Successful Heart Transplantation in a Patient With Triple Infiltrative Cardiomyopathy

Abstract

Background

Although “dual pathology” cardiac amyloidosis cases (amyloid light chain [AL] and transthyretin [TTR]) have been described, the coexistence of cardiac sarcoidosis with TTR amyloidosis is extremely rare, with only 2 case reports described in Japan to date.

Report Summary

We describe a unique case of a triple pathology consisting of cardiac sarcoidosis and both AL and TTR amyloidosis identified in myocardial tissue by liquid chromatography tandem mass spectrometry as well as advanced cardiac magnetic resonance and fluorodeoxyglucose positron emission tomography scans in the same patient.

Discussion-Novelty

To the best of our knowledge, this is not only the first patient with a triple infiltrative cardiac pathology but also the first such patient who underwent successful heart transplantation, with the above pathologies confirmed by the explanted native heart.

Take-Home Message

Coexistence of cardiac sarcoidosis, TTR and AL amyloidosis in the same patient's native heart poses unique therapeutic challenges regarding post-transplantation medical management.

Visual Summary

A 65-year-old African American man, recently retired military veteran, presented initially to an outside hospital 18 months ago with symptoms of progressive (though at the time still described as “mild”) exertion intolerance because of dyspnea and fatigue, which he attributed to COVID-19 infection and deconditioning since his discharge from active-duty military service. He had an echocardiogram demonstrating left ventricular hypertrophy and global hypokinesis with a left ventricular ejection fraction of 20%, and a left heart catheterization that showed no cardiovascular disease, even though both his brain natriuretic peptide and high-sensitivity troponin were elevated. He was discharged on low-dose guideline-directed medical therapy (metoprolol XL, losartan, spironolactone, and dapagliflozin), which, however, was not well tolerated because of the interim development of hypotension and dizziness.

His medical history included pulmonary sarcoidosis, diagnosed by biopsy of mediastinal lymph nodes at an outside Veterans Administration hospital “more than 5 years ago,” after a routine pulmonary function tests performed as part of his military physical examination showed low diffusing lung capacity for carbon monoxide, prompting an “abnormal” computed tomography scan and the biopsy. The records were unavailable, but according to the patient, he received a 6-month course of tapering steroids; his pulmonary tests improved, and his dyspnea resolved until the recent admission. However, he also reported a history of what he considered “unrelated” bilateral carpal tunnel surgeries and an episode of biceps tendon rupture he attributed to a military drill, both remote over 10 years ago. Otherwise, he considered himself healthy and physically active until his recent retirement.

He was referred to our institution for a “second opinion” evaluation that included a repeat echocardiogram with global longitudinal strain strain, a cardiac magnetic resonance, and a fluorodeoxyglucose positron emission tomography (FDG PET) scan. The echocardiogram showed a small left ventricle cavity size (left ventricular end-diastolic diameter 48 mm) with mild left ventricular hypertrophy (16 mm), global hypokinesis with a left ventricular ejection fraction of 25%, mild right ventricle dysfunction (tricuspid annular plane systolic excursion 14 mm), and GLS of −8% with an apical sparing pattern, suggestive of amyloidosis. Cardiac magnetic resonance showed diffuse Gd uptake more consistent with an amyloidosis pattern than a sarcoidosis pattern, although there were also incidental findings of hilar and mediastinal lymphadenopathy, considered “consistent with his known pulmonary sarcoidosis” history. The PET/computed tomography, however, performed after proper fasting and high-protein dietary preparation, was interpreted as “abnormal FDG uptake with patchy myocardial hypermetabolic activity, consistent with myocardial sarcoidosis” (as well as hilar and mediastinal uptake). Further complicating interpretation of his clinical presentation, labs repeated twice were significant for persistently elevated hs-troponin T (115 ng/mL), N-terminal pro–B-type natriuretic peptide (4750 pg/mL) but also a free light chain ratio of 0.25 (lambda 95, kappa 22 mg/dL) and monoclonal lambda spike on urine (but not serum) immunofixation electrophoresis.

Because of all these discrepancies, an endomyocardial biopsy was performed, coupled with a right-heart catheterization (which at that time showed mild pulmonary hypertension with preserved resting cardiac output). The biopsy did not demonstrate any granulomatous tissue, but indeed was positive for Congo red stain, favoring myocardial amyloid as the dominant diagnosis (realizing the limited sensitivity of endomyocardial biopsy for confirmation of cardiac sarcoidosis, given the “patchy” nature of this disease). The working diagnosis at that point was that more likely this patient had a combination of cardiac amyloidosis and pulmonary sarcoidosis (true-unrelated scenario). The biopsy tissue was sent for liquid chromatography analysis to the Mayo Clinic, which returned a diagnosis of dual TTR as well as AL amyloid pathology.

The patient was started on oral TTR stabilizer therapy with tafamidis, and hematology consultation was pursued to investigate concomitant AL and advise on management. In this context, a bone marrow biopsy was obtained that demonstrated a clonal lambda-restricted CD56 and CD117 plasma cell neoplasm. Surprisingly enough, genetic testing to ascertain whether the TTR was hereditary vs “wild type” did not reveal any of the known h-TTR–associated mutations, but instead a heterozygous MyBPC3 mutation (often associated with hypertrophic cardiomyopathy phenotypes)!

In the meantime, the patient continued to progressively decline and agreed to a follow-up right-heart catheterization: this time his cardiac index had sharply declined compared with a year earlier (1.4 vs 2.4 L/min/m²) with still rather mild to moderate elevation of biventricular filling pressures (right atrial pressure 15 mm Hg, pulmonary artery pressure 45/21/32 mm Hg, pulmonary capillary wedge 24 mm Hg). The patient was initiated on intravenous dobutamine, and an intra-aortic balloon pump was implanted. He consented to evaluation for cardiac transplantation while continuing tafamidis therapy; at that time, AL-targeted therapy was deferred until “after the heart transplant” by consensus with hematology, given the overall progression into a state of cardiogenic shock.

Heart transplantation was successfully performed approximately 3 months later. He received basiliximab induction followed by a standard triple immunosuppression regimen with tacrolimus, mycophenolate mofetil, and prednisone, as well as a chemoprophylaxis regimen (valganciclovir, Bactrim, and nystatin). When pathologic analysis of the entire explanted native heart was completed, this verified the presence of cardiac amyloidosis; however, it also identified granuloma formation, consistent with concomitant cardiac sarcoidosis, thus confirming the coexistence of a triple infiltrative cardiomyopathy phenotype (sarcoidosis, AL, and TTR-wt amyloidosis), which becomes even more unusual in a patient with a MyBPC3 genotype.

Case Summary (Including 90-Day Outcome): Future Directions

He has been discharged and has undergone weekly surveillance endomyocardial biopsies with no evidence of clinically significant rejection (acute cellular rejection 1R, antibody mediated rejection 0), preserved cardiac allograft function on echocardiogram, and normal resting hemodynamics consistently for the first 90 days following heart transplantation. As he progresses into the next phase of his outpatient surveillance and treatment, several challenges arise related to his rather unique background. He has already resumed tafamidis therapy to prevent recurrence of TTR amyloidosis in the allograft, while it is expected that he will be maintained on at least a low dose of prednisone and perhaps higher than “protocol-driven” mycophenolate, with annual FDG PET scans for surveillance as far as sarcoidosis. The latter decision also considers the fact that his preoperative PET scans also were significant for hilar and mediastinal adenopathy related to sarcoid, without extensive parenchymal involvement that could have steered in the direction of combined heart-lung transplantation. After hematology consultation, he initiated AL-directed monotherapy with Daratumumab, 3 months after heart transplant. Electrocardiogram, echocardiogram, MRI, and PET imaging are depicted in Figures 1, 2, and 3, respectively. Figure 4 demonstrates the pathologic findings in the explanted native heart.

Figure 1.

The Electrocardiogram Obtained at his Initial Admission Demonstrates Low Voltage Across all Leads, Especially When Contrasted With Echocardiographic Evidence of Concentric Left Ventricular Hypertrophy

Noted is also the presence of Q waves in anterior leads, in the absence of cardiovascular disease on coronary angiography performed during the same admission (“pseudoinfarct” pattern), also often seen in cases of cardiac amyloidosis.

Figure 2.

The Polar Map Reflecting Regional Variation in Longitudinal Strain Pattern With Relative “Apical Sparing” Pattern (“Cherry on Top”) Often Identified as Typical of Cardiac Amyloidosis

Overall GLS was reduced at −8% in this echocardiogram and remained unchanged throughout his clinical course until transplant. ANT = anterior; INF = inferior; LAT = lateral; POST = posterior; SEPT = septal.

Figure 3.

Cardiac MRI and PET Findings

Cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) images provides characteristic imaging of the (A) diffuse late gadolinium enhancement (LGE) (diffuse, subendocardial, or transmural) within the myocardium (white arrows) with (B) high visual signal on T1 map images along the myocardium (white arrows), (C) high native T1 on tissue on precontrast T1 maps with (D) expanded extracellular volume (ECV) (generally T1>1,000 millisecond). The PET scan shows (E) faint suspicious patchy uptake within the myocardium (green arrows), with clear uptake within the hilar lymph nodes (white arrow) and (F) patchy elevation in T2 Map signal that was suspicious for confounding inflammatory disease (segments with >56 millisecond). The CMR scanner was a 1.5-T scanner.

Figure 4.

Pathology Images of Our Patient's Explanted Native Heart

Pathology slides obtained from the native heart demonstrate the copresence of both granuloma formation consistent with cardiac sarcoidosis (B green arrows), as well as diffuse interstitial Congo red stain signifying cardiac amyloidosis (A and B blue arrows). Further tissue analysis performed at the Mayo Clinic laboratory using liquid chromatography tandem mass spectrometry (LC MS/MS) on peptides extracted from Congo red-positive areas of the paraffin-embedded specimen detected a peptide profile consistent with ATTR (transthyretin)-type amyloid deposition and AL (lambda)-type amyloid deposition.

Discussion

Novelty of the case

The concomitant presence of AL and TTR amyloid (either hereditary or wild type) has been previously described,1, 2, 3, 4, 5 although it is still rather rare, compared with the more common coexistence of TTR amyloidosis with monoclonal gammopathy of undetermined significance. An isolated case series of 2 patients from Japan has been reported of coexisting cardiac sarcoidosis with TTR (but not AL) amyloidosis.⁶

Concomitant extracardiac (usually pulmonary) sarcoidosis, coexisting with biopsy-proven systemic AL amyloidosis, with or without^7,8 cardiac involvement, has been described in 3 additional cases (1 identified after heart transplantation.⁹ In additional cases, granulomas identified in the lungs or lymph nodes attributed to sarcoidosis have been shown to reflect reactive AA amyloid deposition, as sequelae of sarcoidosis-mediated chronic inflammation,¹⁰ whereas in another case, AL amyloid was “misdiagnosed” as a sarcoid granuloma in the lungs.¹¹ Noncaseating granulomas mimicking sarcoidosis have also been shown to reflect reactive processes to AL amyloid deposition⁷ as opposed to true sarcoidosis. In our patient's case, the patient had previously been diagnosed with pulmonary sarcoidosis, and the noncaseating granulomas on autopsy were felt to reflect true cardiac sarcoidosis.

However, our patient is, to the best of our knowledge, the first one with histologic confirmation of cardiac AL and TTR (wt.) cardiac amyloidosis, in addition to sarcoidosis, contributing to his cardiomyopathy. The constellation of his prior histologic diagnosis of pulmonary sarcoidosis, present PET findings, and native explanted pathology support independent disorders. Further, he remains the first patient where this combined “triple threat” to his cardiac function has been treated with successful cardiac transplantation. This was because the extracardiac (pulmonary) manifestations of his sarcoidosis were rather limited, not mandating a combined heart-lung transplant. Similarly, although the bone marrow identified the clonal population of plasma cells associated with the lambda-light chain, it was a rather limited (<5%) bordering on the monoclonal gammopathy of undetermined significance definition and not triggering an absolute contraindication or a need for stem cell transplantation, but perhaps an afterthought of balancing standard transplant immunosuppression with intermittent Daratumumab therapy. The latter pattern has already been successfully used in our program in 4 additional heart transplant recipients with AL cardiac amyloidosis, exemplifying our multidisciplinary collaboration with our hematology colleagues.

Finally, genotype-phenotype discrepancy (although per se not totally unique) is another point that may merit further exploration. His heterozygous mutation (Ala1194Thr) has limited association on the ClinVar database with sporadic cases of hypertrophic cardiomyopathy and left ventricular non-compaction cardiomyopathy. A single case of a patient with a mixed restrictive/left ventricular non-compaction phenotype who had sarcoidosis and a heterozygous MyBPC3 mutation has been reported, postulating epigenetic impact of sarcoid myocarditis.¹² To what extent interaction of a potentially abnormal MyBPC3 structure may have influenced the clinical phenotype of our patient remains uncertain. The patient has been offered family cascade screening for his MyBPC3 mutation, which he has deferred after completing his first year of post-transplant recovery and stabilization.

Take-Home Messages

• •To the best of our knowledge, this is the first described case of histologically verified coexistent cardiac sarcoidosis, AL and TTR amyloidosis, progressing from near-asymptomatic status to cardiogenic shock, successfully treated with cardiac transplantation.
• •Although the postoperative outcome so far has been favorable, this pathologic constellation poses unique diagnostic and therapeutic challenges.

Visual Summary.

Timeline From Past Medical History to Diagnosis to Successful Heart Transplantation and Outpatient Follow-Up

AL = amyloidosis; CMR = cardiac magnetic resonance; CT = computed tomography; EMB = endomyocardial biopsy; ICD = implantable cardioverter-defibrillator; LV = left ventricle; PET = positron emission tomography; PYP = pyrophosphate; RHC = right-heart catheterization; RV = right ventricle; TEE = transesophageal echocardiography; TTE = transthoracic echocardiography; TTR = transthyretin.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.