Cardiac Sarcoidosis: Clinical Insights, Diagnosis, and Management Strategies

Abstract

Cardiac sarcoidosis (CS) is a multifaceted inflammatory disease that affects the heart, leading to complications such as arrhythmias, heart failure, and sudden cardiac death. Endomyocardial biopsy is the diagnostic gold standard, but its low sensitivity and risks limit its utility. Imaging modalities, such as cardiac magnetic resonance and positron emission tomography, are critical for diagnosing and managing CS. Additionally, CS treatment primarily involves corticosteroids and immunosuppressive agents to reduce inflammation and control disease progression, although biologics such as tumor necrosis factor-alpha (TNF-α) inhibitors are considered in refractory or steroid-dependent cases. This narrative review revises the existing knowledge on the diagnosis and treatment of CS, providing a comprehensive overview of current strategies.

Graphical abstract

Keywords

cardiac sarcoidosis / imaging / treatment / biologic

1. Introduction

Sarcoidosis is a multisystem inflammatory disorder characterized by the formation of non-caseating granulomas in various organs, most commonly affecting the lungs and intrathoracic lymph nodes [1]. Despite being a relatively rare condition, the diverse clinical manifestations and unpredictable course of sarcoidosis pose significant challenges for its diagnosis and management [2]. While pulmonary involvement is the hallmark of sarcoidosis, its impact on other organs, including the heart, has gained recognition for its clinical significance and potential complications [3].

Cardiac sarcoidosis (CS) represents a unique and potentially life-threatening manifestation of sarcoidosis involving the heart. Although precise epidemiological data remain elusive, CS is increasingly recognized as a significant cause of morbidity and mortality among sarcoidosis patients [3]. The clinical presentation of CS varies widely, ranging from asymptomatic electrocardiographic abnormalities to fatal arrhythmias, heart failure, and sudden cardiac death [4]. The insidious nature of CS, coupled with its heterogeneous clinical features and nonspecific symptoms, often leads to diagnostic delays or misdiagnosis, emphasizing the need for heightened awareness and improved diagnostic strategies [5].

Understanding the pathophysiology of CS is crucial for elucidating its clinical manifestations and guiding therapeutic interventions. The inflammatory cascade underlying sarcoidosis can affect any heart layer, disrupting the electrical conduction system, impairing contractility, and promoting arrhythmogenesis [6]. Moreover, the unpredictable nature of granuloma formation and regression in the myocardium further complicates the clinical course of CS, necessitating a multidisciplinary approach for optimal management [6].

Recently, advances in imaging modalities, such as cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET), have revolutionized the diagnosis and monitoring of CS, enabling early detection of cardiac involvement and guiding therapeutic decisions. Despite these advancements, challenges persist in accurately diagnosing CS, particularly in differentiating it from other cardiac conditions with overlapping clinical features [6].

This review aims to provide a comprehensive overview of the epidemiology, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies for cardiac sarcoidosis. By synthesizing the latest evidence and clinical insights, we seek to enhance awareness and promote optimal care for patients with this complex, often under-recognized condition.

This narrative review revises the existing knowledge on the diagnosis and treatment of CS, aiming to provide a comprehensive overview of current strategies for identifying, monitoring, and managing this complex condition. By consolidating the latest evidence and expert recommendations, it seeks to guide clinicians in optimizing diagnostic accuracy, improving imaging techniques, and tailoring therapeutic approaches to enhance patient outcomes.

2. Etiology and Pathogenesis

Despite extensive research, the exact etiology of sarcoidosis still needs to be discovered; however, sarcoidosis is widely believed to result from an interplay of genetic predisposition, environmental triggers, and dysregulated immune responses [1]. Several studies have identified associations with specific human leukocyte antigen (HLA) alleles, particularly HLA-DRB1 and HLA-DQB1, indicating a genetic predisposition to sarcoidosis development [7, 8, 9]. Additionally, genome-wide association studies have highlighted several candidate genes involved in immune regulation and inflammation, further supporting the genetic component of sarcoidosis [10].

Environmental factors are thought to trigger the development of sarcoidosis in genetically susceptible individuals [1]. Various environmental exposures, including infectious agents (such as mycobacteria, Cutibacterium acnes, and viruses), occupational hazards (such as beryllium, silica, and organic dust), and unidentified antigens, have been implicated as potential triggers [11]. However, no single causative agent has been consistently identified across all cases, suggesting a complex interplay between multiple environmental factors.

The exaggerated immune response that characterizes sarcoidosis pathogenesis is driven by the activation of T lymphocytes and the formation of granulomas [11]. Antigen-presenting cells, such as macrophages and dendritic cells, process and present environmental or self-antigens to CD4+ T helper cells, leading to the release of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-\alpha), interleukin-2 (IL-2), and interferon-gamma (IFN-\gamma) [12]. These cytokines drive the recruitment and activation of additional immune cells, perpetuating the inflammatory cascade and granuloma formation [11].

The pathogenesis of CS shares similarities with systemic sarcoidosis; however, the unique microenvironment of the myocardium and the presence of specialized cardiac cells contribute to distinct clinical manifestations and complications. In CS, inflammatory infiltrates comprising activated macrophages, T lymphocytes, and multinucleated giant cells infiltrate the myocardium, forming non-caseating granulomas [13]. Similar to systemic sarcoidosis, the exact mechanisms triggering myocardial inflammation in CS remain incompletely understood but likely also involve a combination of genetic predisposition, environmental triggers, and dysregulated immune responses [1].

Granulomas within the myocardium can disrupt the normal architecture and function of the heart, leading to fibrosis, myocardial scarring, and conduction abnormalities. Cytokine-mediated inflammation and oxidative stress can further impair cardiomyocyte function, resulting in myocardial dysfunction and heart failure [13]. CS predisposes individuals to various arrhythmias and conduction abnormalities, including atrioventricular block, ventricular tachycardia, and sudden cardiac death, due to the disruption of the cardiac conduction system by granulomas or inflammation [14].

3. Epidemiology

Cardiac involvement occurs in approximately 5% of patients with sarcoidosis, although autopsy studies have suggested that the prevalence might be higher, ranging from 20% to 30% [13]. CS typically affects individuals between the ages of 20 and 60 years, with incidences peaking between 40 and 50 years of age. Moreover, men appear to have a slightly higher prevalence than women [15]. Notably, the prevalence of CS varies across different populations and geographic regions, whereby studies have reported higher rates of CS in Japan compared to Western countries, likely due to differences in genetic predisposition and environmental exposures [16]. The majority of patients with CS also have pulmonary involvement, with estimates ranging from 50% to 90%. Therefore, pulmonary sarcoidosis is considered a significant risk factor for cardiac involvement, particularly in patients with extensive pulmonary fibrosis or respiratory impairment [1].

4. Clinical Manifestations

Sarcoidosis can affect any part of the heart, including the myocardium, endocardium, pericardium, and the conduction system. Cardiac symptoms vary depending on the location, extent, and activity of the disease [17]. The most commonly observed manifestations are cardiac arrhythmias, often presenting as syncope or palpitations [18]. Conduction abnormalities, such as advanced atrioventricular (AV) block, are reported in up to 42% of CS cases [19], typically due to the septal localization of granulomas infiltrating the conduction system [20]. Although transient recovery of AV conduction may occur either spontaneously or with immunosuppressive therapy [21], permanent pacing is often required due to the unpredictable course of the disease [22].

Among tachyarrhythmias, ventricular arrhythmias are the most common at presentation. These include frequent ectopic beats, unsustained ventricular tachycardia, and more severe arrhythmias, such as sustained ventricular tachycardia or ventricular fibrillation [17, 18]. Life-threatening ventricular arrhythmias, sudden cardiac death, and cardiocirculatory arrest account for approximately 30% of CS clinical manifestations [22]. Even in patients with bradyarrhythmia, the mid- to long-term risk of malignant ventricular arrhythmias is sufficiently high that guidelines recommend the implantation of a cardioverter defibrillator rather than a pacemaker [23, 24]. Many patients present with several morphologies of ventricular tachycardias or electrical storms due to the presence of an extensive and complex arrhythmic substrate [25, 26]. In acute sarcoidosis, catheter ablation has poor outcomes [25, 26] and should be postponed until the post-inflammatory stage, as identified by multimodality imaging [27].

Granulomatous infiltration of the atria, causing local inflammation and scarring, may also be responsible for supraventricular tachyarrhythmias, particularly atrial fibrillation and focal atrial tachycardias [19, 28]. Catheter ablation has poor outcomes even in atrial disease, and immunosuppression may help reduce the arrhythmic burden [23]. Heart failure is present in approximately 17% of patients with manifested CS [17]. Meanwhile, presentation with acute decompensated heart failure often results from life-threatening arrhythmias [22]. As recommended by international guidelines, hemodynamically unstable patients may require transfer to tertiary care centers for mechanical circulatory support [23]. Sarcoidosis can also lead directly to ventricular systolic dysfunction, spanning the spectrum from dilated to non-dilated left ventricular cardiomyopathies [29]. Most patients have mildly to moderately reduced left ventricular ejection fraction (LVEF) and signs of diastolic dysfunction [17]. Meanwhile, for stable patients with dyspnea, differential diagnosis should consider pulmonary disease. Right ventricular involvement, while rare in other forms of myocarditis [30], is a common sign of mechanical dysfunction in CS and necessitates differentiation from arrhythmogenic cardiomyopathy [31]. When significant interventricular conduction delays occur, such as from a complete left bundle branch block, cardiac resynchronization therapy is the preferred treatment option [32].

In subclinical CS, the 12-lead electrocardiogram (ECG) is often the first exam to reveal abnormalities during screening, even without symptoms [17]. As illustrated in Fig. 1, the presence of a trifascicular block or unexplained conduction system disease in young or middle-aged patients warrants consideration of CS, among other diseases that affect the interventricular septum [33].

5. Diagnosis

Considering the diverse clinical manifestations of sarcoidosis and the lack of a single definitive diagnostic test, a diagnosis of sarcoidosis entails a multifaceted approach [34]. The initial assessment often involves a thorough clinical evaluation to identify symptoms such as a cough, dyspnea, fatigue, or skin lesions, which may prompt further investigation [35]. Imaging studies, including chest X-rays and high-resolution computed tomography scans, are instrumental in detecting pulmonary involvement and assessing disease extent [36]. Laboratory tests, such as analyzing serum angiotensin-converting enzyme levels, can provide supportive evidence, although these lack specificity [37]. A definitive diagnosis typically requires histological confirmation of non-caseating granulomas obtained through a biopsy of affected tissues, such as the lungs, skin, or lymph nodes [38].

Diagnosing CS presents unique challenges due to its variable clinical presentation and potential for life-threatening complications [39]. Distinct from more frequent presentations of sarcoidosis, CS requires specific cardiac-focused tests. Initial screening often involves an ECG alongside echocardiography to assess for conduction abnormalities, arrhythmias, or structural changes. However, these tests may lack sensitivity for early-stage disease occurrences [40]. Advanced imaging techniques, such as cardiac magnetic resonance (CMR) imaging and PET, are valuable for detecting myocardial inflammation and assessing disease severity [41]. Endomyocardial biopsy (EMB) remains the gold standard for confirming CS but is invasive and carries risks [42]. Given the challenges in diagnosing CS, a high index of suspicion, multidisciplinary collaboration is essential between cardiologists, pulmonologists, and rheumatologists, and the utilization of complementary diagnostic modalities are essentialto ensure the accurate diagnosis and timely initiation of treatment.

5.1 Cardiac Imaging

While EMB remains the gold standard for diagnosing CS, it has low sensitivity and presents a serious complication rate of around 1% [43, 44]. Thus, a combination of extracardiac histological confirmation and myocardial involvement in imaging is sufficient for diagnosing CS [14]. Despite its low sensitivity, trans-thoracic echocardiography (TTE) is often the first-line imaging tool [45]. Findings may include strain abnormalities and changes in myocardial thickness, although the exam can sometimes appear normal; meanwhile, the disease progression often leads to diastolic dysfunction, with LVEF decreasing in advanced stages [46].

CMR and PET are the primary imaging modalities for CS and can be used to assess myocardial changes and disease activity. CMR provides comprehensive information on cardiac anatomy, function, and myocardial composition, including edema, fibrosis, and scarring [47]. However, CS can mimic various cardiomyopathies, with nonspecific findings such as localized dyskinesia, septo-basal thinning, or pericardial effusion [48]. T2-weighted imaging detects myocardial edema, typically in the septum [49]. Thus, late gadolinium enhancement (LGE) is crucial for diagnosing CS, revealing fibrosis in patchy, multifocal patterns sparing the endocardium [50]. As shown in Fig. 2, LGE is often found in the basal and mid-septum, with potential extension to the right ventricle [51], and it is a key prognostic factor [17]. Studies have shown a significant association between LGE and adverse outcomes, including ventricular arrhythmias and mortality [52, 53].

Nuclear imaging, particularly cardiac 18F-fludeoxyglucose (FDG)-PET, plays a central role in detecting myocardial inflammation, with high sensitivity (94–100%) [54]. 18F-FDG-PET is more sensitive than Gallium scintigraphy, Thallium, or Technetium-99m single-photon emission computed tomography for detecting myocardial inflammation [55]. To suppress normal myocardial glucose uptake, patients undergo a specific high-fat, low-carbohydrate diet followed by fasting, which can sometimes lead to inconclusive results in 10–15% of cases [56, 57]. PET scans often show patchy or diffuse myocardial uptake, particularly in the basal septum (Fig. 2). A combined perfusion scan enhances specificity, revealing perfusion defects associated with fibrosis or microcirculation abnormalities [58]. Both “mismatch patterns” of FDG uptake and right ventricular involvement can predict adverse cardiovascular outcomes [59, 60]. PET is also used to monitor treatment responses to immunosuppression [61]. Hybrid PET/MRI scanners combine LGE and FDG uptake and offer a deeper characterization of CS and differentiation between active and inactive disease [62]. Thus, using hybrid PET/MRI scanners also allows for better prognostication, with a lower radiation dose and higher diagnostic performance than individual PET/computed tomography (CT) [63, 64].

Although MRI is the preferred non-invasive tool for myocardial characterization, CT with late contrast enhancement has also shown good accuracy in identifying myocardial scars in inflammatory cardiac diseases [65]. Thus, CT may be particularly useful in patients with implanted devices and for initial assessments in cases where lung involvement is more prevalent [66]. Additionally, combining CT with 18F-FDG-PET can simultaneously provide information about myocardial scarring and disease activity.

5.2 Endomyocardial Biopsy

As reported above, while EMB is the gold standard for the definitive diagnosis of CS as it provides histopathological confirmation of non-caseating granulomas in the myocardium [42], its use in clinical practice is limited by several factors [67]. The primary challenge is the often patchy distribution of granulomas in CS, which can lead to a low diagnostic yield. Studies have shown that the sensitivity of EMB in detecting granulomas in CS can range from 20% to 30%, largely because standard biopsy techniques sample small areas of the heart, often missing the regions involved in the disease. In addition, EMB carries risks, such as cardiac perforation, arrhythmias, and damage to the tricuspid valve, which further limits its widespread use in diagnosing CS [42].

Advancements in imaging technology have enhanced the utility of EMB by improving the ability to target affected areas of the myocardium. CMR and PET allow for identifying areas of active inflammation and scarring. These imaging modalities can guide biopsies to areas of abnormal tissue, significantly increasing the likelihood of detecting granulomas and improving the diagnostic yield of the procedure. In cases where EMB is performed using these targeted approaches, sensitivity may increase, making the biopsy a more valuable diagnostic tool [41].

Despite its limitations, EMB remains an important part of the diagnostic algorithm for CS, particularly in cases where other diagnostic tools fail to provide conclusive evidence. For example, it is especially useful in differentiating CS from other forms of myocarditis, such as giant cell myocarditis, which shares certain clinical and imaging characteristics with CS but has a more aggressive prognosis and requires different treatment strategies. Therefore, a histopathological diagnosis from EMB can significantly impact clinical management decisions, particularly in guiding immunosuppressive therapy or ruling out alternative diagnoses.

The decision to perform an EMB must be carefully considered and based on a balance of clinical suspicion, non-invasive imaging findings, and the potential impact of the biopsy on patient management. Given the risks associated with the procedure, EMB is generally reserved for cases where the diagnosis remains uncertain after extensive evaluation through less invasive methods. In these cases, the diagnostic value of confirming CS through biopsy may outweigh the procedural risks, particularly in patients where establishing the diagnosis would lead to more aggressive treatment strategies. Therefore, while not routinely performed in all suspected cases of CS, EMB can play a decisive role in confirming the diagnosis in selected cases where histological confirmation is essential [42]. Table 1 summarizes the main strengths and weaknesses of PET, CMR, and EMB.

6. Treatment

Sarcoidosis treatment aims to alleviate symptoms, prevent organ damage, and improve quality of life [68, 69, 70, 71]. However, management strategies can vary depending on disease severity, organ involvement, and individual patient factors. Therapeutic interventions encompass pharmacological agents, immunomodulatory therapy, and supportive measures tailored to specific organ manifestations [68].

Corticosteroids are the mainstay of pharmacological therapy for both extracardiac and cardiac manifestations of sarcoidosis, exerting anti-inflammatory effects to suppress granuloma formation and reduce disease activity [72]. Given the potentially life-threatening nature of CS and its association with poor prognosis, higher doses of corticosteroids may be required to control cardiac inflammation. Intravenous pulse methylprednisolone therapy or high-dose oral prednisone regimens may also be utilized to induce remission in severe cases of CS [73].

In addition to corticosteroids, immunosuppressive agents such as methotrexate or azathioprine may be considered steroid-sparing agents or adjunctive therapy in refractory cases. Meanwhile, biologic agents, such as tumor necrosis factor-alpha (TNF-\alpha) inhibitors (e.g., infliximab, adalimumab) and JAK inhibitors, have demonstrated efficacy in refractory cases or steroid-dependent disease [74, 75]. Anti-TNF agents may be particularly beneficial in patients with extrapulmonary manifestations, such as CS, neurosarcoidosis, or ocular involvement [12].

7. American Heart Association Recommendations

The latest American Heart Association (AHA) guidelines, published in 2024, provide a detailed framework for diagnosing and managing CS and emphasize the multidisciplinary and evidence-informed approach previously highlighted throughout this review [76]. These guidelines highlight the complexity of CS diagnosis, given its variable clinical presentations and the challenges in confirming myocardial involvement. The AHA also outlines a tiered treatment strategy, starting with corticosteroids and advancing to immunosuppressive and biological therapies based on disease severity and response to treatment.

7.1 Diagnosis

According to the AHA guidelines and in line with the previously summarized data above, diagnosing CS requires a combination of clinical assessment, advanced imaging modalities, and, when possible, histological confirmation. CMR and PET are the cornerstone imaging techniques, providing critical information about inflammation and myocardial scarring. While CMR offers high sensitivity and prognostic insights, PET detects active granulomatous inflammation and guides therapeutic monitoring. Thus, EMB remains the gold standard but is limited by a low diagnostic yield due to the patchy distribution of granulomas.

7.2 Treatment

The AHA guidelines advocate for a stepwise approach to CS management. Corticosteroids are the first-line therapy, with prednisone (30–40 mg/day) being the standard initial treatment. For severe or life-threatening cases, such as ventricular arrhythmias or cardiogenic shock, high-dose intravenous methylprednisolone may be used to control inflammation rapidly. In cases of steroid-resistant or relapsing disease, steroid-sparing agents such as methotrexate, azathioprine, or mycophenolate are recommended. Biologic therapies, including TNF-\alpha inhibitors such as infliximab and adalimumab, are reserved for refractory cases or situations requiring aggressive intervention early in the disease course. Meanwhile, treatment is tailored to each patient through regular follow-up and imaging-based monitoring, aiming to control inflammation, prevent progression, and improve outcomes. The guidelines underscore the importance of individualized care and interdisciplinary collaboration in managing this challenging condition.

8. Prognosis

The prognosis of CS varies depending on several factors, including the extent of myocardial involvement, clinical presentation, and certainty of diagnosis. Recent cohort studies have reported encouraging survival rates, with 5-year survival consistently at 90% or higher. Poor outcomes are associated with sustained ventricular tachycardia or heart failure at presentation, while atrioventricular block alone tends to promote a better prognosis. Comparatively, de novo or clinically isolated presentations predict worse outcomes, often due to delayed diagnoses and more advanced disease stages. Interestingly, a histologically confirmed diagnosis of myocardial CS portends a worse prognosis compared to a probable diagnosis based on extracardiac findings [14].

Although these factors offer insights into prognosis, it remains unclear whether current treatments significantly improve long-term outcomes. Therefore, further studies are needed to assess the impact of therapeutic interventions on survival and quality of life in CS patients.

9. Conclusions

Sarcoidosis and CS are complex inflammatory disorders that require a multifaceted management approach. While pharmacological agents target systemic inflammation and immune dysregulation, the management of cardiac sarcoidosis necessitates a dual focus on immunomodulatory therapy and cardiological interventions to optimize outcomes and prevent cardiac complications. Multidisciplinary collaboration between rheumatologists, pulmonologists, cardiologists, and other specialists is essential for individualized treatment planning and comprehensive care of patients with sarcoidosis.

References

[1] Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. The New England Journal of Medicine. 2007; 357: 2153–2165. https://doi.org/10.1056/NEJMra071714.

[2] Drent M, Crouser ED, Grunewald J. Challenges of Sarcoidosis and Its Management. The New England Journal of Medicine. 2021; 385: 1018–1032. https://doi.org/10.1056/NEJMra2101555.

[3] Tan JL, Fong HK, Birati EY, Han Y. Cardiac Sarcoidosis. The American Journal of Cardiology. 2019; 123: 513–522. https://doi.org/10.1016/j.amjcard.2018.10.021.

[4] Markatis E, Afthinos A, Antonakis E, Papanikolaou IC. Cardiac sarcoidosis: diagnosis and management. Reviews in Cardiovascular Medicine. 2020; 21: 321–338. https://doi.org/10.31083/j.rcm.2020.03.102.

[5] Serei VD, Fyfe B. The Many Faces of Cardiac Sarcoidosis. American Journal of Clinical Pathology. 2020; 153: 294–302. https://doi.org/10.1093/ajcp/aqz169.

[6] Yatsynovich Y, Dittoe N, Petrov M, Maroz N. Cardiac Sarcoidosis: A Review of Contemporary Challenges in Diagnosis and Treatment. The American Journal of the Medical Sciences. 2018; 355: 113–125. https://doi.org/10.1016/j.amjms.2017.08.009.

[7] Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, Müller-Quernheim J. Sarcoidosis. Lancet (London, England). 2014; 383: 1155–1167. https://doi.org/10.1016/S0140-6736(13)60680-7.

[8] Eldhagen P, Bobbio E, Darlington P, Grunewald J, Eklund A, Polte CL, et al. Phenotypic and HLA-DRB1 allele characterization of Swedish cardiac sarcoidosis patients. International Journal of Cardiology. 2022; 359: 108–112. https://doi.org/10.1016/j.ijcard.2022.04.006.

[9] Sikorova K, Osoegawa K, Kocourkova L, Strnad A, Petrkova J, Fernández-Viña MA, et al. Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment. Frontiers in Medicine. 2023; 10: 1094843. https://doi.org/10.3389/fmed.2023.1094843.

[10] Liao SY, Jacobson S, Hamzeh NY, Culver DA, Barkes BQ, Mroz M, et al. Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility. Human Molecular Genetics. 2023; 32: 2669–2678. https://doi.org/10.1093/hmg/ddad067.

[11] Weeratunga P, Moller DR, Ho LP. Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis. The Journal of Clinical Investigation. 2024; 134: e175264. https://doi.org/10.1172/JCI175264.

[12] Amber KT, Bloom R, Mrowietz U, Hertl M. TNF-α: a treatment target or cause of sarcoidosis? Journal of the European Academy of Dermatology and Venereology: JEADV. 2015; 29: 2104–2111. https://doi.org/10.1111/jdv.13246.

[13] Mathai SV, Patel S, Jorde UP, Rochlani Y. Epidemiology, Pathogenesis, and Diagnosis of Cardiac Sarcoidosis. Methodist DeBakey Cardiovascular Journal. 2022; 18: 78–93. https://doi.org/10.14797/mdcvj.1057.

[14] Lehtonen J, Uusitalo V, Pöyhönen P, Mäyränpää MI, Kupari M. Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis. European Heart Journal. 2023; 44: 1495–1510. https://doi.org/10.1093/eurheartj/ehad067.

[15] Santulli G. Cardiac Sarcoidosis: Updated Insights on Epidemiology and Diagnostic Criteria. The American Journal of Cardiology. 2023; 204: 425–427. https://doi.org/10.1016/j.amjcard.2023.07.123.

[16] Gilotra NA, Griffin JM, Pavlovic N, Houston BA, Chasler J, Goetz C, et al. Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review. Journal of Cardiac Failure. 2022; 28: 113–132. https://doi.org/10.1016/j.cardfail.2021.06.016.

[17] Kouranos V, Sharma R. Cardiac sarcoidosis: state-of-the-art review. Heart (British Cardiac Society). 2021; 107: 1591–1599. https://doi.org/10.1136/heartjnl-2019-316442.

[18] Peretto G, Sala S, Rizzo S, De Luca G, Campochiaro C, Sartorelli S, et al. Arrhythmias in myocarditis: State of the art. Heart Rhythm. 2019; 16: 793–801. https://doi.org/10.1016/j.hrthm.2018.11.024.

[19] Nery PB, Beanlands RS, Nair GM, Green M, Yang J, McArdle BA, et al. Atrioventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged adults. Journal of Cardiovascular Electrophysiology. 2014; 25: 875–881. https://doi.org/10.1111/jce.12401.

[20] Peretto G, Busnardo E, Ferro P, Palmisano A, Vignale D, Esposito A, et al. Clinical Applications of FDG-PET Scan in Arrhythmic Myocarditis. JACC. Cardiovascular Imaging. 2022; 15: 1771–1780. https://doi.org/10.1016/j.jcmg.2022.02.029.

[21] Yodogawa K, Fujimoto Y, Hagiwara K, Oka E, Hayashi H, Murata H, et al. Possibility of steroid therapy without pacemaker implantation in patients with sarcoidosis presenting atrioventricular block. Heart and Vessels. 2022; 37: 1892–1898. https://doi.org/10.1007/s00380-022-02092-1.

[22] Nordenswan HK, Pöyhönen P, Lehtonen J, Ekström K, Uusitalo V, Niemelä M, et al. Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator. Circulation. 2022; 146: 964–975. https://doi.org/10.1161/CIRCULATIONAHA.121.058120.

[23] Birnie DH, Sauer WH, Bogun F, Cooper JM, Culver DA, Duvernoy CS, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014; 11: 1305–1323. https://doi.org/10.1016/j.hrthm.2014.03.043.

[24] Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. European Heart Journal. 2022; 43: 3997–4126. https://doi.org/10.1093/eurheartj/ehac262.

[25] Della Bella P, Peretto G, Paglino G, Bisceglia C, Radinovic A, Sala S, et al. Bipolar radiofrequency ablation for ventricular tachycardias originating from the interventricular septum: Safety and efficacy in a pilot cohort study. Heart Rhythm. 2020; 17: 2111–2118. https://doi.org/10.1016/j.hrthm.2020.06.025.

[26] Siontis KC, Santangeli P, Muser D, Marchlinski FE, Zeppenfeld K, Hoogendoorn JC, et al. Outcomes Associated With Catheter Ablation of Ventricular Tachycardia in Patients With Cardiac Sarcoidosis. JAMA Cardiology. 2022; 7: 175–183. https://doi.org/10.1001/jamacardio.2021.4738.

[27] Berruezo A, Penela D, Jáuregui B, de Asmundis C, Peretto G, Marrouche N, et al. Twenty-five years of research in cardiac imaging in electrophysiology procedures for atrial and ventricular arrhythmias. Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology: Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2023; 25: euad183. https://doi.org/10.1093/europace/euad183.

[28] Fujimoto Y, Matsue Y, Maeda D, Dotare T, Sunayama T, Iso T, et al. Prevalence and prognostic value of atrial fibrillation in patients with cardiac sarcoidosis. European Heart Journal Open. 2023; 3: oead100. https://doi.org/10.1093/ehjopen/oead100.

[29] Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. European Heart Journal. 2023; 44: 3503–3626. https://doi.org/10.1093/eurheartj/ehad194.

[30] Peretto G, Barzaghi F, Cicalese MP, Di Resta C, Slavich M, Benedetti S, et al. Immunosuppressive therapy in childhood-onset arrhythmogenic inflammatory cardiomyopathy. Pacing and Clinical Electrophysiology: PACE. 2021; 44: 552–556. https://doi.org/10.1111/pace.14153.

[31] Philips B, Madhavan S, James CA, te Riele ASJM, Murray B, Tichnell C, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. Circulation. Arrhythmia and Electrophysiology. 2014; 7: 230–236. https://doi.org/10.1161/CIRCEP.113.000932.

[32] Shabtaie SA, Sehrawat O, Lee JZ, Cha YM, Mulpuru SK, Kowlgi NG, et al. Cardiac resynchronization therapy response in cardiac sarcoidosis. Journal of Cardiovascular Electrophysiology. 2022; 33: 2072–2080. https://doi.org/10.1111/jce.15631.

[33] Peretto G, Sala S, Lazzeroni D, Palmisano A, Gigli L, Esposito A, et al. Septal Late Gadolinium Enhancement and Arrhythmic Risk in Genetic and Acquired Non-Ischaemic Cardiomyopathies. Heart, Lung & Circulation. 2020; 29: 1356–1365. https://doi.org/10.1016/j.hlc.2019.08.018.

[34] Sève P, Pacheco Y, Durupt F, Jamilloux Y, Gerfaud-Valentin M, Isaac S, et al. Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis. Cells. 2021; 10: 766. https://doi.org/10.3390/cells10040766.

[35] Soto-Gomez N, Peters JI, Nambiar AM. Diagnosis and Management of Sarcoidosis. American Family Physician. 2016; 93: 840–848.

[36] Jeny F, Bernaudin JF, Cohen Aubart F, Brillet PY, Bouvry D, Nunes H, et al. Diagnosis issues in sarcoidosis. Respiratory Medicine and Research. 2020; 77: 37–45. https://doi.org/10.1016/j.resmer.2019.09.002.

[37] Miliauskas S, Zemaitis M, Sakalauskas R. Sarcoidosis–moving to the new standard of diagnosis? Medicina (Kaunas, Lithuania). 2010; 46: 443–446.

[38] Jameson A, Revels J, Wang LL, Wang DT, Wang SS. Sarcoidosis, the master mimicker. Current Problems in Diagnostic Radiology. 2022; 51: 60–72. https://doi.org/10.1067/j.cpradiol.2020.10.013.

[39] Lynch JP, 3rd, Hwang J, Bradfield J, Fishbein M, Shivkumar K, Tung R. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Seminars in Respiratory and Critical Care Medicine. 2014; 35: 372–390. https://doi.org/10.1055/s-0034-1376889.

[40] Ribeiro Neto ML, Jellis CL, Cremer PC, Harper LJ, Taimeh Z, Culver DA. Cardiac Sarcoidosis. Clinics in Chest Medicine. 2024; 45: 105–118. https://doi.org/10.1016/j.ccm.2023.08.006.

[41] Sohn DW, Park JB. Cardiac sarcoidosis. Heart (British Cardiac Society). 2023; 109: 1132–1138. https://doi.org/10.1136/heartjnl-2022-321379.

[42] Kurashima S, Kitai T, Xanthopoulos A, Skoularigis J, Triposkiadis F, Izumi C. Diagnosis of cardiac sarcoidosis: histological evidence vs. imaging. Expert Review of Cardiovascular Therapy. 2023; 21: 693–702. https://doi.org/10.1080/14779072.2023.2266367.

[43] Casella M, Dello Russo A, Bergonti M, Catto V, Conte E, Sommariva E, et al. Diagnostic Yield of Electroanatomic Voltage Mapping in Guiding Endomyocardial Biopsies. Circulation. 2020; 142: 1249–1260. https://doi.org/10.1161/CIRCULATIONAHA.120.046900.

[44] Chimenti C, Frustaci A. Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period. Circulation. 2013; 128: 1531–1541. https://doi.org/10.1161/CIRCULATIONAHA.13.001414.

[45] Ohira H, Sato T, Manabe O, Oyama-Manabe N, Hayashishita A, Nakaya T, et al. Underdiagnosis of cardiac sarcoidosis by ECG and echocardiography in cases of extracardiac sarcoidosis. ERJ Open Research. 2022; 8: 00516–2021. https://doi.org/10.1183/23120541.00516-2021.

[46] Chiu CZ, Cheng JJ, Nakatani S, Yamagishi M, Miyatake K. Echocardiographic Manifestations in Patients with Cardiac Sarcoidosis. Journal of Medical Ultrasound. 2002; 10: 135–140. https://doi.org/10.1016/S0929-6441(09)60031-X.

[47] Bruno F, Albano D, Agostini A, Benenati M, Cannella R, Caruso D, et al. Imaging of metabolic and overload disorders in tissues and organs. Japanese Journal of Radiology. 2023; 41: 571–595. https://doi.org/10.1007/s11604-022-01379-7.

[48] Jeudy J, Burke AP, White CS, Kramer GBG, Frazier AA. Cardiac sarcoidosis: the challenge of radiologic-pathologic correlation: from the radiologic pathology archives. Radiographics: a Review Publication of the Radiological Society of North America, Inc. 2015; 35: 657–679. https://doi.org/10.1148/rg.2015140247.

[49] Crouser ED, Ono C, Tran T, He X, Raman SV. Improved detection of cardiac sarcoidosis using magnetic resonance with myocardial T2 mapping. American Journal of Respiratory and Critical Care Medicine. 2014; 189: 109–112. https://doi.org/10.1164/rccm.201309-1668LE.

[50] Schulz-Menger J, Wassmuth R, Abdel-Aty H, Siegel I, Franke A, Dietz R, et al. Patterns of myocardial inflammation and scarring in sarcoidosis as assessed by cardiovascular magnetic resonance. Heart (British Cardiac Society). 2006; 92: 399–400. https://doi.org/10.1136/hrt.2004.058016.

[51] Trivieri MG, Spagnolo P, Birnie D, Liu P, Drake W, Kovacic JC, et al. Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2020; 76: 1878–1901. https://doi.org/10.1016/j.jacc.2020.08.042.

[52] Hulten E, Agarwal V, Cahill M, Cole G, Vita T, Parrish S, et al. Presence of Late Gadolinium Enhancement by Cardiac Magnetic Resonance Among Patients With Suspected Cardiac Sarcoidosis Is Associated With Adverse Cardiovascular Prognosis: A Systematic Review and Meta-Analysis. Circulation. Cardiovascular Imaging. 2016; 9: e005001. https://doi.org/10.1161/CIRCIMAGING.116.005001.

[53] Coleman GC, Shaw PW, Balfour PC, Jr, Gonzalez JA, Kramer CM, Patel AR, et al. Prognostic Value of Myocardial Scarring on CMR in Patients With Cardiac Sarcoidosis. JACC. Cardiovascular Imaging. 2017; 10: 411–420. https://doi.org/10.1016/j.jcmg.2016.05.009.

[54] Keijsers RG, Grutters JC, Thomeer M, Du Bois RM, Van Buul MM, Lavalaye J, et al. Imaging the inflammatory activity of sarcoidosis: sensitivity and inter observer agreement of (67)Ga imaging and (18)F-FDG PET. The Quarterly Journal of Nuclear Medicine and Molecular Imaging: Official Publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society Of…. 2011; 55: 66–71.

[55] Chareonthaitawee P, Beanlands RS, Chen W, Dorbala S, Miller EJ, Murthy VL, et al. Joint SNMMI-ASNC Expert Consensus Document on the Role of ¹⁸F-FDG PET/CT in Cardiac Sarcoid Detection and Therapy Monitoring. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 2017; 58: 1341–1353. https://doi.org/10.2967/jnumed.117.196287.

[56] Harisankar CNB, Mittal BR, Agrawal KL, Abrar ML, Bhattacharya A. Utility of high fat and low carbohydrate diet in suppressing myocardial FDG uptake. Journal of Nuclear Cardiology: Official Publication of the American Society of Nuclear Cardiology. 2011; 18: 926–936. https://doi.org/10.1007/s12350-011-9422-8.

[57] Saric P, Young KA, Rodriguez-Porcel M, Chareonthaitawee P. PET Imaging in Cardiac Sarcoidosis: A Narrative Review with Focus on Novel PET Tracers. Pharmaceuticals (Basel, Switzerland). 2021; 14: 1286. https://doi.org/10.3390/ph14121286.

[58] Skali H, Schulman AR, Dorbala S. 18F-FDG PET/CT for the assessment of myocardial sarcoidosis. Current Cardiology Reports. 2013; 15: 352.

[59] Bekki M, Tahara N, Tahara A, Sugiyama Y, Maeda-Ogata S, Honda A, et al. Localization of myocardial FDG uptake for prognostic risk stratification in corticosteroid-naïve cardiac sarcoidosis. Journal of Nuclear Cardiology: Official Publication of the American Society of Nuclear Cardiology. 2022; 29: 2132–2144. https://doi.org/10.1007/s12350-021-02684-w.

[60] Wicks EC, Menezes LJ, Barnes A, Mohiddin SA, Sekhri N, Porter JC, et al. Diagnostic accuracy and prognostic value of simultaneous hybrid 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging in cardiac sarcoidosis. European Heart Journal. Cardiovascular Imaging. 2018; 19: 757–767. https://doi.org/10.1093/ehjci/jex340.

[61] Birnie DH, Nery PB, Ha AC, Beanlands RSB. Cardiac Sarcoidosis. Journal of the American College of Cardiology. 2016; 68: 411–421. https://doi.org/10.1016/j.jacc.2016.03.605.

[62] Dweck MR, Abgral R, Trivieri MG, Robson PM, Karakatsanis N, Mani V, et al. Hybrid Magnetic Resonance Imaging and Positron Emission Tomography With Fluorodeoxyglucose to Diagnose Active Cardiac Sarcoidosis. JACC. Cardiovascular Imaging. 2018; 11: 94–107. https://doi.org/10.1016/j.jcmg.2017.02.021.

[63] Trivieri MG, Robson PM, Vergani V, LaRocca G, Romero-Daza AM, Abgral R, et al. Hybrid Magnetic Resonance Positron Emission Tomography Is Associated With Cardiac-Related Outcomes in Cardiac Sarcoidosis. JACC. Cardiovascular Imaging. 2024; 17: 411–424. https://doi.org/10.1016/j.jcmg.2023.11.010.

[64] Marschner CA, Aloufi F, Aitken M, Cheung E, Thavendiranathan P, Iwanochko RM, et al. Combined FDG PET/MRI versus Standard-of-Care Imaging in the Evaluation of Cardiac Sarcoidosis. Radiology. Cardiothoracic Imaging. 2023; 5: e220292. https://doi.org/10.1148/ryct.220292.

[65] Palmisano A, Vignale D, Tadic M, Moroni F, De Stefano D, Gatti M, et al. Myocardial Late Contrast Enhancement CT in Troponin-Positive Acute Chest Pain Syndrome. Radiology. 2022; 302: 545–553. https://doi.org/10.1148/radiol.211288.

[66] Palmisano A, Vignale D, Peretto G, Busnardo E, Calcagno C, Campochiaro C, et al. Hybrid FDG-PET/MR or FDG-PET/CT to Detect Disease Activity in Patients With Persisting Arrhythmias After Myocarditis. JACC. Cardiovascular Imaging. 2021; 14: 288–292. https://doi.org/10.1016/j.jcmg.2020.03.009.

[67] Ammirati E, Buono A, Moroni F, Gigli L, Power JR, Ciabatti M, et al. State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy. Current Cardiology Reports. 2022; 24: 597–609. https://doi.org/10.1007/s11886-022-01680-x.

[68] Baughman RP, Valeyre D, Korsten P, Mathioudakis AG, Wuyts WA, Wells A, et al. ERS clinical practice guidelines on treatment of sarcoidosis. The European Respiratory Journal. 2021; 58: 2004079. https://doi.org/10.1183/13993003.04079-2020.

[69] Campochiaro C, Farina N, De Luca G, Batani V, Trignani G, Vignale D, et al. Effectiveness and safety of mycophenolate mofetil and rituximab combination therapy for immune idiopathic myopathies. Arthritis Research & Therapy. 2024; 26: 79. https://doi.org/10.1186/s13075-024-03310-z.

[70] Campochiaro C, Tomelleri A, Farina N, Cavalli G, De Luca G, Palmisano A, et al. Myocarditis as a manifestation of Erdheim-Chester Disease: successful use of anti- IL1 and BRAF inhibitor combination therapy. Scandinavian Journal of Rheumatology. 2022; 51: 243–245. https://doi.org/10.1080/03009742.2021.1992846.

[71] Campochiaro C, Farina N, Tomelleri A, Ferrara R, Lazzari C, De Luca G, et al. Tocilizumab for the treatment of immune-related adverse events: a systematic literature review and a multicentre case series. European Journal of Internal Medicine. 2021; 93: 87–94. https://doi.org/10.1016/j.ejim.2021.07.016.

[72] Gerke AK. Treatment of Sarcoidosis: A Multidisciplinary Approach. Frontiers in Immunology. 2020; 11: 545413. https://doi.org/10.3389/fimmu.2020.545413.

[73] Markatis E, Afthinos A, Antonakis E, Papanikolaou IC. Cardiac sarcoidosis: diagnosis and management. Reviews in Cardiovascular Medicine. 2020; 21: 321–338. https://doi.org/10.31083/j.rcm.2020.03.102.

[74] Baker MC, Sheth K, Witteles R, Genovese MC, Shoor S, Simard JF. TNF-alpha inhibition for the treatment of cardiac sarcoidosis [published erratum in Seminars in Arthritis and Rheumatism. 2021; 51: 1390. https://doi.org/10.1016/j.semarthrit.2021.05.009]. Seminars in Arthritis and Rheumatism. 2020; 50: 546–552. https://doi.org/10.1016/j.semarthrit.2019.11.004.

[75] Wang A, Singh K, Ibrahim W, King B, Damsky W. The Promise of JAK Inhibitors for Treatment of Sarcoidosis and Other Inflammatory Disorders with Macrophage Activation: A Review of the Literature. The Yale Journal of Biology and Medicine. 2020; 93: 187–195.

[76] Cheng RK, Kittleson MM, Beavers CJ, Birnie DH, Blankstein R, Bravo PE, et al. Diagnosis and Management of Cardiac Sarcoidosis: A Scientific Statement From the American Heart Association. Circulation. 2024; 149: e1197–e1216. https://doi.org/10.1161/CIR.0000000000001240.