Abstract
Background
Cardiac sarcoidosis (CS) is a rare but clinically significant condition in heart transplant recipients.
Case Summary
A 64-year-old woman with nonischemic cardiomyopathy and heart transplant presented with exertional dyspnea and new reduction in left ventricular ejection fraction. Endomyocardial biopsy, donor-specific antibodies, and imaging were concerning for antibody-mediated rejection versus CS. Empiric treatment for antibody-mediated rejection was initiated, but her left ventricular ejection fraction remained unchanged. Native heart explant was reviewed and was consistent with CS. Methotrexate was started, with clinical and radiographic improvement.
Discussion
Owing to its patchy nature, CS can be difficult to diagnose on biopsy, but cardiac imaging can assist. Heart transplant recipients with known CS have similar outcomes to transplant recipients without CS if they take low-dose steroids indefinitely.
Take-Home Message
The explanted heart should be extensively examined for CS in transplant recipients; if found, clinicians should prescribe CS-effective therapy indefinitely to prevent recurrence.
Key words: cardiac transplant, positron emission tomography, systolic heart failure
Visual Summary
History of Presentation
A 64-year-old woman with prior orthotopic heart transplantation presented with 2 months of exertional dyspnea and orthopnea. Her heart rate was 85 beats/min, blood pressure was 119/82 mm Hg, and oxygen saturation was 94% on ambient air. Physical examination was notable for jugular venous distention to the midneck when lying at 30° as well as trace lower extremity edema up to the calves.
Take-Home Messages
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The explanted heart should be thoroughly examined for sarcoidosis in transplant recipients; if identified, patients should be placed on lifelong steroids to prevent recurrence.
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High-dose steroids with addition of steroid-sparing agents are the mainstay of initial treatment for cardiac sarcoidosis involving the cardiac allograft.
Past Medical History
The patient previously had dilated cardiomyopathy (left ventricular ejection fraction [LVEF]: 22%) of unclear etiology, pulmonary nodules that resolved, and ventricular tachycardia for which she had undergone orthotopic heart transplantation 6 years ago. Her post-transplant course was complicated by acute cellular rejection soon after transplantation as well as leukopenia, which prompted discontinuation of mycophenolate mofetil. Immunosuppressive medications included sirolimus and tacrolimus.
Differential Diagnosis
The initial differential diagnosis for allograft dysfunction included acute cellular rejection, antibody-mediated rejection (AMR), cardiac allograft vasculopathy (CAV), cardiac sarcoidosis (CS), and giant cell myocarditis.
Investigations
Initial laboratory work-up was notable for elevated B-type natriuretic peptide of 423 pg/mL. Electrocardiography showed normal sinus rhythm and right bundle branch block. Transthoracic echocardiography (TTE) demonstrated significant reduction in LVEF from 55% to 29%, with new wall motion abnormalities in the inferior and anteroseptal walls (Video 1, Video 2, Video 3). Coronary angiography subsequently revealed no obstructive disease or CAV, and right heart catheterization showed mildly elevated filling pressures, with a cardiac index of 2.0 L/min/m2 (cardiac output: 3.37 L/min) by thermodilution. Endomyocardial biopsy was not consistent with acute rejection, with negative histochemical staining for complement proteins C3d, C4d, and CD68; however, it showed several granulomas, raising concern for CS (Figure 1).
Figure 1.
Explanted (Native Heart) and Transplanted Endomyocardial Biopsies
(A to C) Histopathologic specimens of explanted (native) heart biopsy performed 6 years prior (hematoxylin and eosin staining): (A) low-power image showing some residual myocytes, large areas of collagenous fibrosis, and lymphocytes (blue cells), overall consistent with lymphocytic infiltrate, and high-power images showing (B) giant cells and (C) non-necrotizing granulomas. (D to F) Histopathologic specimens of transplanted heart biopsy (hematoxylin and eosin staining): (D) low-power image showing inflammatory infiltrate in the myocardium, and (E and F) high-power images showing giant cells and non-necrotizing granulomas.
Histochemical staining was negative for acid-fast bacilli and fungal elements. Further laboratory assessment revealed new high-level de novo donor-specific antibodies (DSAs), including Cw1 (7,045 MFI [mean fluorescence intensity]) and DQ5 (52,453 MFI) antibodies, which, in the setting of allograft dysfunction, was preliminarily consistent with AMR. Notably, the patient's serum angiotensin-converting enzyme level was slightly elevated (87 units/L), but 1,25-dihydroxyvitamin D and calcium levels were normal. Outpatient chest computed tomography (CT) prior to admission showed new right-sided pulmonary nodules, though repeat imaging after admission only showed nonspecific changes. Bronchoscopy was deferred.
Management
The patient was treated with pulse dose intravenous steroids, plasmapheresis, and bortezomib, followed by intravenous immunoglobulin for empiric treatment of AMR. Unfortunately, repeat TTE showed no improvement. The biopsy findings of her transplanted heart prompted re-examination of the initial native heart explant, which had been performed at the time of transplant 6 years prior. The histology of the explant revealed stigmata of CS, though this had not been reported previously (Figure 1). Cardiac magnetic resonance imaging (MRI) and FDG-PET (fluorine-18 fluorodeoxyglucose positron emission tomography) were obtained soon after to further explore the possibility of CS. Cardiac MRI showed patchy late gadolinium enhancement, and FDG PET revealed intense uptake within the left ventricle myocardium that was relatively diffuse though somewhat patchy, as well as moderate uptake in the right ventricle, further raising concern for CS (Figure 2).
Figure 2.
Cardiac MRI Concerning for Cardiac Sarcoidosis
(A) Subendocardial delayed gadolinium enhancement in a nonischemic pattern involving the inferior mid septum of the left ventricle (arrow), (B) subepicardial enhancement in a nonischemic pattern involving the anterior/inferior septum of the left ventricle and the right ventricle (arrows), and (C) transmural late gadolinium enhancement of the entire apex of the left ventricle (arrowheads). MRI = magnetic resonance imaging.
The rheumatology team was consulted, and she was discharged on high-dose steroids and transitioned from sirolimus to mycophenolate mofetil in anticipation of treatment for possible CS and continuation of empiric rejection treatment. Repeat DSAs decreased from prior with this regimen but remained elevated, and both TTE and FDG-PET 6 weeks later remained unchanged. Given the lack of improvement, the patient was ultimately transitioned to methotrexate therapy and high-dose steroids for treatment of recurrent CS in the cardiac allograft.
Outcome and Follow-Up
The patient improved symptomatically while on methotrexate, and FDG-PET/CT demonstrated significant improvement over time (Figure 3). Her LVEF improved to 40%, and repeat DSA levels continued to decline (Cw1: 2,385 MFI; DQ5: 18,412 MFI). Overall, her case is consistent with recurrent CS in the cardiac allograft. She continues intensive CS therapy with methotrexate and steroids as tolerated and ongoing monitoring with FDG-PET and MRI.
Figure 3.
FDG-PET Imaging, Performed Before and During Cardiac Sarcoidosis Treatment With Methotrexate and Steroids, Clearly Illustrates Treatment Response
(A) Before treatment, fused FDG PET/CT transverse, coronal, and sagittal views (top to bottom) and (B) whole-body maximum-intensity projection views revealed intense FDG-uptake in the left ventricle and moderate uptake in the right ventricle. Images after 2 months of treatment showed significant improvement in biventricular uptake, though moderate to intense patchy multifocal uptake persisted, and images at 6 months of treatment showed almost complete resolution of uptake. CT = computed tomography; FDG-PET = fluorine-18 fluorodeoxyglucose positron emission tomography; MTX = methotrexate.
Discussion
It can be challenging to diagnose CS using histopathology owing to the patchy nature of the disease.1 The prevalence of CS is estimated to be 0.1% to 0.5% in patients undergoing heart transplantation, though this rate is increasing, and it is more common in women.2 Patients with CS have elevated levels of circulating biomarkers, including angiotensin-converting enzyme, though levels are not always elevated in patients with active CS.3,4 Recurrence of sarcoidosis in a transplanted heart is rare but has been documented.2 For heart transplant recipients with prior unknown cause of cardiomyopathy, recurrent CS should therefore be considered in the setting of allograft dysfunction in the absence of acute cellular rejection, AMR, or CAV.
Clinicians must have a high index of suspicion for CS clinically and pathologically. Certain infections in immunosuppressed hosts can present microscopically as non-necrotizing perivascular granulomas and should be ruled out using special stains, polymerase chain reaction, and culture, as necessary.5 FDG-PET and cardiac MRI can assist with diagnosis when there is conflicting or limited pathologic evidence of sarcoidosis.1,6 Even then however, these modalities, as with endomyocardial biopsy, have challenges if inflammation from CS has been ongoing for long.7 If there is extensive inflammation, such as seen in this patient, involvement may be transmural on cardiac MRI rather than the typical patchy subepicardial pattern and can mimic ischemic cardiomyopathy.8 Interestingly, after transitioning to treatment with methotrexate, serial FDG PET/CT scans showed a significant decrease in myocardial inflammation. The initial diffuse, intense FDG uptake across the left ventricle transformed into a localized, patchy pattern after 2 months of treatment (Figure 3). This demonstrates the utility of FDG PET/CT in monitoring treatment response and identifying active CS involvement.
Regarding management, this patient was started on steroids and a steroid-sparing agent, in accordance with updated guidance for CS management.6 Though she did not improve on mycophenolate and high-dose steroids initially, she had a significant response to methotrexate. In alignment with this patient's response to methotrexate, there is limited evidence that methotrexate-treated patients may have higher rates of complete resolution of FDG uptake on PET than those taking mycophenolate, though no significant difference between the groups was found when controlling for prednisone dose.9
CS may recur in transplant recipients, especially those with lung and cardiac transplants. It is therefore important to diagnose CS before transplantation, and patients with known CS before transplant should be placed on long-term steroids at transplant to prevent recurrence.2,5,7 Clinicians should have a low threshold to suspect and test for CS in middle-aged women with unexplained nonischemic cardiomyopathy, and if biopsy shows granulomatous inflammation but diagnosis is still unclear, multidisciplinary discussion involving pathology, cardiology, and radiology may be warranted. This patient was not diagnosed with CS before transplant despite histopathologic findings that were recognized years later to have stigmata of CS, and therefore she was placed on a steroid-sparing regimen after the first year without surveillance imaging. She was at higher risk of CS recurrence because of this.
Conclusions
This case outlines the importance of thoroughly examining the explanted heart for CS on pathology. It also demonstrates that clinicians should consider CS in transplant recipients with new allograft failure and elevated DSAs in the absence of clinical AMR, CAV, and acute cellular rejection.
Visual Summary.
Cardiac Sarcoidosis in a Patient With Heart Transplant 6 Years Ago
Initial presentation was remarkable for new allograft dysfunction and high de novo DSAs. Coronary angiogram showed no concern for CAV, and endomyocardial biopsy showed non-necrotizing granulomas without signs of AMR, concerning for possible cardiac sarcoidosis (microscopic analysis of high-power image using hematoxylin and eosin staining). FDG PET/CT showed intense uptake that did not improve with treatment for antibody-mediated rejection but nearly resolved with methotrexate and steroid treatment for cardiac sarcoidosis. AMR = antibody-mediated rejection; CAV = cardiac allograft vasculopathy; CT = computed tomography; DSAs = donor-specific antibodies; FDG PET = fluorine-18 fluorodeoxyglucose positron emission tomography.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this article to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental videos, please see the online version of this paper.
Appendix
Transthoracic Echocardiogram, Apical 4-Chamber View
This view demonstrates biventricular dysfunction with apical akinesis and basal to mid inferoseptal hypokinesis of the left ventricle. The estimated left ventricular ejection fraction was 29%.
Transthoracic Echocardiogram, Apical 2-Chamber View, Contrast-Enhanced Images
This view shows hypokinesis of the basal to mid inferior walls.
Transthoracic Echocardiogram, Parasternal Long-Axis View, Contrast-Enhanced Images
This view demonstrates hypokinesis of the basal to mid anteroseptal segments and prominent thinning of the basal interventricular septum.
References
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Associated Data
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Supplementary Materials
Transthoracic Echocardiogram, Apical 4-Chamber View
This view demonstrates biventricular dysfunction with apical akinesis and basal to mid inferoseptal hypokinesis of the left ventricle. The estimated left ventricular ejection fraction was 29%.
Transthoracic Echocardiogram, Apical 2-Chamber View, Contrast-Enhanced Images
This view shows hypokinesis of the basal to mid inferior walls.
Transthoracic Echocardiogram, Parasternal Long-Axis View, Contrast-Enhanced Images
This view demonstrates hypokinesis of the basal to mid anteroseptal segments and prominent thinning of the basal interventricular septum.