Genetic Cardiomyopathy Mimicking Isolated Cardiac Sarcoidosis: Diagnostic Challenges with Positron Emission Tomography

Sarcoidosis is a systemic infiltrative disease characterized by non-caseating granuloma formation, and its cardiac phenotype is an important prognostic factor.1 Sarcoidosis affecting the heart without extracardiac involvement is termed isolated cardiac sarcoidosis (CS). Isolated CS was once thought to be a rare manifestation of sarcoidosis because of the diagnostic challenge arising from the low sensitivity of endomyocardial biopsy (EMB).2 Considering that the importance of early diagnosis and treatment are critical in managing CS,3 the Japanese Circulation Society (JCS) updated its guidelines to allow a clinical diagnosis of CS using multimodal imaging techniques, such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), even in the absence of histological evidence of non-caseating granulomas.4 Under the situation in which isolated CS can be clinically diagnosed without histological findings, we should pay more attention to differentiating isolated CS from other cardiomyopathies. Here, we describe a 50-year-old male who was clinically diagnosed with isolated CS and prescribed with prednisolone without much effect, and subsequent genetic analysis revealed pathogenic variants in LMNA and TNNT2, representative genes for cardiomyopathy. A 48-year-old man with hypertension and dyslipidaemia presented to a hospital with advanced atrioventricular block (AVB) pointed out during his annual health check-up. He had no family history of heart disease or sudden death, and his electrocardiogram (ECG) 2 years earlier showed a first-degree AVB and left axis deviation (Figure 1A). ECG in the first hospital presentation shows high-degree AVB and multiple morphologically distinct premature ventricular contractions (Figure 1B), and ambulatory ECG monitoring revealed advanced AVB with the longest pause being 1.57 seconds accompanied by escape rhythms. Transthoracic echocardiography (TTE) demonstrated normal cardiac chamber size and function without any regional wall motion abnormalities. He remained asymptomatic and declined further investigation or regular outpatient follow-up. At the age of 50, he complained of mild dyspnoea on exertion, categorized as New York Heart Association Class II, and was diagnosed with atrial fibrillation and complete AVB and referred to our hospital (Figure 1C). He started receiving edoxaban 60 mg/day. Blood test revealed elevated levels of B-type natriuretic peptide at 290.5 pg/mL and high-sensitivity cardiac troponin I at 30.9 pg/mL. Soluble interleukin-2 receptor and angiotensin-converting enzyme levels were within normal ranges. His chest X-ray indicated cardiomegaly. TTE showed a reduced left ventricular ejection fraction of 38% and hypokinesis of the septal and posterior walls of the left ventricle, without regional wall thinning or ventricular aneurysms (Figure 2A and Video S1). Non-contrast computed tomography did not depict any enlarged lymph nodes, pulmonary nodules or other organ abnormalities, and ophthalmologic and dermatologic examinations were unremarkable. Ambulatory ECG detected non-sustained ventricular tachycardia (NSVT). Coronary computed tomographic angiography showed intact coronary arteries. Cardiac magnetic resonance imaging demonstrated a linear pattern of late gadolinium enhancement (LGE) in the mid-wall of the septum, with a reduced ejection fraction and a dilated left ventricle (Figure 2B and Videos S2 and S3). T2-weighted imaging revealed a high signal in the mid-wall of the septum, corresponding to the region of LGE, indicative of myocardial inflammation (Figure S1). Subsequently, a whole-body FDG-PET scan after 18 h of fasting showed a focal FDG uptake in the ventricular septum, typical pattern for CS, but no uptake in other organs (Figure 2C). The multimodal imaging findings and the presence of arrhythmia such as AVB and NSVT were typical for CS, and we clinically diagnosed the patient with isolated CS without performing EMB, as the patient met criteria (a), (c), (d) and (e) in the JCS guideline4 (Table 1). Following his admission, we initiated prednisolone 30 mg (0.5 mg/kg)/day, but continuous ECG monitoring showed frequent NSVTs with multiple morphologies (Figure 2D). The heart team concluded that semi-urgent defibrillator implantation was necessary, and he received a cardiac resynchronization therapy device with defibrillator (CRT-D) while taking prednisolone 25 mg daily and was discharged 7 days after the implantation. However, 10 days after discharge, the wound was partly detached and bleeding, forcing the patient to be readmitted to the hospital. He was treated with prophylactic antibiotics and surgical site compression for 7 days and was discharged with prednisolone 15 mg/day. Despite the initiation of prednisolone therapy, his symptoms and cardiac dysfunction did not improve much, and NSVTs continued to occur. We performed whole-exome sequencing analysis to evaluate the risk of inherited cardiomyopathies and identified two missense variants in TNNT2 (chr1:201364335(hg38), NM_001001430.3, c.422G>A, p.Arg141Gln) and LMNA (chr1:156136096(hg38), NM_170707.4, c.1132A>C, p.Lys378Gln) (Figure 3). The TNNT2 variant has been previously reported as pathogenic in multiple patients with idiopathic cardiomyopathies (ClinVar accession number: VCV000043637.14). In contrast, the LMNA variant is novel and located in exon 6, a known hot-spot region. This region corresponds to part of the coil 2 domain within the central rod domain of lamin A/C and is related to multiple pathogenic missense variants.5 This variant has not been identified in the general population according to the gnomAD and Tohoku Medical Megabank databases and was predicted to be pathogenic by multiple in silico analyses with a Combined Annotation Dependent Depletion score of 26.6 and a Polymorphism Phenotyping v2 score of 0.999. According to the American College of Medical Genetics and Genomics guidelines,6 LMNA p.Lys378Gln was classified as likely pathogenic (PM1, PM2, PP2 and PP3). Therefore, we hypothesized that these variants were involved in the progressive conduction defects and worsened cardiac function. We describe a patient initially diagnosed with isolated CS using a multimodality imaging approach and treated with prednisolone. He had not improved with steroid therapy and was later found to have two likely pathogenic variants in cardiomyopathy-causing LMNA and TNNT2 genes. Although the possibility of an overlap of CS and genetic cardiomyopathy cannot be excluded, this case underscores the importance of early genetic analysis to reconsider an optimal therapeutic strategy for treatment-resistant patients. As patients with CS are at high risk of malignant arrhythmias,7 delays in diagnosis and intervention might worsen the patient's prognosis.3 Despite this, the diagnosis of isolated CS, characterized by the absence of extracardiac involvement,8 is basically challenging due to the low sensitivity of EMB, which is only up to 20%.2 This difficulty had been hindering early and appropriate management of isolated CS. To address this issue, the JCS guidelines proposed clinical diagnostic criteria for isolated CS without histological evidence,4 which enables timely diagnosis and treatment. Since then, clinical data based on the guideline-recommended diagnostic criteria have been accumulated.9 However, like the present case, there are patients fulfilling the clinical criteria for isolated CS, but the presence of pathogenic variants in cardiomyopathy-related genes might actually cause cardiac dysfunction or be a risk factor for exacerbation of the clinical condition. We clinically diagnosed this case as isolated CS without performing EMB because of concerns about possible procedural complications and the fact that a negative biopsy result would not change the management strategy. His clinical course and multimodal imaging findings, including FDG-PET, were strongly suggestive of isolated CS. However, previous studies have shown that cardiomyopathies, such as arrhythmogenic cardiomyopathy, can exhibit FDG uptake in the heart.10 Lal et al. reported that cardiomyopathy-related genetic variants can be identified in patients previously diagnosed with CS.11 Considering the steroid-unresponsiveness and the fact that cardiomyopathy caused by pathogenic LMNA variant can also produce a variety of abnormalities,12 the appropriate diagnosis for this case was dilated cardiomyopathy rather than CS. The CS diagnostic criteria in JCS guidelines4 contribute to improved sensitivity in the diagnosis; however, recent reports, including this case, have highlighted that the criteria might sacrifice diagnostic specificity. To prevent overdiagnosis of CS with improved diagnostic accuracy, genetic analysis could bridge the gap. In this case, high disease activity estimated from high FDG uptake and frequent NSVTs led to early implantation of CRT-D while taking high-dose prednisolone. Unfortunately, this patient suffered from the surgical site complication. He was at high risk of postoperative pocket haematoma due to the need for both CRT-D implantation and anticoagulant.13 Additionally, haematoma and steroid administration are significant risk factors for device infection, which could lead to serious adverse events.14 Although he recovered with conservative management, he remained exposed to a high risk of device infection. Early genetic assessment prior to the strategic decision-making might have provided a rationale for precision medicine, potentially preventing surgical complications. Furthermore, as laminopathy caused by pathogenic LMNA variants has high penetrance, genetic cascade screening can profoundly contribute to high-quality management of family members. TNNT2 encodes the cardiac isoform of troponin T, and LMNA encodes lamin A/C, which provides structural support with the nucleus. Both genes are strongly associated with genetic cardiomyopathy. Because his cardiac phenotypes such as progressive conduction disturbance and atrial fibrillation are often observed in laminopathy,12 his cardiac abnormalities might be caused by the LMNA variant. FDG uptake has also been reported in some cases of LMNA-related cardiomyopathy,11, 15 but not in those with TNNT2 variants. The mechanism of FDG uptake in laminopathy still remains elusive but is possibly explained by (1) myocardial inflammation and associated apoptosis reflecting rapid disease progression and/or (2) activated glucose metabolism in failing myocardium, which warrants further clarification. In conclusion, caution should be exercised when diagnosing isolated CS clinically without a myocardial biopsy, and genetic analysis might be useful for achieving an accurate diagnosis. We thank R. Nakanishi, I. Sakamoto, N. Matsuzaki, T. Miyoshi, Y. Kaneko, Y. Yokota, Y. Chiba, K. Akiba, A. Okamoto and M. Yoshitake for providing support with analysis. None declared. This work was supported by grants from the SENSHIN Medical Research Foundation (to S.N.), the Japan Foundation for Applied Enzymology (to S.N. and Z.D.), the Kanae Foundation for the Promotion of Medical Science (to S.N.), the MSD Life Science Foundation, Public Interest Incorporated Foundation (to S.N.), the Tokyo Biomedical Research Foundation (to S.N.), the Astellas Foundation for Research on Metabolic Disorders (to S.N.), the NOVARTIS Foundation (Japan) for the Promotion of Science (to S.N.), the Japanese Circulation Society (to S.N.), the Takeda Science Foundation (to S.N.), the Cell Science Research Foundation (to S.N.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to S.N.) and the Daiichi Sankyo Foundation of Life Science (to S.N.); a Grant-in-Aid for Scientific Research (A) (to S.N.); a Grant-in-Aid for Scientific Research (S) (to I.K.); the UTEC-UTokyo FSI Research Grant Program (to S.N.); the JST FOREST Program (Grant JPMJFR210U) (to S.N.); a Japan Society for the Promotion of Science Grant-in-Aid for Japan Society for the Promotion of Science fellow (23KJ0434) (to Z.D.); and the Japan Agency for Medical Research and Development (AMED) (JP20ek0109487, JP18km0405209, JP19ek0109406, JP21ek0109543, JP21ek0109569, JP21tm0724601, JP22ama121016, JP22ek0210172, JP22ek0210167, JP22bm1123011, JP23tm0724607, JP23gm4010020, JP23tm0524004, JP23tm0524009, JP23jf0126003, JP24ek0109755 and JP24ek0210205) (to S.N. and I.K.). Figure S1. T2-weighted imaging of cardiac magnetic resonance imaging. The mid-wall of the septum shows high signal intensity, corresponding to the region of late gadolinium enhancement (red arrows). Video S1. Transthoracic echocardiogram. Video S2. Cardiac magnetic resonance imaging. Video S3. Late gadolinium enhancement in short-axis and long-axis four-chamber views. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.