Abstract
Introduction
Cardiac sarcoidosis (CS) is a rare condition with an annual detection rate of 0,31 per 100.000 adults. 1 It is diagnosed in approximately 2%–5% of patients with sarcoidosis with variable presentation according to the geographic region, with prevalences of 10–40 persons per 100,000, in the United States and Europe, respectively. 2 It affects young and middle-aged patients with no sexual predilection, being more frequent in African-Americans. 3 Prevalence in autopsy and imaging studies varies from 20% in the United States to 58% in Japan, where a mortality rate of 88% has been described. Cardiac involvement is usually to the basal septum, atrioventricular (AV) node, bundle of His and focal areas in the ventricular free wall and papillary muscles. 4
Its clinical presentation varies from asymptomatic patients to the presence of cardiac arrhythmias, heart failure, pericardial effusion, pulmonary arterial hypertension and ventricular aneurysms. 4 Sudden death and refractory heart failure are the most feared complications. 5 Its diagnosis can be made definitively by the identification of non-necrotising granulomas in myocardial tissue without alternative cause. Whereas, a probable diagnosis can be made by histological identification of extracardiac sarcoidosis and the support of noninvasive cardiological tests. 6 In diagnostic imaging it is possible to integrate multimodality with echocardiography, cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET-scan) with fluorine-18 fluorodeoxyglucose (18FDS).3,4,7 Imaging findings include one or more of the following: reduced left ventricular ejection fraction (<40%), patchy uptake on dedicated cardiac 18-F fluorodeoxyglucose PET-scan, late gadolinium enhancement on CMR, positive gallium uptake. 6 Early diagnosis allows immunosuppressive and antiarrhythmic treatment, which can halt the progression of the disease. 7
We present a case with chest pain and nonspecific symptoms in which the clinical and multimodal imaging integration in conjunction with findings of extracardiac sarcoidosis were able to diagnose sarcoidosis and its associated cardiac involvement, its diagnostic and therapeutic management is a clinical challenge, which makes it necessary to discuss clinical, diagnostic and therapeutic aspects.
Case Description
A 38-year-old male patient who during the last two months had been presenting with episodes of atypical chest pain and mild deterioration of his functional class, dyspnoea with mild to moderate exertion. An electrocardiogram was performed, with findings of sinus rhythm, altered anterolateral repolarisation and left posterior-inferior hemiblock (Figure 1). Transthoracic echocardiogram and conventional stress test were performed. The stress test was normal, the echocardiogram showed the presence of an image compatible with a thrombus at the apical septal level. Therefore, anticoagulant treatment was decided. At the same time, an evaluation by haematology and rheumatology was requested due to incidental findings of mediastinal lymphadenopathies in images of chest X-ray with CT of the thorax.
Electrocardiogram: Sinus Rhythm with Altered Anterolateral Repolarisation, Left Posterior-inferior Hemiblock.
CMR confirmed apical thrombus with discrete adjacent transmural enhancement, without areas of fibrosis (Figure 2), in addition to multiple mediastinal adenopathies. Due to persistent chest pain, myocardial perfusion was performed under pharmacological stress, with mild-moderate perfusion defect, being taken to coronary arteriography ruling out significant epicardial coronary lesion.
Cardiac Magnetic Resonance Imaging: Mural Thrombus (Blue Arrow), Without Late Gadolinium Enhancement (LGE).
Paraclinical tests showed adequate renal and hepatic function, electrolytes in normal ranges, negative viral and HIV profile, negative antiphospholipid syndrome tests, autoimmune profile with ANA, non-reactive ANCA, negative rheumatoid factor and elevated angiotensin-converting enzyme (109.6 U/L; normal range: 8-52 IU/L). Also, it was evaluated Quantiferon-TB and was negative (Table 1).
Paraclinical Studies Performed.
With suspicion of lymphoproliferative disease, a PET-scan study was performed with findings (Figure 3) of hypermetabolism at the lymph node level suggestive of a granulomatous process. Considering the above findings, it was performed lymph node and lung wedge biopsies with pathological reports of chronic non-necrotising granulomatous inflammation suggestive of sarcoidosis (Figure 4). These biopsies were negative for microorganisms such as fungi and tuberculosis in special stains, which included polymerase chain reaction for Mycobacterium tuberculosis and culture for fungi. Also, brady or tachyarrhythmia was ruled out with a 24-hour Holter ECG and normal BNP (<100 pg/mL). Cardiac biopsy was not considered since the diagnosis of exclusion was made.
PET-scan: Hypermetabolism of Ganglia at Pulmonary Level and Mild Uptake in Heart.
HE Staining of Lung and Lymph Node Tissues. (A) Pattern of multinodular involvement by granulomatous process with multinucleated giant cells and scarce inflammatory infiltrate. (B) Granulomas with abundant epithelioid histiocytes and multinucleated giant cells with crowns of mature lymphocytes that do not penetrate the granulomas. (C) Langhans’ and Touton-type multinucleated giant cells, an asteroid body (red arrow) and collagenous bands. (D) lymph node with granulomatous multinodular involvement pattern with scant residual lymphoid tissue and anthracotic pigment, without extranodal involvement. (E) Thick fibrotic bands accompanying granulomas with few lymphocytes. (F) Epithelioid granulomas with lymphocyte crowns.
Considering the above, anticoagulation, corticosteroids at 1 mg/kg/d, and immunomodulation with methotrexate 20 mg every week were started. After two months, progressive tapering of the steroid was terminated and methotrexate was continued. Also, anticoagulation was continued until resolution of the thrombus was demonstrated by means of follow-up imaging with CMR at eight months. Currently, he has completed one year of follow-up, has negative CRP and the dose of methotrexate is being reduced.
Discussion
CS is difficult to diagnose due to the technical limitation of obtaining tissue samples for histopathological confirmation. However, it usually presents with extracardiac manifestations with frequent pulmonary and lymph node involvement. So histological evaluation of lymph nodes and lungs, as well as, morphological and immunological studies in bronchoalveolar lavage, have been considered appropriate diagnostic strategies.4,7 The presence of histological findings in lymph node and lung in conjunction with one or more of the following is indicative of a probable diagnosis of CS: cardiomyopathy or atrioventricular block responsive to immunosuppression, unexplained reduced left ventricular ejection fraction (<40%), unexplained sustained ventricular tachycardia (spontaneous or induced), 2nd degree (Mobitz type II) or 3rd-degree heart block, patchy uptake on dedicated cardiac 18-F fluorodeoxyglucose PET-scan, late gadolinium, enhancement on CMR, and positive gallium uptake.6,8-10 In the present case, a lymph node biopsy was performed with pathologic report of chronic non-necrotising granulomatous inflammation suggestive of sarcoidosis. A cardiac biopsy was not considered since a diagnosis of CS was made with PET-scan and exclusion of other causes.
Cardiac involvement in sarcoidosis may be asymptomatic or overt. Cardiac manifestations include palpitations, syncope, dyspnoea, heart failure and sudden death. These manifestations depend on the granuloma-infiltrated sites, present in 5% of sarcoidosis patients. 5 After pulmonary sarcoidosis, CS is the second leading cause of death among affected patients.7,11,12 Although screening for CS has not been standardised,4,12 the initial approach to CS includes medical history, physical examination and 12-lead electrocardiogram,4,7 Holter or echocardiogram. These diagnostic tests have demonstrated high sensitivity for detecting CS in patients with a previous diagnosis of pulmonary sarcoidosis.3,4 However, both echocardiogram and 12-lead ECG may be normal in CS. 13 The diagnosis of CS is challenging given the variability of nonspecific clinical symptoms as well as paraclinical findings. 11 Also, the differential diagnostic alternatives are broad, including lymphocytic, eosinophilic, and giant cell myocarditis with acquired and genetic cardiomyopathies, granulomatous infections, and atherosclerotic disease. 14 Diagnostic collaboration across specialities is indispensable regardless of whether cardiologists or a multidisciplinary team are responsible for the diagnosis of CS, and its role is decisive.4,8 Clinically overt cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. In addition, many patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement. This finding is known from autopsy studies, which estimated the prevalence of cardiac involvement in at least 25% of sarcoidosis patients.4,15 Although the clinical features depend on the location, extent and activity of the disease. The main cardiac complications are conduction abnormalities, ventricular arrhythmias, sudden death and heart failure.4,5 Regarding diagnostic methods, it is important to keep in mind that the ECG, although it is part of the study of patients with CS, is a study of low sensitivity and may show nonspecific findings.3,4,11,16 Echocardiography, on the other hand, allows finding heart disease, but does not suggest the aetiology. 11 Among them, the most frequent is idiopathic dilated cardiomyopathy, with global hypokinesia, arrhythmogenic right ventricular cardiomyopathy or idiopathic ventricular aneurysm that could correspond to CS.3,4
Gadolinium contrast-enhanced CMR and PET-Scan are of great diagnostic utility and prognostic evaluation. 16 CMR may show a pattern suggestive of disease, with patchy lateral and basal wall enhancement. CMR is most useful for detecting fibrotic lesions,4,11,16 which generally respects the endocardium and without the distribution of a previous infarct. However, typical patterns of acute myocardial infarction can be found. And it has a high negative predictive value.4,7,11
In several case series of patients with extracardiac sarcoidosis, asymptomatic cardiac involvement has been found in images. Especially in CMR with late enhancement protocol, with a frequency varying between 3.7% and 54.9%.17,18 PET-Scan better detects active CS lesions and their response to treatment. The images are sufficient to establish a diagnosis of CS in most cases, avoiding the need for myocardial biopsy. In the case described in extension imaging, mediastinal lymph nodes were evidenced and the first diagnostic probability was lymphoproliferative disease. So, a PET-scan study was performed with evidence of hypermetabolism at lymph node level suggestive of a granulomatous process.
The histopathologic study in sarcoidosis has a major role in the diagnosis. Although the morphologic findings are nonspecific, the pattern usually described is non-necrotising granulomatous inflammation with perigranulomatous mature lymphocyte crowns and few intragranulomatous lymphocytes. Multinucleated giant cells (Foreign-body, Langhans and Touton types) with asteroid bodies have been described. The lung is one of the most commonly evaluated sites, and involvement may take various morphologies including bronchial involvement to large nodular lesions with characteristic perivascular involvement with associated fibrosis.4,11,15,18
As for treatment, several considerations should be kept in mind. Corticosteroids are currently considered the first-line treatment for CS. 19 Also, there is a high risk of relapsing when corticosteroids are tapered. 20 So the addition of an immunomodulator allows the lower effective dose of corticosteroids to be reduced. 20 These agents include methotrexate, mycophenolate, azathioprine, infliximab, adalimumab and rituximab. 21 Also, interest is emerging in the routine initial use of corticosteroids in combination with steroid-sparing agents. However, there is a lack of data and no consensus at present. 19 Our patient evolved satisfactorily after initiation of combination therapy, with no relapse of the disease or adverse drug-related events, so the present case supports the routine use of combination therapy in CS.
Conclusions
Early detection of cardiac involvement and timely initiation of treatment are the main objectives of CS. Its symptoms are nonspecific and the clinical presentation is not always the most frequent. There is no diagnostic gold standard for CS. CMR and PET-scan are useful tools in the diagnosis and follow-up of these patients. There is still no agreement on the best therapy. In the present case, the combined therapy of corticosteroid and immunomodulator was associated with safe remission.
Abbreviation
ANA: antinuclear antibodies
ANCA: anti-neutrophil cytoplasm antibodies
AV: atrioventricular
BNP: B natriuretic peptide
CMR: cardiac magnetic resonance imaging
CRP: C-reactive protein
CS: cardiac sarcoidosis
ECG: electrocardiogram
HIV: human immunodeficiency virus
PET-scan: positron emission tomography
TBC: tuberculosis
Footnotes
Authors’ Contributions
All authors analyzed and interpreted the patient data, wrote the manuscript, analyzed and interpreted the images, and contributed to the preparation of the manuscript. All authors read and approved the final manuscript.
Availability of Data and Materials
Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.
Consent for Publication
Written informed consent was taken from the patient for publication of this case report and accompanying images.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Ethical Approval
Ethical approval was obtained for the research work by the research ethics committee of the rheumatology clinic of Dr Viviana Parra Izquierdo, being approved in June 2023 with approval number 072/23.
Ethical Considerations
For this case report, it was clearly and thoroughly explained to the patient that his clinical history, laboratory results, diagnostic images and pathology reports could be used for scientific dissemination purposes. The patient was asked to sign the informed consent form, being given to participate in an informed way in the research projects with the aim of strengthening knowledge about his pathology and positively impact future patients with the same condition. The anonymity of the patient’s data was guaranteed. The data and material available for publication are in the manuscript and no information is omitted.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
Patient Consent
The patient provided all the images included in the present study and approved their publication by informed consent.