
    reference_title: Association of longitudinal cardiac troponin trajectory with adverse events in patients with cardiac sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although high-sensitivity cardiac troponins may be sensitive and easily
      repeatable markers of disease activity in patients with cardiac
      sarcoidosis (CS), the association between longitudinal cardiac troponin
      trajectory and adverse events remains unclear.
    explanation: >-
      Establishes hs-cardiac troponin as a repeatable marker of cardiac
      sarcoidosis disease activity, the basis for attaching it to the
      active-inflammation node.
  - reference: PMID:37591415
    reference_title: Association of longitudinal cardiac troponin trajectory with adverse events in patients with cardiac sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Longitudinal cTnT trajectory following PSL initiation was associated with
      adverse cardiac events in patients with CS
    explanation: >-
      Supports the prognostic endpoint context: it is the cumulative trajectory,
      not a single value, that carries the signal.
  - reference: PMID:40445485
    reference_title: Screening for cardiac involvement in patients with sarcoidosis using AIIMS algorithm.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      16% and 19% of patients were positive for Troponin I and NT-Pro BNP
      respectively
    explanation: >-
      Gives the proportion of a screened sarcoidosis cohort positive for
      troponin. Partial because this quantifies screening yield in sarcoidosis
      generally rather than troponin behaviour within established cardiac
      sarcoidosis.
- name: Elevated NT-proBNP
  presence: Elevated
  context: >-
    N-terminal pro-B-type natriuretic peptide reports ventricular wall stress
    and is elevated in cardiac sarcoidosis independently of ejection fraction and
    pulmonary artery pressure. It discriminates cardiac involvement well
    (AUC 0.913) but does not identify pulmonary hypertension in the same
    patients, so it is a cardiac-involvement marker rather than a general
    sarcoidosis severity marker.
  readouts:
  - target: Progressive Ventricular Dysfunction and Heart Failure
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated NT-proBNP reports the ventricular wall stress and contractile
      failure that this node represents.
    evidence:
    - reference: PMID:21086902
      reference_title: Significance of plasma NT-proBNP levels as a biomarker in the assessment of cardiac involvement and pulmonary hypertension in patients with sarcoidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Plasma NT-proBNP showed good accuracy in identifying patients with
        cardiac sarcoidosis (area under the ROC curve; AURC = 0.913).
      explanation: >-
        The specific measurement behind this readout, with its discrimination
        quantified as an area under the ROC curve.
  evidence:
  - reference: PMID:21086902
    reference_title: Significance of plasma NT-proBNP levels as a biomarker in the assessment of cardiac involvement and pulmonary hypertension in patients with sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma NT-proBNP levels were significantly higher in patients with cardiac
      sarcoidosis (p < 0.0001).
    explanation: Directly establishes NT-proBNP elevation in cardiac sarcoidosis.
  - reference: PMID:21086902
    reference_title: Significance of plasma NT-proBNP levels as a biomarker in the assessment of cardiac involvement and pulmonary hypertension in patients with sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stepwise regression analysis showed that presence of cardiac sarcoidosis,
      decreased ejection fraction and increased sPAP were all independently
      associated with higher plasma NT-proBNP levels.
    explanation: >-
      Supports the independence claim in the context field, and ties the marker
      to reduced ejection fraction - the phenotype of the target node.
  - reference: PMID:21086902
    reference_title: Significance of plasma NT-proBNP levels as a biomarker in the assessment of cardiac involvement and pulmonary hypertension in patients with sarcoidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with sarcoidosis, plasma NT-proBNP levels are a useful
      biomarker to identify cardiac involvement, but not to identify PH.
    explanation: >-
      Records the specific scope of the marker, preventing it being read as a
      general sarcoidosis-severity readout.
  notes: >-
    Systemic sarcoidosis activity markers - serum ACE, soluble IL-2 receptor,
    CRP and ESR - are deliberately NOT duplicated here; they are curated in
    kb/disorders/Sarcoidosis.yaml because they report the systemic granulomatous
    process rather than the cardiac lesion. Only the two cardiac-specific
    biomarkers that attach to nodes in this entry's pathograph are curated here.
    No serum biomarker independently establishes a diagnosis of cardiac
    sarcoidosis.
progression:
- phase: Survival in clinically manifest disease
  notes: >-
    Contemporary survival in manifest cardiac sarcoidosis is reported as roughly
    90-96% at 5 years and 80-90% at 10 years in specialist series; a nationwide
    Finnish series including autopsy-detected cases reported 85% at 5 years and
    76% at 10 years from symptom onset. The difference between these figures
    reflects ascertainment - the nationwide series includes cases first
    identified at death.
  evidence:
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent outcome data indicate 90% to 96% 5-year survival in manifest CS
      with the 10-year figures ranging from 80% to 90%.
    explanation: Gives the specialist-series survival estimates.
  - reference: PMID:31230070
    reference_title: "Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Kaplan-Meier estimate (95% CI) of survival from symptom onset was 85%
      (80-90%) at 5 years and 76% (68-84%) at 10 years.
    explanation: Gives the nationwide-registry survival estimates for contrast.
differential_diagnoses:
- name: Arrhythmogenic right ventricular cardiomyopathy
  disease_term:
    preferred_term: arrhythmogenic right ventricular cardiomyopathy
    term:
      id: MONDO:0016587
      label: arrhythmogenic right ventricular cardiomyopathy
  description: >-
    Isolated cardiac sarcoidosis and ARVC overlap closely: both produce right
    ventricular scar, ventricular arrhythmia, and conduction abnormality in a
    structurally abnormal heart. The dismech ARVC entry reciprocally lists
    cardiac sarcoidosis as one of its own key differentials.
  evidence:
  - reference: PMID:33070538
    reference_title: "Cardiac sarcoidosis: diagnosis and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      isolated cardiac sarcoidosis is difficult to differentiate from other
      causes of arrhythmogenic cardiomyopathy
    explanation: >-
      Directly states the diagnostic difficulty separating isolated cardiac
      sarcoidosis from arrhythmogenic cardiomyopathy.
discussions:
- discussion_id: gap_cardiac_sarcoidosis_immunosuppression_arrhythmia_mortality
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does immunosuppression in cardiac sarcoidosis reduce ventricular arrhythmia
    burden or mortality, or only recover atrioventricular conduction and
    stabilize left ventricular function?
  attaches_to:
  - pathophysiology#Active Granulomatous Myocardial Inflammation
  - pathophysiology#Scar-Mediated Re-entrant Ventricular Tachyarrhythmia
  rationale: >-
    The curated treatment chain models corticosteroids as inhibiting the active
    inflammatory node, which is well supported for AV conduction recovery and for
    prevention of LV functional deterioration. It is deliberately NOT extended to
    the scar-mediated arrhythmia node, because the systematic review of 34
    publications and 1297 patients found no randomized trials and explicitly
    declined to draw conclusions for ventricular arrhythmia and mortality. This
    matters mechanistically: if arrhythmic risk is carried by fixed scar rather
    than by active inflammation, suppressing inflammation should not be expected
    to abolish it, and the persistence of VT after PET normalization is
    consistent with that. Curators must not add a treatment edge from
    immunosuppression to the arrhythmia node on current evidence.
  proposed_experiments:
  - experiment_id: exp_cardiac_sarcoidosis_rct_arrhythmic_endpoints
    name: Randomized trial of immunosuppression with arrhythmic endpoints
    description: >-
      A randomized controlled trial of corticosteroid-based versus
      steroid-sparing immunosuppression in clinically manifest cardiac
      sarcoidosis, powered for device-detected ventricular arrhythmia burden and
      all-cause mortality rather than for imaging surrogates.
  evidence:
  - reference: PMID:34472360
    reference_title: "Corticosteroid and Immunosuppressant Therapy for Cardiac Sarcoidosis: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data quality is too limited to draw conclusions for ventricular
      arrhythmias and mortality.
    explanation: >-
      The systematic review's own statement of the evidence gap this discussion
      records.
- discussion_id: gap_cardiac_sarcoidosis_sex_race_phenotype_modifiers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do sex and race modify the presenting phenotype and arrhythmic risk of
    cardiac sarcoidosis, and does this reflect biology or differential
    ascertainment and treatment?
  attaches_to:
  - pathophysiology#Myocardial Non-Caseating Granuloma Formation
  - pathophysiology#Progressive Ventricular Dysfunction and Heart Failure
  rationale: >-
    A tertiary-center cohort of 252 patients found that women and Black patients
    more often presented with symptomatic heart failure, while male sex carried
    more than twice the adjusted hazard of ventricular arrhythmia - i.e. the same
    granulomatous lesion appears to distribute its downstream consequences
    differently by sex and race. Treatment also differed by group. Nothing in the
    curated mechanism explains this, and the study cannot separate a biological
    modifier of the granulomatous or fibrotic response from differences in
    referral, diagnosis, and management.
  evidence:
  - reference: PMID:37062472
    reference_title: Sex and Race Differences in Cardiac Sarcoidosis Presentation, Treatment and Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At presentation with CS, females vs males (P = 0.001) and Black vs White
      individuals (P = 0.001) more commonly had symptomatic heart failure (HF),
      with HF most common in Black females
    explanation: Documents the sex and race differences in presenting phenotype.
  - reference: PMID:37062472
    reference_title: Sex and Race Differences in Cardiac Sarcoidosis Presentation, Treatment and Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Male sex had an adjusted hazard ratio of 2.34 (95% CI 1.13, 4.80;
      P = 0.021) for ventricular arrhythmia.
    explanation: Quantifies the sex difference in arrhythmic risk that this gap concerns.
- discussion_id: gap_cardiac_sarcoidosis_criteria_framework_discordance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which of the three competing cardiac sarcoidosis criteria frameworks (2014
    HRS, 2016 JCS, WASOG) identifies the patients who actually have myocardial
    granulomas, given that they classify substantially different fractions of the
    same cohort?
  attaches_to:
  - pathophysiology#Myocardial Non-Caseating Granuloma Formation
  - pathophysiology#Active Granulomatous Myocardial Inflammation
  rationale: >-
    This entry curates three diagnostic frameworks because no one of them is
    authoritative, and they are not interchangeable. Applied to the same
    324-patient cohort of histologically proven sarcoidosis with suspected
    cardiac involvement, the HRS consensus criteria classified 22.7% of women and
    36.0% of men as having cardiac sarcoidosis, while the 2016 JCS criteria
    classified 8.0% and 19.3% - roughly a two- to threefold difference in the
    same patients. Because definite diagnosis requires myocardial biopsy and
    biopsy sensitivity is low, there is no accessible gold standard against which
    to adjudicate, so the disagreement cannot currently be resolved by
    comparison to truth. This is not a curation gap in this entry; it is the
    defining clinical problem of the disease, and it propagates into every
    cohort-derived number curated here - prevalence, phenotype frequencies, and
    treatment-response rates all depend on which framework selected the cohort.
  proposed_experiments:
  - experiment_id: exp_cardiac_sarcoidosis_criteria_head_to_head_outcome_anchored
    name: Outcome-anchored head-to-head comparison of HRS, JCS and WASOG criteria
    description: >-
      Apply all three frameworks prospectively to a single multicentre cohort of
      patients with suspected cardiac sarcoidosis and adjudicate them not against
      each other but against hard downstream outcomes (device-detected
      ventricular arrhythmia, heart failure hospitalization, sudden cardiac
      death) and, where tissue becomes available through transplantation or
      autopsy, against myocardial histology. Report reclassification between
      frameworks and the outcome yield of the patients each framework uniquely
      captures or uniquely misses.
  evidence:
  - reference: PMID:34546787
    reference_title: Sex Differences in Patients With Suspected Cardiac Sarcoidosis Assessed by Cardiovascular Magnetic Resonance Imaging.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      less often met criteria for a clinical diagnosis of cardiac sarcoidosis
      (Heart Rhythm Society consensus criteria, 22.7% versus 36.0%; P=0.012 and
      2016 Japanese Circulation Society guideline criteria, 8.0% versus 19.3%;
      P=0.005), indicating lesser cardiac involvement
    explanation: >-
      Reports both frameworks applied to the same cohort, giving the paired
      percentages that quantify their discordance. The paper's own subject is
      sex differences, so the framework comparison is read off its data rather
      than being its stated conclusion.
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Definite diagnosis of CS requires myocardial biopsy and histopathology,
      but a sufficient diagnostic likelihood can be achieved by combining
      extracardiac histology of sarcoidosis with clinical manifestations and
      findings on cardiac imaging.
    explanation: >-
      Establishes that the frameworks exist precisely because the histologic gold
      standard is usually unavailable, which is why the discordance cannot be
      adjudicated directly.
notes: >-
  Scope. This entry models the CARDIAC arm of sarcoidosis: the myocardial
  mechanism chain, the cardiac phenotypes it produces, the cardiac-specific
  diagnostic pathway and criteria frameworks, cardiac-specific biomarkers, and
  the cardiac treatment repertoire and trial landscape. Deliberately OUT of
  scope, and curated in kb/disorders/Sarcoidosis.yaml instead, are the
  sarcoidosis-general layers that are not cardiac-specific: genetic
  susceptibility (HLA-DQB1*06:01, familial clustering, TLR3/ANXA11 and other
  association signals), environmental and occupational exposures, and the
  systemic activity biomarkers (serum ACE, soluble IL-2 receptor, CRP, ESR).
  Duplicating those here would restate the parent entry rather than add to it.

  Relationship to the sibling dismech entries. kb/disorders/Sarcoidosis.yaml
  models the systemic disease and carries a "Cardiac Sarcoidosis" subtype with
  four cardiac phenotypes, but no cardiac pathophysiology: its pathograph stops
  at generic Granuloma Formation and Fibrotic Tissue Remodeling. This entry adds
  the cardiac-specific mechanism arm - myocardial granulomatous infiltration,
  the reversible active-inflammation stage, conduction-axis involvement producing
  AV block, post-inflammatory replacement fibrosis, scar-mediated re-entrant
  ventricular tachyarrhythmia, and progressive ventricular dysfunction - plus
  the three competing cardiac diagnostic criteria frameworks (2014 HRS, 2016 JCS,
  WASOG), the cardiac diagnostic pathway (echocardiography, CMR, FDG-PET,
  endomyocardial biopsy, ECG), the two node-attached cardiac biomarkers
  (hs-cardiac troponin, NT-proBNP), the cardiac treatment repertoire
  (corticosteroids, methotrexate maintenance, TNF inhibitors, ICD, pacing,
  ablation, transplantation), and the cardiac-sarcoidosis trial landscape.
  kb/disorders/Neurosarcoidosis.yaml is the organ-specific precedent this entry
  follows. MONDO:0001707 also appears in
  kb/disorders/Arrhythmogenic_Right_Ventricular_Cardiomyopathy.yaml as a
  differential-diagnosis cross-reference; that link is reciprocated here.

  Phenotypes considered and NOT added. Pericardial effusion, ventricular
  premature beats, and late gadolinium enhancement were reviewed as candidate
  phenotypes. No quotable cardiac-sarcoidosis-specific statement was found in
  the cached references for the first two, so adding them would have meant
  unevidenced content; late gadolinium enhancement is an imaging finding already
  modelled as the Myocardial Fibrosis phenotype plus the cardiac MRI diagnosis
  entry, and is not separately curated as a phenotype.
datasets:
- accession: geo:GSE205734
  title: Transcriptional and immune landscape of cardiac sarcoidosis
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SPATIAL_TRANSCRIPTOMICS
  sample_count: 7
  publication: PMID:36111531
  notes: >-
    Identified by GEO DataSets index search for Cardiac_Sarcoidosis
    (scripts/discover_datasets.py) and verified with just verify-datasets.
    Relevance triaged manually: cardiac sarcoidosis is named in the GEO series
    title and the material is human cardiac tissue, so this is a DIRECT match
    rather than a gene- or word-only hit. Title, sample count, and organism are
    GEO's own values. No evidence block: a bulk-generated dataset record carries
    provenance notes rather than a manufactured abstract quote.
- accession: geo:GSE314910
  title: Spatial transcriptomic signatures of cardiac sarcoidosis
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SPATIAL_TRANSCRIPTOMICS
  sample_count: 12
  notes: >-
    Identified by GEO DataSets index search for Cardiac_Sarcoidosis
    (scripts/discover_datasets.py) and verified with just verify-datasets.
    Cardiac sarcoidosis is named in the GEO series title. No linked publication
    was indexed at the time of curation.
- accession: geo:GSE319770
  title: Integrative Molecular Analyses of Inflammatory and Autoimmune Signals in Cardiac Sarcoidosis [snRNA-Seq]
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 41
  publication: PMID:42206386
  notes: >-
    Identified by GEO DataSets index search for Cardiac_Sarcoidosis
    (scripts/discover_datasets.py) and verified with just verify-datasets.
    Cardiac sarcoidosis is named in the GEO series title. Companion Xenium
    series of the same study is geo:GSE319771.
- accession: geo:GSE319771
  title: Integrative Molecular Analyses of Inflammatory and Autoimmune Signals in Cardiac Sarcoidosis [Xenium]
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 18
  publication: PMID:42206386
  notes: >-
    Identified by GEO DataSets index search for Cardiac_Sarcoidosis
    (scripts/discover_datasets.py) and verified with just verify-datasets.
    Cardiac sarcoidosis is named in the GEO series title. Companion snRNA-seq
    series of the same study is geo:GSE319770. GEO's own platform typing for
    this Xenium in-situ series is recorded as MICROARRAY by the discovery index.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Cardiac Sarcoidosis: Disease-Characteristics Research Report

Edison Scientific Literature 26 citations 2026-08-19T09:18:14.398529

Cardiac Sarcoidosis: Disease-Characteristics Research Report

Executive summary

Cardiac sarcoidosis (CS; MONDO:0001707) is an immune-mediated, non-necrotizing granulomatous myocarditis that may accompany systemic sarcoidosis or occur as apparently isolated cardiac disease. Active granulomatous inflammation and later replacement fibrosis injure the conduction system and myocardium, producing atrioventricular (AV) block, ventricular arrhythmias, heart failure, and sudden cardiac death. Clinical cardiac involvement is recognized in approximately 2–5% of sarcoidosis cases, whereas imaging and autopsy studies suggest much more frequent occult involvement. No single biomarker, gene, or test establishes the diagnosis; contemporary practice integrates clinical phenotype, extracardiac histology, cardiac magnetic resonance (CMR), fluorodeoxyglucose positron-emission tomography (FDG-PET), and selectively targeted endomyocardial biopsy (EMB). (sivalokanathan2024exploringtherole pages 5-7, sivalokanathan2024exploringtherole pages 1-2, trivieri2020challengesincardiac pages 1-3)

The evidence base remains limited. Glucocorticoids are first-line therapy, but randomized evidence defining dose, duration, mortality benefit, or optimal steroid-sparing treatment is lacking. The strongest observational evidence supports recovery of AV conduction and preservation of ventricular function. Recent research emphasizes multimodality imaging, macrophage-directed imaging, IL-1 and JAK inhibition, preclinical inflammatory biomarkers, and genetics-informed phenotype classification. (trivieri2020challengesincardiac pages 4-6, trivieri2020challengesincardiac pages 12-14, NCT06868381 chunk 1, NCT07159074 chunk 1, NCT06660732 chunk 1)

Domain	Key evidence/data	Suggested ontology terms	Evidence type/limitations
Definition / identifier	Immune-mediated granulomatous myocarditis occurring in systemic sarcoidosis or as isolated cardiac disease; MONDO:0001707	MONDO:0001707; MeSH: Sarcoidosis; NCIT: Granuloma	Disease-level aggregated literature/resources; no single universally accepted molecular definition (OpenTargets Search: cardiac sarcoidosis, sivalokanathan2024exploringtherole pages 5-7, trivieri2020challengesincardiac pages 1-3)
Epidemiology	Clinically recognized cardiac involvement occurs in a minority of sarcoidosis cases, while occult involvement is substantially higher on imaging/autopsy; higher burden reported in Black patients and Northern European populations; adult-onset predominates	HP:0001627 Abnormality of the cardiovascular system; PATO: adult onset	Estimates vary widely by ascertainment method and geography; underdiagnosis is common (sivalokanathan2024exploringtherole pages 5-7, sivalokanathan2024exploringtherole pages 1-2, trivieri2020challengesincardiac pages 1-3, sivalokanathan2024exploringtherole pages 4-5, poyhonen202430yeartrendsin pages 11-11)
Etiology / genetics	Multifactorial disease with immune, environmental, and genetic contributions; familial clustering reported; HLA and non-HLA susceptibility associations implicated, but no established monogenic causal gene for cardiac sarcoidosis	GO:0001817 regulation of cytokine production; HP:0000007 Autosomal recessive inheritance not established; HP:0012275 Multifactorial inheritance	Mostly association data and extrapolation from systemic sarcoidosis; gene-level target evidence remains sparse (OpenTargets Search: cardiac sarcoidosis, sivalokanathan2024exploringtherole pages 5-7, trivieri2020challengesincardiac pages 4-6, zoppa2024phenotypesandserum pages 9-11, kullberg2024unravelinggeneticmysteries pages 1-5)
Phenotypes	Common presentations include atrioventricular block, bundle branch block, ventricular arrhythmias, premature ventricular complexes, heart failure, reduced LVEF, syncope, and sudden cardiac death; isolated and systemic forms both occur	HP:0011710 Atrioventricular block; HP:0001644 Dilated cardiomyopathy; HP:0001663 Ventricular arrhythmia; HP:0001279 Syncope; HP:0001645 Sudden cardiac death	Phenotype frequencies depend on referral cohort and diagnostic pathway; many cases are subclinical (sivalokanathan2024exploringtherole pages 5-7, sivalokanathan2024exploringtherole pages 1-2, trivieri2020challengesincardiac pages 20-21, sivalokanathan2024exploringtherole pages 4-5)
Immune mechanism	Non-necrotizing granulomas composed of macrophages/epithelioid cells and CD4+ T cells; Th1-skewed cytokines (IL-2, TNF, IFN-γ) promote granulomatous inflammation, with downstream fibrosis and electrical instability	GO:0006954 inflammatory response; GO:0001816 cytokine production; CL:0000623 natural killer cell; CL:0000863 inflammatory macrophage; CL:0000624 CD4-positive, alpha-beta T cell	Mechanistic model derived largely from systemic sarcoidosis plus cardiac clinicopathologic correlation; causative antigen(s) unresolved (sivalokanathan2024exploringtherole pages 5-7, trivieri2020challengesincardiac pages 1-3, trivieri2020challengesincardiac pages 4-6)
Anatomy	Primary site is myocardium, especially ventricular myocardium and conduction system; right ventricular involvement can occur; downstream effects include scar/fibrosis and ventricular dysfunction	UBERON:0002084 heart; UBERON:0002349 myocardium; UBERON:0002405 cardiac ventricle; UBERON:0010000 cardiac conduction system	Imaging-pathology concordance is strong, but lesion distribution is patchy (trivieri2020challengesincardiac pages 20-21, trivieri2020challengesincardiac pages 9-11)
Diagnostics	EMB is highly specific but insensitive because of patchy disease; reported EMB sensitivity ~20–30% (unguided yield ~25%, up to ~50% with image/voltage guidance). CMR with LGE: sensitivity ~91–99% and specificity ~98–100% in one review; extracardiac-screening studies report sensitivity 75–100% and specificity 76–78%. FDG-PET: sensitivity ~71–91% and specificity ~74–89%; meta-analytic benchmark often cited near 89%/78%	NCIT: Endomyocardial Biopsy; NCIT: Cardiac Magnetic Resonance Imaging; NCIT: Positron Emission Tomography; HP:0030972 Late gadolinium enhancement	Performance varies by preparation protocol, case definition, and cohort enrichment; HRS/WASOG/JCS criteria are not fully concordant (nagai2026thediagnosisand pages 4-6, trivieri2020challengesincardiac pages 9-11)
Prognosis	Major risks are ventricular tachyarrhythmia, heart failure progression, conduction disease, and sudden death; combined perfusion defect plus abnormal FDG uptake linked to ~4-fold higher annual VT/death rates; RV FDG uptake linked to ~5-fold higher event rates	HP:0001644 Dilated cardiomyopathy; HP:0004756 Ventricular tachycardia; HP:0001635 Congestive heart failure; HP:0001645 Sudden cardiac death	Prognosis is strongly imaging-dependent; survival estimates vary and recent nationwide numeric survival data were not fully extractable here (sivalokanathan2024exploringtherole pages 5-7, trivieri2020challengesincardiac pages 9-11)
Treatment response	First-line therapy is glucocorticoids; reasonable initial prednisone dose often 30–40 mg/day. In systematic review, AV conduction improved in 76/178 (42.7%) treated patients versus 0/21 untreated; combined steroid plus steroid-sparing therapy may reduce relapse compared with steroids alone	NCIT: Prednisone; NCIT: Methotrexate; NCIT: Azathioprine; NCIT: Mycophenolate Mofetil; NCIT: Infliximab; NCIT: Implantable Cardioverter-Defibrillator	No randomized standard-of-care trials for most agents; evidence mostly observational, with stronger support for AV block and LVEF stabilization than for mortality reduction (trivieri2020challengesincardiac pages 12-14)
Active experimental trials	Phase 2/2a studies are testing IL-1 and JAK-axis inhibition and new imaging approaches: rilonacept (REPAIR-CS), baricitinib, Tc-99m tilmanocept SPECT/CT, 64Cu-DOTATATE macrophage PET/CT, SGLT1/2-assisted myocardial glucose suppression for FDG-PET, PET/MRI prognostic studies, diagnostic-criteria and biomaterial registries, and a cardiac sarcoidosis QoL tool study	NCIT: Rilonacept; NCIT: Baricitinib; NCIT: Anakinra; NCIT: Single Photon Emission Computed Tomography; NCIT: Positron Emission Tomography/Magnetic Resonance Imaging	Most are early-phase, small, single-center, and without posted results yet; endpoints are commonly imaging-based rather than hard outcomes (NCT06868381 chunk 1, NCT07159074 chunk 1, NCT06660732 chunk 1, NCT04017936 chunk 2)

Table: This compact table summarizes the main knowledge-base domains for cardiac sarcoidosis, including disease definition, pathobiology, diagnostics, prognosis, treatment response, and ongoing trials. It is designed as a concise scaffold for a fuller cited report.

1. Disease information

Definition and scope

CS is best defined as granulomatous inflammation of the myocardium, with or without clinically evident extracardiac sarcoidosis. Histology shows compact, non-necrotizing granulomas containing macrophages/epithelioid histiocytes, multinucleated giant cells, and predominantly CD4-positive T lymphocytes. This finding is characteristic but not pathognomonic; infectious and other inflammatory causes must be excluded. A useful exact statement from a 2024 review is: “Sarcoidosis is a multifaceted and multisystemic inflammatory disorder, the etiology of which remains unknown.” [Sivalokanathan, June 2024; DOI URL: https://doi.org/10.3390/cardiogenetics14020009]. (sivalokanathan2024exploringtherole pages 5-7, sivalokanathan2024exploringtherole pages 1-2, trivieri2020challengesincardiac pages 1-3)

Identifiers and synonyms

MONDO: MONDO:0001707, cardiac sarcoidosis. Open Targets recognizes this entity but returned no curated disease–target associations, consistent with the absence of an established single therapeutic target or causal gene. (OpenTargets Search: cardiac sarcoidosis)
MeSH: Sarcoidosis and Heart Diseases are generally combined; a unique cardiac-sarcoidosis MeSH descriptor was not established in the retrieved evidence.
ICD-10-CM: D86.85, sarcoid myocarditis, is the most specific commonly used code; coding systems may also use D86.9 plus a cardiac-manifestation code.
ICD-11, OMIM, Orphanet: no confidently verified disease-specific identifier was recovered. CS is not an established Mendelian OMIM disorder.
Synonyms: sarcoid myocarditis, myocardial sarcoidosis, cardiac involvement in sarcoidosis, isolated cardiac sarcoidosis, sarcoid cardiomyopathy.
Data provenance: the report concerns aggregated disease-level evidence, not individual EHR records. Cohort statistics may nevertheless originate from registries, imaging databases, pathology series, or administrative health records.

2. Etiology, risk, and protective factors

Causal model

The cause is unknown and is probably multifactorial: genetically susceptible individuals encounter one or more environmental or microbial antigens, develop persistent antigen presentation and Th1-skewed cellular immunity, form granulomas, and subsequently develop myocardial injury and fibrosis. This is susceptibility rather than classical Mendelian causation. (sivalokanathan2024exploringtherole pages 5-7, trivieri2020challengesincardiac pages 1-3, trivieri2020challengesincardiac pages 4-6)

Genetic susceptibility

Familial clustering is reported in approximately 3.6–9.6% of sarcoidosis, monozygotic twins have markedly elevated risk, and first-degree relatives of affected Black patients have approximately threefold higher risk. A 2024 review cites an approximately 80-fold twin risk, although that estimate pertains to sarcoidosis broadly rather than specifically to cardiac involvement. HLA and non-HLA alleles influence susceptibility and phenotype; reported cardiac associations include HLA-DQB1*06:01, but replication and ancestry-specific interpretation are required. (sivalokanathan2024exploringtherole pages 5-7)

Recent systemic-sarcoidosis studies provide candidate phenotype modifiers rather than CS-causal genes. An ocular-cardio-cutaneous-CNS phenotype was associated with LOC102723568 and TLR3 variants; other extrapulmonary associations included CCL18, RAB23, and ZNF451. A December 2024 preprint found chronicity associations at rs3135356 (OR 3.13), rs2395162 (OR 2.34), and rs1049550 (OR 0.68), with gene-based signals at CLIC1 and ANXA11. These findings are not validated CS diagnostic variants. (zoppa2024phenotypesandserum pages 9-11, kullberg2024unravelinggeneticmysteries pages 1-5)

Knowledge-base conclusion: no established causal gene, pathogenic germline variant, somatic variant, chromosomal abnormality, inheritance pattern, penetrance estimate, carrier frequency, founder mutation, or clinically actionable modifier gene exists for CS. Accordingly, ClinVar-style pathogenic-variant classification, gnomAD carrier frequencies, cascade genetic testing, and genotype-directed treatment are not applicable at present. Open Targets likewise returned zero associated targets for MONDO:0001707. (OpenTargets Search: cardiac sarcoidosis)

Environment, occupation, lifestyle, and infection

Reported sarcoidosis associations include musty odors, pine pollen, insecticides, and occupational exposure to metals, talc, or silica. These are epidemiological signals, not proven CS-specific causes. Putative microbial antigens—particularly Cutibacterium acnes and mycobacterial antigens—remain hypotheses; sarcoidosis is not considered contagious, and no infectious agent fulfills causal criteria. Smoking, alcohol, diet, and exercise have no validated CS-specific causal or protective effect. (sivalokanathan2024exploringtherole pages 5-7)

Protective factors and gene–environment interaction

No reproducible genetic protective variant or environmental protective intervention has been established for CS. The leading interaction model is HLA-dependent antigen presentation after exposure, followed by persistent macrophage–T-cell activation. This model is biologically plausible but has not yielded a validated individual risk calculator.

3. Phenotypes

CS is predominantly adult-onset, often insidious, but may present abruptly with high-grade AV block, sustained ventricular tachycardia (VT), or cardiac arrest. Severity and progression are highly variable; silent inflammation, episodic activity, chronic scar, and progressive cardiomyopathy can coexist. (sivalokanathan2024exploringtherole pages 1-2, sivalokanathan2024exploringtherole pages 4-5)

Phenotype	Characteristics and impact	Suggested HPO term
AV/conduction block	Common sentinel presentation, especially unexplained high-grade block in a younger or middle-aged adult; may cause presyncope, syncope, fatigue, or sudden death	HP:0011710 Atrioventricular block; HP:0031546 Complete heart block
Bundle-branch/intraventricular conduction delay	Reflects septal or conduction-system disease; variable and potentially progressive	HP:0011711 Abnormality of cardiac conduction
Premature ventricular complexes/VT/VF	Episodic palpitations or syncope through sustained VT, ventricular fibrillation, and arrest; major QoL and mortality burden	HP:0004308 Ventricular premature beat; HP:0004756 Ventricular tachycardia; HP:0001663 Ventricular arrhythmia
Heart failure/reduced LVEF	Dyspnea, exercise intolerance, edema, and advanced pump failure; severity ranges from mild dysfunction to transplantation	HP:0001635 Congestive heart failure; HP:0001644 Dilated cardiomyopathy; HP:0012664 Reduced ejection fraction
Sudden cardiac death	May be the first recognized manifestation; one review cites rates up to 14% in selected CS populations	HP:0001645 Sudden cardiac death (sivalokanathan2024exploringtherole pages 5-7)
Syncope/presyncope	Usually secondary to bradyarrhythmia or tachyarrhythmia and materially restricts driving and employment	HP:0001279 Syncope
Atrial arrhythmia	Atrial fibrillation and other supraventricular arrhythmias occur but are less specific	HP:0005110 Atrial fibrillation
Pericardial involvement/chest pain	Less frequent; may mimic ischemia or myocarditis	HP:0001698 Pericardial effusion; HP:0100749 Chest pain
Subclinical myocardial inflammation/scar	Abnormal CMR or PET despite absent cardiac symptoms; approximately 20–25% of pulmonary/systemic cases may harbor silent cardiac disease in some series	HP:0030972 Late gadolinium enhancement (sivalokanathan2024exploringtherole pages 4-5)

Formal per-phenotype prevalence estimates are difficult to generalize because referral, diagnostic, and device cohorts differ markedly. Sarcoidosis overall can remit spontaneously, but scar-mediated CS may remain arrhythmogenic after inflammation resolves. A completed 130-participant study, NCT05145023, was designed to develop and validate a CS-specific health-related QoL instrument, reflecting a recognized gap in disease-specific patient-reported outcomes.

4. Genetic and molecular information

CS is polygenic/multifactorial, not a monogenic cardiomyopathy. There is therefore no recommended “CS gene panel.” In an apparent isolated inflammatory/arrhythmogenic cardiomyopathy, a hereditary cardiomyopathy panel or exome/genome sequencing may instead identify a phenocopy—such as desmosomal arrhythmogenic cardiomyopathy, LMNA-related cardiomyopathy, or other inherited disease—but does not confirm sarcoidosis.

Candidate pathways include HLA class II antigen presentation, TNF/NF-κB, interferon signaling, Toll-like receptor signaling, chemokine axes such as CXCL9/CXCL10–CXCR3, and possibly mTOR-related macrophage persistence. Systemic-sarcoidosis network analysis identified 493 viral-defense/innate-immunity genes and 684 genes related to noncoding-RNA processes; these remain research-level observations rather than clinical molecular diagnostics. (zoppa2024phenotypesandserum pages 9-11)

Epigenetic, cardiac single-cell, spatial-transcriptomic, proteomic, metabolomic, and lipidomic data remain sparse. Spatial transcriptomics and mass-spectrometry imaging are emerging methods for mapping sarcoid granulomas, but no clinically validated CS molecular signature has resulted. Absence of a curated Open Targets association further argues against assigning a single causal protein. (OpenTargets Search: cardiac sarcoidosis)

5. Environmental information

Organic and inorganic exposures may initiate disease in susceptible hosts, but no exposure is necessary or sufficient. Occupational histories should document metal work, mineral/silica or talc exposure, insecticides, mold/musty environments, and relevant infectious risks because these also inform the differential diagnosis. There is no evidence-based dietary or exercise intervention that prevents granuloma formation. Exercise prescriptions should instead be individualized after arrhythmia and ventricular-function assessment. (sivalokanathan2024exploringtherole pages 5-7)

Immunosuppressed patients require ordinary infection-risk mitigation, vaccination review, and latent tuberculosis/hepatitis screening before biologic therapy. These measures prevent treatment complications, not CS itself.

6. Mechanism and pathophysiology

Causal chain

Upstream susceptibility and trigger: HLA/non-HLA background plus unidentified inhaled, occupational, or microbial antigen.
Antigen presentation: recruited monocytes differentiate into macrophages/antigen-presenting cells and activate CD4-positive T cells.
Granuloma formation: Th1 cytokines—IL-2, TNF-α, and IFN-γ—maintain macrophage activation. Macrophages release IL-1, IL-6, IL-8, IL-12, IL-15, IL-18, and TNF-α. (trivieri2020challengesincardiac pages 4-6)
Active myocardial injury: patchy edema and inflammatory-cell infiltration injure cardiomyocytes and conduction tissue; glucose-avid immune cells produce focal FDG uptake.
Downstream remodeling: granulomas resolve, persist, or evolve into replacement fibrosis. Scar causes conduction slowing, re-entry VT, wall-motion abnormalities, reduced LVEF, and heart failure.
Clinical manifestations: AV block, VT/VF, syncope, heart failure, or sudden death. Continued arrhythmia after PET normalization can reflect fixed scar rather than active inflammation.

A possible Th1-to-Th2 transition may favor fibrosis in chronic disease. No protein misfolding, enzyme deficiency, ion-channel mutation, or primary metabolic block defines CS. Metabolic imaging instead exploits increased glucose consumption by activated inflammatory cells. (trivieri2020challengesincardiac pages 4-6)

Suggested GO biological-process terms: GO:0006954 inflammatory response; GO:0071222 cellular response to lipopolysaccharide/antigenic stimulus where contextually justified; GO:0001816 cytokine production; GO:0042110 T-cell activation; GO:0006955 immune response; GO:0002376 immune system process; GO:0001525 angiogenesis; GO:0042060 wound healing; GO:0030198 extracellular-matrix organization; GO:0062023 collagen-containing extracellular matrix.

Suggested Cell Ontology terms: CL:0000235 macrophage; CL:0000863 inflammatory macrophage; CL:0000624 CD4-positive alpha-beta T cell; CL:0000813 memory T cell; CL:0000576 monocyte; CL:0000182 hepatocyte-like “epithelioid” is inappropriate—use macrophage lineage plus pathology annotation; CL:0000746 cardiac muscle cell; CL:0000057 fibroblast.

7. Anatomical structures affected

Primary organ: heart, particularly patchy ventricular myocardium and the conduction system. Suggested terms: UBERON:0000948 heart, UBERON:0002349 myocardium, UBERON:0002084 cardiac muscle tissue, UBERON:0002405 cardiac ventricle.
Common sites: basal interventricular septum, left-ventricular subepicardial/mid-wall myocardium, papillary muscles, and right ventricle. Distribution is often multifocal and asymmetric rather than lateralized.
Cells/tissues: cardiomyocytes are injured secondarily; macrophages, giant cells, lymphocytes, fibroblasts, and collagenous scar dominate lesions.
Subcellular level: no disease-specific organelle lesion is established. Nuclear transcriptional programs, macrophage lysosomal/phagocytic compartments, mitochondria under inflammatory stress, and extracellular matrix are relevant but nonspecific.
Secondary organs: lungs and thoracic lymph nodes are most frequent systemic sites; skin, eyes, nervous system, liver, and other organs may provide safer biopsy targets. More than 90% of systemic sarcoidosis patients may have an abnormal chest radiograph, with bilateral hilar adenopathy in 50–85% and parenchymal opacity in 20–65%. (sivalokanathan2024exploringtherole pages 1-2)

8. Temporal development

Typical onset is adult, commonly between 25 and 45 years for sarcoidosis broadly, although later presentation occurs. Disease may be acute—e.g., sudden AV block or VT—or chronic and insidious. Systemic sarcoidosis is often categorized as acute (≤2 years) or chronic/persistent (approximately ≥3–5 years), but this staging does not map cleanly onto cardiac activity. (sivalokanathan2024exploringtherole pages 4-5)

A practical cardiac sequence is: subclinical inflammation → clinically active granulomatous myocarditis → mixed inflammation and fibrosis → scar-dominant cardiomyopathy. Activity fluctuates, and relapse may follow immunosuppression withdrawal. Early immunosuppression before marked LVEF decline appears more effective; treatment within six months was associated with LVEF improvement, whereas delay beyond six months predicted poorer response in observational data. (trivieri2020challengesincardiac pages 12-14)

For sarcoidosis overall, 30–50% or more may remit spontaneously, but cardiac involvement is not safely managed by extrapolating pulmonary remission rates. A 2024 Swedish nested case–control study found 44 inflammatory plasma proteins elevated before diagnosis among 152 cases and 341 controls; mean lead time was 13.4 years, and 27 remained associated ≥10 years before diagnosis. This supports a preclinical inflammatory phase, although it was not CS-specific. [Arkema et al., September 2024; https://doi.org/10.1183/13993003.00277-2024].

9. Inheritance and population

Sarcoidosis prevalence estimates vary from approximately 1–40 per 100,000 globally to 141–160 per 100,000 in selected northern-latitude populations; incidence estimates span approximately 1–36 per 100,000/year. Clinical CS occurs in about 2–5% of sarcoidosis, whereas imaging or autopsy detects myocardial involvement in approximately 20–25% and, in selected postmortem series, 25–58%. These ranges must not be conflated: they reflect different case definitions and ascertainment. (sivalokanathan2024exploringtherole pages 5-7, sivalokanathan2024exploringtherole pages 1-2, trivieri2020challengesincardiac pages 1-3, sivalokanathan2024exploringtherole pages 4-5, zoppa2024phenotypesandserum pages 1-2)

Black/African-American and Northern European populations have a higher systemic burden; African-American patients may present roughly a decade earlier and with more severe disease. Japanese cohorts have historically shown a disproportionate cardiac contribution to sarcoidosis mortality. Sex estimates vary by cohort, but systemic sarcoidosis generally shows modest female predominance, approximately 1.2–1.5:1 in a recent review. (trivieri2020challengesincardiac pages 1-3, zoppa2024phenotypesandserum pages 1-2)

A 2024 Finnish nationwide study documented increasing recognized CS incidence over 30 years, likely reflecting heightened awareness and advanced imaging as well as possible true change. Precise cohort estimates were not recoverable from the available excerpt and should not be inferred. [Pöyhönen et al., August 2024; https://doi.org/10.1016/j.jacadv.2024.101102]. (poyhonen202430yeartrendsin pages 11-11)

Classical inheritance concepts—autosomal dominant/recessive transmission, penetrance, anticipation, germline mosaicism, carrier frequency, and consanguinity—are not applicable.

10. Diagnostics

Diagnostic criteria

Three major frameworks coexist:

2014 Heart Rhythm Society (HRS): either myocardial histology or a clinical pathway requiring histologically proven extracardiac sarcoidosis plus compatible cardiac findings after exclusion of alternatives.
WASOG: grades probability of organ involvement and emphasizes granulomatous evidence.
Japanese Circulation Society/JMHW revisions: major/minor criteria, with a pathway for isolated CS and greater reliance on CMR and FDG-PET.

HRS and WASOG show relatively high concordance, whereas agreement with JCS is lower. Thus, a knowledge-base entry should preserve the criterion set and year used rather than treating all “clinical CS” labels as equivalent. (nagai2026thediagnosisand pages 4-6, trivieri2020challengesincardiac pages 9-11)

Recommended evaluation

History/examination: palpitations, syncope, exertional dyspnea, chest pain, family history, extracardiac symptoms, exposure/infection history.
ECG and ambulatory monitoring: AV block, bundle-branch block, ventricular ectopy, nonsustained/sustained VT, pathological Q waves, or repolarization abnormalities.
Echocardiography: LVEF, regional wall motion, septal thinning/thickening, aneurysm, RV function, and strain. A normal echocardiogram does not exclude CS.
CMR: LGE identifies necrosis/fibrosis, often in nonischemic subepicardial or mid-myocardial patterns; T1/T2 mapping can support active injury. One recent review reports sensitivity 91–99% and specificity 98–100%, whereas screening studies report sensitivity 75–100% and specificity 76–78%, illustrating strong spectrum and reference-standard effects. (nagai2026thediagnosisand pages 4-6, trivieri2020challengesincardiac pages 9-11)
FDG-PET plus perfusion imaging: identifies metabolically active inflammation and helps monitor treatment. Reported sensitivity is 71–91% and specificity 74–89%; a commonly cited pooled benchmark is approximately 89%/78%. High-fat/low-carbohydrate preparation and prolonged fasting are essential to suppress physiological myocardial uptake. (nagai2026thediagnosisand pages 4-6, trivieri2020challengesincardiac pages 9-11)
Biopsy: extracardiac tissue is preferred when available. EMB is highly specific but has only approximately 20–30% sensitivity or ~25% unguided yield because lesions are patchy. Imaging- or voltage-guided biopsy may raise yield toward 50%. A negative EMB does not exclude CS. (nagai2026thediagnosisand pages 4-6, trivieri2020challengesincardiac pages 9-11)

Biomarkers

Troponin and BNP/NT-proBNP measure myocardial injury and hemodynamic stress; elevated high-sensitivity troponin correlates with active FDG uptake. ACE, soluble IL-2 receptor, CRP/ESR, calcium, liver tests, and blood counts characterize systemic disease or treatment safety but are insufficiently specific for diagnosis. No validated serum biomarker independently establishes CS. miR-126 and miR-223 have been reported higher in CS than controls but remain investigational. (trivieri2020challengesincardiac pages 4-6)

Systemic-sarcoidosis estimates include sIL-2R thresholds of 4,700 U/L for chronicity prediction and 482 U/mL with 84.2% sensitivity/53.6% specificity in a separate context; these assay- and cohort-specific cutoffs should not be adopted as CS diagnostic thresholds. (zoppa2024phenotypesandserum pages 9-11)

Differential diagnosis

Key exclusions are ischemic cardiomyopathy, lymphocytic/viral myocarditis, giant-cell myocarditis, arrhythmogenic cardiomyopathy, LMNA and other genetic cardiomyopathies, hypertrophic or dilated cardiomyopathy, cardiac amyloidosis, Chagas disease where epidemiologically relevant, tuberculosis/fungal granulomatous disease, hypersensitivity myocarditis, and cardiac lymphoma. Coronary-territory scar favors ischemia; diffuse subendocardial LGE favors amyloid; desmosomal variants and characteristic structural patterns favor inherited arrhythmogenic cardiomyopathy. Histology and microbiology are essential when infection or giant-cell myocarditis is possible.

Screening and genetic testing

Patients with extracardiac sarcoidosis should undergo symptom review and ECG; many centers add echocardiography. Abnormal symptoms, ECG, Holter, or echo warrant CMR and/or FDG-PET. Universal advanced-imaging screening of all asymptomatic patients remains controversial. No newborn, population, carrier, prenatal, or cascade-genetic screening is recommended. WES/WGS, CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing have no routine role unless evaluating an alternative inherited cardiomyopathy.

11. Outcome and prognosis

Major adverse outcomes are sustained VT/VF, complete heart block, progressive biventricular failure, device shocks, transplantation, and sudden death. Morbidity includes exercise limitation, fatigue, anxiety over arrhythmias/device therapy, inability to drive or work, and cumulative immunosuppressive toxicity. Heart failure and ventricular arrhythmias account for most CS morbidity and mortality. (trivieri2020challengesincardiac pages 1-3)

Strong adverse markers include reduced LVEF or RV function, extensive CMR LGE, RV involvement, active FDG uptake, perfusion defects, prior VT, syncope, and high-grade AV block. Combined perfusion defect plus abnormal FDG uptake was associated with approximately fourfold higher annual VT/death rates, and RV FDG uptake with approximately fivefold higher event rates. CMR scar burden may outperform PET activity for long-term major-event prediction because fixed fibrosis remains arrhythmogenic after inflammation subsides. (trivieri2020challengesincardiac pages 9-11)

Selected reviews cite sudden-death rates up to 14%, but universal 5- and 10-year survival figures cannot be given reliably because outcomes vary by era, diagnostic criteria, phenotype, and referral setting. Modern imaging, ICD use, immunosuppression, and heart-failure treatment have improved outcomes, yet robust treatment-versus-no-treatment life-expectancy estimates are unavailable. (sivalokanathan2024exploringtherole pages 5-7)

12. Treatment

Immunosuppression

Glucocorticoids are first-line for clinically active CS. Prednisone 30–40 mg/day is a commonly proposed initial regimen, followed by gradual taper guided by symptoms, ventricular function, arrhythmias, biomarkers, and PET activity; no universally validated dose or duration exists. Earlier treatment, before advanced ventricular dysfunction and fibrosis, appears more effective. (trivieri2020challengesincardiac pages 12-14)

Steroid-sparing agents include methotrexate, azathioprine, mycophenolate mofetil, and leflunomide; cyclophosphamide is reserved for selected refractory severe disease. TNF-α inhibitors—particularly infliximab—are used in refractory disease after infection screening and careful heart-failure assessment. Evidence is predominantly retrospective and should not be interpreted as regulatory approval specifically for CS.

A systematic review of 34 reports encompassing 1,297 patients found no randomized trials and only two good-quality studies. Among 178 treated patients with AV conduction disease, 76 (42.7%) improved, versus 0 of 21 untreated patients. Treatment was associated with prevention of LVEF deterioration, but evidence was inadequate to conclude a ventricular-arrhythmia or mortality benefit. The authors’ exact conclusion was: “The data quality is too limited to draw conclusions for ventricular arrhythmias and mortality.” [Fazelpour et al., September 2021; https://doi.org/10.1161/JAHA.121.021183]. Combination immunosuppression reduced relapse from 46% to 17% in one observational comparison, and prednisone plus methotrexate showed persistent five-year benefit over prednisone alone in another. (trivieri2020challengesincardiac pages 12-14)

Cardiac and interventional management

Treat HFrEF with guideline-directed therapy as tolerated.
Pacemaker implantation is indicated for clinically important bradycardia/AV block, but an ICD is often favored because future VT/VF risk may persist even if conduction recovers.
Antiarrhythmics, commonly amiodarone or sotalol, may be used with specialist oversight.
Catheter ablation treats recurrent scar-mediated VT but recurrence is common when inflammation remains active or the substrate is extensive.
Cardiac resynchronization is appropriate under standard criteria.
Mechanical circulatory support and heart transplantation are options for refractory end-stage disease; recurrence in the graft is reported but uncommon.

Suggested NCIT intervention concepts include Prednisone, Methotrexate, Azathioprine, Mycophenolate Mofetil, Infliximab, Anakinra, Rilonacept, Baricitinib, Implantable Cardioverter-Defibrillator, Cardiac Pacemaker, Catheter Ablation, Cardiac Resynchronization Therapy, and Heart Transplantation.

Experimental and recent trials

REPAIR-CS, NCT06660732: recruiting Phase II randomized trial, 60 participants; rilonacept 320-mg loading dose then 160 mg weekly added to standard treatment. Primary endpoint is change in FDG-positive myocardial segments through 24 weeks; started March 5, 2025, with no posted results. (NCT06660732 chunk 1)
NCT06868381: Phase IIa open-label baricitinib 4 mg/day, planned enrollment 10, not yet recruiting; estimated start April 1, 2026. Primary endpoint is resolution of cardiac FDG uptake; QoL and ACE, hs-troponin I, NT-proBNP, ESR, and CRP are secondary measures. No results posted. (NCT06868381 chunk 1)
MAGiC-ART, NCT04017936: completed 17-participant pilot of anakinra/IL-1 blockade; results were published in May 2023, but the retrieved record did not provide sufficient quantitative efficacy data for reliable extraction. (NCT04017936 chunk 2)
NCT07159074: recruiting Phase II diagnostic study of Tc-99m tilmanocept SPECT/CT, 15 participants, correlating macrophage-directed uptake with FDG-PET and CMR; started September 17, 2025. No results posted. (NCT07159074 chunk 1)
Other registered research includes 64Cu-DOTATATE macrophage PET/CT (NCT06131112; recruiting, n=76), PET/MRI prognosis (NCT05954507; recruiting, n=180), SGLT1/2-assisted myocardial glucose suppression (NCT06510894; recruiting, n=40), diagnostic-criteria validation (NCT04737317; recruiting, n=100), and biomaterial collection (NCT05793398; planned, n=100).

No gene, cell, RNA, or CRISPR therapy is established or in routine clinical development for CS. Pharmacogenomic dosing is not standard; ordinary drug-specific safety monitoring remains essential.

13. Prevention

Primary prevention: none is proven because the causal antigen is unknown. There is no CS vaccine, prophylactic drug, validated exposure-avoidance program, or genetic reproductive intervention.

Secondary prevention: recognize occult cardiac disease in systemic sarcoidosis through symptom review, ECG, and selected ambulatory monitoring/echocardiography, followed by CMR/PET when abnormalities or high clinical suspicion exist. Evaluate unexplained high-grade AV block or VT for CS before labeling it idiopathic.

Tertiary prevention: suppress active inflammation; monitor ventricular function, rhythm, and PET activity; use ICD/pacing where indicated; apply guideline-directed heart-failure therapy; manage osteoporosis, diabetes, infection, and other immunosuppression toxicities; and provide vaccination and rehabilitation advice. Genetic counseling may explain familial aggregation and multifactorial risk, but predictive family genetic testing is not available.

14. Other species and natural disease

Naturally occurring systemic granulomatous disease and granulomatous myocarditis occur in animals, but a well-validated spontaneous veterinary analogue of human CS—with comparable epidemiology, genetics, and diagnostic criteria—was not identified. Consequently, no reliable NCBI Taxon/VBO breed association, orthologous causal gene, zoonotic transmission pathway, or cross-species carrier state can be assigned. Human sarcoidosis is not considered zoonotic or transmissible.

15. Model organisms and experimental systems

No single model reproduces the full human syndrome of patchy cardiac granulomas, relapsing inflammation, fibrosis, conduction block, and VT. Experimental sarcoidosis models include antigen- or C. acnes-induced murine granulomas, mycobacterial-protein models, macrophage/T-cell cultures, and human tissue imaging. Most primarily model pulmonary granuloma biology rather than cardiac electrophysiology. Their value lies in studying antigen presentation, macrophage persistence, TNF/IFN signaling, and fibrosis; their limitations are uncertain initiating antigen, strain dependence, noncardiac predominance, and incomplete chronic scar/arrhythmia phenotypes.

Human explanted hearts, EMB material, extracardiac granulomas, and induced-pluripotent-stem-cell cardiomyocytes exposed to inflammatory mediators can address cell injury but do not recreate multicellular granuloma architecture. Emerging spatial transcriptomics and matrix-assisted laser-desorption/ionization imaging can map cell neighborhoods and molecular gradients in human granulomas, but remain discovery tools rather than validated models or diagnostics.

Evidence appraisal and knowledge-base cautions

Human clinical evidence: strongest for imaging diagnosis/risk stratification, device-based prevention, and observational improvement in AV conduction/LVEF with immunosuppression.
Mechanistic evidence: principally extrapolated from systemic sarcoidosis, pathology, and immune profiling; the initiating antigen remains unknown.
Genetic evidence: association-level and phenotype-modifying, not Mendelian or clinically diagnostic.
Model-organism evidence: sparse for cardiac-specific disease and weaker than human clinicopathologic evidence.
Direct-quote limitation: exact short quotations were included only where supported by retrieved text. PMID values were not consistently available in the retrieved records; DOI URLs and publication dates are therefore supplied rather than inventing PMIDs.
Critical implementation rule: retain the diagnostic framework, imaging-preparation protocol, ancestry, ascertainment method, and evidence type with every knowledge-base assertion. Clinical, autopsy, and imaging prevalence estimates are not interchangeable.

References

(sivalokanathan2024exploringtherole pages 5-7): Sanjay Sivalokanathan. Exploring the role of genetics in sarcoidosis and its impact on the development of cardiac sarcoidosis. Cardiogenetics, 14:106-121, Jun 2024. URL: https://doi.org/10.3390/cardiogenetics14020009, doi:10.3390/cardiogenetics14020009. This article has 5 citations.
(sivalokanathan2024exploringtherole pages 1-2): Sanjay Sivalokanathan. Exploring the role of genetics in sarcoidosis and its impact on the development of cardiac sarcoidosis. Cardiogenetics, 14:106-121, Jun 2024. URL: https://doi.org/10.3390/cardiogenetics14020009, doi:10.3390/cardiogenetics14020009. This article has 5 citations.
(trivieri2020challengesincardiac pages 1-3): Maria Giovanna Trivieri, Paolo Spagnolo, David Birnie, Peter Liu, Wonder Drake, Jason C. Kovacic, Robert Baughman, Zahi A. Fayad, and Marc A. Judson. Challenges in cardiac and pulmonary sarcoidosis: jacc state-of-the-art review. Journal of the American College of Cardiology, 76 16:1878-1901, Oct 2020. URL: https://doi.org/10.1016/j.jacc.2020.08.042, doi:10.1016/j.jacc.2020.08.042. This article has 254 citations and is from a highest quality peer-reviewed journal.
(trivieri2020challengesincardiac pages 4-6): Maria Giovanna Trivieri, Paolo Spagnolo, David Birnie, Peter Liu, Wonder Drake, Jason C. Kovacic, Robert Baughman, Zahi A. Fayad, and Marc A. Judson. Challenges in cardiac and pulmonary sarcoidosis: jacc state-of-the-art review. Journal of the American College of Cardiology, 76 16:1878-1901, Oct 2020. URL: https://doi.org/10.1016/j.jacc.2020.08.042, doi:10.1016/j.jacc.2020.08.042. This article has 254 citations and is from a highest quality peer-reviewed journal.
(trivieri2020challengesincardiac pages 12-14): Maria Giovanna Trivieri, Paolo Spagnolo, David Birnie, Peter Liu, Wonder Drake, Jason C. Kovacic, Robert Baughman, Zahi A. Fayad, and Marc A. Judson. Challenges in cardiac and pulmonary sarcoidosis: jacc state-of-the-art review. Journal of the American College of Cardiology, 76 16:1878-1901, Oct 2020. URL: https://doi.org/10.1016/j.jacc.2020.08.042, doi:10.1016/j.jacc.2020.08.042. This article has 254 citations and is from a highest quality peer-reviewed journal.
(NCT06868381 chunk 1): Matthew C. Baker. A Trial of Baricitinib in Patients With Cardiac Sarcoidosis. Stanford University. 2026. ClinicalTrials.gov Identifier: NCT06868381
(NCT07159074 chunk 1): Repurposing Tilmanocept for Cardiac Sarcoidosis. Duke University. 2025. ClinicalTrials.gov Identifier: NCT07159074
(NCT06660732 chunk 1): Andrew N Rosenbaum. Rilonacept in Subjects With Cardiac Sarcoidosis. Mayo Clinic. 2025. ClinicalTrials.gov Identifier: NCT06660732
(OpenTargets Search: cardiac sarcoidosis): Open Targets Query (cardiac sarcoidosis, 0 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(sivalokanathan2024exploringtherole pages 4-5): Sanjay Sivalokanathan. Exploring the role of genetics in sarcoidosis and its impact on the development of cardiac sarcoidosis. Cardiogenetics, 14:106-121, Jun 2024. URL: https://doi.org/10.3390/cardiogenetics14020009, doi:10.3390/cardiogenetics14020009. This article has 5 citations.
(poyhonen202430yeartrendsin pages 11-11): Pauli Pöyhönen, Jukka Lehtonen, Diana Velikanova, Piia Simonen, Valtteri Uusitalo, Henriikka Mälkönen, Hanna-Kaisa Nordenswan, Tapani Vihinen, Kari Kaikkonen, Petri Haataja, Tuomas Kerola, Tuomas T. Rissanen, Ville Vepsäläinen, Aleksi Alatalo, Päivi Pietilä-Effati, and Markku Kupari. 30-year trends in the incidence, characteristics, and outcome of cardiac sarcoidosis in a nationwide cohort. Aug 2024. URL: https://doi.org/10.1016/j.jacadv.2024.101102, doi:10.1016/j.jacadv.2024.101102. This article has 13 citations.
(zoppa2024phenotypesandserum pages 9-11): Matteo Della Zoppa, Francesco Rocco Bertuccio, Ilaria Campo, Fady Tousa, Mariachiara Crescenzi, Sara Lettieri, Francesca Mariani, Angelo Guido Corsico, Davide Piloni, and Giulia Maria Stella. Phenotypes and serum biomarkers in sarcoidosis. Diagnostics, 14:709, Mar 2024. URL: https://doi.org/10.3390/diagnostics14070709, doi:10.3390/diagnostics14070709. This article has 18 citations.
(kullberg2024unravelinggeneticmysteries pages 1-5): Susanna Kullberg, Pernilla Darlington, David Ellinghaus, Antje Prasse, Tomoko Iseda, Olga Chuquimia, Anders Eklund, Stefan Schreiber, Joachim Müller-Quernheim, Ingrid Kockum, Åsa Wheelock, Leonid Padyukov, Mehdi S. Mirsaeidi, Paolo Spagnolo, and Natalia V. Rivera. Unraveling genetic mysteries: phenotype-shaping profiles in chronic sarcoidosis. MedRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.29.24319750, doi:10.1101/2024.12.29.24319750. This article has 2 citations.
(trivieri2020challengesincardiac pages 20-21): Maria Giovanna Trivieri, Paolo Spagnolo, David Birnie, Peter Liu, Wonder Drake, Jason C. Kovacic, Robert Baughman, Zahi A. Fayad, and Marc A. Judson. Challenges in cardiac and pulmonary sarcoidosis: jacc state-of-the-art review. Journal of the American College of Cardiology, 76 16:1878-1901, Oct 2020. URL: https://doi.org/10.1016/j.jacc.2020.08.042, doi:10.1016/j.jacc.2020.08.042. This article has 254 citations and is from a highest quality peer-reviewed journal.
(trivieri2020challengesincardiac pages 9-11): Maria Giovanna Trivieri, Paolo Spagnolo, David Birnie, Peter Liu, Wonder Drake, Jason C. Kovacic, Robert Baughman, Zahi A. Fayad, and Marc A. Judson. Challenges in cardiac and pulmonary sarcoidosis: jacc state-of-the-art review. Journal of the American College of Cardiology, 76 16:1878-1901, Oct 2020. URL: https://doi.org/10.1016/j.jacc.2020.08.042, doi:10.1016/j.jacc.2020.08.042. This article has 254 citations and is from a highest quality peer-reviewed journal.
(nagai2026thediagnosisand pages 4-6): Toshiyuki Nagai, Toshifumi Tamura, and Toshihisa Anzai. The diagnosis and management of cardiac sarcoidosis. Internal Medicine, Jan 2026. URL: https://doi.org/10.2169/internalmedicine.7161-26, doi:10.2169/internalmedicine.7161-26. This article has 2 citations and is from a peer-reviewed journal.
(NCT04017936 chunk 2): Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis. Virginia Commonwealth University. 2020. ClinicalTrials.gov Identifier: NCT04017936
(zoppa2024phenotypesandserum pages 1-2): Matteo Della Zoppa, Francesco Rocco Bertuccio, Ilaria Campo, Fady Tousa, Mariachiara Crescenzi, Sara Lettieri, Francesca Mariani, Angelo Guido Corsico, Davide Piloni, and Giulia Maria Stella. Phenotypes and serum biomarkers in sarcoidosis. Diagnostics, 14:709, Mar 2024. URL: https://doi.org/10.3390/diagnostics14070709, doi:10.3390/diagnostics14070709. This article has 18 citations.

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Definitions

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Related Datasets

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Cardiac Sarcoidosis: Disease-Characteristics Research Report

Executive summary

1. Disease information

Definition and scope

Identifiers and synonyms

2. Etiology, risk, and protective factors

Causal model

Genetic susceptibility

Environment, occupation, lifestyle, and infection

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Diagnostic criteria

Recommended evaluation

Biomarkers

Differential diagnosis

Screening and genetic testing

11. Outcome and prognosis

12. Treatment

Immunosuppression

Cardiac and interventional management

Experimental and recent trials

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Evidence appraisal and knowledge-base cautions

Artifacts

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