Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review

Abstract

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia and/or heart failure. Diagnosis of cardiac sarcoidosis can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of cardiac sarcoidosis. Mainstay therapy for cardiac sarcoidosis is immunosuppression, however no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in cardiac sarcoidosis call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.

“For many reasons [sarcoidosis] attracts attention and presents feature of great interest. It can no longer be considered a rarity.” -W.T. Longcope (Sarcoidosis: The Frank Billings Lecture; 1941) (1)

Introduction

When Warfield T. Longcope discoursed on sarcoidosis in the Frank Billings Lecture in 1941, his intention was to convey his fascination with the mysterious disease and to convince to his audience that sarcoidosis was not a rarity. Eighty years later, we remain fascinated with the disease where, as Longcope stated then, “the cause …. is obscure” and are increasingly convinced that cardiac sarcoidosis (CS) remains an underrecognized cause of nonischemic cardiomyopathy (1). Sarcoidosis is a systemic granulomatous inflammatory disease that most commonly affects the lungs (2). The heart may be involved in upwards of a quarter of patients with sarcoidosis and may be the sole organ involved in some cases (3, 4). Cardiovascular disease is the primary driver of morbidity and mortality in patients with sarcoidosis (5). Yet, the diagnosis of CS remains a challenge with no prospective data to guide treatment. Advancements in cardiac imaging have resulted in increased recognition of CS among patients with heart failure (HF) and are increasingly used to identify patients who may benefit from further therapies. The increased prevalence, associated morbidity including advanced stages of HF or refractory arrhythmia, as well as treatment implications (namely use of immunosuppression) warrant raised awareness of CS in the HF community.

With this state-of-the-art review, we integrate existing literature to describe the pathobiology and epidemiology of CS, address diagnostic challenges, and propose treatment strategies including advanced HF therapies. Furthermore, we highlight the need for a multidisciplinary approach to patient care, outline existing knowledge gaps, and propose future collaborative investigation in CS.

Pathobiology of Sarcoidosis

Sarcoidosis is a systemic inflammatory disorder resulting from the combined effects of genetic susceptibility and environmental exposures (6). Disease-specific adaptive and innate immune responses contribute to non-necrotizing granulomatous inflammation. Enhanced interferon gamma (IFN_ɣ) expression by CD4+ T cells defines a type 1 T helper cell (Th1) phenotype that is associated with chronic active disease and clinical outcomes in sarcoidosis (7). The identification that the majority of IFN_ɣ expressing CD4+ T cells in pulmonary sarcoidosis bear a Th17 surface phenotype provides insight that proinflammatory Th1 7 cells contribute to sarcoidosis through their ability to migrate to sites of disease and functionally transform into non-classical Th1 cells (8). Regulatory T cell (Treg) function may be impaired in sarcoidosis, and disease activity may reflect interactions between proinflammatory Th17 and Treg pathways (9).

Some of the earliest genetic studies in sarcoidosis have associated HLA alleles in the major histocompatibility complex (MHC) with sarcoidosis clinical phenotypes, including risk of CS (10). The preferential recruitment of T cells expressing the V-alpha 2.3 T cell receptor sequence into the lungs of patients expressing the MHC class II HLA-DR3 allele underscores the role of gene-environment interactions and supports the notion that the adaptive inflammatory response in sarcoidosis is directed against an antigen (11).

More recent studies identify traces of a mycobacterial protein (catalase peroxidase) in sarcoidosis tissue extracts that elicit antigen-specific cytokine responses (IFN_ɣ, tumor necrosis factor [TNF], IL17) in sarcoidosis patients according to clinical phenotype (12, 13). Augmented responses to toll-like receptor-2 (TLR2) stimulation, including enhanced induction of TNF, have been demonstrated with additional studies identifying serum amyloid A as an innate ligand abundant in sarcoidosis that up-regulates cytokine responses, including TNF, in part through TLR2 stimulation (14–16).

Although much attention is focused on lymphocytes in directing inflammation in sarcoidosis, macrophages remain the dominant constituent of the sarcoidosis granuloma, with many studies demonstrating the presence of classically activated M1 macrophages (17). More recently, the presence of non-classical M2 macrophages was associated with myonecrosis and myofibrosis in skeletal muscle involved by sarcoidosis (18). Interestingly, pre-clinical models of myocarditis also implicate M2-polarized macrophages in disease pathogenesis (19). In fact, multiple disease-related mechanisms implicated in sarcoidosis (IFN_ɣ, Th17, TLR2, M1 vs M2 macrophages) have been demonstrated to be relevant in the pathogenesis of myocarditis, providing insight into the mechanism and rising prevalence of CS (20), as summarized in Central Illustration (Figure 1).

Figure 1. (Central Figure) Sarcoidosis-Related Cardiomyopathy: Pathobiology to Clinical Manifestations.

Environmental, genetic, and immunologic factors influence the formation and maintenance of granulomas which may manifest in multiple organ systems. Granulomatous infiltration may result in clinically manifest or silent cardiac sarcoidosis and subsequent sarcoidosis cardiomyopathy. Phenotypically, inflammation and infiltration can lead to an active myocarditis stage or patients may develop fibrosis and a resultant restrictive or dilated cardiomyopathy. Immunosuppression is used to reduce myocardial inflammation and resultant clinical endpoints, while use of heart failure guideline directed medical therapies is extrapolated from data in non-sarcoidosis cardiomyopathies to prevent remodeling and improve heart failure outcomes. A subset of patients may progress to advanced, end-stage heart failure or develop refractory ventricular arrhythmia prompting consideration of advanced heart failure therapies. ARNI = angiotensin receptor neprilysin inhibitor; BB = beta-blocker; CM = cardiomyopathy; CRT = cardiac resynchronization therapy; GDMT = guideline directed medical therapy; ICD = implantable cardioverter defibrillator; LVAD = left ventricular assist device; MCS = mechanical circulatory support; MRA = mineralocorticoid receptor agonist; SGLT2i = sodium-glucose cotransporter-2 inhibitor.

Epidemiology and Prevalence

Though sarcoidosis occurs worldwide and may affect men and women of all ages and race or ethnicities, incidence varies widely. For example, higher rates are found in African Americans and Northern Europeans. The US Black Women’s Health Study reported a 2% prevalence of sarcoidosis that was associated with a significantly higher mortality rate ratio for all age groups (21). Given the observed familial and ethnic clustering, a genetic basis for sarcoidosis has also been postulated (6, 22).

Sex-specific differences in systemic sarcoidosis are inferred from reports that prevalence is associated with African American women, and that a second peak incidence is observed in older women (21, 23, 24). In contrast, the few published North American cohorts of CS are predominantly male while autopsy and screening cohorts suggest an equal sex distribution (4, 25–28).

Though clinically manifest CS is currently believed to be present in only ~5% of patients with biopsy-proven extracardiac sarcoidosis, autopsy and cardiac imaging studies estimate a 25% or higher prevalence of CS among patients with sarcoidosis (3, 29, 30). Prevalence of CS has been noted to be increasing over time, perhaps due to increased awareness of diagnosis, advances in cardiac imaging, and changing environmental factors (4).

Diagnosis of Cardiac Sarcoidosis

The diagnosis of CS relies on a high index of suspicion with the requisite integration of clinical, imaging, and histopathologic data. Clinicians must utilize “pattern recognition” skills to incorporate clues from the patient history and clinical data from multiple organs. The definite diagnosis of CS is made when there is histologic evidence of cardiac granulomatous inflammation and alternative causes of this immune response have been excluded.

When to Suspect CS

Screening for CS is currently recommended in only symptomatic patients with extracardiac sarcoidosis (31). This recommendation was made prior to the recent publication of registry data from Denmark of ~12,000 sarcoidosis patients (without established diagnosis of CS) demonstrating these patients were at significantly higher risk for adverse cardiovascular events (HF, ventricular arrhythmias/sudden cardiac death, and all-cause mortality) when compared with matched control individuals (5). There are several clinical scenarios that should prompt consideration for the diagnosis of CS particularly in patients without a prior diagnosis of extracardiac sarcoidosis, as outlined in Table 1.

Table 1.

Clinical scenarios in which to suspect a new diagnosis of cardiac sarcoidosis.

No prior history of extracardiac sarcoidosis	Known (biopsy proven or clinically suspected) history of extracardiac sarcoidosis
Sustained monomorphic ventricular tachycardia or aborted sudden cardiac death of unexplained etiology	Symptoms: palpitations, syncope
Advanced atrioventricular block such as second- or third-degree heart block in individuals 60 years of age or younger	Electrocardiogram abnormalities: premature atrial or ventricular complexes, bundle branch block, conduction disease, arrhythmia
Unexplained regional ventricular wall motion abnormalities, ventricular wall thinning or aneurysm	Ventricular wall motion abnormality or dysfunction, perfusion defects on cardiac imaging
Unexplained cardiomyopathy or heart failure

Atrioventricular block (AVB) may be the first and most common presentation of CS, reported in 42% of patients in a series from Finland (32). The first manifestation of CS may alternatively be ventricular arrhythmias. Nery and colleagues prospectively demonstrated that 4 of 14 (28%) patients with unexplained monomorphic ventricular tachycardia (VT) had CS as the underlying cause (33). Ekstrom et al found that the frequency of sudden cardiac death as the presenting CS manifestation was 14% in a series of 351 CS patients (32). HF or cardiomyopathy may be the presenting clinical feature (<20% of all CS cases), and CS may result in varied cardiomyopathy phenotypes as described below (32). However, CS diagnosis may be delayed and recognized only at time of heart transplant or left ventricular assist device therapy (LVAD) (34).

Diagnostic Criteria for CS

Multiple diagnostic criteria have been proposed for CS. The Japanese Ministry of Health and Welfare (JMHW) initially developed 2 routes to diagnosis of CS: 1) histological (biopsy-confirmed CS) and 2) clinical (extracardiac sarcoidosis established by tissue diagnosis and fulfillment of major and minor criteria) (35). In 2014, the Heart Rhythm Society (HRS) criteria further refined pathways to diagnosis of CS “definite” and “probable” CS (31). The Japanese Circulation Society updated the 2007 JMHW CS criteria to establish the first diagnostic pathway to clinical CS without histologic proof of disease in addition to the diagnosis of isolated (“possible”) CS (Table 2) (36). Recognizing the inherent uncertainty regarding the diagnosis of sarcoidosis, the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) Organ Assessment Instrument established 3 categories for likelihood of organ involvement based on expert opinion: highly probable, probable, and possible, yet CS specific criteria using these categories are lacking (37).

Table 2.

Diagnostic criteria for cardiac sarcoidosis.

Heart Rhythm Society Guidelines (31)

Japanese Circulation Society (36)

Two pathways to a diagnosis of CS that require histologic diagnosis. 1. Definite CS Histological Diagnosis from myocardial tissue in (non-caseating granuloma) with no alternative cause identified) 2. Probable CS* a) There is a histological diagnosis of extracardiac sarcoidosis and b) One or more of following is present:  ● Steroid +/− immunosuppressant responsive cardiomyopathy or heart block  ● Unexplained reduced LVEF (<40%)  ● Unexplained sustained (spontaneous or induced) VT  ● Mobitz type II 2nd degree heart block or 3rd degree heart block  ● Patchy uptake on dedicated cardiac PET (in a pattern consistent with CS)  ● Late Gadolinium Enhancement on CMR (in a pattern consistent with CS)  ● Positive gallium uptake (in a pattern consistent with CS) c) Other causes for the cardiac manifestation(s) have been reasonably excluded *Probable involvement is considered adequate to establish a clinical diagnosis of CS

Allows for clinical diagnosis of CS without histological proof in addition to the diagnosis of isolated CS. 1. Isolated possible CS Gallium scintigraphy or 18F-FDG PET reveals abnormally high tracer accumulation in the heart and at least three other criteria of the major criteria below are satisfied. 2. Clinical findings that satisfy the following strongly suggest the presence of cardiac involvement: a) Two or more of the five major criteria are satisfied -or- b) One of the five major criteria and two or more of the three minor criteria are satisfied Major criteria  ● High-grade AV block or fatal VA  ● Basal thinning of the ventricular septum or abnormal ventricular wall anatomy (ventricular aneurysm, thinning of the middle or upper ventricular septum, regional ventricular wall thickening)  ● LV contractile dysfunction (LVEF< 50%)  ● 67Ga citrate scintigraphy or 18F-FDG PET reveals abnormally high tracer accumulation in the heart  ● Gadolinium-enhanced MRI reveals delayed contrast enhancement of the myocardium Minor criteria  ● Abnormal ECG findings: VAs (NSVT, multifocal or frequent PVCs), bundle branch block, axis deviation, or abnormal Q waves  ● Perfusion defects on myocardial perfusion scintigraphy  ● Endomyocardial biopsy: Monocyte infiltration and moderate or severe myocardial interstitial fibrosis

AV: atrioventricular; CS: cardiac sarcoidosis; ECG: electrocardiogram; FDG-PET: 18F- fluorodeoxyglucose positron emission tomography; LV: left ventricular; LVEF: left ventricular ejection fraction; NSVT: nonsustained ventricular tachycardia; PVC: premature ventricular contraction.

The absence of accepted diagnostic guidelines has created a lack of consensus regarding the key elements for disease identification which highlights the importance of multispecialty collaboration to establish the diagnosis of CS. The diagnosis of CS often requires recognition, and further evaluation, of extracardiac manifestations (Table 3). It is notable that none of the aforementioned diagnostic tools have been prospectively validated in large CS cohorts, resulting in low concordance between diagnostic criteria when applied to patients clinically judged to have CS (38, 39).

Table 3.

Extracardiac signs and symptoms that should prompt further evaluation of sarcoidosis organ involvement to aid in confirmation of cardiac sarcoidosis diagnosis.

Signs and Symptoms	Suggested Organ Involvement	Further recommended evaluation considerations
Cough Dyspnea on exertion Chest pain	Pulmonary	Chest imaging Lung function testing with diffusing capacity
Any skin rash including nodules around eyes, nose, ears	Cutaneous	Referral to dermatology for possible biopsy
Sensorineural hearing loss Vertigo Headache Numbness or weakness	Neurologic	Magnetic resonance imaging with contrast and referral to neurology
Elevated calcium	Calcium/Vitamin D dysregulation	Vitamin D 25, Vitamin D 1,25, and intact parathyroid hormone levels
Elevated liver enzymes	Liver	Gastroenterology referral
Eye pain and/or redness Light sensitivity Bright lights in vision	Ocular	Ophthalmology referral Yearly eye exams for screening

Laboratory testing

Laboratory tests evaluated as serum biomarkers of CS include angiotensin-converting enzyme, lysozyme, serum soluble IL-2 receptor, and serum/urine calcium. However, none are established screening tools for CS (29, 40). The role of cardiac serum markers in CS such as high sensitivity troponin and brain natriuretic peptide warrant further investigation.

Electrocardiogram (ECG)

ECG may serve as the first cardiac diagnostic test to prompt further work up if conduction system disease, heart block or ventricular arrhythmia are captured (Table 4). Though symptomatic CS patients may have ECG abnormalities, they are uncommon in asymptomatic CS (<10%) (29). Continuous ambulatory ECG monitoring (such as Holter) may help detect arrhythmias and response to immunosuppressive therapy (41).

Table 4.

Cardiac diagnostic modalities: role and possible findings in cardiac sarcoidosis.

Diagnostic Modality	Role in screening	Findings	Role in diagnosis and management	Role in prognostication
ECG	Lacks sensitivity for screening. Sensitivity can be increased with use of continuous cardiac monitoring such as Holter.	Bundle branch and/or fascicular block Pathologic Q waves Low voltage PACs, PVCs AV Block
TTE	Lacks sensitivity	Left or right ventricular systolic and/or diastolic dysfunction LV or RV dilatation Wall motion abnormality Ventricular wall thinning (such as the basal septum), resulting in akinesis, dyskinesis and/or aneurysm formation Restrictive cardiomyopathy features such as ventricular hypertrophy, restrictive filling pattern Impaired global longitudinal strain		GLS associated with worse prognosis in patients with or without cardiac involvement of sarcoidosis
CMR	High sensitivity; modest specificity	LGE typically in multifocal pattern	Helps establish likelihood of CS	LGE associated with increased VT and mortality risk
FDG-PET	High sensitivity; modest specificity	Focal patchy cardiac FDG uptake, often with matched perfusion abnormalities Extracardiac FDG uptake	Identification of biopsy sites of active disease (lymph nodes) Mismatch pattern aids in diagnosis Serial imaging to monitor treatment response	Cardiac FDG uptake associated with increased VT and mortality risk
Endomyocardial Biopsy	Low sensitivity (<25%)	Noncaseating granulomatous infiltration of myocytes	Allows definitive diagnosis of CS	+EMB for CS associated with decreased survival

AV: atrioventricular; CMR: cardiac magnetic resonance imaging; CS: cardiac sarcoidosis; ECG: electrocardiogram; EMB: endomyocardial biopsy; FDG-PET: 18F-fluorodeoxyglucose positron emission tomography; GLS: global longitudinal strain; LGE: late gadolinium enhancement; LV: left ventricular; PAC: premature atrial contraction; PVC: premature ventricular contraction; RV: right ventricular; TTE: transthoracic echocardiogram; VT: ventricular tachycardia

Echocardiography

CS patients may manifest a wide variety of transthoracic echocardiographic (TTE) abnormalities highlighted in Table 4 (42, 43). Increased wall thickness mimicking a hypertrophic phenotype as well as restrictive cardiomyopathy have been reported (44). Clinically overt CS has been associated with higher likelihood of abnormal echocardiographic features when compared to occult CS disease, however, TTE is highly insensitive as a screening tool (29, 45). Impaired LV global longitudinal strain (GLS) may offer diagnostic and prognostic utility (46).

Advanced Cardiac Imaging

The increasing recognition of CS as a significant cause of cardiovascular disease can be linked to the advent of advanced cardiac imaging, most notably cardiac magnetic resonance imaging (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).

CMR imaging allows for the diagnosis of CS, especially among individuals with proven extracardiac sarcoidosis (31, 37). CMR provides information on structural abnormalities (wall thinning, aneurysm, chamber dilatation), left and right ventricular function, and an assessment regarding the presence and extent of myocardial scar (fibrosis) (43, 47, 48). The principle means of detecting CS by CMR is the presence of late gadolinium enhancement (LGE) typically in a multifocal pattern involving the basal to mid septum of the LV that can extend into the RV. The LGE is most often subepicardial or midmyocardial, but on rare occasions it can also be subendocardial and mimic a myocardial infarction (47). While dense LGE most commonly reflects fibrosis, patchy LGE can at times reflect edema (expanding the extracellular matrix) and even improve following immunosuppressive treatment (47, 49). Though CMR is the most robust imaging test to detect scar, it is more limited for the detection of inflammation. T2 sequences, including more recent T2 mapping techniques, can detect the presence of myocardial edema, but this technique has limited sensitivity to detecting myocardial inflammation among patients with CS and has a limited correlation with FDG-PET imaging. Extracellular volume mapping can quantify the extracellular volume fraction (which can be increased from scar or edema), but the use of this parameter in detecting CS requires further validation, especially among patients who do not have LGE.

The diagnostic accuracy of CMR (presence of LGE) has been compared to CS diagnostic criteria, with sensitivity >90% (3, 50, 51). In a study of 321 biopsy-confirmed sarcoidosis patients, CMR was shown to be the most sensitive and specific diagnostic test for CS when compared to ECG, Holier, and TTE (51). Multiple studies have revealed that the presence of LGE on CMR is associated with future adverse CV events, including death, arrhythmia and HF (3, 51, 52).

FDG-PET is currently the best clinical tool for the assessment of myocardial inflammation in CS (48, 53). FDG-PET imaging takes advantage of the fact that inflammatory cells (macrophages and CD4+ T cells) present in sarcoid granulomas have a high energy demand requiring increased glycolysis and therefore glucose (FDG=glucose analog) utilization (48). Suppression of baseline myocardial FDG uptake via fasting and adoption of a very low carbohydrate diet allows for visualization of FDG uptake by inflammatory cells. The optimal PET protocol used to evaluate CS requires rest myocardial perfusion, cardiac and whole body FDG-PET imaging. FDG-PET imaging provides a good diagnostic accuracy for CS based on a meta-analysis of 164 patients (sensitivity 89%, specificity 78%) (54). However, a limitation of this study – similar to other studies that have been performed to evaluate the diagnostic accuracy of CS – is that it used the JMHW as a reference standard when imaging is likely more accurate.

Several single center studies have demonstrated the prognostic value of FDG-PET imaging in the prediction of adverse events including VT and death (55, 56). In a study of 118 patients with known or suspected CS, those with abnormal myocardial perfusion and active inflammation detected by PET were at a 4-fold increased risk for death or VT (55). FDG-PET imaging may also identify a tissue biopsy source, such as FDG avid lymph nodes, for diagnostic confirmation. Because FDG may also be abnormal in the setting of hibernating myocardium, significant coronary artery disease should be excluded, for example through coronary CT imaging or invasive angiography. The addition of FDG-PET imaging to CMR can help improve CS diagnostic likelihood and potentially reclassify patients, as demonstrated by Vita and colleagues (57). Serial PET imaging allows assessment of response to immunosuppressive therapy and weaning of prednisone (Figure 2) (27).

Figure 2. Representative 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) images from a patient with cardiac sarcoidosis.

In a patient with cardiac and pulmonary sarcoidosis, baseline cardiac FDG-PET images (Panel A) demonstrate a moderate sized area of abnormal FDG uptake extending to medial and basal segments of the inferior and inferoseptal wall. After treatment with prednisone and mycophenolate mofetil, there is resolution of cardiac FDG uptake (Panel B).

Endomyocardial Biopsy

Currently, the identification of granulomatous inflammation via myocardial tissue biopsy remains the only definitive way to diagnose CS (Figure 3). If histologic evidence of sarcoidosis has not been confirmed via extracardiac tissue biopsy (such as in the case of possible isolated CS), endomyocardial biopsy is advised (31, 58). Additionally, in those patients presenting with acute onset cardiomyopathy with hemodynamic compromise, ventricular arrhythmia and/or conduction disease, consensus guidelines suggest endomyocardial biopsy to rule out more fulminant diagnoses such as giant cell myocarditis (58). However, the patchy and focal nature of CS results in low diagnostic sensitivity, estimated to be <25% (31, 59). Intracardiac electrogram-guided biopsy has demonstrated increased diagnostic yield but this approach is not common in practice (60). Prior studies have demonstrated that an endomyocardial biopsy positive for CS may connote a worse prognosis than a negative biopsy (61).

Figure 3. Pathologic findings from an explanted heart after transplantation.

A: Gross pathology of explanted heart demonstrating extensive granulomatous infiltration of the myocardium. B: Explant heart tissue histopathology (hematoxylin and eosin stain) demonstrating patchy, non-caseating granulomas; C: Microscopic view demonstrating multinucleated giant cell.

Diagnostic modalities in CS are summarized in Table 4.

Diagnostic Challenges

There are several specific challenges to an accurate and timely diagnosis of CS:

Asymptomatic and/or subclinical disease:

Cardiac involvement in sarcoidosis can be both asymptomatic and subclinical (46, 51). In a prospective study of 321 biopsy-proven sarcoidosis patients who underwent cardiac evaluation, 4.7% diagnosed with CS based on HRS criteria were both asymptomatic and without abnormalities on baseline standard cardiac evaluation (51). Studies have also demonstrated that sarcoidosis patients without clinically manifest CS but with LGE on CMR or abnormal LV GLS have significantly worse outcomes (46, 62). Asymptomatic and/or subclinical disease remains part of the CS burden and it is important that contemporary diagnostic protocols continue to take these presentations into account.

Isolated CS and possible CS without histologic diagnosis:

A challenge unique to CS is the lack of a designated diagnostic pathway for cardiac disease in the absence of extracardiac findings, known as isolated CS. The general consensus is that isolated CS represents ~25% of CS patients (4, 63, 64). Implications of the diagnostic difficulties posed by isolated CS include: 1) Frequently delayed or missed CS diagnosis, with obvious consequences regarding timely initiation of disease-specific therapies; 2) Contribution to significant global variability in diagnosis of CS, with discrepant access to expensive advanced imaging modalities and subspecialists likely to impact on diagnosis rates in more limited economic regions and countries; and 3) A persistent degree of clinician uncertainty regarding diagnostic pathways coupled with the potential complexity of therapies outside of standard non-ischemic cardiomyopathy protocols (i.e., immunosuppressive therapy). An additional consideration is the group of patients with suspected CS who lack a histologic diagnosis often referred to as possible (or presumed) CS. The Japanese Circulation Society established a first diagnostic pathway to clinical CS without histologic diagnosis known as possible CS (Table 2) (36). A recent publication from the Mayo clinic compared a cohort defined as “presumed” CS patients (without any histologic evidence of sarcoidosis, but with unexplained high-grade atrioventricular block or ventricular arrhythmia and findings suggestive of CS on either CMR or PET) with patients meeting HRS criteria and found no difference in the primary end point of hospitalization-free and overall survival at 10 years (65).

Phenotypically similar cardiac syndromes:

The wide spectrum of presentations and clinical phenotypes of CS can each in turn have specific differential diagnoses with alternative treatment strategies and related prognoses, thereby requiring clinician awareness and expertise to enable targeted phenotype-driven investigative work-up. This challenge is compounded by: 1) commonality in key clinical manifestations across many diagnoses, 2) the lower prevalence, and thus expertise in, not just CS but also many of its possible differential diagnoses and 3) lack of universal availability of diagnostic testing and interpretation. These phenotypically similar cardiac syndromes and their work up are summarized in Table 5 (66, 67). Thus, a multidisciplinary specialist team led by a HF cardiologist, and incorporating electrophysiology, cardiac imaging, cardiovascular genetics and cardiac pathology expertise are often required to both reliably rule out alternative disease states and accurately rule in CS.

Table 5.

Phenotypically similar cardiac syndromes to consider in evaluation of a patient with possible cardiac sarcoidosis.

Syndrome	Further evaluation
Acute myocarditis syndromes including giant cell, eosinophilic and lymphocytic myocarditis.	Endomyocardial biopsy
Chronic inflammatory cardiomyopathies including chronic viral myocarditis, Chagas disease and connective tissue disease-related.	Thorough history for potential identification of exposures and underlying connective tissue diseases
Genetic cardiomyopathies including arrhythmogenic cardiomyopathies and laminopathies.	At minimum 3-generational family history; genetic testing including cardiomyopathy panel
Restrictive cardiomyopathies including hypertrophic and infiltrative (amyloidosis, Fabry’s) cardiomyopathies.	Thorough history and exam; diagnostic testing including serum free light chains, genetic testing, technetium pyrophosphate scintigraphy and/or endomyocardial biopsy
Other granulomatous diseases, including infectious etiologies.	Thorough history for exposures; tissue testing for infectious etiologies including fungi, mycobacterium; expert pathologic review to distinguish etiology

Clinical Presentations of CS

Cardiomyopathy

Cardiac sarcoidosis, either in early inflammatory stages or late fibrotic stages, can manifest as cardiomyopathy with reduced ventricular function with patients experiencing symptoms of congestive and/or low output HF (Central Illustration/Figure 1). However, as befits the theme of the mutable presentations of CS noted thus far, the cardiomyopathy of CS can present as LV systolic dysfunction, predominant RV systolic dysfunction, or HF with preserved biventricular systolic function. For patients with known extracardiac sarcoidosis, a recent retrospective study found that the 10-year incidence of clinical HF was 3%, which is approximately twice that of the general population (5). In a study of patients with histologically-confirmed CS, the minority (9-27%) had symptomatic HF at presentation, despite the majority having a reduced LVEF, signaling the need for a low threshold for imaging studies evaluating ventricular function (4). A diagnosis of HF at presentation signified a poor outcome, with a 10-year transplant-free survival of only 53% compared to 83% for the total cohort (4).

RV involvement specifically is also associated with poor clinical outcomes in CS. RV pathology may be due to direct granulomatous involvement or the load imposed on the RV due to long-standing pulmonary sarcoidosis and/or LV failure. RV involvement defined by LGE on CMR or FDG-avidity on PET is associated with higher risk for ventricular tachyarrhythmia and death(55, 62). While isolated RV CS is rare in larger CS cohorts, multiple reports exist of CS as a phenotypic mimic of arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins (68, 69). Curiously, Asimaki et al observed similar marked reduction in plakoglobin in 23 patients with histologically-diagnosed CS (70). Further investigation is needed to determine the molecular mechanisms underlying the phenotypic overlap between ARVC and RV-involving CS.

Both granulomatous inflammation and subsequent fibrosis can also lead to reduced ventricular compliance and diastolic dysfunction, resulting in HF with preserved ejection fraction. In severe cases, this can result in a restrictive cardiomyopathy (71). Thus, clinicians should maintain a high index of suspicion for CS involvement in patients with HF symptoms, even in the presence of normal biventricular systolic function.

Though neurohormonally-targeted HF guideline-directed medical therapies have not been prospectively tested in patients with CS, benefit may be extrapolated from existing large HF studies (72). These agents include inhibitors of the renin-angiotensin-aldosterone system, neprilysin inhibitors, beta blockers (keeping in mind the balance of HF and arrhythmia benefit with risk of worsening conduction disease), and SGLT2 inhibitors (73). Diuretics should be used to treat volume overload as needed.

Regarding safety of exercise in patients with CS related cardiomyopathy, one may follow established consensus recommendations for myocarditis, which recommend exercise restriction for 3–6 months to allow treatment of active inflammation (74). In patients with HF, cardiac rehabilitation and exercise training has been shown to improve functional capacity and quality of life (75).

Electrophysiologic manifestations and management

Ventricular arrhythmias (VA) may be the presenting feature of CS and are associated with mortality (31, 76). Myocardial scar, from a combination of infiltrating granulomas and structural remodeling following acute inflammation, remains the primary substrate for VA in CS (77). In CS patients with chronic scar, VA manifests as monomorphic VA due to the mechanism of re-entry. Given the patchy distribution within the myocardium (coupled with the possible co-existence of scar and inflammation), it is common to have CS patients presenting with multiple VA morphologies. Nonetheless, there tends to be a predominance involving the ventricular basal septum or the inferolateral LV (78). Frequent premature ventricular contractions and polymorphic VT can occur; however, this should raise suspicion of the presence of active inflammation triggering the VA.

The role of immunosuppression in management of VA is discussed below (79). Anti-arrhythmic drugs (AAD), particularly class III AAD such as sotalol and amiodarone, may be used to treat monomorphic VT in CS. Among those with recurrent VA or who do not tolerate AAD, catheter ablation effectively reduces VT burden and implantable cardioverter defibrillator (ICD) shocks. In a meta-analysis of 5 studies that included 83 patients with CS undergoing catheter ablation, freedom from recurrent VA was modest at 46%; however, 88% had a clinically significant reduction in arrhythmia burden (80). Surgical sympathectomy has emerged as an alternative strategy for refractory VT management with excellent reported short-term outcomes (81).

Identifying CS patients who are at increased risk of arrhythmic sudden cardiac death is a clinical challenge. Patients with CS and normal LVEF may be at increased risk of VA (82, 83). Among those with preserved ventricular function, there is an association with LGE and FDG with VA (76, 83). However, in one cohort of patients who underwent both CMR and PET, only those that had LGE on CMR had an arrhythmic event in follow-up, and no patients with FDG uptake alone had VA (84). Given the high prevalence of LGE in CS, and significant association with outcomes, an electrophysiology study with programmed electrical stimulation may provide prognostic information, with an excellent negative predictive value (83, 85).

CS has a predilection for involving the intraventricular septum and thus conduction system disease, to include bundle branch blocks and second or third-degree AVB, is common. In a series of 110 Finnish patients with histologically confirmed CS, 32% had third-degree AVB requiring permanent pacemaker implantation (4). Advanced AVB is associated with a higher risk of VA. Thus, there is a Class IIa guideline recommendation for implanting a primary prevention ICD when pacemaker is indicated, even in patients with preserved LVEF (86). Among patients with HF and an LVEF <50% needing a high burden of pacing or who have left bundle branch block, chronic resynchronization therapy reduces HF hospitalizations and mortality (87).

With improved cardiac monitoring and diagnostic testing, recent studies suggest a 20-30% prevalence of atrial arrhythmias in CS patients (88). Mechanisms include cardiac inflammation, direct atrial granulomatous involvement leading to fibrosis, and left atrial remodeling due to HF-related increased atrial pressure. In a study of 50 CS patients, those with atrial fibrillation had larger left atrial volumes, lower left atrial ejection fractions, and lower left atrial strain than patients with no history of atrial fibrillation (89). Further, all patients with qualitative atrial FDG uptake on PET had atrial fibrillation (89). Optimal anticoagulation threshold and rhythm control strategies require further investigate in CS patients with atrial fibrillation.

There is still much to learn in the arrhythmic management of sarcoidosis patients. Ventricular arrhythmia risk stratification currently lacks sensitive and specific markers, particularly among those with preserved LV function. Management of arrhythmias in CS requires an integrated program with HF specialist and clinical electrophysiologist to tailor HF and immunosuppressive therapy as well as identify patients appropriate for catheter ablation.

Immunosuppressive Treatment

Immunosuppression is the mainstay treatment for active sarcoidosis. Medications include corticosteroids, steroid sparing disease modifying agents and biologic agents, with a primary goal of reducing sarcoidosis related inflammation. Figure 4 depicts a proposed strategy for immunosuppressive therapy and monitoring in CS.

Figure 4. Proposed immunosuppression treatment and monitoring algorithm for patients with cardiac sarcoidosis.

Patients with active cardiac sarcoidosis may be treated with immunosuppression treatment in the form of corticosteroids, with the possible addition of steroid sparing and/or biologic agents. Cardiac imaging and clinical assessment are key to monitoring response to therapy including side effects. There are several considerations for monitoring patients on immunosuppression therapy, as highlighted in panel on right.

Corticosteroids

Though corticosteroids are considered first-line agents for the treatment of active CS there remains a lack of robust data to support use in improving long term survival. Generally, initiation of immunosuppression should be prompt, with the goal of minimizing corticosteroid exposure while maintaining response to therapy. However, there is little agreement on optimal dose or duration of corticosteroid therapy, and the therapeutic role in subclinical CS is unclear (29). While early practice may have favored higher doses of prednisone early in the clinical course, several studies suggest that a lower initial prednisone dose of 30-40 mg daily may be adequate without any detrimental effect on mortality or FDG responsiveness (27, 90, 91).

Studies assessing clinical response to corticosteroid therapy in CS are limited to small, retrospective analyses. In a systematic review Sadek et al. demonstrated that 27/57 (47.4%) patients with CS and AVB demonstrated an improvement in AV conduction whereas 0/16 patients who did not receive corticosteroids recovered AV conduction (92). In contrast, a 25-year Finnish study reported a much lower rate of recovery of AVB (20%) in 35 patients treated with corticosteroids (4). How this outcome relates to a possible survival benefit related to corticosteroid use is unclear given that outcomes of fatal cardiac events (cardiac death or VA) for those who present with advanced AVB are similar to those who present with VT or HF (93).

Studies describing the response of LV dysfunction to corticosteroid therapy are contradictory (4, 92, 94). While Sadek and colleagues reported that patients with mild to moderate LV dysfunction improved or remained stable and those with severely depressed LV function did not, Kandolin et al reported that only those with severe LV dysfunction (LVEF < 35%) demonstrated improvement after 12 months of prednisone therapy (4). Reduction in cardiac FDG uptake has been shown to correlate with improvements in LVEF, with improvements more evident in those with mild to moderate LV dysfunction (95). Similarly, the results assessing the response of VAs to corticosteroids are discordant which may be confounded by AAD use. In a 68 CS patient series by Segawa et al., 70% of the 20 patients who had VA after initiation of corticosteroids had a VA event in the first year, suggesting a possible pro-arrhythmic effect of corticosteroids (96). Confounding the study is the lack of CMR LGE data to determine whether chronic scar was the main contributor to VA. Indeed, presence of active inflammation is an important predictor of response to corticosteroids in those with VAs (79).

Chronic corticosteroid treatment requires close monitoring for side effects as summarized in Figure 4. Role of Pneumocystis jiroveci prophylaxis while on prednisone in sarcoidosis is debated, as these patients have been demonstrated to have lower rates of pneumocystis infection compared to other chronic high-risk conditions, perhaps due to the immune stimulated rather than deficient state in sarcoidosis (97).

Steroid Sparing Agents

Steroid sparing agents (SSA) are increasingly incorporated into the treatment regimen for CS, with the goal of minimizing long-term corticosteroid exposure. The most used SSA are methotrexate and mycophenolate mofetil (MMF), with additional agents including azathioprine, leflunomide, among others. However, identification of the ideal SSA and whether SSA should be initiated upfront or in response to lack of clinical and imaging improvement after prednisone monotherapy is unknown. Methotrexate is an antimetabolite which inhibits purine and pyrimidine biosynthesis. Data support its use in pulmonary sarcoidosis, although there is a paucity of evidence in cardiac disease. Rosenthal et al described CS treatment with methotrexate ± low-dose prednisone with 15 of 25 patients (60%) achieving complete resolution of cardiac FDG uptake at follow-up (98). The actively enrolling CHASM-CS study (NCT03593759), comparing low dose prednisone/methotrexate combination with standard dose prednisone (maximum 30 mg daily) for 6 months, is poised to add much needed data to the field (99). MMF is an inhibitor of inosine monophosphate dehydrogenase, thus inhibiting proliferation of B and T lymphocytes and suppressing the immune and inflammatory responses (100). Several small studies suggest that MMF is effective in the treatment of extracardiac sarcoidosis while facilitating prednisone taper (101, 102). Hamzeh et al. described the use of MMF in 37 patients with pulmonary sarcoidosis, 10 of whom had cardiac involvement (101). Of the 7 patients with available data, 6 had improvement or resolution of cardiac inflammation on FDG-PET at 6 months indicating a possible role for its use in CS. Adverse effects are generally dose related and tend to occur in approximately 20% of patients, with one study reporting an 8% discontinuation rate of MMF (101).

Biologic Agents

Treatment with biologic agents in sarcoidosis is typically considered third or fourth line despite more widespread use in other inflammatory and autoimmune conditions. TNF-α is elevated in chronic HF and plays an integral role in the development of granulomatous inflammation in sarcoidosis, suggesting a possible role for TNF-α targeted therapy. However, early studies investigating the role of TNF-α inhibitors in the treatment of HF did not yield favorable results. Clinical studies (RENEWAL and ATTACH Trials) assessing the utility of these agents in symptomatic systolic HF patients showed an increased risk of death or HF hospitalization in those patients treated with the higher dose (10mg/kg) infliximab leading to an FDA warning regarding the use of TNF-α inhibitors in patients with moderate to severe HF (103).

Despite these prior results, there is growing interest in CS treatment with TNF-α inhibitors. Infliximab, a monoclonal anti TNF-α IgG antibody, has been shown to be a feasible treatment in refractory CS (104, 105). Baker et al described the use of TNF-α inhibitors in 20 patients with CS, 17 of whom had evidence of worsening disease on cardiac imaging despite prednisone use (106). After 12 months of infliximab treatment, all 17 had resolution of disease activity on cardiac imaging while the mean dose of prednisone decreased from 23 mg to 4 mg daily and there was no worsening in LV function. Notably, 5 of these patients had an LVEF ≤ 30% prior to initiation of TNF-α inhibitor. In a multicenter cohort of 38 New York Heart Association class I-III CS patients, treatment with infliximab or adalimumab demonstrated significant decrease in corticosteroid dose, decrease in cardiac FDG uptake and good tolerability from a HF perspective (105). Adverse events are not uncommon however, particularly infectious complications, exacerbation of HF, increased risk of malignancy and infusion reactions (infliximab) (104–107). Lastly, B cell inhibition via rituximab has been described in case reports and is of interest given recent implication of B cells in sarcoid granulomas. Further investigation is warranted regarding optimal timing of biologic initiation (Figure 4).

Advanced Heart Failure Therapies in CS

Despite treatment, a subset of patients with CS will progress to advanced heart failure (AHF). In a combined North American cohort, Fussner and colleagues described 15% of patients developing end-stage disease, manifested by the need for ventricular assist device (VAD), heart transplantation, or death (26). AHF, particularly in those with isolated CS, may carry a worse prognosis related to an increased risk for LV systolic dysfunction or VAs (108). Appropriate patients should be considered for AHF therapies that can improve survival and quality of life, specifically cardiac transplantation and VAD implantation.

AHF Therapy Outcomes (Cardiac Transplantation and VAD)

Consideration of heart transplantation and VAD placement in CS has historically been met with hesitancy due to the perceived risk of systemic sarcoidosis and recurrence in the cardiac allograft. Consensus guidelines are additionally limited. The International Society for Heart and Lung Transplantation heart transplantation listing criteria includes CS under the category of restrictive cardiomyopathies due to infiltrative/inflammatory disease and emphasize the importance of pre-transplant diagnosis so that peri-transplant care can be appropriately coordinated (109). With improvements in advanced cardiac imaging and heightened clinical awareness, the number of CS patients receiving AHF therapies is increasing (110).

Studies reporting outcomes of CS patients undergoing heart transplantation or LVAD are summarized in Table 6. Analyses from the United Network for Organ Sharing have demonstrated similar or better post-transplant survival outcomes for patients undergoing transplant for CS as compared to other cardiomyopathies (110, 111). Limited data exist regarding long-term outcomes of CS patients undergoing mechanical circulatory support (MCS), including registry studies, summarized in Table 6 (110, 112).

Table 6:

Studies of Advanced Heart Failure Therapies in Cardiac Sarcoidosis

Study	Publication Year	Study Design	Sample Size (# of CS patients)	Findings
Heart Transplantation
Zaidi(111)	2007	● Retrospective analysis of UNOS Registry ● October 1997- September 2005	65	●  One-year post-transplant survival significantly better for CS vs. non-CS patients (87.7% vs. 84.5%, p = 0.03)
Crawford(110)	2018	● Retrospective analysis of UNOS registry ● January 2006 - December 2015	148	● CS patients had similar 1-year (91% vs 90%) and 5-year (83% vs 77%) post-transplant freedom from mortality compared to non-CS patients ● Similar 5-year freedom from primary graft failure between CS and non-CS patients
Akashi(113)	2012	● Single center, retrospective analysis ● 1997 - 2010	14	● 8 of 14 patients were diagnosed with CS after transplant via explant cardiac tissue ● CS patients showed a trend toward higher mortality than non-CS patients (1- and 5-year survival, 78.5 versus 87.2%, 52.4 versus 76.2%, respectively, p = 0.09). ● 2 of 14 patients had CS recurrence post-transplant.
Perkel(118)	2013	● Single center, retrospective analysis ● January 1991 - July 2010	19	● No significant differences between CS and non-CS groups in terms of 1st-year freedom from any treated rejection (79% vs. 90%), 5-year post-transplant survival (79% vs. 83%), and 5-year freedom from CAV (68% vs. 78%) ● No recurrence of sarcoidosis in the cardiac allograft. ● Three patients (16%) experienced recurrence of extracardiac sarcoidosis, with no mortality.
Left Ventricular Assist Device
Crawford(110)	2018	● Retrospective analysis of UNOS registry patients undergoing BTT MCS ● January 2006 - December 2015	34	● 34 patients received MCS pre-transplant: 31 LVAD, 1 total artificial heart, and 2 biventricular support ● 20 of 34 (59%) underwent heart transplantation, a proportion similar to non-CS (63%) MCS patients ● Post-transplant survival similar to non-CS patients undergoing BTT MCS (89%)
Patel(112)	2017	● Retrospective analysis of INTERMACS Registry ● April 2008 - March 2014 ● Compared RCM patients who underwent LV AD implantation to DCM and HCM patients	17 (94 total RCM)	● No specific data regarding CS patient outcomes provided ● RCM patients had similar 1- and 2-year survival (74% and 61%) when compared to DCM and HCM patients

BTT: Bridge to transplantation; CAV: Cardiac allograft vasculopathy; DCM: dilated cardiomyopathy; HCM: hypertrophic cardiomyopathy; INTERMACS: Interagency Registry for Mechanically Assisted Circulatory Support; MCS: Mechanical circulatory support; RCM: Restrictive cardiomyopathy; UNOS: United Network for Organ Sharing

Existing data include either single center or registry-based analyses where the diagnosis is made prior to AHF therapy, thereby excluding patients diagnosed with CS post-operatively on LVAD or native heart explant tissue (34, 113–115). Current registry data also lack granular details such CS diagnostic criteria met and pre-operative pathology. A delayed, post-surgical diagnosis limits pre- and perioperative considerations outlined below and in Figure 5. A recent study compared the survival of known CS patients undergoing LVAD/transplant to those diagnosed with CS after LVAD/transplant and found no difference (116).

Figure 5. Considerations for Patients with Cardiac Sarcoidosis Undergoing Heart Transplantation and/or Left Ventricular Assist Device Implantation Through Operative Phases of Care.

There are unique clinical considerations for patients with cardiac sarcoidosis related advanced heart failure who are being evaluated for heart transplantation and/or LVAD. Additionally, a confirmed diagnosis of cardiac sarcoidosis on native heart pathology impacts short and long-term post-operative care.

Legend: FC = functional capacity; LV = left ventricular; LVAD = left ventricular assist device; QOL = quality of life; RV = right ventricular.

Preoperative considerations

When evaluating patient candidacy for AHF therapies, special considerations specific to CS should be considered, including a thorough assessment of the extent of extracardiac organ involvement and immunosuppression related end-organ complications. For example, advanced interstitial lung disease may result in sarcoidosis related pulmonary hypertension and be a limitation to heart transplantation candidacy due to concern for post-operative allograft dysfunction. Regarding LVAD evaluation, RV failure risk should be assessed, including extent of RV CS involvement and invasive hemodynamics. CS patients presenting primarily with refractory VA may benefit from a direct transplantation approach.

Perioperative considerations

Immunosuppression therapy for CS warrants reassessment in the peri-operative period. Considerations include risk of adrenal insufficiency and wound healing in the setting of long-term prednisone therapy. Though CS patients may share pathophysiologic similarities with their non-CS counterparts, specific clinical phenotypes such as refractory VA, predominant RV failure, or restrictive hemodynamics may be more common among CS patients and impact the transplant listing strategy. A recent analysis showed that the revised Organ Procurement and Transplant Network transplant allocation policy change has been effective for patients with infiltrative/restrictive cardiomyopathies (including CS), leading to increased transplantation rates and reduced waitlist mortality without an effect on early post-transplant outcomes (117).

Post-Transplant/MCS care

Post-transplantation, the general approach has been to maintain indefinite low dose prednisone therapy in patients transplanted for CS in addition to their antimetabolite (i.e. mycophenolate mofetil) and calcineurin inhibitor agents, the latter of which notably have not been shown to be effective in treating sarcoidosis. Contemporary single-center series reported no sarcoidosis recurrence in the cardiac allograft (118), though there exists a theoretical risk and published case reports, typically in setting of weaning off corticosteroids (113). Patients undergoing LVAD may also continue immunosuppression, weighing the benefits of sarcoidosis disease suppression with LVAD-related infection risk. Optimal immunosuppressive management in CS patients post-transplant or LVAD remains undefined. Surveillance of cardiac and extracardiac inflammation post-operatively is reasonable using FDG-PET imaging to guide treatment strategy, though there is no consensus on surveillance timing. Based on the complexity and systemic nature of sarcoidosis, management by a multispecialty sarcoidosis team in collaboration with the heart transplant/LVAD team is advised.

Patient Perspective and Disparities in Care

A diagnosis of sarcoidosis can be life altering due to the physical, psychological, and financial burden of the disease. Patients experience worse health-related quality of life, higher rates of depression, and loss of income and work days compared to those without sarcoidosis (119–122). Prioritizing the patient and family perspective in sarcoidosis care through shared decision making and patient advisory panels is fundamental. Social determinants of health have an established impact on outcomes in sarcoidosis. For example, low-income individuals with sarcoidosis report significant barriers to care, including access to medications, higher rates of hospitalization, new sarcoidosis related comorbidities, and immunosuppression related side effects when compared to higher income individuals (123–125). Black individuals have more severe organ involvement at time of diagnosis, higher mortality and hospitalization rates, and are less likely to have clinical recovery from sarcoidosis compared to non-Hispanic whites (124, 126). While genetic differences might exist, factors such as access to care and structural racism are more likely contributors to the racial health disparities seen in sarcoidosis. Regarding sex disparities, females with sarcoidosis have higher rates of hospitalizations, more severe organ involvement, higher rates of depressive symptoms, higher amounts of work loss, and worse health-related quality of life compared to males (120, 122, 124, 127, 128). Additionally, one study of patients with sarcoidosis found females were more likely to be prescribed eye drops, pain killers, and non-steroidal anti-inflammatory drugs for the treatment of symptoms while males were more likely to receive corticosteroids, highlighting a potential disparity in symptom attribution to sarcoidosis. Women have also been underrepresented in retrospective cohort studies of CS, however the reason is unclear and could be due to sex-based differences in presentation, diagnosis and organ involvement. The impact of race and sex on CS requires further evaluation, considering both biologic and social determinants of health.

Interdisciplinary Approach to CS: Bedside to Bench

As outlined, sarcoidosis is a systemic disease with varied clinical manifestations that requires interdisciplinary care. Figure 6 illustrates some of the key components of such an interdisciplinary care team, which may come together within a single institution or across institutions. Collaborating clinicians may be systemic sarcoidosis specialists partnering with HF cardiologists, electrophysiologists and cardiac imaging experts. Additionally, pharmacist engagement is important to co-manage the complex polypharmacy, drug-drug interactions and potential side effects of immunosuppression, HF guideline directed medical therapies and antiarrhythmic drugs. These medications often require navigation of insurance systems for use approval and coverage highlighting the need for social work and care coordination engagement. Nursing (including registered nurses and nurse practitioners) is essential for comprehensive symptom assessment and real-time medication management. Should patients progress to needing AHF therapies, their care naturally falls under the purview of multifaceted transplant and/or LVAD teams, including cardiac surgeons and transplant/LVAD coordinators (who are often registered nurses). Additionally, the psychosocial burden of a sarcoidosis diagnosis cannot be underestimated. Psychiatry, social work, community health workers and palliative care may partner with patients as they navigate their diagnosis and ongoing needs to ensure care is reflective of the patient’s values and health goals. Further, informal and family caregivers are often an under-recognized but essential part of chronic disease management. Creating infrastructure to engage and support caregivers of patients with CS is essential for improving quality of life for both patient and caregiver. Finally, identifying community and professional organizational support outside of the immediate care team (e.g., support groups, community health organizations, institutional support resources) may enhance and extend care beyond patients’ disease treatment needs.

Figure 6. Bedside to Bench Interdisciplinary Approach to Cardiac Sarcoidosis.

Multidisciplinary care providers and patient connections work together to provide holistic, person-centered care to the individual with sarcoidosis cardiomyopathy. This care produces clinical and patient-reported outcome measures for inclusion in a proposed multi-institution cardiac sarcoidosis registry. These data can then be used by diverse investigators to produce interventions to improve clinical care, outcomes, and patient quality of life.

Beyond the patient care team, collaborative efforts among scientists and clinicians are necessary to study disease mechanisms, develop preclinical models, and engage in translational and biobehavioral research (Figure 6). Funding and clinical trial opportunities may be more limited in rare diseases. Creating a multi-institution patient registry that includes diverse, pre-defined measures (e.g., biospecimens, clinical outcomes, patient-reported outcomes, clinical imaging) will allow for more seamless, standardized integration to generate hypotheses and achieve progress in identifying potential biomarkers for monitoring treatment response, developing targeted therapies, and improving clinical and patient-reported outcomes in CS.

Conclusion

Though Dr. Warfield T. Longcope impressed upon us that sarcoidosis should no longer be considered a rare entity exactly 80 years ago, the condition is still considered by many to be a rare disease. However, cardiomyopathy due to sarcoidosis is increasingly prevalent and warrants improved awareness. Diagnosis presents challenges due to limited expertise, phenotypic overlaps and dependence on often elusive histopathology. Recognition of CS carries implications not only for prompt initiation of immunosuppressive therapies to control downstream effects of granulomatous inflammation, but also for adjustment of peri-transplant/LVAD management. Interdisciplinary and cross-collaborative approaches are needed to improve our understanding and management of CS.

Highlights.

• Cardiac sarcoidosis (CS) may result in nonischemic cardiomyopathy.

• Sarcoidosis related cardiomyopathy requires unique evaluation and treatment strategies.

• Specific considerations for mechanical support and heart transplantation exist.

• Interdisciplinary team engagement is paramount in comprehensive CS patient care.

• Multi-institutional collaboration is required for future progress in the field of CS.

Manuscript Abbreviations

AAD

Anti-arrhythmic drugs

AHF

advanced heart failure

ARVC

arrhythmogenic right ventricular cardiomyopathy

AVB

atrioventricular block

CMR

cardiac magnetic resonance

CS

cardiac sarcoidosis

ECG

electrocardiogram

FDG-PET

18F-fluorodeoxyglucose positron emission tomography

GLS

global longitudinal strain

HF

heart failure

HFpEF

HF with preserved ejection fraction

HRS

Heart Rhythm Society

ICD

implantable cardioverter defibrillator

IFNɣ

interferon gamma

JMHW

Japanese Ministry of Health and Welfare

LGE

late gadolinium enhancement

LV

left ventricular

LVAD

left ventricular assist device therapy

LVEF

left ventricular ejection fraction

MCS

mechanical circulatory support

MHC

major histocompatibility complex

MMF

mycophenolate mofetil

RV

right ventricular

SSA

Steroid sparing agents

Th1

type 1 T helper cell

TLR2

toll-like receptor-2

TNF

tumor necrosis factor

Treg

Regulatory T cell

TTE

transthoracic echocardiographic

VA

ventricular arrhythmia

VT

ventricular tachycardia

WASOG

World Association of Sarcoidosis and Other Granulomatous diseases