Prompt diagnosis of a wild-type transthyretin cardiac amyloidosis: Role of multimodality imaging : Journal of the Chinese Medical Association

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Case Report

Prompt diagnosis of a wild-type transthyretin cardiac amyloidosis: Role of multimodality imaging

Lim, Su Shena; Kuo, Linga,b; Chang, Fu-Pangb,c; Chang, Chun-China,b; Yu, Wen-Chunga,b,*

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Journal of the Chinese Medical Association: November 2022 - Volume 85 - Issue 11 - p 1101-1105
doi: 10.1097/JCMA.0000000000000817
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Abstract

1. INTRODUCTION

Cardiac amyloidosis (CA) is a protein misfolding disorder characterized by the extracellular deposition of amyloid fibrils in the myocardium. Most clinical presentations of CA are due to transthyretin amyloidosis (ATTR) or light chain (AL) amyloidosis. Wild-type ATTR (ATTRwt), also called senile systemic amyloidosis, does not result from a genetic mutation in the transthyretin gene (TTR). This condition was previously considered to be exclusive to older people. Here, we present a rare case of ATTRwt in a relatively young patient.

2. CASE REPORT

A 66-year-old man presented to the emergency department of the study hospital with a complaint of progressive shortness of breath for the last 2 weeks. He had type 2 diabetes mellitus, hypertension, and dyslipidemia. The patient was regularly followed up at the endocrinology outpatient department of the study hospital; during this period, he reported limb numbness and low back pain for 6 years. Laboratory findings indicated that his blood sugar level was in the normal range (glycated hemoglobin level, 5.4%). Electromyography and nerve conduction velocity tests revealed sensorimotor polyneuropathy and decreased bilateral median nerve conduction velocity. The patient had a diagnosis of diabetic neuropathy and ligamentum flavum hypertrophy causing spinal stenosis at C7–T1 and L2–S1. Therefore, he underwent decompression and L4–S1 posterolateral fusion surgery 3 years ago. Unfortunately, his symptoms of limb numbness and low back pain persisted after the surgery. He experienced progressive exertional dyspnea 2 weeks before the index admission and initially sought medical assistance at the emergency department of the study hospital. Chest radiography revealed the presence of cardiomegaly and pulmonary congestion. Laboratory findings indicated elevated levels of cardiac biomarkers (creatine kinase, 522 U/L; troponin I, 0.10 ng/mL) and N-terminal pro B-type natriuretic peptide (5074 pg/mL). Thus, acute coronary syndrome and heart failure were diagnosed. Subsequent coronary artery angiography revealed 80% stenosis over the left anterior descending artery, and the patient underwent stent deployment. However, progressive shortness of breath recurred within 2 months. A review of the patient’s previous 12-lead electrocardiography data revealed sinus rhythm with low voltage on his limb leads (Fig. 1A). Transthoracic echocardiography indicated an increased thickness of the left ventricular (LV) wall (Fig. 1B). The LV ejection fraction was 50% with the hypokinesia of the basal inferior and inferior–lateral segments. Two-dimensional speckle-tracking echocardiography (STE) revealed reduced global longitudinal strain (LS) of −13.5% with apical sparing (average apical LS/[average basal LS + mid LS] = 1.5) (Fig. 1C). Echocardiography findings indicated CA. Moreover, cardiac magnetic resonance (CMR) imaging showed a high native T1 value (Fig. 2A and B), increased extracellular volume fraction (Fig. 2C and D), and diffused subendocardial late gadolinium enhancement (LGE; Fig. 2E and F) with apical sparing. These findings also suggested CA. Further investigations were performed for a differential diagnosis of ATTR and AL amyloidosis. Serum free κ-to-λ light chain ratio was within the normal range (κ, 48.36 mg/L; λ, 38.58 mg/L; κ/λ:1.25). Immunoelectrophoresis performed using serum and urine transthyretin samples revealed no monoclonal spike. The results of technetium-99m pyrophosphate (99mTc-PYP) scintigraphy showed myocardial uptake (Perugini grade 3; Fig. 3A and B), which strongly indicated ATTR. Further genetic analyses revealed no pathological variants of TTR. Owing to the patient’s relatively young age at ATTRwt diagnosis, endomyocardial biopsy (EMB) was performed. The pathology had hypertrophic myocardial tissue with amyloid deposition (Fig. 4A). In tissue samples stained with Congo red, the amyloid fibrils exhibited apple-green birefringence under polarized light (Fig. 4B). Electron microscopy showed the deposition of randomly oriented amyloid fibrils (diameter, 8–12 nm) in the interstitium (Fig. 4C). Immunofluorescence results for the κ and λ light chains were negative. The result of immunohistochemical staining for transthyretin was positive (Fig. 4D). Thus, ATTRwt was confirmed.

F1
Fig. 1:
A, Electrocardiogram showing sinus rhythm and low voltage on the limb leads of the patient. B, Echocardiography showed the presence of concentric left ventricular hypertrophy. C, Two-dimensional speckle-tracking echocardiography revealed reduced global longitudinal strain (LS) of −13.4% and relative apical sparing (= average apical LS/[average basal LS + mid LS] × 1.5).
F2
Fig. 2:
A, Native T1 map and the 17-segment American Heart Association (AHA) T1 polar map (B) obtained through cardiac magnetic resonance (CMR) imaging showed a diffusely elevated native T1 value of 1,512 ± 193 ms (2A and 2B). Extracellular volume (ECV) map (C) and the 17-segment AHA ECV polar map (D) showed a diffusely elevated ECV fraction of 47% ± 9%, with a maximum value of approximately 66% at the basal inferoseptal wall of the left ventricle. Contrast-enhanced CMR images obtained in the short-axis view of basal left ventricular (LV) segment and three-chamber view showed diffused subendocardial late gadolinium enhancement (LGE) at the basal to mid LV segments (yellow arrowhead); LGE was also observed at the atrial wall (red arrowhead; E and F).
F3
Fig. 3:
Standard planar images (technetium-99m pyrophosphate scintigraphy) (A) and axial fused single-photon emission computed tomography/computed tomography images (B), which were acquired 1 h after the injection of radiotracer, revealed high-grade (Perugini grade 3) myocardial uptake.
F4
Fig. 4:
Histological findings obtained using endomyocardial specimens—hematoxylin and eosin–stained tissue sections—showed hypertrophic myocardial tissue with amyloid deposition (A); Congo red staining (B); and amyloid fibril observed under an electron microscope (C) and with the use of transthyretin antibody (D).

3. DISCUSSION

CA is an underrecognized cause of heart failure with preserved LV ejection fraction. Among the several types of amyloidosis, ATTR and AL amyloidosis are primarily responsible for most clinical cases of CA. ATTR-CA is a protein misfolding disorder characterized by the extracellular deposition of transthyretin-containing amyloid fibrils in the myocardium.1 The following are the two distinct types of ATTR-CA: ATTRwt-CA and familial ATTR-CA (ATTRv-CA). As mentioned, ATTRwt-CA was previously believed to develop exclusively in older adults (average age at diagnosis: 75 years).2 However, an increasing number of cases has been reported in relatively young patients, such as our patient, which suggests that this condition is underdiagnosed in relatively young individuals. Our patient with ATTRwt presented with peripheral neuropathy, which was difficult to differentiate from diabetic neuropathy. Although peripheral (sensorimotor) or autonomic neuropathy is common in patients with ATTRv-CA, it may also be present in patients with ATTRwt-CA.2,3 A recent retrospective study indicated an increase in the prevalence (30.5%) of neuropathic symptoms in patients with ATTRwt-CA.4 Our patient managed type 2 diabetes well for a short period; hence, peripheral neuropathy in this patient might have developed due to ATTRwt-CA. The initial manifestations of ATTRwt-CA may include carpal tunnel syndrome and spinal stenosis, which may precede cardiac complications by several years.5,6 Studies have indicated a considerable delay in the diagnosis of CA; a retrospective cohort study demonstrated that the average time from the first cardiac manifestation to ATTR diagnosis was 34 months.7–9 A prolonged delay in diagnosis is associated with advanced LV diastolic dysfunction and limited treatment options because highly effective therapies for heart failure are poorly tolerated by patients in the advanced stage of the disease. Recently, the American Society of Nuclear Cardiology emphasized the use of multimodality imaging for patients with suspected CA, highlighting the advantages of echocardiography, CMR, and radionuclide imaging in the screening, diagnosis, and management of CA.10

CA typically presents with cardiac and extracardiac signs and symptoms, which are investigated using the following effective means: clinical assessment, physical examination, electrocardiogram, laboratory biomarkers, and cardiac imaging. These signs and symptoms are called red flags and include the following: bilateral carpal tunnel syndrome, ruptured long head of the biceps tendon (Popeye’s sign), polyneuropathy and dysautonomia, low voltage on the electrocardiogram, increased troponin levels on multiple occasions, increased LV wall thickness, decreased LS with apical sparing on echocardiography, and characteristic LGE patterns on CMR imaging.11,12 The early detection of these signs and symptoms prompts the initiation of screening measures even in asymptomatic individuals. In the present case, the unexplainable LV wall thickening despite well-controlled hypertension, pericardial effusion, and decreased LS with apical sparing on echocardiography were the earliest signs of CA. The patient’s anamneses of bilateral carpal tunnel syndrome and lumbar spinal stenosis further supported this diagnosis. The results of electrocardiography revealed low voltage on the limb leads of our patient but not on his precordial leads; this was consistent with his clinical presentation data, which indicated the development of peripheral neuropathy before the occurrence of cardiac symptoms. This finding can be attributed to the higher accumulation of nonconducting amyloid fibrils in the extremities than in the myocardium. Peripheral edema may also result in a lower voltage on limb leads.

A definitive diagnosis of ATTRwt-CA was made using EMB and subsequent genotyping. However, EMB is associated with several risks, including myocardial perforation and tamponade; hence, it should not be widely adopted for screening. Several noninvasive diagnostic modalities are available for early screening. Echocardiography is the most convenient noninvasive diagnostic tool. It can be used to investigate any possible increase in LV wall thickness and diastolic dysfunction at an early stage of the disease. The myocardium may also exhibit a granular or sparkling appearance.13–15 STE is an advanced echocardiographic technique that helps differentiate CA from other causes of LV hypertrophy. For patients with CA, STE reveals restricted basal speckle longitudinal movement compared with apical movement, where LS has a relative apical sparing pattern in a bull’s eye plot.13–15 Furthermore, the changes in the electrocardiogram of patients with CA include low voltage on the limb leads and a pseudoinfarction pattern.16 99mTc-PYP nuclear imaging has high sensitivity and specificity for differentiating patients with ATTR-CA17,18 and can help diagnose cardiac involvement preceding overt echocardiographic, cardiac biomarker, or clinical signs.19 CMR imaging has a substantial diagnostic value for patients with CA. Typical findings for these patients include restrictive morphology, abnormal gadolinium kinetics, elevated native T1 value, and extracellular volume expansion on T1 mapping.20,21 Although CA can be diagnosed using multimodal cardiac imaging, its initial symptoms are nonspecific and the diagnosis is usually made in the late stage when the symptoms of heart failure have already occurred. Early detection is thus crucial to improve the outcomes of patients with CA by using advanced treatment options.

In conclusion, through this case report, we aim to raise awareness regarding the incidence of ATTRwt-CA in the relatively young population. The early presentations of CA are nonspecific and frequently lead to delay in diagnosis and thus poor prognosis. Advanced multimodality cardiac imaging facilitates the early and accurate diagnosis of CA.

ACKNOWLEDGMENTS

This work was supported in part by grant from Taipei Veterans General Hospital (VTA111-V1-5-2).

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Keywords:

99mTc-PYP scintigraphy; Cardiac amyloidosis; Cardiac magnetic resonance; Echocardiography; Wild-type TTR amyloidosis

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