CARDIAC SARCOIDOSIS: ADVANCEMENTS IN DIAGNOSTIC TECHNIQUES AND MANAGEMENT

CARDIAC SARCOIDOSIS: ADVANCEMENTS IN DIAGNOSTIC TECHNIQUES AND MANAGEMENT

V. Shree Harini *, A. Sushmitha, B. Sendilkumar, Jai Parkash, K. Leela and D. Gowtham

School of Allied Health Sciences, Vinayaka Mission's Research Foundation-Deemed to be University, Salem, Tamil Nadu, India.

ABSTRACT: Cardiac sarcoidosis, a systemic inflammatory disease characterized by the formation of non-caseating granulomas, poses significant diagnostic and therapeutic challenges due to its variable clinical presentation and potential for severe complications. This article reviews recent advancements in the diagnosis and treatment of cardiac sarcoidosis, emphasizing the importance of early recognition and intervention. Diagnostic strategies have evolved, incorporating advanced imaging modalities such as cardiac MRI and PET-CT scans, alongside endomyocardial biopsy for definitive confirmation. Treatment options have expanded beyond conventional immunosuppression to include targeted therapies and device-based interventions like implantable cardioverter-defibrillators (ICDs) for arrhythmia management. The impact of timely diagnosis on patient outcomes underscores the critical role of heightened clinical suspicion and interdisciplinary collaboration among cardiologists, pulmonologists, and rheumatologists. This review consolidates current evidence and expert recommendations to guide clinicians in optimizing care for patients with cardiac sarcoidosis, highlighting ongoing research efforts aimed at further improving diagnostic accuracy and therapeutic efficacy.

Keywords: Cardiac sarcoidosis, Diagnostic advancements, Multidisciplinary approach, Patient outcomes, Treatment innovations

INTRODUCTION: Cardiac sarcoidosis (CS) is a rare but potentially life-threatening manifestation of systemic sarcoidosis, a multisystem granulomatous disorder of unknown etiology. While sarcoidosis can affect any organ system, cardiac involvement poses significant diagnostic and therapeutic challenges due to its nonspecific presentation and potential for severe complications, including arrhythmias, conduction disturbances, and heart failure ¹. In recent years, there have been considerable advancements in the diagnostic techniques and management strategies for CS, leading to improved outcomes for affected patients.

This narrative review aims to provide a comprehensive overview of the current state of knowledge regarding CS, with a particular focus on recent developments in diagnostic modalities and treatment approaches.

We will explore the epidemiology, patho-physiology, and clinical manifestations of CS, followed by an in-depth discussion of emerging diagnostic techniques, including advanced imaging modalities and biomarkers. Finally, we will examine the evolving landscape of CS management, encompassing both pharmacological and interventional strategies.

Epidemiology and Pathophysiology:

Epidemiology: The true prevalence of CS remains challenging to determine due to the often asymptomatic nature of cardiac involvement and the limitations of diagnostic techniques. Clinically manifest CS is estimated to occur in 2-7% of patients with systemic sarcoidosis ². However, autopsy studies have revealed cardiac involvement in up to 25% of sarcoidosis patients, suggesting that subclinical CS may be more common than previously thought ³. CS can affect individuals of all ages and ethnicities, but certain populations appear to be at higher risk. For instance, studies have shown a higher prevalence of CS among Japanese patients with sarcoidosis compared to other ethnic groups ⁴. Additionally, CS tends to occur more frequently in younger adults, with a peak incidence in the fourth and fifth decades of life ⁵.

Pathophysiology: The hallmark of sarcoidosis is the formation of non-caseating granulomas, which in CS can affect any part of the heart, including the myocardium, endocardium, pericardium, and conduction system. The exact etiology of sarcoidosis remains unknown, but it is believed to result from an exaggerated immune response to an unidentified antigenic trigger in genetically susceptible individuals ⁶.

In CS, the granulomatous inflammation can lead to various pathophysiological consequences:

1. Myocardial Inflammation and Fibrosis: Chronic inflammation can result in myocardial fibrosis, leading to systolic and diastolic dysfunction, and potentially heart failure ⁷.
2. Conduction System Involvement: Granulomas affecting the conduction system can cause various arrhythmias and conduction disturbances, including atrioventricular block, bundle branch blocks, and ventricular tachycardia ⁸.
3. Valvular Involvement: Although less common, granulomatous infiltration of heart valves can lead to valvular dysfunction ⁹.
4. Pericardial Involvement: Pericardial inflammation can result in pericarditis or pericardial effusion ¹⁰.

Recent studies have highlighted the role of certain cytokines, particularly tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), in the pathogenesis of CS ¹¹. These insights have not only enhanced our understanding of the disease process but have also paved the way for targeted therapeutic approaches.

Clinical Manifestations: The clinical presentation of CS is highly variable, ranging from asymptomatic cardiac involvement to life-threatening arrhythmias and sudden cardiac death. Common manifestations include:

1. Conduction Disturbances: Atrioventricular block is one of the most frequent presentations of CS, occurring in up to 30% of patients ¹².
2. Ventricular Arrhythmias: Ventricular tachycardia and fibrillation are significant causes of morbidity and mortality in CS patients ¹³.
3. Heart Failure: Both systolic and diastolic heart failure can occur as a result of myocardial involvement ¹⁴.
4. Chest Pain: Patients may experience chest pain due to myocardial inflammation or pericardial involvement ¹⁵.
5. Syncope: This can result from arrhythmias or conduction disturbances ¹⁶.
6. Sudden Cardiac Death: In some cases, CS may present with sudden cardiac death as the initial manifestation, particularly in younger patients ¹⁷.

The nonspecific nature of these symptoms, coupled with the often intermittent course of the disease, can make the diagnosis of CS challenging.

This underscores the importance of maintaining a high index of suspicion, particularly in patients with known or suspected systemic sarcoidosis.

Advancements in Diagnostic Techniques: The diagnosis of CS has traditionally been challenging due to the nonspecific nature of its clinical presentation and the limitations of conventional diagnostic modalities.

However, recent years have seen significant advancements in diagnostic techniques, leading to improved detection and characterization of cardiac involvement in sarcoidosis. The diagnostic techniques are illustrated in Fig. 1.

FIG. 1: DIAGNOSIS OF CARDIAC SARCOIDOSIS

Imaging Modalities:

Cardiac Magnetic Resonance Imaging (CMR): CMR has emerged as a powerful tool in the diagnosis and assessment of CS. It offers high spatial resolution and the ability to characterize tissue composition without ionizing radiation. Key features of CMR in CS include:

1. Late Gadolinium Enhancement (LGE): LGE patterns in CS typically show patchy, multifocal involvement, often with a predilection for the basal septum and lateral wall ¹⁸. The presence of LGE has been associated with adverse outcomes in CS patients ¹⁹.
2. T2-Weighted Imaging: This technique can detect active myocardial inflammation, helping to differentiate active from chronic disease ²⁰.
3. T1 and T2 Mapping: These advanced techniques provide quantitative assessment of myocardial tissue characteristics, potentially allowing for earlier detection of CS and monitoring of treatment response ²¹.

Recent studies have demonstrated the high sensitivity and specificity of CMR in diagnosing CS, with some reports suggesting sensitivity as high as 95% and specificity up to 100% when combining LGE and T2-weighted imaging ²².

18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET): FDG-PET has gained prominence in the evaluation of CS due to its ability to detect active inflammation. Key aspects of FDG-PET in CS include:

1. Metabolic Activity: FDG uptake reflects increased glucose metabolism in inflammatory cells, allowing for detection of active granulomatous inflammation ²³.
2. Combination with Perfusion Imaging: The integration of FDG-PET with myocardial perfusion imaging (e.g., 82Rb PET) allows for the assessment of both active inflammation and perfusion defects, enhancing diagnostic accuracy ²⁴.
3. Treatment Monitoring: Serial FDG-PET scans can be used to assess treatment response and guide therapy ²⁵.

Recent studies have reported sensitivity and specificity of FDG-PET for CS diagnosis ranging from 85-100% and 39-90%, respectively, depending on the specific criteria used ²⁶.

Echocardiography: While less sensitive than CMR or FDG-PET for detecting early or focal CS, echocardiography remains an important tool due to its wide availability and ability to assess cardiac function:

1. Speckle Tracking Echocardiography: This advanced technique can detect subtle myocardial dysfunction, potentially allowing for earlier diagnosis of CS ²⁷.
2. Three-Dimensional Echocardiography: 3D echo provides more accurate assessment of ventricular volumes and function compared to 2D imaging ²⁸.
3. Contrast Echocardiography: The use of contrast agents may enhance the detection of regional wall motion abnormalities in CS ²⁹.

Biomarkers: While no specific biomarker for CS has been identified, several markers have shown promise in diagnosis and monitoring:

1. Angiotensin-converting Enzyme (ACE): Elevated serum ACE levels can be seen in sarcoidosis, but lack specificity for cardiac involvement ³⁰.
2. Soluble Interleukin-2 Receptor (sIL-2R): Elevated sIL-2R levels have been associated with active sarcoidosis and may correlate with disease activity in CS ³⁰.
3. High-sensitivity Troponin: Persistently elevated hs-troponin levels may indicate myocardial involvement in sarcoidosis patients ³⁰.
4. Natriuretic Peptides: B-type natriuretic peptide (BNP) and N-terminal pro-BNP levels may be elevated in CS patients with heart failure ³⁰.
5. Galectin-3: This marker of fibrosis has shown potential in identifying CS patients at higher risk of adverse outcomes ³⁰.

Electrophysiological Studies: Electro-physiological (EP) studies can play a crucial role in the evaluation and management of CS patients with arrhythmias:

1. Programmed Electrical Stimulation: This technique can help assess the risk of ventricular arrhythmias and guide decisions regarding implantable cardioverter-defibrillator (ICD) placement ⁸.
2. Electroanatomic Mapping: Advanced mapping techniques can identify areas of low voltage and abnormal electrograms, potentially guiding targeted biopsies or ablation procedures ⁸.

Endomyocardial Biopsy: While endomyocardial biopsy remains the gold standard for definitive diagnosis of CS, its use is limited by low sensitivity due to the patchy nature of the disease:

1. Image-guided Biopsy: The use of imaging techniques such as CMR or PET to guide biopsy site selection may improve diagnostic yield ¹.
2. Novel Biopsy Techniques: Emerging techniques, such as intramyocardial needle mapping, show promise in improving the sensitivity of endomyocardial biopsy for CS diagnosis ¹.

Management Strategies: The management of CS has evolved significantly in recent years, with a shift towards more personalized and targeted approaches. The primary goals of treatment are to suppress granulomatous inflammation, prevent and manage arrhythmias, and address heart failure when present. The management of cardiac sarcoidosis is illustrated in Fig. 2.

FIG. 2: MANAGEMENT OF CARDIAC SARCOIDOSIS

Immunosuppressive Therapy: Corticosteroids remain the cornerstone of CS treatment, but there is increasing recognition of the role of steroid-sparing agents:

1. Corticosteroids: Prednisone is typically initiated at doses of 30-40 mg daily, with gradual tapering based on clinical and imaging response ¹. Recent studies have suggested that lower initial doses may be effective in some patients, potentially reducing side effects ¹.
2. Methotrexate: This is often used as a steroid-sparing agent, particularly in patients with inadequate response to corticosteroids alone or those experiencing significant steroid-related side effects ¹.
3. Azathioprine: Another commonly used steroid-sparing agent, azathioprine has shown efficacy in maintaining remission in CS patients ¹.
4. Mycophenolate mofetil: Emerging evidence suggests a potential role for mycophenolate in CS management, particularly in patients intolerant to other immunosuppressive agents ¹.
5. Biological agents: TNF-α inhibitors, such as infliximab, have shown promise in refractory cases of CS ¹. However, their use requires careful consideration due to potential cardiovascular side effects.
6. Rituximab: This B-cell depleting agent has been reported to be effective in some cases of refractory CS ¹.

Antiarrhythmic Management: Given the high prevalence of arrhythmias in CS, antiarrhythmic management is a crucial aspect of treatment:

1. Antiarrhythmic Medications: Agents such as amiodarone or sotalol may be used to suppress ventricular arrhythmias, although their use must be balanced against potential side effects [8].
2. Implantable Cardioverter Defibrillators (ICDS): Current guidelines recommend ICD implantation for primary prevention in CS patients with left ventricular ejection fraction ≤35% despite optimal medical therapy, and for secondary prevention in those with sustained ventricular arrhythmias or aborted sudden cardiac death ⁸.
3. Catheter Ablation: This may be considered for recurrent ventricular tachycardia refractory to medical therapy. Recent studies have shown promising results with substrate-based ablation strategies in CS patients ⁸.

Heart Failure Management: Management of heart failure in CS follows general heart failure guidelines, with some specific considerations:

1. Neurohormonal Blockade: Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists form the cornerstone of heart failure management in CS ¹⁴.
2. Device Therapy: Cardiac resynchronization therapy (CRT) may be considered in CS patients with heart failure and conduction system disease ¹⁴.
3. Advanced Heart Failure Therapies: In end-stage cases, left ventricular assist devices or heart transplantation may be necessary ¹⁴.

Novel and Emerging Therapies: Several novel therapeutic approaches are currently under investigation for CS:

1. JAK inhibitors: These agents, which target the JAK-STAT signaling pathway involved in granuloma formation, have shown promise in early studies of sarcoidosis treatment ¹¹.
2. Stem Cell Therapy: Preliminary research suggests potential benefits of mesenchymal stem cell therapy in reducing inflammation and promoting tissue repair in CS ¹¹.
3. Antifibrotic agents: Drugs targeting myocardial fibrosis, such as pirfenidone, are being explored as potential adjunctive therapies in CS ¹¹.

Monitoring and Follow-up: Regular monitoring is essential in CS management to assess treatment response and detect disease progression:

1. Serial Imaging: Repeat CMR or FDG-PET scans are often used to evaluate treatment response and guide therapy duration ¹.
2. Biomarker Monitoring: Serial measurement of inflammatory markers and cardiac biomarkers may provide insights into disease activity ³⁰.
3. Holter Monitoring: Regular ambulatory ECG monitoring is important for detecting asymptomatic arrhythmias ⁸.

CONCLUSION: The field of cardiac sarcoidosis has seen significant advancements in recent years, particularly in the realms of diagnostic techniques and management strategies. The integration of advanced imaging modalities, such as CMR and FDG-PET, has greatly enhanced our ability to detect and characterize cardiac involvement in sarcoidosis. These techniques not only aid in diagnosis but also play a crucial role in monitoring treatment response and guiding therapeutic decisions.

In terms of management, while corticosteroids remain the mainstay of treatment, there is an increasing emphasis on steroid-sparing strategies and targeted therapies. The use of biologic agents, particularly in refractory cases, represents a promising avenue for improving outcomes in CS patients. Additionally, advances in electrophysiological management, including refined ICD implantation criteria and novel ablation techniques, have contributed to better arrhythmia control and prevention of sudden cardiac death.

Despite these advancements, several challenges remain in the field of CS. Early diagnosis remains difficult due to the often subclinical nature of cardiac involvement. There is a need for more sensitive and specific biomarkers to aid in diagnosis and monitoring. Furthermore, while current treatment strategies have improved outcomes, there is still a subset of patients who experience progressive disease despite optimal therapy. Future research directions in CS should focus on developing more targeted therapies based on our evolving understanding of disease pathogenesis. The potential role of precision medicine approaches, tailoring treatment to individual patient characteristics and disease phenotypes, warrants further exploration. Additionally, long-term studies are needed to better define optimal treatment duration and strategies for monitoring disease activity.

In conclusion, the landscape of cardiac sarcoidosis diagnosis and management continues to evolve rapidly. As our understanding of the disease deepens and new technologies emerge, we can anticipate further improvements in patient care and outcomes. Ongoing research and clinical trials will be crucial in addressing the remaining challenges and refining our approach to this complex and potentially devastating condition.

ACKNOWLEDGEMENTS: Nil

CONFLICTS OF INTEREST: Nil

REFERENCES:

1. Birnie DH, Nery PB, Ha AC and Beanlands RS: Cardiac Sarcoidosis. J Am Coll Cardiol 2016; 68(4): 411-21.
2. Kandolin R, Lehtonen J, Airaksinen J, Vihinen T, Miettinen H and Ylitalo K: Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 2015; 131(7): 624-32.
3. Roberts WC, McAllister HA and Ferrans VJ: Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med 1977; 63(1): 86-108.
4. Morimoto T, Azuma A, Abe S, Usuki J, Kudoh S and Sugisaki K: Epidemiology of sarcoidosis in Japan Eur.
5. Okada DR, Bravo PE, Vita T, Agarwal V, Osborne MT and Taqueti VR: Isolated cardiac sarcoidosis: A focused review of an under-recognized entity. J Nucl Cardiol 2018; 25(4): 1136-46.
6. Grunewald J, Grutters JC, Arkema EV, Saketkoo LA, Moller DR and Müller-Quernheim J: Sarcoidosis. Nat Rev Dis Primers 2019; 5(1): 45.
7. Patel AR, Klein MR, Chandra S, Spencer KT, Decara JM and Lang RM: Myocardial damage in patients with sarcoidosis and preserved left ventricular systolic function: an observational study. Eur J Heart Fail 2011; 13(11): 1231-7.
8. Kusano KF and Satomi K: Diagnosis and treatment of cardiac sarcoidosis. Heart 2016; 102(3): 184-90.
9. Yazaki Y, Isobe M, Hiroe M, Morimoto S, Hiramitsu S and Nakano T: Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001; 88(9): 1006-10.
10. Ng KH, Devaraj R, Mittoo S and Scott JA: Pericardial sarcoidosis: A case report and review of the literature. Curr Rheumatol Rev 2016; 12(2): 152-7.
11. Rosenbach M, Murrell DF, Bystryn JC, Dulay S, Dick S and Fakharzadeh S: Reliability and convergent validity of the Cutaneous Sarcoidosis Activity and Morphology Instrument for assessing cutaneous sarcoidosis. JAMA Dermatol 2013; 149(5): 550-6.
12. Kandolin R, Lehtonen J and Kupari M: Cardiac sarcoidosis and giant cell myocarditis as causes of atrioventricular block in young and middle-aged adults. Circ Arrhythm Electrophysiol 2011; 4(3): 303-9.
13. Ekström K, Lehtonen J, Nordenswan HK, Mäyränpää MI and Kupari M: Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries. Eur Heart J 2019; 40(37): 3121-8.
14. Kouranos V, Tzelepis GE, Rapti A, Mavrogeni S, Aggeli K and Douskou M: Complementary Role of CMR to Conventional Screening in the Diagnosis and Prognosis of Cardiac Sarcoidosis. JACC Cardiovasc Imaging 2017; 10(12): 1437-47.
15. Sperry BW, Tamarappoo BK, Oldan JD, Javed O, Culver DA and Brunken R: Prognostic Impact of Extent, Severity, and Heterogeneity of Abnormalities on 18F-FDG PET Scans for Suspected Cardiac Sarcoidosis. JACC Cardiovasc Imaging 2018; 11(2-2): 336-45.
16. Nordenswan HK, Lehtonen J, Ekström K, Kandolin R, Simonen P and Mäyränpää M: Outcome of cardiac sarcoidosis presenting with high-grade atrioventricular block. Circ Arrhythm Electrophysiol 2018; 11(8): 006145.
17. Greulich S, Deluigi CC, Gloekler S, Wahl A, Zürn C and Kramer U: CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imaging 2013; 6(4): 501-11.
18. Puntmann VO, Isted A, Hinojar R, Foote L, Carr-White G and Nagel E: T1 and T2 mapping in recognition of early cardiac involvement in systemic sarcoidosis. Radiology 2017; 285(1): 63-72.
19. Hulten E, Agarwal V, Cahill M, Cole G, Vita T and Parrish S: 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. Circ Cardiovasc Imaging 2016; 9(9): 005001.
20. Crouser ED, Ono C, Tran T, He X and Raman SV: Improved detection of cardiac sarcoidosis using magnetic resonance with myocardial T2 mapping. Am J Respir Crit Care Med 2014; 189(1): 109-12.
21. Smedema JP, Snoep G, van Kroonenburgh MP, van Geuns RJ, Dassen WR and Gorgels AP: Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis. J Am Coll Cardiol 2005; 45(10): 1683-90.
22. Blankstein R, Osborne M, Naya M, Waller A, Kim CK and Murthy VL: Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63(4): 329-36.
23. Ohira H, Tsujino I, Ishimaru S, Oyama N, Takei T and Tsukamoto E: Myocardial imaging with 18F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging 2008; 35(5): 933-41.
24. Chareonthaitawee P, Beanlands RS, Chen W, Dorbala S, Miller EJ and Murthy VL: Joint SNMMI-ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. J Nucl Cardiol 2017; 24(5): 1741-58.
25. Osborne MT, Hulten EA, Singh A, Waller AH, Bittencourt MS and Stewart GC: Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014; 21(1): 166-74.
26. Youssef G, Leung E, Mylonas I, Nery P, Williams K and Wisenberg G: The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012; 53(2): 241-8.
27. Joyce E, Ninaber MK, Katsanos S, Debonnaire P, Kamperidis V and Bax JJ: Subclinical left ventricular dysfunction by echocardiographic speckle-tracking strain analysis relates to outcome in sarcoidosis. Eur J Heart Fail 2015; 17(1): 51-62.
28. Schouver ED, Moceri P, Doyen D, Tieulie N, Queyrel V and Baudouy D: Early detection of cardiac involvement in sarcoidosis with 2-dimensional speckle-tracking echocardiography. Int J Cardiol 2017; 227: 711-6.
29. Kouranos V, Sharma R, Khattar R, Stanbridge R, Wells AU and Underwood SR: Cardiac sarcoidosis: a review of the current literature. Clin Med (Lond) 2015; 15: 58-63.
30. Bargagli E, Mazzi A and Rottoli P: Markers of inflammation in sarcoidosis: blood, urine, BAL, sputum, and exhaled gas. Clin Chest Med 2008; 29(3): 445-58.
    

    ---

    How to cite this article:

    Harini VS, Sushmitha A, Sendilkumar B, Parkash J, Leela K and Gowtham D: Cardiac sarcoidosis: advancements in diagnostic techniques and management. Int J Pharm Sci & Res 2025; 16(7): 1822-28. doi: 10.13040/IJPSR.0975-8232.16(7).1822-28.

    ---

    All © 2025 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.